U.S. patent application number 11/264738 was filed with the patent office on 2006-03-30 for aza hydroxylated ethyl amine compounds.
This patent application is currently assigned to Pharmacia & Upjohn Company. Invention is credited to Rebecca S. Centko, Robert Allan Chrusciel, Heinrich Schostarez.
Application Number | 20060069264 11/264738 |
Document ID | / |
Family ID | 27404155 |
Filed Date | 2006-03-30 |
United States Patent
Application |
20060069264 |
Kind Code |
A1 |
Schostarez; Heinrich ; et
al. |
March 30, 2006 |
Aza hydroxylated ethyl amine compounds
Abstract
Disclosed are compounds of formula: ##STR1## and
pharmaceutically acceptable salts and esters thereof, useful in
treating and/or preventing Alzheimer's disease and other similar
diseases, wherein R.sub.N, R.sub.C, R.sub.1, R.sub.2 and R.sub.20
are defined herein. These compounds include inhibitors of the
beta-secretase enzyme that are useful in the treatment of
Alzheimer's disease and other diseases characterized by deposition
of A beta peptide in a mammal. The compounds of the invention are
useful in pharmaceutical compositions and methods of treatment to
reduce A beta peptide formation.
Inventors: |
Schostarez; Heinrich;
(Portage, MI) ; Chrusciel; Robert Allan; (Portage,
MI) ; Centko; Rebecca S.; (Portage, MI) |
Correspondence
Address: |
MCDONNELL BOEHNEN HULBERT & BERGHOFF LLP
300 S. WACKER DRIVE
32ND FLOOR
CHICAGO
IL
60606
US
|
Assignee: |
Pharmacia & Upjohn
Company
|
Family ID: |
27404155 |
Appl. No.: |
11/264738 |
Filed: |
November 1, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10152601 |
May 22, 2002 |
6960664 |
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11264738 |
Nov 1, 2005 |
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60292856 |
May 22, 2001 |
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60301355 |
Jun 27, 2001 |
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60360601 |
Mar 1, 2002 |
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Current U.S.
Class: |
548/195 |
Current CPC
Class: |
A61P 25/16 20180101;
C07C 243/32 20130101; A61P 43/00 20180101; A61P 25/00 20180101;
C07C 243/28 20130101; C07C 311/16 20130101; C07C 311/49 20130101;
A61P 25/28 20180101 |
Class at
Publication: |
548/195 |
International
Class: |
C07D 277/44 20060101
C07D277/44 |
Claims
1. A compound of the formula II: ##STR621## or a pharmaceutically
acceptable salt thereof, where Rc is (I) --C.sub.1-C.sub.10 alkyl
optionally substituted with one, two or three groups independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6
alkoxy, --O-phenyl, --NR.sub.1-aR.sub.1-b, --OC.dbd.O
NR.sub.1-aR.sub.1-b, --S(.dbd.O).sub.0-2 R.sub.1-a,
--NR.sub.1-aC.dbd.O NR.sub.1-aR.sub.1-b, --C.dbd.O
NR.sub.1-aR.sub.1-b, and --S(.dbd.O).sub.2 NR.sub.1-aR.sub.1-b
wherein R.sub.1-a and R.sub.1-b at each occurrence are
independently H or C.sub.1-C.sub.6 alkyl, (II)
--(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl where cycloalkyl
can be optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, --O-phenyl, --CO.sub.2H,
--CO.sub.2--(C.sub.1-C.sub.4 alkyl), and --NR.sub.1-aR.sub.1-b
(III) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where R.sub.C-x
and R.sub.C-y are independently selected from the group consisting
of --H, C.sub.1-C.sub.4 alkyl optionally substituted with 1 or 2
--OH, C.sub.1-C.sub.4 alkoxy optionally substituted with 1, 2, or 3
halogen, --(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl containing one or two double bonds,
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or R.sub.C-x and R.sub.C-y are taken together with the
carbon to which they are attached to form a carbocycle of three,
four, five, six or seven carbon atoms, where one carbon atom is
optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein R.sub.C-aryl
is phenyl, which is optionally substituted with 1, 2, or 3 groups
that are independently: (1) C.sub.1-C.sub.6 alkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--O.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (2) --OH, (3) --NO.sub.2, (4) halogen, (5)
--CO.sub.2H, (6) --C.ident.N, (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are independently selected from the group consisting of:
(a) --H, (b) --C.sub.1-C.sub.6 alkyl optionally substituted with
one substituent selected from the group consisting of: (i) --OH,
and (ii) --NH.sub.2, (c) --C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently --F,
--Cl, --Br, --I, or OH, (d) --C.sub.3-C.sub.7 cycloalkyl, (e)
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.2-C.sub.6 alkenyl (h) --C.sub.2-C.sub.6 alkynyl (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R.sub.1-aryl wherein R.sub.1-aryl at each occurrence is
independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl,
or tetralinyl each of which is optionally substituted with 1, 2, 3,
or 4 groups that are independently: (i) C.sub.1-C.sub.6 alkyl
optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (ii)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (iii) C.sub.2-C.sub.6 alkynyl optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of -F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (iv)
--F, Cl, --Br and --I, (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with 1, 2, or 3 --F, (vi) --NR.sub.N-2R.sub.N-3, (vii)
--OH, (viii) --C.ident.N, (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (x)
--CO--(C.sub.1-C.sub.4 alkyl), (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (xii) --CO--NR.sub.1-aR.sub.1-b,
or (xiii) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), (k)
--R.sub.1-heteroaryl wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, where
the R.sub.1-heteroaryl group is optionally substituted with 1, 2,
3, or 4 groups that are independently: (i) C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b, --C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (ii) C.sub.2-C.sub.6
alkenyl optionally substituted with 1, 2, or 3 groups that are
independently --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (iii)
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
groups that are independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, (iv) --F, --Cl, --Br and --I,
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with one, two,
or three --F, (vi) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3. (vii)
--OH, (viii) --C.ident.N, (ix) (CH.sub.2).sub.0-4--C.sub.3-C.sub.7
cycloalkyl, optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6
alkyl), (xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3,
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), (11)
--(CH.sub.2).sub.0-4--CO--(CH.sub.2).sub.0-4 (C.sub.3-C.sub.7
cycloalkyl), (12) --(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle wherein
R.sub.1-heterocycle at each occurrence is independently selected
from the group consisting of morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heterocycle group replaces the hydrogen
atom and its bond, where heterocycle is optionally substituted with
1, 2, 3, or 4 groups that are independently: (a) C.sub.1-C.sub.6
alkyl optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --NR.sub.1-aR.sub.1-b--C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (b) C.sub.2-C.sub.6 alkenyl
with one or two double bonds, optionally substituted with one, two
or three substituents independently selected from the group
consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b (c)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b (d) halogen, (e) C.sub.1-C.sub.6 alkoxy, (f)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two, or
three --F, (g) --NR.sub.N-2R.sub.N-3, (h) --OH, (i) --C.ident.N,
(j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.7 cycloalkyl), optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and (o)
.dbd.O, (p) --(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein R.sub.N-4 at each
occurrence is independently selected from the group consisting of
morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl,
thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,
homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where
each group is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.6 alkyl, (16)
--(CH.sub.2).sub.0-4--CO.sub.2--R.sub.N-5 where R.sub.N-5 at each
occurrence is independently selected from the group consisting of:
(a) C.sub.1-C.sub.6 alkyl, (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl), (c) C.sub.2-C.sub.6 alkenyl,
(d) C.sub.2-C.sub.6 alkynyl, (e) C.sub.3-C.sub.7 cycloalkyl, and
(f) --(CH.sub.2).sub.0-4--(R.sub.1-heteroaryl), (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3 (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), (20)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl), (21)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5.sub.-)--CO.sub.2--R.sub.N-5,
(22) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--N(R.sub.N-5).sub.2, (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 where R.sub.100
is independently H or C.sub.1-C.sub.4 alkyl, (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl) wherein the alkyl
group is optionally substituted with one, two, three, four, or five
substituents independently selected from the group consisting of F,
Cl, Br, and I, (35) --(CH.sub.2).sub.0-4--(C.sub.3-C.sub.8
cycloalkyl), (36) C.sub.2-C.sub.6 alkenyl optionally substituted
with C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, and (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2;
(IV) --(CR.sub.C-xR.sub.C-y).sub.0-4-R.sub.C-heteroaryl wherein
R.sub.C-heteroaryl at each occurrence is independently selected
from the group consisting of pyridinyl, pyrimidinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl,
isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzoisothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,
beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl, pteridinyl,
benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,
quinazolinonyl, pyrazopyridyl, benzooxadiazolyl,
dihydropyrimidinonyl, dihydrobenzofuranonyl, where the
R.sub.C-heteroaryl group is bonded by any atom of the parent
R.sub.C-heteroaryl group substituted by hydrogen such that the new
bond to the R
.sub.C-heteroaryl group replaces the hydrogen atom and its bond,
where heteroaryl is optionally substituted 1, 2, 3, or 4 groups
that are independently: (1) C.sub.1-C.sub.6 alkyl, optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (2) --OH, (3) --NO.sub.2, (4) --F, --Cl,
--Br, --I, (5) --CO--OH, (6) --C.ident.N, (V) C.sub.2-C.sub.10
alkenyl optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, --O-phenyl, and --NR.sub.1-aR.sub.1-b, (VI)
C.sub.2-C.sub.10 alkynyl optionally substituted with one, two or
three substituents independently selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, and
--NR.sub.1-aR.sub.1-b, (VII) --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH, (VIII)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2, (IX)
--(CH.sub.2).sub.0-6--C(.dbd.NR.sub.1-a) (NR.sub.1-aR.sub.1-b);
where R.sub.N is (I) R.sub.N-1--X.sub.N-- where X.sub.N is --CO--,
and where R.sub.N-1 is selected from the group consisting of: (A)
phenyl, which is optionally substituted with one, two or three of
the following substituents which can be the same or different and
are: (1) C.sub.1-C.sub.6 alkyl, optionally substituted with one,
two or three substituents selected from the group consisting of
C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, wherein R.sub.1-a and R.sub.1-b at each
occurrence are independently H or C.sub.1-C.sub.6 alkyl, (2) --OH,
(3) --NO.sub.2, (4) --F, --Cl, --Br, --I, (5) --CO.sub.2H, (6)
--C.ident.N, (7) --(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3
where R.sub.N-2 and R.sub.N-3 are the same or different and are
selected from the group consisting of: (a) --H, (b)
--C.sub.1-C.sub.8 alkyl optionally substituted with one substituent
selected from the group consisting of: (i) --OH, (ii) --NH.sub.2,
(iii) phenyl, (c) --C.sub.1-C.sub.6 alkyl optionally substituted
with 1, 2, or 3 groups that are independently --F, --Cl, --Br, or
--I, (d) --C.sub.3-C.sub.8 cycloalkyl, (e) --(C.sub.1-C.sub.2
alkyl)-(C.sub.3-C.sub.8 cycloalkyl), (f) --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g) --C.sub.2-C.sub.6 alkenyl,
(h) --C.sub.2-C.sub.6 alkynyl, (i) --C.sub.1-C.sub.6 alkyl chain
with one double bond and one triple bond, (j) --R.sub.1-aryl,
wherein R.sub.1-aryl at each occurrence is independently phenyl,
naphthyl, indanyl, indenyl, dihydronaphthyl, or tetralinyl each of
which is optionally substituted with 1, 2, 3, or 4 groups that are
independently: (i) C.sub.1-C.sub.6 alkyl optionally substituted
with one, two or three substituents independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy, (ii) C.sub.2-C.sub.6 alkenyl with one or
two double bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, (iii) C.sub.2-C.sub.6 alkynyl
optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (iv) --F, Cl, --Br and --I, (v)
--C.sub.1-C.sub.6 alkoxy optionally substituted with 1, 2, or 3
--F, (vi) --NR.sub.N-2R.sub.N-3, (vii) --OH, (viii) --C.ident.N,
(ix) C.sub.3-C.sub.7 cycloalkyl, optionally substituted with 1, 2,
or 3 groups that are selected from the group consisting of --F,
--Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
and --NR.sub.1-aR.sub.1-b, (x) --CO--(C.sub.1-C.sub.4 alkyl), (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (xii) --CO--NR.sub.1-aR.sub.1-b,
or (xiii) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), (k)
--R.sub.1-heteroaryl, wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, where
the R.sub.1-heteroaryl group is optionally substituted with 1, 2,
3, or 4 groups that are independently: (i) C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b, --C.ident.N,
--CF.sub.3, and C.sub.3-C.sub.3 alkoxy, (ii) C.sub.2-C.sub.6
alkenyl optionally substituted with 1, 2, or 3 groups that are
independently --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, (iii)
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, (iv)
--F, --Cl, --Br and --I, (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three --F, (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (vii) --OH, (viii)
--C.ident.N, (ix) (CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6
alkyl), (xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3,
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, (l) --R.sub.1-heterocyle,
wherein R.sub.1-heterocycle at each occurrence is independently
selected from the group consisting of morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heterocycle group replaces the hydrogen
atom and its bond, where heterocycle is optionally substituted with
1, 2, 3, or 4 groups that are independently: (a) C.sub.1-C.sub.6
alkyl optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --NR.sub.1-aR.sub.1-b--C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (b) C.sub.2-C.sub.6 alkenyl
with one or two double bonds, optionally substituted with one, two
or three substituents independently selected from the group
consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b (c)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.-b (d) halogen, (e) C.sub.1-C.sub.6 alkoxy, (f)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two, or
three --F, (g) --NR.sub.N-2R.sub.N-3, (h) --OH, (i) --C.ident.N,
(j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.8 cycloalkyl), optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and (o)
.dbd.O, (p) --(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein R.sub.N-4 is selected
from the group consisting of phenyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,
pyrrolinyl, thienyl, pyrazolyl, pyridyl N-oxide, oxazolyl,
thiazolyl, imidazolyl, and pyrrolidinyl where each group is
optionally substituted with one, two, three, or four groups that
are independently C.sub.1-C.sub.6 alkyl, (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 where R.sub.N-5 is selected
from the group consisting of: (a) C.sub.1-C.sub.6 alkyl, (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl), (c) C.sub.2-C.sub.6 alkenyl,
(d) C.sub.2-C.sub.6 alkynyl, (e)
--(CH.sub.2).sub.0-2--C.sub.3-C.sub.8 cycloalkyl, (f)
--(CH.sub.2).sub.0-2--(R.sub.1-heteroaryl), and (g)
--(CH.sub.2).sub.0-2--(R.sub.1-heterocycle), (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), (19)
--(CH.sub.2).sub.0-4--SO.sub.2 (C.sub.1-C.sub.12 alkyl), (20)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl), (21)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--O--R.sub.N-5, (22)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--N(R.sub.N-5).sub.2,
(23) --(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, (24)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--R.sub.N-2, (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 wherein R.sub.100
at each occurrence is independently --H or C.sub.1-C.sub.4 alkyl,
(29) --(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5) , (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), (35)
C.sub.3-C.sub.8 cycloalkyl, (36) C.sub.2-C.sub.6 alkenyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (37) C.sub.2-C.sub.6 alkynyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (38) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--SO.sub.2--R.sub.N-2, ( 39)
--(CH.sub.2).sub.1-4--(C.sub.3-C.sub.8 cycloalkyl), (B)
--R.sub.N-heteroaryl where R.sub.N-heteroaryl is selected from the
group consisting of pyridinyl, indolyl, indolinyl, isoindolyl,
imidazolyl, isoxazolyl, oxazolyl, thiazolyl, indolizinyl and
isochromanyl, where the R.sub.N-heteroaryl group is bonded by any
atom of the parent R.sub.N-heteroaryl group substituted by hydrogen
such that the new bond to the R.sub.N-heteroaryl group replaces the
hydrogen atom and its bond, where heteroaryl is optionally
substituted with one, two, three, or four of: (1) C.sub.1-C.sub.6
alkyl, optionally substituted with one, two or three substituents
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (2) --OH, (3)
--NO.sub.2, (4) --F, --Cl, --Br, --I, (5) --CO.sub.2H, (6)
--C.ident.N, (7) --(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), (20)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl), (21)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--O--R.sub.N-5, (22)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--N(R
.sub.N-5).sub.2, (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2, (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, (33)
--(CH.sub.2).sub.004--S--(R.sub.N-5), (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), (35)
C.sub.3-C.sub.8 cycloalkyl, (36) C.sub.2-C.sub.6 alkenyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (37) C.sub.2-C.sub.6 alkynyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (38) --(CH.sub.2).sub.0-4--N(--H or
R.sub.N-5)--SO.sub.2--R.sub.N-2, (39)
--(CH.sub.2).sub.1-4--C.sub.3-C.sub.8 cycloalkyl, (C)
R.sub.N-aryl--W--R.sub.N-aryl, (D)
R.sub.N-aryl--W--R.sub.N-heteroaryl, (E)
R.sub.N-aryl--W--R.sub.1-heterocycle, (F)
R.sub.N-heteroaryl--W--R.sub.N-aryl, (G)
R.sub.N-heteroaryl--W--R.sub.N-heteroaryl, (H)
R.sub.N-heteroaryl--W--R.sub.N-1-heterocycle, (I)
R.sub.N-heterocycle--W--R.sub.N-aryl, (J)
R.sub.N-heterocycle--W--R.sub.N-heteroaryl, (K)
R.sub.N-heterocycle--W--R.sub.N-1-heterocycle, where W is (19)
--(CH.sub.2).sub.1-4--, (20) --O--, (21) --S(O).sub.0-2--, (22)
--N(R.sub.N-5)--, (23) --CO--; or (24) a bond; (II)
--CO--(C.sub.1-C.sub.6 alkyl)-M-(C.sub.1-C.sub.6 alkyl), where M is
S, SO or SO.sub.2, and wherein each alkyl is unsubstituted or
substituted with one, two, or three of substituents independently
selected from the group consisting of: (A)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (B) --NH--CO--O--R.sub.N-8, (C)
--NR.sub.N-2R.sub.N-3; where R.sub.1 is --(CH.sub.2).sub.n1-phenyl,
where n.sub.1 is zero or one, and which is optionally substituted
with one, two, three or four of the following substituents on the
phenyl ring: (A) C.sub.1-C.sub.6 alkyl optionally substituted with
one, two or three substituents selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (B) C.sub.2-C.sub.6 alkenyl with one or two
double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (C) C.sub.2-C.sub.6 alkynyl with one or two
triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (D) --F, Cl, --Br or --I, (F)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two or
three of --F, (G) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined below, (H) --OH, (I) --C.ident.N, (J)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (K) --CO--(C.sub.1-C.sub.4 alkyl), (L)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (M) --CO--NR.sub.1-aR.sub.1-b, (N)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); and where R.sub.2 is (I)
-(Z)-C.sub.1-C.sub.6 alkyl, where Z is a bond, --C(O)--,
--CO.sub.2-- or --SO.sub.2--, wherein the alkyl group is optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.7 alkyl
(optionally substituted with C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.3 alkoxy), --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
--NR.sub.1-aR.sub.1-b where R.sub.1-a and R.sub.1-b are
independently --H or C.sub.1-C.sub.6 alkyl, and --OC.dbd.O
NR.sub.1-aR.sub.1-b, (II)
-(Z)-CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), (III)
-(Z)-CH.sub.2--CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
(IV) -(Z)-C.sub.2-C.sub.6 alkenyl with one or two double bonds,
optionally substituted with one, two or three substituents selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (V)
-(Z)-C.sub.2-C.sub.6 alkynyl with one or two triple bonds,
optionally substituted with one, two or three substituents selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (VI)
-(Z)-(CH.sub.2).sub.n1--(R.sub.1-aryl), where Z is a bond, CO,
CO.sub.2 or SO.sub.2, where n.sub.1 is zero or one and where
R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl and indanyl,
indenyl, dihydronaphthalyl, or tetralinyl optionally substituted
with one, two, three or four of the following substituents on the
aryl ring: (A) C.sub.1-C.sub.6 alkyl optionally substituted with
one, two or three substituents selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (B) C.sub.2-C.sub.6 alkenyl with one or two
double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (C) C.sub.2-C.sub.6 alkynyl with one or two
triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (D) --F, Cl, --Br or --I, (F)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two or
three of --F, (G) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined below, (H) --OH, (I) --C.ident.N, (J)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (K) --CO--(C.sub.1-C.sub.4 alkyl), (L)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (M) --CO--NR.sub.1-aR.sub.1-b, (N)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), (VII)
-(Z)-(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is as
defined above and where R.sub.1-heteroaryl is selected from the
group consisting of: pyridinyl, pyrimidinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl,
isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, 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, where the
R.sub.1-heteroaryl group is bonded to --(CH.sub.2).sub.n1-- by any
ring atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.1-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
optionally substituted with one, two, three or four of: (1)
C.sub.1-C.sub.6 alkyl optionally substituted with one, two or three
substituents selected from the-group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (2)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (3)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (4) --F, Cl,
--Br or --I, (6) --C.sub.1-C.sub.6 alkoxy optionally substituted
with one, two, or three of --F, (7) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined below, (8) --OH, (9)
--C.ident.N. (10) C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (11)
--CO--(C.sub.1-C.sub.4 alkyl), (12)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (13) --CO--NR.sub.1-aR.sub.1-b, or
(14) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), with the proviso that
when n.sub.1 is zero R.sub.1-heteroaryl is not bonded to the carbon
chain by nitrogen, or (VIII)
-(Z)-(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-heterocycle is selected from the group
consisting of: morpholinyl, thiomorpholinyl, thiomorpholinyl
S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homomorpholinyl S-oxide, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl
dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl,
dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl
S,S-dioxide, homothiomorpholinyl S-oxide, where the
R.sub.1-heterocycle group is bonded by any atom of the parent
R.sub.1-heterocycle group substituted by hydrogen such that the new
bond to the R.sub.1-heterocycle group replaces the hydrogen atom
and its bond, where heterocycle is optionally substituted with one,
two, three or four: (1) C.sub.1-C.sub.6 alkyl optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (2) C.sub.2-C.sub.6 alkenyl with one or two
double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (3) C.sub.2-C.sub.6 alkynyl with one or two
triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (4) --F, Cl, --Br, or --I, (5)
C.sub.1-C.sub.6 alkoxy, (6) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three --F, (7) --NR.sub.N-2R.sub.N-3
where R.sub.N-2 and R.sub.N-3 are as defined below, (8) --OH, (9)
--C.ident.N, (10) C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (11)
--CO--(C.sub.1-C.sub.4 alkyl), (12)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (13) --CO--NR.sub.1-aR.sub.1-b,
(14) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), (15) .dbd.O, with the
proviso that when n.sub.1 is zero R.sub.1-heterocycle is not bonded
to the carbon chain by nitrogen; and where R.sub.20 is H or
C.sub.1-6 alkyl or alkenyl.
2. A compound according to claim 1, wherein Rc is
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where R.sub.C-x and
R.sub.C-y are independently selected from the group consisting of
--H, C.sub.1-C.sub.4 alkyl optionally substituted with 1 or 2 --OH,
C.sub.1-C.sub.4 alkoxy optionally substituted with 1, 2, or 3
halogen, --(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl containing one or two double bonds,
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or R.sub.C-x and R.sub.C-y are taken together with the
carbon to which they are attached to form a carbocycle of three,
four, five, six or seven carbon atoms, where one carbon atom is
optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein R.sub.C-aryl
is phenyl, which is optionally substituted with 1, 2, or 3 groups
that are independently: (1) C.sub.1-C.sub.6 alkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (2) --OH, (3) --NO.sub.2, (4) halogen, (5)
--CO.sub.2H, (6) --C.ident.N.
3. A compound according to claim 1, wherein Rc is
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where R.sub.C-x and
R.sub.C-y are independently selected from the group consisting of
--H, C.sub.1-C.sub.4 alkyl optionally substituted with 1 or 2 --OH,
C.sub.1-C.sub.4 alkoxy optionally substituted with 1, 2, or 3
halogen, --(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl containing one or two double bonds,
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or R.sub.C-x and R.sub.C-y are taken together with the
carbon to which they are attached to form a carbocycle of three,
four, five, six or seven carbon atoms, where one carbon atom is
optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl is selected
from the group consisting of pyridinyl, indolyl, indolinyl,
isoindolyl, imidazolyl, isoxazolyl., oxazolyl, thiazolyl,
indolizinyl and isochromanyl.
4. A compound according to claim 1, of the formula: ##STR622##
5. A compound according to claim 1, of the formula: ##STR623##
6. A compound according to claim 1, of the formula: ##STR624##
7. A compound according to claim 1, of the formula: ##STR625##
8. A compound according to claim 1, of the formula: ##STR626##
9. A compound of the formula III: ##STR627## or a pharmaceutically
acceptable salt thereof wherein R.sub.1 represents phenyl
(C.sub.1-C.sub.6)alkyl where the phenyl is optionally substituted
with up to three groups independently selected from halogen,
hydroxy, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, amino,
nitro, trifluoromethyl, cyano, mono(C.sub.1-C.sub.2)alkylamino and
di(C.sub.1-C.sub.2)alkylamino; R.sub.a and R.sub.b independently
represent hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
mono- or di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6
alkyl sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, trifluoromethyl, mono(C.sub.1-C.sub.6)alkylaminocarbonyl,
or di(C.sub.1-C.sub.6)alkylaminocarbonyl and provided that not both
R.sub.a and R.sub.b are hydrogen simultaneously; R.sub.c represents
hydrogen, or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl each of which is optionally substituted
with halogen, hydroxy, amino, cyano, or trifluoromethyl; R.sub.d
represents phenyl optionally substituted with hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7
cycloalkyl, C.sub.3-C.sub.7 cycloalkyl(C.sub.1-C.sub.6)alkyl,
C.sub.3-C.sub.7 cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano,
amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, mono- or
di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6 alkyl
sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl; or
C.sub.1-C.sub.6 alkyl optionally substituted with hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, cyano,
amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, or trifluoromethyl; and R.sub.20
represents hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, or trifluoromethyl.
10. A compound according to claim 9, wherein R.sub.1 is benzyl
where the phenyl is optionally substituted.
11. A compound according to claim 10, wherein the phenyl is
substituted with one or two groups independently selected from
halogen, hydroxy, C.sub.1-C.sub.3 alkyl, amino, and
trifluoromethyl.
12. A compound according to claim 11, wherein phenyl is substituted
with two groups independently selected from halogen, hydroxy, and
trifluoromethyl.
13. A compound according to claim 12, wherein phenyl is
disubstituted with halogen.
14. A compound according to claim 13, wherein R.sub.1 is
3,5-difluorobenzyl.
15. A compound according to claim 12, wherein R.sub.a and R.sub.b
are different and R.sub.b represents mono- or
di(C.sub.1-C.sub.6)alkylaminocarbonyl.
16. A compound according to claim 12, wherein R.sub.d is phenyl
optionally substituted with C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, amino, hydroxy, or halogen.
17. A compound according to claim 12, wherein R.sub.c is hydrogen
or C.sub.1-C.sub.4 alkyl.
18. A compound according to claim 17, wherein R.sub.c is
C.sub.1-C.sub.3 alkyl.
19. A compound according to claim 12, wherein R.sub.d is
C.sub.1-C.sub.6 lower alkyl and R.sub.20 is hydrogen.
20. A compound according to claim 12, which has the formula IV:
##STR628##
21. A compound according to claim 20, wherein R.sub.1 is benzyl
where the phenyl is disubstituted with chloro or fluoro; R.sub.c is
C.sub.1-C.sub.3 alkyl; R.sub.d is C.sub.1-C.sub.6 lower alkyl;
R.sub.20 is hydrogen or C.sub.1-C.sub.6 alkyl; and R.sub.b is
di(C.sub.1-C.sub.6)alkylaminocarbonyl attached to the 3-position of
the phenyl group.
22. A compound of the formula V: ##STR629## or a pharmaceutically
acceptable salt thereof wherein R.sub.1 represents phenyl
(C.sub.1-C.sub.6)alkyl where the phenyl is optionally substituted
with up to three groups independently selected from halogen,
hydroxy, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, amino,
nitro, trifluoromethyl, cyano, mono(C.sub.1-C.sub.2)alkylamino and
di(C.sub.1-C.sub.2)alkylamino; R.sub.a and R.sub.b independently
represent hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
mono- or di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6
alkyl sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, trifluoromethyl, mono(C.sub.1-C.sub.6)alkylaminocarbonyl,
or di(C.sub.1-C.sub.6)alkylaminocarbonyl and provided that not both
R.sub.a and R.sub.b are hydrogen simultaneously; R.sub.c represents
hydrogen, or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl each of which is optionally substituted
with halogen, hydroxy, amino, cyano, or trifluoromethyl; R.sub.d
represents phenyl optionally substituted with hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7
cycloalkyl, C.sub.3-C.sub.7 cycloalkyl(C.sub.1-C.sub.6)alkyl,
C.sub.3-C.sub.7 cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano,
amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, mono- or
di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6 alkyl
sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl; or
C.sub.1-C.sub.6 alkyl optionally substituted with hydroxy,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy, halogen, cyano,
amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, or trifluoromethyl; and R.sub.20
represents hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, or trifluoromethyl.
23. A compound according to claim 22, wherein R.sub.1 is benzyl
where the phenyl is optionally substituted.
24. A compound according to claim 23, wherein the phenyl is
substituted with one or two groups independently selected from
halogen, hydroxy, C.sub.1-C.sub.3 alkyl, amino, and
trifluoromethyl.
25. A compound according to claim 24, wherein phenyl is substituted
with two groups independently selected from halogen, hydroxy, and
trifluoromethyl.
26. A compound according to claim 25, wherein phenyl is
disubstituted with halogen.
27. A compound according to claim 26, wherein R.sub.1 is
3,5-difluorobenzyl.
28. A compound according to claim 25, wherein R.sub.a and R.sub.b
are different and R.sub.b represents
C.sub.1-C.sub.6)alkylsulfonylamino.
29. A compound according to claim 25, wherein R.sub.d is phenyl
optionally substituted with C.sub.1-C.sub.3 alkyl, -C.sub.1-C.sub.3
alkoxy, amino, hydroxy, or halogen.
30. A compound according to claim 25, wherein R.sub.c is hydrogen
or C.sub.1-C.sub.4 alkyl.
31. A compound according to claim 30, wherein R.sub.c is
C.sub.1-C.sub.3 alkyl.
32. A compound according to claim 25, wherein R.sub.d is
C.sub.1-C.sub.6 lower alkyl and R.sub.20 is hydrogen.
33. A compound according to claim 25, which has the formula VI:
##STR630##
34. A compound according to claim 33, wherein R.sub.1 is benzyl
where the phenyl is disubstituted with chloro or fluoro; R.sub.c is
C.sub.1-C.sub.3 alkyl; R.sub.d is C.sub.1-C.sub.6 lower alkyl;
R.sub.20 is hydrogen or C.sub.1-C.sub.6 alkyl; and R.sub.b is
alkylsulfonylamino attached to the 2-position of the thiazolyl
group.
35. A compound according to claim 1, selected from the group
consisting of: ##STR631## ##STR632## ##STR633## ##STR634##
##STR635## ##STR636## ##STR637## ##STR638## ##STR639## ##STR640##
##STR641## ##STR642## ##STR643## ##STR644## ##STR645## ##STR646##
##STR647## ##STR648## ##STR649## ##STR650## ##STR651## ##STR652##
##STR653## ##STR654## ##STR655## ##STR656## ##STR657## ##STR658##
##STR659## ##STR660## ##STR661## ##STR662## ##STR663## ##STR664##
##STR665## ##STR666## ##STR667## ##STR668## ##STR669## ##STR670##
##STR671## ##STR672## ##STR673## ##STR674## ##STR675## ##STR676##
##STR677##
36. A method of treating a patient who has, or in preventing a
patient from getting, a disease or condition selected from the
group consisting of Alzheimer's disease, for helping prevent or
delay the onset of Alzheimer's disease, for treating patients with
mild cognitive impairment (MCI) and preventing or delaying the
onset of Alzheimer's disease in those who would progress from MCI
to AD, for treating Down's syndrome, for treating humans who have
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,
for treating cerebral amyloid angiopathy and preventing its
potential consequences, i.e. single and recurrent lobar
hemorrhages, for treating other degenerative dementias, including
dementias of mixed vascular and degenerative origin, dementia
associated with Parkinson's disease, dementia associated with
progressive supranuclear palsy, dementia associated with cortical
basal degeneration, diffuse Lewy body type of Alzheimer's disease
and who is in need of such treatment which comprises administration
of a therapeutically effective amount of a compound selected from
the group consisting of an aza hydroxylated ethyl amine of the
formula II: ##STR678## or a pharmaceutically acceptable salt
thereof, where Rc is (I) --C.sub.1-C.sub.10 alkyl optionally
substituted with one, two or three groups independently selected
from the group consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O--phenyl,
--NR.sub.1-aR.sub.1-b, --OC.dbd.O NR.sub.1-aR.sub.1-b,
--S(.dbd.O).sub.0-2 R.sub.1-a, --NR.sub.1-aC.dbd.O
NR.sub.1-aR.sub.1-b, --C.dbd.O NR.sub.1-aR.sub.1-b, and
--S(.dbd.O).sub.2 NR.sub.1-aR.sub.1-b wherein R.sub.1-a and
R.sub.1-b at each occurrence are independently H or C.sub.1-C.sub.6
alkyl, (II) --(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8)cycloalkyl where
cycloalkyl can be optionally substituted with one, two or three
substituents independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, --CO.sub.2H,
--CO.sub.2--(C.sub.1-C.sub.4 alkyl), and --NR.sub.1-aR.sub.1-b
(III) --(CR.sub.C-xR.sub.C-y).sub.0-4-R.sub.C-aryl where R.sub.C-x
and R.sub.C-y are independently selected from the group consisting
of --H, C.sub.1-C.sub.4 alkyl optionally substituted with 1 or 2
--OH, C.sub.1-C.sub.4 alkoxy optionally substituted with 1, 2, or 3
halogen, --(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl,
C.sub.2-C.sub.6 alkenyl containing one or two double bonds,
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or R.sub.C-x and R.sub.C-y are taken together with the
carbon to which they are attached to form a carbocycle of three,
four, five, six or seven carbon atoms, where one carbon atom is
optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein R.sub.2-aryl
is phenyl, which is optionally substituted with 1, 2, or 3 groups
that are independently: (1) C.sub.1-C.sub.6 alkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (2) --OH, (3) --NO.sub.2, (4) halogen, (5)
--CO.sub.2H, (6) --C.ident.N, (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are independently selected from the group consisting of:
(a) --H, (b) --C.sub.1-C.sub.6 alkyl optionally substituted with
one substituent selected from the group consisting of: (i) --OH,
and (ii) --NH.sub.2, (c) --C.sub.1-C.sub.6 alkyl optionally
substituted with 1, 2, or 3 groups that are independently --F,
--Cl, --Br, --I, or OH, (d) --C.sub.3-C.sub.7 cycloalkyl, (e)
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), (g)
--C.sub.2-C.sub.6 alkenyl (h) --C.sub.2-C.sub.6 alkynyl (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, (j) --R.sub.1-aryl wherein R.sub.1-aryl at each occurrence is
independently phenyl, naphthyl, indanyl, indenyl, dihydronaphthyl,
or tetralinyl each of which is optionally substituted with 1, 2, 3,
or 4 groups that are independently: (i) C.sub.1-C.sub.6 alkyl
optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (ii)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents independently
selected from the group consisting of. --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (iii) C.sub.2-C.sub.6 alkynyl optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (iv)
--F, Cl, --Br and --I, (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with 1, 2, or 3 --F, (vi) --NR.sub.N-2R.sub.N-3, (vii)
--OH, (viii) --C.ident.N, (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (x)
--CO--(C.sub.1-C.sub.4 alkyl), (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (xii) --CO--NR.sub.1-aR.sub.1-b,
or (xiii) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), (k)
--R.sub.1-heteroaryl wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, where
the R.sub.1-heteroaryl group is optionally substituted with 1, 2,
3, or 4 groups that are independently: (i) C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b, --C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (ii) C.sub.2-C.sub.6
alkenyl optionally substituted with 1, 2, or 3 groups that are
independently --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (iii)
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
groups that are independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, (iv) --F, --Cl, --Br and --I,
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with one, two,
or three --F. (vi) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (vii)
--OH, (viii) --C.ident.N, (ix) (CH.sub.2).sub.0-4--C.sub.3-C.sub.7
cycloalkyl, optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6
alkyl), (xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3,
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), (11)
--(CH.sub.2).sub.0-4--CO--(CH.sub.2).sub.0-4(C.sub.3-C.sub.7
cycloalkyl), (12) --(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle wherein
R.sub.1-heterocycle at each occurrence is independently selected
from the group consisting of morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heterocycle group replaces the hydrogen
atom and its bond, where heterocycle is optionally substituted with
1, 2, 3, or 4 groups that are independently: (a) C.sub.1-C.sub.6
alkyl optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --NR.sub.1-aR.sub.1-b--C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (b) C.sub.2-C.sub.6 alkenyl
with one or two double bonds, optionally substituted with one, two
or three substituents independently selected from the group
consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b (c)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b (d) halogen, (e) C.sub.1-C.sub.6 alkoxy, (f)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two, or
three --F, (g) --NR.sub.N-2R.sub.N-3, (h) --OH, (i) --C.ident.N,
(j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.7 cycloalkyl), optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, (m)
--(CH.sub.2).sub.0-4CO--NR.sub.1-aR.sub.1-b, (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and (o)
.dbd.O, (p) --(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein R.sub.N-4 at each
occurrence is independently selected from the group consisting of
morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl, pyrazolyl,
thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,
homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where
each group is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.6 alkyl, (16)
--(CH.sub.2).sub.0-4--CO.sub.2--R.sub.N-5 where R.sub.N-5 at each
occurrence is independently selected from the group consisting of:
(a) C.sub.1-C.sub.6 alkyl, (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl), (c) C.sub.2-C.sub.6 alkenyl,
(d) C.sub.2-C.sub.6 alkynyl, (e) C.sub.3-C.sub.7 cycloalkyl, and
(f) --(CH.sub.2).sub.0-4--(R.sub.1-heteroaryl), (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3 (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), (20)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl), (21)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO.sub.2--R.sub.N-5, (22)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--N(R.sub.N-5).sub.2,
(23) --(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 where R.sub.100
is independently H or C.sub.1-C.sub.4 alkyl, (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl) wherein the alkyl
group is optionally substituted with one, two, three, four, or five
substituents independently selected from the group consisting of F,
Cl, Br, and I, (35) --(CH.sub.2).sub.0-4--(C.sub.3-C.sub.8
cycloalkyl), (36) C.sub.2-C.sub.6 alkenyl optionally substituted
with C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, and (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2;
(IV) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl wherein
R.sub.C-heteroaryl at each occurrence is independently selected
from the group consisting of pyridinyl, pyrimidinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl,
isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzoisothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, thienyl, pyrrolyl, oxadiazolyl,
thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,
beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl, pteridinyl,
benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,
quinazolinonyl, pyrazopyridyl, benzooxadiazolyl,
dihydropyrimidinonyl, dihydrobenzofuranonyl,
where the R.sub.C-heteroaryl group is bonded by any atom of the
parent R.sub.C-heteroaryl group substituted by hydrogen such that
the new bond to the R.sub.C-heteroaryl group replaces the hydrogen
atom and its bond, where heteroaryl is optionally substituted 1, 2,
3, or 4 groups that are independently: (1) C.sub.1-C.sub.6 alkyl,
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (2) --OH, (3)
--NO.sub.2, (4) --F, --Cl, --Br, --I, (5) --CO--OH, (6)
--C.ident.N, (V) C.sub.2-C.sub.10 alkenyl optionally substituted
with one, two or three substituents independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
--O-phenyl, and --NR.sub.1-aR.sub.1-b, (VI) C.sub.2-C.sub.10
alkynyl optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, --O-phenyl, and --NR.sub.1-aR.sub.1-b,
(VII) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH,
(VIII) --CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2,
(IX) --(CH.sub.2).sub.0-6--C(.dbd.NR.sub.1-a)
(NR.sub.1-aR.sub.1-b); where R.sub.N is (I) R.sub.N-1--X.sub.N--
where X.sub.N is --CO--, and where R.sub.N-1 is selected from the
group consisting of: (A) phenyl, which is optionally substituted
with one, two or three of the following substituents which can be
the same or different and are: (1) C.sub.1-C.sub.6 alkyl,
optionally substituted with one, two or three substituents selected
from the group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl,
--Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, wherein R.sub.1-a and R.sub.1-b
at each occurrence are independently H or C.sub.1-C.sub.6 alkyl,
(2) --OH, (3) --NO.sub.2, (4) --F, --Cl, --Br, --I, (5)
--CO.sub.2H, (6) --C.ident.N, (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are the same-or different and are selected from the group
consisting of: (a) --H, (b) --C.sub.1-C.sub.8 alkyl optionally
substituted with one substituent selected from the group consisting
of: (i) --OH, (ii) --NH.sub.2, (iii) phenyl, (c) --C.sub.1-C.sub.8
alkyl optionally substituted with 1, 2, or 3 groups that are
independently --F, --Cl, --Br, or --I, (d) --C.sub.3-C.sub.8
cycloalkyl, (e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8
cycloalkyl), (f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3
alkyl), (g) --C.sub.2-C.sub.6 alkenyl, (h) --C.sub.2-C.sub.6
alkynyl, (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, (j) --R.sub.1-aryl, wherein R.sub.1-aryl at each
occurrence is independently phenyl, naphthyl, indanyl, indenyl,
dihydronaphthyl, or tetralinyl each of which is optionally
substituted with 1, 2, 3, or 4 groups that are independently: (i)
C.sub.1-C.sub.6 alkyl optionally substituted with one, two or three
substituents independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy, (ii) C.sub.2-C.sub.6 alkenyl with one or two double bonds,
optionally substituted with one, two or three substituents
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (iii) C.sub.2-C.sub.6 alkynyl optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (iv)
--F, Cl, --Br and --I, (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with 1, 2, or 3 --F, (vi) --NR.sub.N-2R.sub.N-3, (vii)
--OH, (viii) --C.ident.N, (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (x)
--CO--(C.sub.1-C.sub.4 alkyl), (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (xii) --CO--NR.sub.1-aR.sub.1-b,
or (xiii) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), (k)
--R.sub.1-heteroaryl, wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, where
the R.sub.1-heteroaryl group is optionally substituted with 1, 2,
3, or 4 groups that are independently: (i) C.sub.1-C.sub.6 alkyl
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b, --C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (ii) C.sub.2-C.sub.6
alkenyl optionally substituted with 1, 2, or 3 groups that are
independently --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, (iii)
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, (iv)
--F, --Cl, --Br and --I, (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three --F, (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (vii) --OH, (viii)
--C.ident.N, (ix) (CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6
alkyl), (xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3,
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, (l) --R.sub.1-heterocyle,
wherein R.sub.1-heterocycle at each occurrence is independently
selected from the group consisting of morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
where the R.sub.1-heterocycle group is bonded by any atom of the
parent R.sub.1-heterocycle group substituted by hydrogen such that
the new bond to the R.sub.1-heterocycle group replaces the hydrogen
atom and its bond, where heterocycle is optionally substituted with
1, 2, 3, or 4 groups that are independently: (a) C.sub.1-C.sub.6
alkyl optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, halogen, --OH, --SH, --NR.sub.1-aR.sub.1-b--C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, (b) C.sub.2-C.sub.6 alkenyl
with one or two double bonds, optionally substituted with one, two
or three substituents independently selected from the group
consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b (c)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b (d) halogen, (e) C.sub.1-C.sub.6 alkoxy, (f)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two, or
three --F, (g) --NR.sub.N-2R.sub.N-3, (h) --OH, (i) --C.ident.N,
(j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.8 cycloalkyl), optionally
substituted with 1, 2, or 3 groups independently selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and (o)
.dbd.O, (p) --(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein R.sub.N-4 is selected
from the group consisting of phenyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,
pyrrolinyl, thienyl, pyrazolyl, pyridyl N-oxide, oxazolyl,
thiazolyl, imidazolyl, and pyrrolidinyl where each group is
optionally substituted with one, two, three, or four groups that
are independently C.sub.1-C.sub.6 alkyl, (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 where R.sub.N-5 is selected
from the group consisting of: (a) C.sub.1-C.sub.6 alkyl, (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl). (c) C.sub.2-C.sub.6 alkenyl,
(d) C.sub.2-C.sub.6 alkynyl, (e)
--(CH.sub.2).sub.0-2--C.sub.3-C.sub.8 cycloalkyl, (f)
--(CH.sub.2).sub.0-2--(R.sub.1-heteroaryl), and (g)
--(CH.sub.2).sub.0-2--(R.sub.1-heterocycle), (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), (20)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl), (21)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--O--R.sub.N-5, (22)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--N(R.sub.N-5).sub.2,
(23) --(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, (24)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--R.sub.N-2, (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 wherein R.sub.100
at each occurrence is independently --H or C.sub.1-C.sub.4 alkyl,
(29) --(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), (35)
C.sub.3-C.sub.8 cycloalkyl, (36) C.sub.2-C.sub.6 alkenyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (37) C.sub.2-C.sub.6 alkynyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (38) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--SO.sub.2--R.sub.N-2, (39)
--(CH.sub.2).sub.1-4--(C.sub.3-C.sub.8 cycloalkyl), (B)
--R.sub.N-heteroaryl where R.sub.N-heteroaryl is selected from the
group consisting of pyridinyl, indolyl, indolinyl, isoindolyl,
imidazolyl, isoxazolyl, oxazolyl, thiazolyl, indolizinyl and
isochromanyl, where the R.sub.N-heteroaryl group is bonded by any
atom of the parent R.sub.N-heteroaryl group substituted by hydrogen
such that the new bond to the R.sub.N-heteroaryl group replaces the
hydrogen atom and its bond, where heteroaryl is optionally
substituted with one, two, three, or four of: (1) C.sub.1-C.sub.6
alkyl, optionally substituted with one, two or three substituents
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (2) --OH, (3)
--NO.sub.2, (4) --F, --Cl, --Br, --I, (5) --CO.sub.2H, (6)
--C.ident.N, (7) --(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), (12)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aryl, (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), (19)
--(CH.sub.2).sub.0-4--SO.sub.2-(C.sub.1-C.sub.12 alkyl), (20)
--(CH.sub.2).sub.0-4--SO.sub.2
--(C.sub.3-C.sub.8 cycloalkyl), (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, (22) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5 )--CO--N(R.sub.N-5).sub.2, (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2, (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), (35)
C.sub.3-C.sub.8 cycloalkyl, (36) C.sub.2-C.sub.6 alkenyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (37) C.sub.2-C.sub.6 alkynyl optionally
substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, (38) --(CH.sub.2).sub.0-4--N(--H or
R.sub.N-5)--SO.sub.2--R.sub.N-2, (39)
--(CH.sub.2).sub.1-4--C.sub.3-C.sub.8 cycloalkyl, (C)
R.sub.N-aryl--W--R.sub.N-aryl, (D)
R.sub.N-aryl--W--R.sub.N-heteroaryl, (E)
R.sub.N-aryl--W--R.sub.1-heterocycle, (F)
R.sub.N-heteroaryl--W--R.sub.N-aryl, (G)
R.sub.N-heteroaryl--W--R.sub.N-heteroaryl, (H)
R.sub.N-heteroaryl--W--R.sub.N-1-heterocycle, (I)
R.sub.N-heterocycle--W--R.sub.N-aryl, (J)
R.sub.N-heterocycle--W--R.sub.N-heteroaryl, (K)
R.sub.N-heterocycle--W--R.sub.N-1-heterocycle, where W is (25)
--(CH.sub.2).sub.1-4--, (26) --O--, (27) --S(O).sub.0-2--, (28)
--N(R.sub.N-5)--, (29) --CO--; or (30) a bond; (II)
--CO--(C.sub.1-C.sub.6 alkyl)-M-(C.sub.1-C.sub.6 alkyl), where M is
S, SO or SO.sub.2, and wherein each alkyl is unsubstituted or
substituted with one, two, or three of substituents independently
selected from the group consisting of: (A)
--NH--CO--(C.sub.1-C.sub.6 alkyl), (B) --NH--CO--O--R.sub.N-8, (C)
--NR.sub.N-2R.sub.N-3; where R.sub.1 is (CH.sub.2).sub.n1-phenyl,
where n.sub.1 is zero or one, and which is optionally substituted
with one, two, three or four of the following substituents on the
phenyl ring: (A) C.sub.1-C.sub.6 alkyl optionally substituted with
one, two or three substituents selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (B) C.sub.2-C.sub.6 alkenyl with one or two
double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (C) C.sub.2-C.sub.6 alkynyl with one or two
triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (D) --F, Cl, --Br or --I, (F)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two or
three of --F, (G) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined below, (H) --OH, (I) --C.ident.N, (J)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (K) --CO--(C.sub.1-C.sub.4 alkyl), (L)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (M) --CO--NR.sub.1-aR.sub.1-b, (N)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl); and where R.sub.2 is (I)
-(Z)-C.sub.1-C.sub.6 alkyl, where Z is a bond, --C(O)--,
--CO.sub.2-- or --SO.sub.2--, wherein the alkyl group is optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.7 alkyl
(optionally substituted with C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.3 alkoxy), --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
--NR.sub.1-aR.sub.1-b where R.sub.1-a and R.sub.1-b are
independently --H or C.sub.1-C.sub.6 alkyl, and --OC.dbd.O
NR.sub.1-aR.sub.1-b, (II)
-(Z)-CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl), (III)
-(Z)-CH.sub.2--CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
(IV) -(Z)-C.sub.2-C.sub.6 alkenyl with one or two double bonds,
optionally substituted with one, two or three substituents selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (V)
-(Z)-C.sub.2-C.sub.6 alkynyl with one or two triple bonds,
optionally substituted with one, two or three substituents selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (VI)
-(Z)-(CH.sub.2).sub.n1--(R.sub.1-aryl), where Z is a bond, CO,
CO.sub.2 or SO.sub.2, where n, is zero or one and where
R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl and indanyl,
indenyl, dihydronaphthalyl, or tetralinyl optionally substituted
with one, two, three or four of the following substituents on the
aryl ring: (A) C.sub.1-C.sub.6 alkyl optionally substituted with
one, two or three substituents selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (B) C.sub.2-C.sub.6 alkenyl with one or two
double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (C) C.sub.2-C.sub.6 alkynyl with one or two
triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (D) --F, Cl, --Br or --I, (F)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two or
three of --F, (G) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined below, (H) --OH, (I) --C.ident.N, (J)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (K) --CO--(C.sub.1-C.sub.4 alkyl), (L)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (M) --CO--NR.sub.1-aR.sub.1-b, (N)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), (VII)
-(Z)-(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where n.sub.1 is as
defined above and where R.sub.1-heteroaryl is selected from the
group consisting of: pyridinyl, pyrimidinyl, quinolinyl,
benzothienyl, indolyl, indolinyl, pryidazinyl, pyrazinyl,
isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl, phthalazinyl,
imidazolyl, isoxazolyl, pyrazolyl, oxazolyl, thiazolyl,
indolizinyl, indazolyl, benzothiazolyl, benzimidazolyl,
benzofuranyl, furanyl, 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, where the
R.sub.1-heteroaryl group is bonded to --(CH.sub.2).sub.n1-- by any
ring atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.1-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
optionally substituted with one, two, three or four of: (1)
C.sub.1-C.sub.6 alkyl optionally substituted with one, two or three
substituents selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (2)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (3)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (4) --F, Cl,
--Br or --I, (6) --C.sub.1-C.sub.6 alkoxy optionally substituted
with one, two, or three of --F, (7) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined below, (8) --OH, (9)
--C.ident.N, (10) C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (11)
--CO--(C.sub.1-C.sub.4 alkyl), (12)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (13) --CO--NR.sub.1-aR.sub.1-b, or
(14) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), with the proviso that
when n.sub.1 is zero R.sub.-heteroaryl is not bonded to the carbon
chain by nitrogen, or (VIII)
-(Z)-(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where n.sub.1 is as
defined above and R.sub.1-heterocycle is selected from the group
consisting of: morpholinyl, thiomorpholinyl, thiomorpholinyl
S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homomorpholinyl S-oxide, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl
dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl,
dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl
S,S-dioxide, homothiomorpholinyl S-oxide, where the
R.sub.1-heterocycle group is bonded by any atom of the parent
R.sub.1-heterocycle group substituted by hydrogen such that the new
bond to the R.sub.1-heterocycle group replaces the hydrogen atom
and its bond, where heterocycle is optionally substituted with one,
two, three or four: (1) C.sub.1-C.sub.6 alkyl optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (2) C.sub.2-C.sub.6 alkenyl with one or two
double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (3) C.sub.2-C.sub.6 alkynyl with one or two
triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, (4) --F, Cl, --Br, or --I, (5)
C.sub.1-C.sub.6 alkoxy, (6) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three --F, (7) --NR.sub.N-2R.sub.N-3
where R.sub.N-2 and R.sub.N-3 are as defined below, (8) --OH, (9)
--C.ident.N, (10) C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, (11)
--CO--(C.sub.1-C.sub.4 alkyl), (12)
--SO.sub.2--NR.sub.1-aR.sub.1-b, (13) --CO--NR.sub.1-aR.sub.1-b,
(14) --SO.sub.2--(C.sub.1-C.sub.4 alkyl), (15) .dbd.O, with the
proviso that when n.sub.1 is zero R.sub.1-heterocycle is not bonded
to the carbon chain by nitrogen; and where R.sub.20 is H or
C.sub.1-6 alkyl or alkenyl.
Description
BACKGROUND OF THE INVENTION
[0001] 1 . Field of the Invention
[0002] This invention relates to aza hydroxylated ethyl amine
derivatives and more specifically to such compounds that are useful
in the treatment and/or prevention of Alzheimer's disease and
similar diseases. More specifically the invention relates to
substituted aza hydroxy ethyl amines that are capable of inhibiting
beta-secretase, an enzyme that cleaves amyloid precursor protein to
produce amyloid beta peptide (A beta), a major component of the
amyloid plaques found in the brains of Alzheimer's sufferers.
[0003] 2. Description of Related Art
[0004] Alzheimer's disease (AD) is a progressive degenerative
disease of the brain primarily associated with aging. Clinical
presentation of AD is characterized by loss of memory, cognition,
reasoning, judgment, and orientation. As the disease progresses,
motor, sensory, and linguistic abilities are also affected until
there is global impairment of multiple cognitive functions. These
cognitive losses occur gradually, but typically lead to severe
impairment and eventual death in the range of four to twelve
years.
[0005] Alzheimer's disease is characterized by two major pathologic
observations in the brain: neurofibrillary tangles and beta amyloid
(or neuritic) plaques, comprised predominantly of an aggregate of a
peptide fragment know as A beta. Individuals with AD exhibit
characteristic beta-amyloid deposits in the brain (beta amyloid
plaques) and in cerebral blood vessels (beta amyloid angiopathy) as
well as neurofibrillary tangles. Neurofibrillary tangles occur not
only in Alzheimer's disease but also in other dementia-inducing
disorders. On autopsy, large numbers of these lesions are generally
found in areas of the human brain important for memory and
cognition.
[0006] Smaller numbers of these lesions in a more restricted
anatomical distribution are found in the brains of most aged humans
who do not have clinical AD. Amyloidogenic plaques and vascular
amyloid angiopathy also characterize the brains of individuals with
Trisomy 21 (Down's Syndrome), Hereditary Cerebral Hemorrhage with
Amyloidosis of the Dutch-Type (HCHWA-D), and other
neurodegenerative disorders. Beta-amyloid is a defining feature of
AD, now believed to be a causative precursor or factor in the
development of disease. Deposition of A beta in areas of the brain
responsible for cognitive activities is a major factor in the
development of AD. Beta-amyloid plaques are predominantly composed
of amyloid beta peptide (A beta, also sometimes designated betaA4).
A beta peptide is derived by proteolysis of the amyloid precursor
protein (APP) and is comprised of 39-42 amino acids. Several
proteases called secretases are involved in the processing of
APP.
[0007] Cleavage of APP at the N-terminus of the A beta peptide by
beta-secretase and at the C-terminus by one or more
gamma-secretases constitutes the beta-amyloidogenic pathway, i.e.
the pathway by which A beta is formed. Cleavage of APP by
alpha-secretase produces alpha-sAPP, a secreted form of APP that
does not result in beta-amyloid plaque formation. This alternate
pathway precludes the formation of A beta peptide. A description of
the proteolytic processing fragments of APP is found, for example,
in U.S. Pat. Nos. 5,441,870; 5,721,130; and 5,942,400.
[0008] An aspartyl protease has been identified as the enzyme
responsible for processing of APP at the beta-secretase cleavage
site. The beta-secretase enzyme has been disclosed using varied
nomenclature, including BACE, Asp, and Memapsin. See, for example,
Sindha et al., 1999, Nature 402:537-554 (p 501) and published PCT
application WO00/17369.
[0009] Several lines of evidence indicate that progressive cerebral
deposition of beta-amyloid peptide (A beta) plays a seminal role in
the pathogenesis of AD and can precede cognitive symptoms by years
or decades. See, for example, Selkoe, 1991, Neuron 6:487. Release
of A beta from neuronal cells grown in culture and the presence of
A beta in cerebrospinal fluid (CSF) of both normal individuals and
AD patients has been demonstrated. See, for example, Seubert et
al., 1992, Nature 359:325-327.
[0010] It has been proposed that A beta peptide accumulates as a
result of APP processing by beta-secretase, thus inhibition of this
enzyme's activity is desirable for the treatment of AD. In vivo
processing of APP at the beta-secretase cleavage site is thought to
be a rate-limiting step in A beta production, and is thus a
therapeutic target for the treatment of AD. See for example,
Sabbagh, M., et al., 1997, Alz. Dis. Rev. 3, 1-19.
[0011] BACE1 knockout mice fail to produce A beta, and present a
normal phenotype. When crossed with transgenic mice that over
express APP, the progeny show reduced amounts of A beta in brain
extracts as compared with control animals (Luo et al., 2001 Nature
Neuroscience 4:231-232). This evidence further supports the
proposal that inhibition of beta-secretase activity and reduction
of A beta in the brain provides a therapeutic method for the
treatment of AD and other beta amyloid disorders.
[0012] At present there are no effective treatments for halting,
preventing, or reversing the progression of Alzheimer's disease.
Therefore, there is an urgent need for pharmaceutical agents
capable of slowing the progression of Alzheimer's disease and/or
preventing it in the first place.
[0013] Compounds that are effective inhibitors of beta-secretase,
that inhibit beta-secretase-mediated cleavage of APP, that are
effective inhibitors of A beta production, and/or are effective to
reduce amyloid beta deposits or plaques, are needed for the
treatment and prevention of disease characterized by amyloid beta
deposits or plaques, such as AD. Various pharmaceutical agents have
been proposed for the treatment of Alzheimer's disease but without
any real success.
[0014] At present there are no effective treatments for halting,
preventing, or reversing the progression of Alzheimer's disease.
There is an urgent need for compounds capable of slowing A-beta
peptide production and/or deposition in the brain, which presents a
therapeutic approach to treatment of Alzheimer's disease.
SUMMARY OF THE INVENTION
[0015] The invention provides compounds of the formula below,
pharmaceutical compositions containing the compounds, and methods
useful in the treatment of Alzheimer's disease. More specifically,
it provides compounds that are capable of inhibiting
beta-secretase, an enzyme that cleaves amyloid precursor protein to
produce A beta peptide, a major component of the amyloid plaques
found in the brains of Alzheimer's sufferers.
[0016] Accordingly, in a broad aspect, the invention is provides
towards compounds of formula I: ##STR2## and pharmaceutically
acceptable salts or esters thereof, where Rc is
[0017] (I) --C.sub.1-C.sub.10 alkyl optionally substituted with
one, two or three groups independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl,
--NR.sub.1-aR.sub.1-b, --OC.dbd.ONR.sub.1-aR.sub.1-b,
--S(.dbd.O).sub.0-2R.sub.1-a,
--NR.sub.1-aC.dbd.ONR.sub.1-aR.sub.1-b, --C.dbd.O
NR.sub.1-aR.sub.1-b, and --S(.dbd.O).sub.2NR.sub.1-aR.sub.1-b
wherein
[0018] R.sub.1-a and R.sub.1-b at each occurrence are independently
H or C.sub.1-C.sub.6 alkyl,
[0019] (II) --(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl
where cycloalkyl can be optionally substituted with one, two or
three substituents independently selected from the group consisting
of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, --CO.sub.2H,
--CO.sub.2--(C.sub.1-C.sub.4 alkyl), and --NR.sub.1-aR.sub.1-b
[0020] (III) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where
R.sub.C-x and R.sub.C-y are independently selected from the group
consisting of [0021] --H, [0022] C.sub.1-C.sub.4 alkyl optionally
substituted with 1 or 2 --OH, [0023] C.sub.1-C.sub.4 alkoxy
optionally substituted with 1, 2, or 3 halogen, [0024]
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl, [0025]
C.sub.2-C.sub.6 alkenyl containing one or two double bonds, [0026]
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
[0027] phenyl, or [0028] R.sub.C-x and R.sub.C-y are taken together
with the carbon to which they are attached to form a carbocycle of
three, four, five, six or seven carbon atoms, where one carbon atom
is optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.c-aryl, wherein [0029]
R.sub.C-aryl at each occurrence is independently phenyl; naphthyl;
tetralinyl; indanyl; dihydronaphthyl; or
6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl, each of which is
optionally substituted with 1, 2, or 3 groups that are
independently: [0030] (1) C.sub.1-C.sub.6 alkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0031] (2) --OH, [0032] (3) --NO.sub.2,
[0033] (4) halogen, [0034] (5) --CO.sub.2H, [0035] (6) --C.ident.N,
[0036] (7) --(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where
[0037] R.sub.N-2 and R.sub.N-3 are independently selected from the
group consisting of: [0038] (a) --H, [0039] (b) --C.sub.1-C.sub.6
alkyl optionally substituted with one substituent selected from the
group consisting of: [0040] (i) --OH, and [0041] (ii) --NH.sub.2,
[0042] (c) --C.sub.1-C.sub.6 alkyl optionally substituted with 1,
2, or 3 groups that are independently --F, --Cl, --Br, --I, or OH,
[0043] (d) --C.sub.3-C.sub.7 cycloalkyl, [0044] (e)
--(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.7 cycloalkyl), [0045] (f)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), [0046] (g)
--C.sub.2-C.sub.6 alkenyl [0047] (h) --C.sub.2-C.sub.6 alkynyl
[0048] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, [0049] (j) --R.sub.1-aryl wherein R.sub.1-aryl at
each occurrence is independently phenyl, naphthyl, indanyl,
indenyl, dihydronaphthyl, or tetralinyl each of which is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[0050] (i) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy, [0051] (ii) C.sub.2-C.sub.6 alkenyl with
one or two double bonds, optionally substituted with one, two or
three substituents independently selected from the group consisting
of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0052] (iii) C.sub.2-C.sub.6
alkynyl optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0053] (iv) --F, Cl, --Br and --I, [0054]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with 1, 2, or 3
--F, [0055] (vi) --NR.sub.N-2R.sub.N-3, [0056] (vii) --OH, [0057]
(viii) --C.ident.N, [0058] (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0059] (x) --CO--(C.sub.1-C.sub.4 alkyl), [0060] (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [0061] (xii)
--CO--NR.sub.1-aR.sub.1-b, or [0062] (xiii)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), [0063] (k)
--R.sub.1-heteroaryl wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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,
dihydroquinolirionyl, 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, and benzothiopyranyl S,S-dioxide, [0064]
where the R.sub.1-heteroaryl group is optionally substituted with
1, 2, 3, or 4 groups that are independently: [0065] (i)
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, [0066] (ii)
C.sub.2-C.sub.6 alkenyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0067] (iii) C.sub.2-C.sub.6 alkynyl optionally substituted with 1,
2, or 3 groups that are independently selected from the group
consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0068] (iv) --F,
--Cl, --Br and --I, [0069] (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three --F, [0070] (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0071] (vii) --OH,
[0072] (viii) --C.ident.N, [0073] (ix)
(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0074] (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6 alkyl), [0075]
(xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0076]
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0077] (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [0078] (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and [0079] (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, [0080] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [0081] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [0082] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), [0083] (11)
--(CH.sub.2).sub.0-4--CO--(CH.sub.2).sub.0-4 (C.sub.3-C.sub.7
cycloalkyl), [0084] (12) --(CH.sub.2).sub.0-4--CO--R.sub.1-aryl,
[0085] (13) --(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [0086]
(14) --(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle wherein [0087]
R.sub.1-heterocycle at each occurrence is independently selected
from the group. consisting of morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
[0088] where the R.sub.1-heterocycle group is bonded by any atom of
the parent R.sub.1-heterocycle group substituted by hydrogen such
that the new bond to the R.sub.1-heterocycle group replaces the
hydrogen atom and its bond, where heterocycle is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[0089] (a) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sub.1-aR.sub.1-b--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy, [0090] (b) C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b [0091] (c) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b [0092] (d) halogen, [0093] (e)
C.sub.1-C.sub.6 alkoxy, [0094] (f) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [0095] (g)
--NR.sub.N-2R.sub.N-3, [0096] (h) --OH, [0097] (i) --C.ident.N,
[0098] (j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.7 cycloalkyl),
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0099] (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), [0100] (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, [0101] (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, [0102] (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and [0103]
(o) .dbd.O, [0104] (p)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- [0105] (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- [0106] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein [0107] R.sub.N-4 at
each occurrence is independently selected from the group consisting
of morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl,
pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,
homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where
each group is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.6 alkyl, [0108] (16)
--(CH.sub.2).sub.0-4--CO.sub.2--R.sub.N-5 where [0109] R.sub.N-5 at
each occurrence is independently selected from the group consisting
of: [0110] (a) C.sub.1-C.sub.6 alkyl, [0111] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl) [0112] (c) C.sub.2-C.sub.6
alkenyl, [0113] (d) C.sub.2-C.sub.6 alkynyl, [0114] (e)
C.sub.3-C.sub.7 cycloalkyl, and [0115] (f)
--(CH.sub.2).sub.0-4--(R.sub.1-heteroaryl) [0116] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3 [0117] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [0118] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl) [0119]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl)
[0120] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO.sub.2--R.sub.N-5, [0121] (22)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--N(R.sub.N-5).sub.2,
[0122] (23) --(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [0123]
(24) --(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2,
[0124] (25) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0125] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0126] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl) [0127] (28)
--(CH.sub.2).sub.0-4--O--P--(O)--(OR.sub.100).sub.2 where R.sub.100
is independently H or C.sub.1-C.sub.4 alkyl, [0128] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [0129] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [0130] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [0131] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [0132] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5) [0133] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl) wherein the alkyl
group is optionally substituted with one, two, three, four, or five
substituents independently selected from the group consisting of F,
Cl, Br, and I, [0134] (35) --(CH.sub.2).sub.0-4--(C.sub.3-C.sub.8
cycloalkyl), [0135] (36) C.sub.2-C.sub.6 alkenyl optionally
substituted with C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, [0136] (37) C.sub.2-C.sub.6 alkynyl
optionally substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br,
--I, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
or --NR.sub.1-aR.sub.1-b, and [0137] (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2;
[0138] (IV) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroary
wherein [0139] R.sub.C-heteroaryl at each occurrence is
independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzoisothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,
beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl, pteridinyl,
benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,
quinazolinonyl, pyrazopyridyl, benzooxadiazolyl,
dihydropyrimidinonyl, dihydrobenzofuranonyl, pyridinyl-N-oxide,
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,
and benzothiopyranyl S,S-dioxide,
[0140] where the R.sub.C-heteroaryl group is bonded by any atom of
the parent R.sub.C-heteroaryl group substituted by hydrogen such
that the new bond to the R.sub.C-heteroaryl group replaces the
hydrogen atom and its bond, where heteroaryl is optionally
substituted 1, 2, 3, or 4 groups that are independently: [0141] (1)
C.sub.1-C.sub.6 alkyl, optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0142] (2) --OH, [0143] (3) --NO.sub.2,
[0144] (4) --F, --Cl, --Br, --I, [0145] (5) --CO--OH, [0146] (6)
--C.ident.N, [0147] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0148] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [0149] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl with one, two
or three double bonds), [0150] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl with one, two
or three triple bonds), [0151] (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.7 cycloalkyl), [0152] (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl where R.sub.1-aryl is as
defined above, [0153] (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [0154] (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, [0155] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4, [0156] (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5, [0157] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0158] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [0159] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), [0160]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl),
[0161] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, [0162] (22) --(CH.sub.2).sub.0-4--N(H
or R.sub.N-5)--CO--N(R.sub.N-5).sub.2, [0163] (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [0164] (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, [0165]
(25) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0166] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0167] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [0168] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 where R.sub.100
is --H or C.sub.1-C.sub.4 alkyl, [0169] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [0170] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [0171] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5) , [0172] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [0173] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5) [0174] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), [0175]
(35) C.sub.3-C.sub.7 cycloalkyl, [0176] (36) C.sub.2-C.sub.6
alkenyl optionally substituted with C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0177] (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0178] (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[0179] (39) --(CH.sub.2).sub.0-4--(C.sub.3-C.sub.7 cycloalkyl),
[0180] (V)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl--R.sub.101--R.sub.C-aryl,
[0181] (VI)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl--R.sub.101--R.sub.C-heteroa-
ryl,
[0182] (VII)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl--R.sub.101--R.sub.C-a-
ryl,
[0183] (VIII)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl--R.sub.101--R.sub.C-h-
eteroaryl,
[0184] (IX)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl--R.sub.101--R.sub.1-heteroc-
ycle,
[0185] (X)
--(CR.sub.c-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl--R.sub.101--R.sub.1-h-
eterocycle,
[0186] (XI)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.1-heterocycle--R.sub.101--R.sub.C--
aryl,
[0187] (XII)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.1-heterocycle--R.sub.101--R.sub.C--
heteroaryl,
[0188] (XIII)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.1-heterocycle--R.sub.101--R.sub.1--
heterocycle, wherein [0189] R.sub.101 is a bond,
(CH.sub.2).sub.0-4, --O--, --NH--, or --N(C.sub.1-C.sub.6
alkyl)
[0190] (XIV)
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.1-heterocycle,
[0191] (XV)
--[C(R.sub.C-1)(R.sub.C-2)].sub.1-3--CO--N(R.sub.C-3).sub.2 where
R.sub.C-1 and R.sub.C-2 are the same or different and are selected
from the group consisting of: [0192] (A) --H, [0193] (B)
--C.sub.1-C.sub.6 alkyl, optionally substituted with one, two or
three substituents independently selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, and
--NR.sub.1-aR.sub.1-b, [0194] (C) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, and
--NR.sub.1-aR.sub.1-b, [0195] (D) C.sub.2-C.sub.6 alkynyl
optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, --O-phenyl, and --NR.sub.1-aR.sub.1-b,
[0196] (E) --(CH.sub.2).sub.1-2--S(O).sub.0-2--(C.sub.1-C.sub.6
alkyl) [0197] (F) --(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, --O-phenyl, and --R.sub.1-aR.sub.1-b,
[0198] (G) --(C.sub.1-C.sub.4 alkyl)-R.sub.1-aryl, [0199] (H)
--(C.sub.1-C.sub.4 alkyl)-R.sub.C-heteroaryl, [0200] (I)
--(C.sub.1-C.sub.4 alkyl)-R.sub.1-heterocycle, [0201] (J)
--R.sub.C-heteroaryl, [0202] (K) --R.sub.1-heterocycle, [0203] (M)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.0-4--R.sub.1-aryl
where R.sub.C-4 is --O--, --S-- or --NR(C.sub.1-C.sub.6 alkyl)-,
[0204] (N)
--(CH.sub.2).sub.1-4--R.sub.C-4--(CH.sub.2).sub.0-4--R.sub.C-heteroaryl,
[0205] (O) --R.sub.1-aryl, and where [0206] R.sub.C-3 at each
occurrence is independently: [0207] (A) --H, [0208] (B)
--C.sub.1-C.sub.6 alkyl optionally substituted with one, two or
three substituents independently selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, and
--NR.sub.1-aR.sub.1-b, [0209] (C) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, and
--NR.sub.1-aR.sub.1-b, [0210] (D) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, and
--NR.sub.1-aR.sub.1-b, [0211] (E)
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl,
--Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6
alkoxy, --O-phenyl, and --NR.sub.1-aR.sub.1-b, [0212] (F)
--R.sub.1-aryl, [0213] (G) --R.sub.C-heteroaryl, [0214] (H)
--R.sub.1-heterocycle, [0215] (I) --(C.sub.1-C.sub.4
alkyl)-R.sub.1-aryl, [0216] (J) --(C.sub.1-C.sub.4
alkyl)-R.sub.C-heteroaryl, [0217] (K) --(C.sub.1-C.sub.4
alkyl)-R.sub.1-heterocycle,
[0218] (XVI) --CH(R.sub.C-aryl).sub.2,
[0219] (XVII) --CH(R.sub.C-heteroaryl).sub.2,
[0220] (XVIII) --CH(R.sub.C-aryl)(R.sub.C-heteroaryl),
[0221] (XIX) -cyclopentyl, -cyclohexyl, or -cycloheptyl ring fused
to R.sub.C-aryl or R.sub.C-heteroaryl or R.sub.1-heterocycle where
R.sub.C-aryl or R.sub.C-heteroaryl or R.sub.1-heterocycle are as
defined above where one carbon of cyclopentyl, cyclohexyl, or
-cycloheptyl is optionally replaced with NH, NR.sub.N-5, O,
S(.dbd.O).sub.0-2, and where cyclopentyl, cyclohexyl, or
-cycloheptyl can be optionally substituted with one or two
--C.sub.1-C.sub.3 alkyl, --F, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, .dbd.O, or --NR.sub.1-aR.sub.1-b,
[0222] (XX) C.sub.2-C.sub.10 alkenyl optionally substituted with
one, two or three substituents independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
--O-phenyl, and --NR.sub.1-aR.sub.1-b,
[0223] (XXI) C.sub.2-C.sub.10 alkynyl optionally substituted with
one, two or three substituents independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
--O-phenyl, and --NR.sub.1-aR.sub.1-b,
[0224] (XXI)
--(CH.sub.2).sub.0-1--CHR.sub.C-6--(CH.sub.2).sub.0-1--R.sub.C-aryl
wherein R.sub.C-6 is --(CH.sub.2).sub.0-6--OH,
[0225] (XXII)
--(CH.sub.2).sub.0-1--CHR.sub.C-6--(CH.sub.2).sub.0-1R.sub.C-heteroaryl,
[0226] (XXIII) --CH(--R.sub.C-aryl or
R.sub.C-heteroaryl)--CO--O(C.sub.1-C.sub.4 alkyl),
[0227] (XXIV) --CH(--CH.sub.2--OH)--CH(--OH)-alkyl-NO.sub.2,
[0228] (XXV) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6
alkyl)-OH,
[0229] (XXVII)
--CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2,
[0230] (XXVIII) --H, and
[0231] (XXIX)
--(CH.sub.2).sub.0-6--C(.dbd.NR.sub.1-a)(NR.sub.1-aR.sub.1-b);
where R.sub.N is
[0232] (I) R.sub.N-1--X.sub.N-- where X.sub.N is selected from the
group consisting of: [0233] (A) --CO--, [0234] (B) --SO.sub.2--,
[0235] (C) --(CR'''R''').sub.1-6 wherein [0236] R''' and R''' at
each occurrence are the same or different and are --H or
C.sub.1-C.sub.4 alkyl, [0237] (D)
--CO--(CR''R''').sub.1-6--X.sub.N-1 wherein [0238] X.sub.N-1 is
selected from the group consisting of --O--, --S-- and --NR''--,
[0239] (E) a single bond, and [0240] (F)
--CO--(CR'R''').sub.1-6--
[0241] where R.sub.N-1 is selected from the group consisting of:
[0242] (A) R.sub.N-aryl wherein R.sub.N-aryl at each occurrence is
independently phenyl; naphthyl; tetralinyl; indanyl; indenyl;
dihydronaphthyl; or 6,7,8,9-tetrahydro-5H-benzo[a]cycloheptenyl;
each of which is optionally substituted with one, two or three of
the following substituents which can be the same or different and
are: [0243] (1) C.sub.1-C.sub.6 alkyl, optionally substituted with
one, two or three substituents selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0244] wherein R.sub.1-a and R.sub.1-b at
each occurrence are independently H or C.sub.1-C.sub.6 alkyl,
[0245] (2) --OH, [0246] (3) --NO.sub.2, [0247] (4) --F, --Cl, --Br,
--I, [0248] (5) --CO.sub.2H, [0249] (6) --C.ident.N, [0250] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are the same or different and are selected from the group
consisting of: [0251] (a) --H, [0252] (b) --C.sub.1-C.sub.8 alkyl
optionally substituted with one substituent selected from the group
consisting of: [0253] (i) --OH, [0254] (ii) --NH.sub.2, [0255]
(iii) phenyl, [0256] (c) --C.sub.1-C.sub.8 alkyl optionally
substituted with 1, 2, or 3 groups that are independently --F,
--Cl, --Br, or --I, [0257] (d) --C.sub.3-C.sub.8 cycloalkyl, [0258]
(e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8 cycloalkyl), [0259]
(f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl) [0260] (g)
--C.sub.2-C.sub.6 alkenyl, [0261] (h) --C.sub.2-C.sub.6 alkynyl,
[0262] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, [0263] (j) --R.sub.1-aryl, wherein R.sub.1-aryl at
each occurrence is independently phenyl, naphthyl, indanyl,
indenyl, dihydronaphthyl, or tetralinyl each of which is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[0264] (i) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy, [0265] (ii) C.sub.2-C.sub.6 alkenyl with
one or two double bonds, optionally substituted with one, two or
three substituents independently selected from the group consisting
of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0266] (iii) C.sub.2-C.sub.6
alkynyl optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0267] (iv) --F, Cl, --Br and --I, [0268]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with 1, 2, or 3
--F, [0269] (vi) --NR.sub.N-2R.sub.N-3, [0270] (vii) --OH, [0271]
(viii) --C.ident.N, [0272] (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0273] (x) --CO--(C.sub.1-C.sub.4 alkyl), [0274] (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [0275] (xii)
--CO--NR.sub.1-aR.sub.1-b, or [0276] (xiii)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl) [0277] (k)
--R.sub.1-heteroaryl, wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, [0278]
where the R.sub.1-heteroaryl group is optionally substituted with
1, 2, 3, or 4 groups that are independently: [0279] (i)
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, [0280] (ii)
C.sub.2-C.sub.6 alkenyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b,
[0281] (iii) C.sub.2-C.sub.6 alkynyl optionally substituted with 1,
2, or 3 groups that are independently --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, [0282] (iv) --F, --Cl, --Br and --I, [0283]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with one, two,
or three --F, [0284] (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0285] (vii) --OH,
[0286] (viii) --C.ident.N, [0287] (ix)
(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0288] (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6 alkyl), [0289]
(xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0290]
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0291] (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [0292] (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and [0293] (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, [0294] (l)
--R.sub.1-heterocyle, wherein [0295] R.sub.1-heterocycle at each
occurrence is independently selected from the group consisting of
morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,
thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
[0296] where the R.sub.1-heterocycle group is bonded by any atom of
the parent R.sub.1-heterocycle group substituted by hydrogen such
that the new bond to the R.sub.1-heterocycle group replaces the
hydrogen atom and its bond, where heterocycle is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[0297] (a) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --H, --SH,
--NR.sub.1-aR.sub.1-b--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy, [0298] (b) C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b [0299] (c) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b [0300] (d) halogen, [0301] (e)
C.sub.1-C.sub.6 alkoxy, [0302] (f) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [0303] (g)
NR.sub.N-2R.sub.N-3, [0304] (h) --OH, [0305] (i) --C.ident.N,
[0306] (j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.8 cycloalkyl),
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0307] (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), [0308] (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, [0309] (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, [0310] (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and [0311]
(o) .dbd.O, [0312] (p)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- [0313] (q)
--(CH.sub.2).sub.0-4--N (R.sub.N-2)--C(O)-- [0314] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [0315] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl) [0316] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl) [0317] (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), [0318] (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, [0319] (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [0320] (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, [0321] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein R.sub.N-4 is selected
from the group consisting of phenyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,
pyrrolinyl, thienyl, pyrazolyl, pyridyl N-oxide, oxazolyl,
thiazolyl, imidazolyl, and pyrrolidinyl where each group is
optionally substituted with one, two, three, or four groups that
are independently C.sub.1-C.sub.6 alkyl, [0322] (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 where R.sub.N-5 is selected
from the group consisting of: [0323] (a) C.sub.1-C.sub.6 alkyl,
[0324] (b) --(CH.sub.2).sub.0-2--(R.sub.1-aryl), [0325] (c)
C.sub.2-C.sub.6 alkenyl, [0326] (d) C.sub.2-C.sub.6 alkynyl, [0327]
(e) --(CH.sub.2).sub.0-2--C.sub.3-C.sub.8 cycloalkyl, [0328] (f)
--(CH.sub.2).sub.0-2--(R.sub.1-heteroaryl), and [0329] (g)
--(CH.sub.2).sub.0-2--(R.sub.1-heterocycle), [0330] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0331] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [0332] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), [0333]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl),
[0334] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, [0335] (22) --(CH.sub.2).sub.0-4--N(H
or R.sub.N-5)--CO--N(R.sub.N-5).sub.2, [0336] (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [0337] (24)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--R.sub.N-2, [0338] (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0339] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0340] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [0341] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 wherein [0342]
R.sub.100 at each occurrence is independently --H or
C.sub.1-C.sub.4 alkyl, [0343] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [0344] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [0345] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [0346] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [0347] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [0348] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), [0349]
(35) C.sub.3-C.sub.8 cycloalkyl, [0350] (36) C.sub.2-C.sub.6
alkenyl optionally substituted with C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0351] (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0352] (38)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[0353] (39) --(CH.sub.2).sub.1-4--(C.sub.3-C.sub.8 cycloalkyl),
[0354] (B) --R.sub.N-heteroaryl where R.sub.N-heteroaryl is
selected from the group consisting of: pyridinyl, pyrimidinyl,
quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,
pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,
phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,
thiazolyl, indolizinyl, indazolyl, benzisothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, henoxazinyl, phenothiazinyl,
pteridinyl, benzothiazolyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl, dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl, pyridinyl-N-oxide,
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, imidazopyrazolyl, quinazolinonyl,
pyrazopyridyl, benzooxadiazolyl, dihydropyrimidinonyl, and
dihydrobenzfuranonyl, [0355] where the R.sub.N-heteroaryl group is
bonded by any atom of the parent R.sub.N-heteroaryl group
substituted by hydrogen such that the new bond to the R
.sub.N-heteroaryl group replaces the hydrogen atom and its bond,
where heteroaryl is optionally substituted with one, two, three, or
four of: [0356] (1) C.sub.1-C.sub.6 alkyl, optionally substituted
with one, two or three substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0357] (2) --OH, [0358] (3) --NO.sub.2,
[0359] (4) --F, --Cl, --Br, --I, [0360] (5) --CO.sub.2H, [0361] (6)
--C.ident.N, [0362] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0363] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [0364] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [0365] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), [0366] (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), [0367] (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, [0368] (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [0369] (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, [0370] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 [0371] (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 [0372] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0373] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [0374] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), [0375]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl),
[0376] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, [0377] (22) --(CH.sub.2).sub.0-4--N(H
or R.sub.N-5)--CO--N(R.sub.N-5).sub.2, [0378] (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [0379] (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, [0380]
(25) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0381] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0382] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [0383] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2, [0384] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [0385] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [0386] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [0387] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [0388] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [0389] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), [0390]
(35) C.sub.3-C.sub.8 cycloalkyl, [0391] (36) C.sub.2-C.sub.6
alkenyl optionally substituted with C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0392] (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0393] (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[0394] (39) --(CH.sub.2).sub.1-4--C.sub.3-C.sub.8 cycloalkyl,
[0395] (C) R.sub.N-aryl--W--R.sub.N-aryl, [0396] (D)
R.sub.N-aryl--W--R.sub.N-heteroaryl, [0397] (E)
R.sub.N-aryl--W--R.sub.1-heterocycle, [0398] (F)
R.sub.N-heteroaryl--W--R.sub.N-aryl, [0399] (G)
R.sub.N-heteroaryl--W--R.sub.N-heteroaryl, [0400] (H)
R.sub.N-heteroaryl--W--R.sub.N-1-heterocycle, [0401] (I)
R.sub.N-heterocycle--W--R.sub.N-aryl, [0402] (J)
R.sub.N-heterocycle--W--R.sub.N-heteroaryl, [0403] (K)
R.sub.N-heterocycle--W--R.sub.N-1-heterocycle, [0404] where W is
[0405] (1) --(CH.sub.2).sub.1-4--, [0406] (2) --O--, [0407] (3)
--S(O).sub.0-2--, [0408] (4) --N(R.sub.N-5)--, [0409] (5) --CO--;
or [0410] (6) a bond;
[0411] (II) --CO--(C.sub.1-C.sub.10 alkyl) wherein the alkyl is
optionally substituted with one two or three substituents
independently selected from the group consisting of: [0412] (A)
--OH, [0413] (B) --C.sub.1-C.sub.6 alkoxy, [0414] (C)
--C.sub.1-C.sub.6 thioalkoxy, [0415] (D) --CO--O--R.sub.N-8 where
[0416] R.sub.N-8 at each occurrence is independently --H,
C.sub.1-C.sub.6 alkyl or -phenyl, [0417] (E)
--CO--NR.sub.N-2R.sub.N-3, [0418] (F) --CO--R.sub.N-4, [0419] (G)
--SO.sub.2--(C.sub.1-C.sub.8 alkyl) [0420] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3, [0421] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0422] (J)
--NH--CO--O--R.sub.N-8, [0423] (K) --NR.sub.N-2R.sub.N-3, [0424]
(L) --R.sub.N-4, [0425] (M) --O--CO--(C.sub.1-C.sub.6 alkyl),
[0426] (N) --O--CO--NR.sub.N-8R.sub.N-8, [0427] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0428] (P) --O--(C.sub.1-C.sub.6
alkyl optionally substituted with one, two, or three of --F, --Cl,
--Br, --I), [0429] (Q) --NH--SO.sub.2--(C.sub.1-C.sub.6 alkyl),
[0430] (R) halogen, [0431] (S) --N(H or
R.sub.N-5)--SO.sub.2--R.sub.N-2, [0432] (T) --N(H or
R.sub.N-5)--CO--(R.sub.N-2), and [0433] (U)
--SO.sub.2--R.sub.N-2,
[0434] (III) --CO--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6
alkyl) wherein each alkyl is unsubstituted or independently
substituted with one, two, or three substituents selected from the
group consisting of: [0435] (A) --OH, [0436] (B) --C.sub.1-C.sub.6
alkoxy, [0437] (C) --C.sub.1-C.sub.6 thioalkoxy, [0438] (D)
--CO--O--R.sub.N-8, [0439] (E) --CO--NR.sub.N-2R.sub.N-3, [0440]
(F) --CO--R.sub.N-4, [0441] (G) --SO.sub.2--(C.sub.1-C.sub.8
alkyl), [0442] (H) --SO.sub.2--NR.sub.N-2R.sub.N-3, [0443] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0444] (J)
--NH--CO--O--R.sub.N-8, [0445] (K) --NR.sub.N-2R.sub.N-3, [0446]
(L) --R.sub.N-4, [0447] (M) --O--CO--(C.sub.1-C.sub.6 alkyl),
[0448] (N) --O--CO--NR.sub.N-8R.sub.N-8, [0449] (O)
--O--(C.sub.1-C.sub.5 alkyl)-CO.sub.2H, [0450] (P)
--O--(C.sub.1-C.sub.6 alkyl optionally substituted with one, two,
or three groups that are independently --F, --Il, --Br, or --I),
[0451] (Q) --NH--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [0452] (R)
halogen, [0453] (S) --N(H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[0454] (T) --N(H or R.sub.N-5)--CO--(R.sub.N-2), and [0455] (U)
--SO.sub.2--R.sub.N-2,
[0456] (IV) --CO--(C.sub.1-C.sub.6
alkyl)-S--(C.sub.1-C.sub.6-alkyl) wherein each alkyl is
unsubstituted or substituted with one, two, or three of
substituents independently selected from the group consisting of:
[0457] (A) --OH, [0458] (B) --C.sub.1-C.sub.5 alkoxy, [0459] (C)
--C.sub.1-C.sub.6 thioalkoxy, [0460] (D) --CO--O--R.sub.N-8, [0461]
(E) --CO--NR.sub.N-2R.sub.N-3, [0462] (F) --CO--R.sub.N-4, [0463]
(G) --SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0464] (H)
--SO.sub.2--NR.sub.N-2R.sub.N-3, [0465] (I)
--NH--CO--(C.sub.1-C.sub.6 alkyl), [0466] (J)
--NH--CO--O--R.sub.N-8, [0467] (K) --NR.sub.N-2R.sub.N-3, [0468]
(L) --R.sub.N-4, [0469] (M) --O--CO--(C.sub.1-C.sub.6 alkyl),
[0470] (N) --O--CO--NR.sub.N-8R.sub.N-8, [0471] (O)
--O--(C.sub.1-C.sub.5 alkyl)-COOH, [0472] (P) --O--(C.sub.1-C.sub.6
alkyl optionally substituted with one, two, or three groups that
are independently --F, --Cl, --Br, or --I), [0473] (Q)
--NH--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [0474] (R) halogen, [0475]
(S) --N(H or R.sub.N-5)--SO.sub.2--R.sub.N-2, [0476] (T) --N(H or
R.sub.N-5)--CO--(R.sub.N-2), and [0477] (U)
--SO.sub.2--R.sub.N-2,
[0478] (V)
--CO--CH(--(CH.sub.2).sub.0-2--O--R.sub.N-10)--(CH.sub.2).sub.0-2--R.sub.-
N-aryl/R.sub.N-heteroaryl) wherein [0479] R.sub.N-10 is selected
from the group consisting of: [0480] (A) --H, [0481] (B)
C.sub.1-C.sub.6 alkyl, [0482] (C) C.sub.3-C.sub.8 cycloalkyl,
[0483] (D) C.sub.2-C.sub.6 alkenyl with one double bond, [0484] (E)
C.sub.2-C.sub.6 alkynyl with one triple bond, [0485] (F)
R.sub.1-aryl, [0486] (G) R.sub.N-heteroaryl, [0487] (H)
R.sub.N-heterocycle,
[0488] (VI) --CO--(C.sub.3-C.sub.8 cycloalkyl) where the cycloalkyl
group is optionally substituted with one or two substituents
independently selected from the group consisting of: [0489] (A)
--(CH.sub.2).sub.0-4--OH, [0490] (B)
--(CH.sub.2).sub.0-4--C.sub.1-C.sub.6 alkoxy, [0491] (C)
--(CH.sub.2).sub.0-4--C.sub.1-C.sub.6 thioalkoxy, [0492] (D)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-8, [0493] (E)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0494] (F)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4, [0495] (G)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.8 alkyl), [0496] (H)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0497] (I)
--(CH.sub.2).sub.0-4--NH--CO--(C.sub.1-C.sub.6 alkyl), [0498] (J)
--NH--CO--O--R.sub.N-8, [0499] (K)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0500] (L)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0501] (M)
--O--CO--(C.sub.1-C.sub.6 alkyl), [0502] (N)
--O--CO--NR.sub.N-8R.sub.N-8, [0503] (O) --O--(C.sub.1-C.sub.6
alkyl)-CO.sub.2H, [0504] (P) --O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, or three groups that are independently
selected from --F, --Cl, --Br, and --I), [0505] (Q)
--NH--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [0506] (R) halogen, [0507]
(S) --N(H or R.sub.N-5)--SO.sub.2--R.sub.N-2, and [0508] (T) --N(H
or R.sub.N-5)--CO--(R.sub.N-2), and [0509] (U)
--SO.sub.2--R.sub.N-2; where R.sub.1 and R.sub.2 are independently
H, aryl, heteroaryl, or
[0510] (I) C.sub.1-C.sub.6 alkyl, optionally substituted with one,
two or three substituents selected from the group consisting of
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.7 alkyl (optionally
substituted with C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.3 alkoxy),
--F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, --NR.sub.1-aR.sub.1-b where R.sub.1-a and
R.sub.1-b are independently --H or C.sub.1-C.sub.6 alkyl, and
--OC.dbd.O NR.sub.1-aR.sub.1-b,
[0511] (II) --CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
[0512] (III) --CH.sub.2--CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6
alkyl),
[0513] (IV) C.sub.2-C.sub.6 alkenyl with one or two double bonds,
optionally substituted with one, two or three substituents selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0514] (V) C.sub.2-C.sub.6 alkynyl with one or two triple bonds,
optionally substituted with one, two or three substituents selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0515] (VI) --(CH.sub.2).sub.n1(R.sub.1-aryl) where n.sub.1 is zero
or one and where R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl and
indanyl, indenyl, dihydronaphthalyl, or tetralinyl optionally
substituted with one, two, three or four of the following
substituents on the aryl ring: [0516] (A) C.sub.1-C.sub.6 alkyl
optionally substituted with one, two or three substituents selected
from the group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl,
--Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0517] (B) C.sub.2-C.sub.6
alkenyl with one or two double bonds, optionally substituted with
one, two or three substituents selected from the group consisting
of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0518] (C) C.sub.2-C.sub.6
alkynyl with one or two triple bonds, optionally substituted with
one, two or three substituents selected from the group consisting
of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0519] (D) --F, Cl, --Br or --I,
[0520] (F) --C.sub.1-C.sub.6 alkoxy optionally substituted with
one, two or three of --F, [0521] (G) --NR.sub.N-2R.sub.N-3 where
R.sub.N-2 and R.sub.N-3 are as defined below, [0522] (H) --OH,
[0523] (I) --C.ident.N, [0524] (J) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with one, two or three substituents selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0525] (K) --CO--(C.sub.1-C.sub.4 alkyl), [0526] (L)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [0527] (M)
--CO--NR.sub.1-aR.sub.1-b, [0528] (N) --SO.sub.2--(C.sub.1-C.sub.4
alkyl),
[0529] (VII) --(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where
n.sub.1 is as defined above and where R.sub.1-heteroaryl is
selected from the group consisting of:
[0530] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,
indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,
quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,
pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, 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, where the
R.sub.1-heteroaryl group is bonded to --(CH.sub.2).sub.n1-- by any
ring atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.1-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
optionally substituted with one, two, three or four of: [0531] (1)
C.sub.1-C.sub.6 alkyl optionally substituted with one, two or three
substituents selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0532] (2)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0533] (3)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0534] (4) --F,
Cl, --Br or --I, [0535] (6) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three of --F, [0536] (7)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined
below, [0537] (8) --OH, [0538] (9) --C.ident.N, [0539] (10)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0540] (11) --CO--(C.sub.1-C.sub.4 alkyl),
[0541] (12) --SO.sub.2--NR.sub.1-aR.sub.1-b, [0542] (13)
--CO--NR.sub.1-aR.sub.1-b, or [0543] (14)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), with the proviso that when
n.sub.1 is zero R.sub.1-heteroaryl is not bonded to the carbon
chain by nitrogen, or
[0544] (VIII) --(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where
n.sub.1 is as defined above and R.sub.1-heterocycle is selected
from the group consisting of: [0545] morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homomorpholinyl S-oxide, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl
dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl,
dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl
S,S-dioxide, homothiomorpholinyl S-oxide, where the
R.sub.1-heterocycle group is bonded by any atom of the parent
R.sub.1-heterocycle group substituted by hydrogen such that the new
bond to the R.sub.1-heterocycle group replaces the hydrogen atom
and its bond, where heterocycle is optionally substituted with one,
two, three or four: [0546] (1) C.sub.1-C.sub.6 alkyl optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0547] (2) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b. [0548] (3) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0549] (4) --F, Cl, --Br, or --I, [0550] (5)
C.sub.1-C.sub.6 alkoxy, [0551] (6) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [0552] (7)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined
below, [0553] (8) --OH, [0554] (9) --C.ident.N, [0555] (10)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0556] (11) --CO--(C.sub.1-C.sub.4 alkyl)
[0557] (12) --SO.sub.2--NR.sub.1-aR.sub.1-b, [0558] (13)
--CO--NR.sub.1-aR.sub.1-b, [0559] (14) --SO.sub.2--(C.sub.1-C.sub.4
alkyl), [0560] (15) .dbd.O, with the proviso that when n.sub.1 is
zero R.sub.1-heterocycle is not bonded to the carbon chain by
nitrogen; and where R.sub.20 is H or C.sub.1-6 alkyl or
alkenyl.
[0561] In alternative broad aspect, the invention provides
compounds of formula I, wherein each of the R.sub.2 groups
(I)-(VIII) is attached to the nitrogen carrying R.sub.20 by -Z-,
wherein Z is --C(O)--, --CO.sub.2 or --SO.sub.2--.
[0562] The invention also provides compounds, compositions, kits,
and methods for inhibiting beta-secretase-mediated cleavage of
amyloid precursor protein (APP). More particularly, the compounds,
compositions, and methods of the invention are effective to inhibit
the production of A-beta peptide and to treat and/or prevent any
human or veterinary disease or condition associated with a
pathological form of A-beta peptide.
[0563] The invention also include methods of treating a patient who
has, or in preventing a patient from getting, a disease or
condition selected from the group consisting of Alzheimer's
disease, for helping prevent or delay the onset of Alzheimer's
disease, for treating patients with mild cognitive impairment (MCI)
and preventing or delaying the onset of Alzheimer's disease in
those who would progress from MCI to AD, for treating Down's
syndrome, for treating humans who have Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type, for treating
cerebral amyloid angiopathy and preventing its potential
consequences, i.e. single and recurrent lobar hemorrhages, for
treating other degenerative dementias, including dementias of mixed
vascular and degenerative origin, dementia associated with
Parkinson's disease, frontotemporal dementias with parkinsonism
(FTDP), dementia associated with progressive supranuclear palsy,
dementia associated with cortical basal degeneration, or diffuse
Lewy body type of Alzheimer's disease and who is in need of such
treatment, which includes administration of a therapeutically
effective amount of a compound of formula (I), or a
pharmaceutically acceptable salt or ester thereof.
[0564] The compounds of the invention possess beta-secretase
inhibitory activity. The inhibitory activities of the compounds of
the invention is readily demonstrated, for example, using one or
more of the assays described herein or known in the art.
[0565] In an embodiment, this method of treatment can be used where
the disease is Alzheimer's disease.
[0566] In an embodiment, this method of treatment can help prevent
or delay the onset of Alzheimer's disease.
[0567] In an embodiment, this method of treatment can be used where
the disease is mild cognitive impairment.
[0568] In an embodiment, this method of treatment can be used where
the disease is Down's syndrome.
[0569] In an embodiment, this method of treatment can be used where
the disease is Hereditary Cerebral Hemorrhage with Amyloidosis of
the Dutch-Type.
[0570] In an embodiment, this method of treatment can be used where
the disease is cerebral amyloid angiopathy.
[0571] In an embodiment, this method of treatment can be used where
the disease is degenerative dementias.
[0572] In an embodiment, this method of treatment can be used where
the disease is diffuse Lewy body type of Alzheimer's disease.
[0573] In an embodiment, this method of treatment can treat an
existing disease.
[0574] In an embodiment, this method of treatment can prevent a
disease from developing.
[0575] In an embodiment, this method of treatment can employ
therapeutically effective amounts: for oral administration from
about 0.1 mg/day to about 1,000 mg/day; for parenteral, sublingual,
intranasal, intrathecal administration from about 0.5 to about 100
mg/day; for depo administration and implants from about 0.5 mg/day
to about 50 mg/day; for topical administration from about 0.5
mg/day to about 200 mg/day; for rectal administration from about
0.5 mg to about 500 mg.
[0576] In an embodiment, this method of treatment can employ
therapeutically effective amounts: for oral administration from
about 1 mg/day to about 100 mg/day; and for parenteral
administration from about 5 to about 50 mg daily.
[0577] In an embodiment, this method of treatment can employ
therapeutically effective amounts for oral administration from
about 5 mg/day to about 50 mg/day.
[0578] The invention also includes a pharmaceutical composition
which includes a compound of formula (I), or a pharmaceutically
acceptable salt or ester thereof.
[0579] The invention also includes the use of a compound of formula
(I), or a pharmaceutically acceptable salt or ester thereof, for
the manufacture of a medicament for use in treating a patient who
has, or in preventing a patient from getting, a disease or
condition selected from the group consisting of Alzheimer's
disease, for helping prevent or delay the onset of Alzheimer's
disease, for treating patients with mild cognitive impairment (MCI)
and preventing or delaying the onset of Alzheimer's disease in
those who would progress from MCI to AD, for treating Down's
syndrome, for treating humans who have Hereditary Cerebral
Hemorrhage with Amyloidosis of the Dutch-Type, for treating
cerebral amyloid. angiopathy and preventing its potential
consequences, i.e. single and recurrent lobar hemorrhages, for
treating other degenerative dementias, including dementias of mixed
vascular and degenerative origin, dementia associated with
Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, diffuse Lewy body type of Alzheimer's disease and who
is in need of such treatment.
[0580] In an embodiment, this use of a compound of the formula
hereinabove can be employed where the disease is Alzheimer's
disease.
[0581] In an embodiment, this use of a compound of the formula
hereinabove can help prevent or delay the onset of Alzheimer's
disease.
[0582] In an embodiment, this use of a compound of the formula
hereinabove can be employed where the disease is mild cognitive
impairment.
[0583] In an embodiment, this use of a compound of the formula
hereinabove can be employed where the disease is Down's
syndrome.
[0584] In an embodiment, this use of a compound of the formula
hereinabove can be employed where the disease is Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type.
[0585] In an embodiment, this use of a compound of the formula
hereinabove can be employed where the disease is cerebral amyloid
angiopathy.
[0586] In an embodiment, this use of a compound of the formula
hereinabove can be employed where the disease is degenerative
dementias.
[0587] In an embodiment, this use of a compound of the formula
hereinabove can be employed where the disease is diffuse Lewy body
type of Alzheimer's disease.
[0588] In an embodiment, this use of a substituted amine employs a
pharmaceutically acceptable salt selected from the group consisting
of salts of the following acids hydrochloric, hydrobromic,
hydroiodic, nitric, sulfuric, phosphoric, citric, methanesulfonic,
CH.sub.3--(CH.sub.2).sub.n--COOH where n is 0 through 4,
HOOC--(CH.sub.2).sub.n--COOH where n is as defined above,
HOOC--CH.dbd.CH--COOH, and phenyl-COOH.
[0589] The invention also includes methods for inhibiting
beta-secretase activity, for inhibiting cleavage of amyloid
precursor protein (APP), in a reaction mixture, 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; for
inhibiting production of amyloid beta peptide (A beta) in a cell;
for inhibiting the production of beta-amyloid plaque in an animal;
and for treating or preventing a disease characterized by
beta-amyloid deposits in the brain. These methods each include
administration of a therapeutically effective amount of a compound
of formula (I), or a pharmaceutically acceptable salt or ester
thereof.
[0590] The invention also includes a method for inhibiting
beta-secretase activity, including exposing said beta-secretase to
an effective inhibitory amount of a compound of formula, or a
pharmaceutically acceptable salt or ester thereof.
[0591] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of less
than 50 micromolar.
[0592] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
micromolar or less.
[0593] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 1
micromolar or less.
[0594] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
nanomolar or less.
[0595] In an embodiment, this method includes exposing said
beta-secretase to said compound in vitro.
[0596] In an embodiment, this method includes exposing said
beta-secretase to said compound in a cell.
[0597] In an embodiment, this method includes exposing said
beta-secretase to said compound in a cell in an animal.
[0598] In an embodiment, this method includes exposing said
beta-secretase to said compound in a human.
[0599] The invention also includes a method for inhibiting cleavage
of amyloid precursor protein (APP), in a reaction mixture, 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, including exposing said reaction mixture to an effective
inhibitory amount of a compound of formula (I), or a
pharmaceutically acceptable salt or ester thereof.
[0600] In an embodiment, this method employs a cleavage site:
between Met652 and Asp653, numbered for the APP-751 isotype;
between Met 671 and Asp 672, 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.
[0601] In an embodiment, this method exposes said reaction mixture
in vitro.
[0602] In an embodiment, this method exposes said reaction mixture
in a cell.
[0603] In an embodiment, this method exposes said reaction mixture
in an animal cell.
[0604] In an embodiment, this method exposes said reaction mixture
in a human cell.
[0605] The invention also includes a method for inhibiting
production of amyloid beta peptide (A beta) in a cell, including
administering to said cell an effective inhibitory amount of a
compound of formula (I), or a pharmaceutically acceptable salt or
ester thereof.
[0606] In an embodiment, this method includes administering to an
animal.
[0607] In an embodiment, this method includes administering to a
human.
[0608] The invention also includes a method for inhibiting the
production of beta-amyloid plaque in an animal, including
administering to said animal an effective inhibitory amount of a
compound of formula (I), or a pharmaceutically acceptable salt or
ester thereof.
[0609] In an embodiment, this method includes administering to a
human.
[0610] The invention also includes a method for treating or
preventing a disease characterized by beta-amyloid deposits in the
brain including administering to a patient an effective therapeutic
amount of a hydroxyethylene compound of formula (I), or a
pharmaceutically acceptable salt or ester thereof.
[0611] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of less
than 50 micromolar.
[0612] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
micromolar or less.
[0613] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 1
micromolar or less.
[0614] In an embodiment, this method employs a compound that
inhibits 50% of the enzyme's activity at a concentration of 10
nanomolar or less.
[0615] In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 0.1 to about 1000
mg/day.
[0616] In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 15 to about 1500
mg/day.
[0617] In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 1 to about 100
mg/day.
[0618] In an embodiment, this method employs a compound at a
therapeutic amount in the range of from about 5 to about 50
mg/day.
[0619] In an embodiment, this method can be used where said disease
is Alzheimer's disease.
[0620] In an embodiment, this method can be used where said disease
is Mild Cognitive Impairment, Down's Syndrome, or Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch Type.
[0621] The invention also includes a composition including
beta-secretase complexed with a compound of formula (I), or a
pharmaceutically acceptable salt or ester thereof.
[0622] The invention also includes a method for producing a
beta-secretase complex including exposing beta-secretase to a
compound of formula (I), or a pharmaceutically acceptable salt or
ester thereof, in a reaction mixture under conditions suitable for
the production of said complex.
[0623] In an embodiment, this method employs exposing in vitro.
[0624] In an embodiment, this method employs a reaction mixture
that is a cell.
[0625] The invention also includes a component kit including
component parts capable of being assembled, in which at least one
component part includes a compound of formula I enclosed in a
container.
[0626] In an embodiment, this component kit-includes lyophilized
compound, and at least one further component part includes a
diluent.
[0627] The invention also includes a container kit including a
plurality of containers, each container including one or more unit
dose of a compound of formula (I), or a pharmaceutically acceptable
salt or ester thereof.
[0628] In an embodiment, this container kit includes each container
adapted for oral delivery and includes a tablet, gel, or
capsule.
[0629] In an embodiment, this container kit includes each container
adapted for parenteral delivery and includes a depot product,
syringe, ampoule, or vial.
[0630] In an embodiment, this container kit includes each container
adapted for topical delivery and includes a patch, medipad,
ointment, or cream.
[0631] The invention also includes an agent kit including a
compound of formula (I), or a pharmaceutically acceptable salt or
ester thereof; and one or more therapeutic agent selected from the
group consisting of an antioxidant, an anti-inflammatory, a gamma
secretase inhibitor, a neurotrophic agent, an acetyl cholinesterase
inhibitor, a statin, an A beta peptide, and an anti-A beta
antibody.
[0632] The invention also includes a composition including: a
compound of formula (I), or a pharmaceutically acceptable salt or
ester thereof; and an inert diluent or edible carrier.
[0633] In an embodiment, this composition includes a carrier that
is an oil.
[0634] The invention also includes a composition including: a
compound of formula (I), or a pharmaceutically acceptable salt or
ester thereof; and a binder, excipient, disintegrating agent,
lubricant, or gildant.
[0635] The invention also includes a composition including: a
compound of formula (I), or a pharmaceutically acceptable salt or
ester thereof; disposed in a cream, ointment, or patch.
DETAILED DESCRIPTION OF THE INVENTION As noted above, the invention
provides compounds of formula I:
[0636] ##STR3## where R.sub.N, R.sub.C, R.sub.1, R.sub.2 and
R.sub.20 are as defined above, and pharmaceutically acceptable
salts and esters thereof.
[0637] In a preferred embodiment, the invention provides for
compounds of formula II: ##STR4## or a pharmaceutically acceptable
salt thereof, where Rc is
[0638] (I) --C.sub.1-C.sub.10 alkyl optionally substituted with
one, two or three groups independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl,
--NR.sub.1-aR.sub.1-b, --OC.dbd.ONR.sub.1-aR.sub.1-b,
--S(.dbd.O).sub.0-2R.sub.1-a,
--NR.sub.1-aC.dbd.ONR.sub.1-aR.sub.1-b,
--C.dbd.ONR.sub.1-aR.sub.1-b, and
--S(.dbd.O).sub.2NR.sub.1-aR.sub.1-b wherein
[0639] R.sub.1-a and R.sub.1-b at each occurrence are independently
H or C.sub.1-C.sub.6 alkyl,
[0640] (II) --(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl
where cycloalkyl can be optionally substituted with one, two or
three substituents independently selected from the group consisting
of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, --CO.sub.2H,
--CO.sub.2--(C.sub.1-C.sub.4 alkyl), and --NR.sub.1-aR.sub.1-b
[0641] (III) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where
R.sub.C-x and R.sub.C-y are independently selected from the group
consisting of [0642] --H, [0643] C.sub.1-C.sub.4 alkyl optionally
substituted with 1 or 2 --OH, [0644] C.sub.1-C.sub.4 alkoxy
optionally substituted with 1, 2, or 3 halogen, [0645]
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl, [0646]
C.sub.2-C.sub.6 alkenyl containing one or two double bonds, [0647]
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or [0648] R.sub.C-x and R.sub.C-y are taken together with
the carbon to which they are attached to form a carbocycle of
three, four, five, six or seven carbon atoms, where one carbon atom
is optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein [0649]
R.sub.C-aryl is phenyl, which is optionally substituted with 1, 2,
or 3 groups that are independently: [0650] (1) C.sub.1-C.sub.6
alkyl, optionally substituted with one, two or three substituents
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0651] (2) --OH, [0652] (3)
--NO.sub.2, [0653] (4) halogen, [0654] (5) --CO.sub.2H, [0655] (6)
--C.ident.N, [0656] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where [0657]
R.sub.N-2 and R.sub.N-3 are independently selected from the group
consisting of: [0658] (a) --H, [0659] (b) --C.sub.1-C.sub.6 alkyl
optionally substituted with one substituent selected from the group
consisting of: [0660] (i) --OH, and [0661] (ii) --NH.sub.2, [0662]
(c) --C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --Br, --I, or OH, [0663]
(d) --C.sub.3-C.sub.7 cycloalkyl, [0664] (e) --(C.sub.1-C.sub.2
alkyl)-(C.sub.3-C.sub.7 cycloalkyl), [0665] (f) --(C.sub.1-C.sub.6
alkyl)-O--(C.sub.1-C.sub.3 alkyl), [0666] (g) --C.sub.2-C.sub.6
alkenyl [0667] (h) --C.sub.2-C.sub.6 alkynyl [0668] (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, [0669] (j) --R.sub.1-aryl wherein R.sub.1-aryl at each
occurrence is independently phenyl, naphthyl, indanyl, indenyl,
dihydronaphthyl, or tetralinyl each of which is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[0670] (i) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy, [0671] (ii) C.sub.2-C.sub.6 alkenyl with
one or two double bonds, optionally substituted with one, two or
three substituents independently selected from the group consisting
of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0672] (iii) C.sub.2-C.sub.6
alkynyl optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0673] (iv) --F, Cl, --Br and --I, [0674]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with 1, 2, or 3
--F, [0675] (vi) --NR.sub.N-2R.sub.N-3, [0676] (vii) --OH, [0677]
(viii) --C.ident.N, [0678] (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0679] (x) --CO--(C.sub.1-C.sub.4 alkyl), [0680] (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [0681] (xii)
--CO--NR.sub.1-aR.sub.1-b, or [0682] (xiii)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), [0683] (k)
--R.sub.1-heteroaryl wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, [0684]
where the R.sub.1-heteroaryl group is optionally substituted with
1, 2, 3, or 4 groups that are independently: [0685] (i)
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, [0686] (ii)
C.sub.2-C.sub.6 alkenyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0687] (iii) C.sub.2-C.sub.6 alkynyl optionally substituted with 1,
2, or 3 groups that are independently selected from the group
consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0688] (iv) --F,
--Cl, --Br and --I, [0689] (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three --F, [0690] (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0691] (vii) --OH,
[0692] (viii) --C.ident.N, [0693] (ix)
(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0694] (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6 alkyl), [0695]
(xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0696]
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0697] (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [0698] (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and [0699] (xv)
(CH.sub.2).sub.0-4--N (R.sub.N-2)--C(O)--, [0700] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [0701] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [0702] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), [0703] (11)
--(CH.sub.2).sub.0-4--CO--(CH.sub.2).sub.0-4(C.sub.3-C.sub.7
cycloalkyl), [0704] (12) --(CH.sub.2).sub.0-4--CO--R.sub.1-aryl,
[0705] (13) --(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [0706]
(14) --(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle wherein [0707]
R.sub.1-heterocycle at each occurrence is independently selected
from the group consisting of morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
[0708] where the R.sub.1-heterocycle group is bonded by any atom of
the parent R.sub.1-heterocycle group substituted by hydrogen such
that the new bond to the R.sub.1-heterocycle group replaces the
hydrogen atom and its bond, where heterocycle is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[0709] (a) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sub.1-aR.sub.1-b--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy, [0710] (b) C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b [0711] (c) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b [0712] (d) halogen, [0713] (e)
C.sub.1-C.sub.6 alkoxy, [0714] (f) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [0715] (g)
--NR.sub.N-2R.sub.N-3, [0716] (h) --OH, [0717] (i) --C.ident.N,
[0718] (j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.7 cycloalkyl),
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0719] (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), [0720] (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, [0721] (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, [0722] (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl) , and
[0723] (o) .dbd.O, [0724] (p)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- [0725] (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- [0726] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein [0727] R.sub.N-4 at
each occurrence is independently selected from the group consisting
of morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl,
pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,
homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where
each group is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.6 alkyl, [0728] (16)
--(CH.sub.2).sub.0-4--CO.sub.2--R.sub.N-5 where [0729] R.sub.N-5 at
each occurrence is independently selected from the group consisting
of: [0730] (a) C.sub.1-C.sub.6 alkyl, [0731] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl), [0732] (c) C.sub.2-C.sub.6
alkenyl, [0733] (d) C.sub.2-C.sub.6 alkynyl, [0734] (e)
C.sub.3-C.sub.7 cycloalkyl, and [0735] (f)
--(CH.sub.2).sub.0-4--(R.sub.1-heteroaryl), [0736] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3 [0737] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [0738] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), [0739]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl),
[0740] (21) --(CH.sub.2).sub.0-4--(H or
R.sub.N-5)--CO.sub.2--R.sub.N-5, [0741] (22)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--N(R.sub.N-5).sub.2,
[0742] (23) --(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [0743]
(24) --(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2,
[0744] (25) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0745] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0746] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [0747] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 where R.sub.100
is independently H or C.sub.1-C.sub.4 alkyl, [0748] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [0749] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [0750] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [0751] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [0752] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [0753] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl) wherein the alkyl
group is optionally substituted with one, two, three, four, or five
substituents independently selected from the group consisting of F,
Cl, Br, and I, [0754] (35) --(CH.sub.2).sub.0-4--(C.sub.3-C.sub.8
cycloalkyl), [0755] (36) C.sub.2-C.sub.6 alkenyl optionally
substituted with C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, [0756] (37) C.sub.2-C.sub.6 alkynyl
optionally substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br,
--I, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
or --NR.sub.1-aR.sub.1-b, and [0757] (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2;
[0758] (IV) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl
wherein R.sub.C-heteroaryl at each occurrence is independently
selected from the group consisting of pyridinyl, pyrimidinyl,
quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,
pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,
phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,
thiazolyl, indolizinyl, indazolyl, benzoisothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,
beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl, pteridinyl,
benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,
quinazolinonyl, pyrazopyridyl, benzooxadiazolyl,
dihydropyrimidinonyl, dihydrobenzofuranonyl,
[0759] where the R.sub.C-heteroaryl group is bonded by any atom of
the parent R.sub.C-heteroaryl group substituted by hydrogen such
that the new bond to the R.sub.C-heteroaryl group replaces the
hydrogen atom and its bond, where heteroaryl is optionally
substituted 1, 2, 3, or 4 groups that are independently: [0760] (1)
C.sub.1-C.sub.6 alkyl, optionally substituted with 1, 2, or 3
groups independently selected from the group consisting of
C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0761] (2) --OH, [0762] (3) --NO.sub.2,
[0763] (4) --F, --Cl, --Br, --I, [0764] (5) --CO--OH, [0765] (6)
--C.ident.N, [0766] (V) C.sub.2-C.sub.10 alkenyl optionally
substituted with one, two or three substituents independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, --O-phenyl, and --NR.sub.1-aR.sub.1-b,
[0767] (VI) C.sub.2-C.sub.10 alkynyl optionally substituted with
one, two or three substituents independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
--O-phenyl, and --NR.sub.1-aR.sub.1-b, [0768] (VII)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH, [0769]
(VIII) --CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2,
[0770] (IX)
--(CH.sub.2).sub.0-6--C(.dbd.NR.sub.1-a)(NR.sub.1-aR.sub.1-b),
where R.sub.N is
[0771] (I) R.sub.N-1--X.sub.N-- where X.sub.N is --CO--, and where
R.sub.N-1 is selected from the group consisting of: [0772] (A)
phenyl, which is optionally substituted with one, two or three of
the following substituents which can be the same or different and
are: [0773] (1) C.sub.1-C.sub.6 alkyl, optionally substituted with
one, two or three substituents selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0774] wherein R.sub.1-a and R.sub.1-b at
each occurrence are independently H or C.sub.1-C.sub.6 alkyl,
[0775] (2) --OH, [0776] (3) --NO.sub.2, [0777] (4) --F, --Cl, --Br,
--I, [0778] (5) --CO.sub.2H, [0779] (6) --C.ident.N, [0780] (7)
--(CH.sub.2).sub.0-4--O--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are the same or different and are selected from the group
consisting of: [0781] (a) --H, [0782] (b) --C.sub.1-C.sub.8 alkyl
optionally substituted with one substituent selected from the group
consisting of: [0783] (i) --OH, [0784] (ii) --NH.sub.2, [0785]
(iii) phenyl, [0786] (c) --C.sub.1-C.sub.8 alkyl optionally
substituted with 1, 2, or 3 groups that are independently --F,
--Cl, --Br, or --I, [0787] (d) --C.sub.3-C.sub.8 cycloalkyl, [0788]
(e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8 cycloalkyl), [0789]
(f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl), [0790]
(g) --C.sub.2-C.sub.6 alkenyl, [0791] (h) --C.sub.2-C.sub.6
alkynyl, [0792] (i) --C.sub.1-C.sub.6 alkyl chain with one double
bond and one triple bond, [0793] (j) --R.sub.1-aryl, wherein
R.sub.1-aryl at each occurrence is independently phenyl, naphthyl,
indanyl, indenyl, dihydronaphthyl, or tetralinyl each of which is
optionally substituted with 1, 2, 3, or 4 groups that are
independently: [0794] (i) C.sub.1-C.sub.6 alkyl optionally
substituted with one, two or three substituents independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b, --C.ident.N,
--CF.sub.3, and C.sub.1-C.sub.3 alkoxy, [0795] (ii) C.sub.2-C.sub.6
alkenyl with one or two double bonds, optionally substituted with
one, two or three substituents independently selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0796] (iii)
C.sub.2-C.sub.6 alkynyl optionally substituted with 1, 2, or 3
groups that are independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [0797] (iv) --F, Cl, --Br and
--I, [0798] (v) --C.sub.1-C.sub.6 alkoxy optionally substituted
with 1, 2, or 3 --F, [0799] (vi) --NR.sub.N-2R.sub.N-3, [0800]
(vii) --OH, [0801] (viii) --C.ident.N, [0802] (ix) C.sub.3-C.sub.7
cycloalkyl, optionally substituted with 1, 2, or 3 groups that are
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0803] (x) --CO--(C.sub.1-C.sub.4 alkyl),
[0804] (xi) --SO.sub.2--NR.sub.1-aR.sub.1-b, [0805] (xii)
--CO--NR.sub.1-aR.sub.1-b, or [0806] (xiii)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl) [0807] (k)
--R.sub.1-heteroaryl, wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, [0808]
where the R.sub.1-heteroaryl group is optionally substituted with
1, 2, 3, or 4 groups that are independently: [0809] (i)
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, [0810] (ii)
C.sub.2-C.sub.6 alkenyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b,
[0811] (iii) C.sub.2-C.sub.6 alkynyl optionally substituted with 1,
2, or 3 groups that are independently --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, [0812] (iv) --F, --Cl, --Br and --I, [0813]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with one, two,
or three --F, [0814] (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0815] (vii) --OH,
[0816] (viii) --C.ident.N, [0817] (ix)
(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[0818] (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6 alkyl), [0819]
(xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0820]
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0821] (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [0822] (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and [0823] (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, [0824] (l)
--R.sub.1-heterocyle wherein [0825] R.sub.1-heterocycle at each
occurrence is independently selected from the group consisting of
morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,
thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
[0826] where the R.sub.1-heterocycle group is bonded by any atom of
the parent R.sub.1-heterocycle group substituted by hydrogen such
that the new bond to the R.sub.1-heterocycle group replaces the
hydrogen atom and its bond, where heterocycle is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[0827] (a) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sub.1-aR.sub.1-b--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy, [0828] (b) C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b [0829] (c) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b [0830] (d) halogen, [0831] (e)
C.sub.1-C.sub.6 alkoxy, [0832] (f) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [0833] (g)
--NR.sub.N-2R.sub.N-3, [0834] (h) --OH, [0835] (i) --C.ident.N,
[0836] (j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.8 cycloalkyl),
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0837] (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), [0838] (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, [0839] (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, [0840] (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and [0841]
(o) .dbd.O, [0842] (p)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- [0843] (q)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- [0844] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [0845] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [0846] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), [0847] (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), [0848] (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, [0849] (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [0850] (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, [0851] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein R.sub.N-4 is selected
from the group consisting of phenyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,
pyrrolinyl, thienyl, pyrazolyl, pyridyl N-oxide, oxazolyl,
thiazolyl, imidazolyl, and pyrrolidinyl where each group is
optionally substituted with one, two, three, or four groups that
are independently C.sub.1-C.sub.6 alkyl, [0852] (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 where R.sub.N-5 is selected
from the group consisting of: [0853] (a) C.sub.1-C.sub.6 alkyl,
[0854] (b) --(CH.sub.2).sub.0-2--(R.sub.1-aryl) [0855] (c)
C.sub.2-C.sub.6 alkenyl, [0856] (d) C.sub.2-C.sub.6 alkynyl, [0857]
(e) --(CH.sub.2).sub.0-2--C.sub.3-C.sub.8 cycloalkyl, [0858] (f)
--(CH.sub.2).sub.0-2--(R.sub.1-heteroaryl), and [0859] (g)
--(CH.sub.2).sub.0-2--(R.sub.1-heterocycle), [0860] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0861] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [0862] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), [0863]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl),
[0864] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, [0865] (22) --(CH.sub.2).sub.0-4--N(H
or R.sub.N-5)--CO--N(R.sub.N-5).sub.2, [0866] (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [0867] (24)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--R.sub.N-2, [0868] (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0869] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0870] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [0871] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 wherein [0872]
R.sub.100 at each occurrence is independently --H or
C.sub.1-C.sub.4 alkyl, [0873] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [0874] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [0875] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [0876] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [0877] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [0878] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), [0879]
(35) C.sub.3-C.sub.8 cycloalkyl, [0880] (36) C.sub.2-C.sub.6
alkenyl optionally substituted with C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0881] (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0882] (38)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[0883] (39) --(CH.sub.2).sub.1-4--(C.sub.3-C.sub.8 cycloalkyl),
[0884] (B) --R.sub.N-heteroaryl where R.sub.N-heteroaryl is
selected from the group consisting of pyridinyl, indolyl,
indolinyl, isoindolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl,
indolizinyl and isochromanyl, [0885] where the R.sub.N-heteroaryl
group is bonded by any atom of the parent R.sub.N-heteroaryl group
substituted by hydrogen such that the new bond to the
R.sub.N-heteroaryl group replaces the hydrogen atom and its bond,
where heteroaryl is optionally substituted with one, two, three, or
four of: [0886] (1) C.sub.1-C.sub.6 alkyl, optionally substituted
with one, two or three substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0887] (2) --OH, [0888] (3) --NO.sub.2,
[0889] (4) --F, --Cl, --Br, --I, [0890] (5) --CO.sub.2H, [0891] (6)
--C.ident.N, [0892] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [0893] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [0894] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [0895] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), [0896] (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), [0897] (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, [0898] (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [0899] (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, [0900] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 [0901] (16)
--CH.sub.2).sub.0-4--CO--O--R.sub.N-5 [0902] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [0903] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [0904] (19)
--(CH.sub.2).sub.0-4--SO.sub.2(C.sub.1-C.sub.12 alkyl), [0905] (20)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl),
[0906] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, [0907] (22) --(CH.sub.2).sub.0-4--N(H
or R.sub.N-5)--CO--N(R.sub.N-5).sub.2, [0908] (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [0909] (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, [0910]
(25) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [0911] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [0912] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [0913] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2, [0914] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [0915] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [0916] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [0917] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [0918] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [0919] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), [0920]
(35) C.sub.3-C.sub.8 cycloalkyl, [0921] (36) C.sub.2-C.sub.6
alkenyl optionally substituted with C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0922] (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [0923] (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[0924] (39) --(CH.sub.2).sub.1-4--C.sub.3-C.sub.8 cycloalkyl,
[0925] (C) R.sub.N-aryl--W--R.sub.N-aryl, [0926] (D)
R.sub.N-aryl--W--R.sub.N-heteroaryl, [0927] (E)
R.sub.N-aryl--W--R.sub.1-heterocycle, [0928] (F)
R.sub.N-heteroaryl--W--R.sub.N-aryl, [0929] (G)
R.sub.N-heteroaryl--W--R.sub.N-heteroaryl, [0930] (H)
R.sub.N-heteroaryl--W--R.sub.N-1-heterocycle, [0931] (I)
R.sub.N-heterocycle--W--R.sub.N-aryl, [0932] (J)
R.sub.N-heterocycle--W--R.sub.N-heteroaryl, [0933] (K)
R.sub.N-heterocycle--W--R.sub.N-1-heterocycle, [0934] where W is
[0935] (7) --(CH.sub.2).sub.1-4--, [0936] (8) --O--, [0937] (9)
--S(O).sub.0-2--, [0938] (10) --N(R.sub.N-5)--, [0939] (11) --CO--;
or [0940] (12) a bond;
[0941] (II) --CO--(C.sub.1-C.sub.6 alkyl)-M-(C.sub.1-C.sub.6
alkyl), where M is S, SO or SO.sub.2, and wherein each alkyl is
unsubstituted or substituted with one, two, or three of
substituents independently selected from the group consisting of:
[0942] (A) --NH--CO--(C.sub.1-C.sub.6 alkyl), [0943] (B)
--NH--CO--O--R.sub.N-8, [0944] (C) --NR.sub.N-2R.sub.N-3; where
R.sub.1 is
[0945] --(CH.sub.2).sub.n1-phenyl, where n.sub.1 is zero or one,
and which is optionally substituted with one, two, three or four of
the following substituents on the phenyl ring: [0946] (A)
C.sub.1-C.sub.6 alkyl optionally substituted with one, two or three
substituents selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, ----SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0947] (B)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0948] (C)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0949] (D) --F,
Cl, --Br or --I, [0950] (F) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two or three of --F, [0951] (G)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined
below, [0952] (H) --OH, [0953] (I) --C.ident.N, [0954] (J)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0955] (K) --CO--(C.sub.1-C.sub.4 alkyl),
[0956] (L) --SO.sub.2--NR.sub.1-aR.sub.1-b, [0957] (M)
--CO--NR.sub.1-aR.sub.1-b, [0958] (N) --SO.sub.2--(C.sub.1-C.sub.4
alkyl); and where R.sub.2 is
[0959] (I) -(Z)-C.sub.1-C.sub.6 alkyl, where Z is a bond, --C(O),
--CO.sub.2-- or --SO.sub.2--, wherein the alkyl group is optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.7 alkyl
(optionally substituted with C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.3 alkoxy), --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
--NR.sub.1-aR.sub.1-b where R.sub.1-a and R.sub.1-b are
independently --H or C.sub.1-C.sub.6 alkyl, and
--OC.dbd.ONR.sub.1-aR.sub.1-b,
[0960] (II) -(Z)-CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6
alkyl),
[0961] (III)
-(Z)-CH.sub.2--CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl)
[0962] (IV) -(Z)-C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b,
[0963] (V) -(Z)-C.sub.2-C.sub.6 alkynyl with one or two triple
bonds, optionally substituted with one, two or three substituents
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b,
[0964] (VI) -(Z)-(CH.sub.2).sub.n1--(R.sub.1-aryl), where Z is a
bond, CO, CO.sub.2 or SO.sub.2, where n.sub.1 is zero or one and
where R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl and indanyl,
indenyl, dihydronaphthalyl, or tetralinyl optionally substituted
with one, two, three or four of the following substituents on the
aryl ring: [0965] (A) C.sub.1-C.sub.6 alkyl optionally substituted
with one, two or three substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0966] (B) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
NR.sub.1-aR.sub.1-b. [0967] (C) C.sub.2-C.sub.6 alkynyl with one or
two triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0968] (D) --F, Cl, --Br or --I, [0969] (F)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two or
three of --F, [0970] (G) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined below, [0971] (H) --OH, [0972] (I)
--C.ident.N, [0973] (J) C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0974] (K)
--CO--(C.sub.1-C.sub.4 alkyl), [0975] (L)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [0976] (M)
--CO--NR.sub.1-aR.sub.1-b, [0977] (N) --SO.sub.2--(C.sub.1-C.sub.4
alkyl),
[0978] (VII) -(Z)-(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where
n.sub.1 is as defined above and where R.sub.1-heteroaryl is
selected from the group consisting of:
[0979] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,
indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,
quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,
pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, 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,
[0980] where the R.sub.1-heteroaryl group is bonded to
--(CH.sub.2).sub.n1-- by any ring atom of the parent
R.sub.N-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.1-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is optionally substituted with one, two,
three or four of: [0981] (1) C.sub.1-C.sub.6 alkyl optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0982] (2) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0983] (3) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0984] (4) --F, Cl, --Br or --I, [0985] (6)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two, or
three of --F, [0986] (7) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined below, [0987] (8) --OH, [0988] (9)
--C.ident.N, [0989] (10) C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [0990] (11)
--CO--(C.sub.1-C.sub.4 alkyl), [0991] (12)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [0992] (13)
--CO--NR.sub.1-aR.sub.1-b, or [0993] (14)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), with the proviso that when
n.sub.1 is zero R.sub.1-heteroaryl is not bonded to the carbon
chain by nitrogen, or
[0994] (VIII) -(Z)-(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where
n.sub.1 is as defined above and R.sub.1-heterocycle is selected
from the group consisting of: [0995] morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homomorpholinyl S-oxide, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl
dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl,
dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl
S,S-dioxide, homothiomorpholinyl S-oxide, where the
R.sub.1-heterocycle group is bonded by any atom of the parent
R.sub.1-heterocycle group substituted by hydrogen such that the new
bond to the R.sub.1-heterocycle group replaces the hydrogen atom
and its bond, where heterocycle is optionally substituted with one,
two, three or four: [0996] (1) C.sub.1-C.sub.6 alkyl optionally
substituted with one, two or three substituents select-ed from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0997] (2) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0998] (3) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [0999] (4) --F, Cl, --Br, or --I, [1000] (5)
C.sub.1-C.sub.6 alkoxy, [1001] (6) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [1002] (7)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined
below, [1003] (8) --OH, [1004] (9) --C.ident.N, [1005] (10)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1006] (11) --CO--(C.sub.1-C.sub.4 alkyl),
[1007] (12) --SO.sub.2--NR.sub.1-aR.sub.1-b, [1008] (13)
--CO--NR.sub.1-aR.sub.1-b, [1009] (14) --SO.sub.2--(C.sub.1-C.sub.4
alkyl) [1010] (15) .dbd.O, with the proviso that when n.sub.1 is
zero R.sub.1-heterocycle is not bonded to the carbon chain by
nitrogen; and where R.sub.20 is H or C.sub.1-6 alkyl or
alkenyl.
[1011] In another preferred embodiment relative to formula II, Rc
is --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where R.sub.C-x
and R.sub.C-y are independently selected from the group consisting
of [1012] --H, [1013] C.sub.1-C.sub.4 alkyl optionally substituted
with 1 or 2 --OH, [1014] C.sub.1-C.sub.4 alkoxy optionally
substituted with 1, 2, or 3 halogen, [1015]
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl, [1016]
C.sub.2-C.sub.6 alkenyl containing one or two double bonds, [1017]
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or [1018] R.sub.C-x and R.sub.C-y are taken together with
the carbon to which they are attached to form a carbocycle of
three, four, five, six or seven carbon atoms, where one carbon atom
is optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein [1019]
R.sub.C-aryl is phenyl, which is optionally substituted with 1, 2,
or 3 groups that are independently: [1020] (1) C.sub.1-C.sub.6
alkyl, optionally substituted with one, two or three substituents
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [1021] (2) --OH, [1022] (3)
--NO.sub.2, [1023] (4) halogen, [1024] (5) --CO.sub.2H, [1025] (6)
--C.ident.N.
[1026] In yet another preferred embodiment, Rc is
--(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl aryl where R.sub.C-x
and R.sub.C-y are independently selected from the group consisting
of [1027] --H, [1028] C.sub.1-C.sub.4 alkyl optionally substituted
with 1 or 2 --OH, [1029] C.sub.1-C.sub.4 alkoxy optionally
substituted with 1, 2, or 3 halogen, [1030]
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl, [1031]
C.sub.2-C.sub.6 alkenyl containing one or two double bonds, [1032]
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or [1033] R.sub.C-x and R.sub.C-y are taken together with
the carbon to which they are attached to form a carbocycle of
three, four, five, six or seven carbon atoms, where one carbon atom
is optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein
[1034] --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl is
selected from the group consisting of pyridinyl, indolyl,
indolinyl, isoindolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl,
indolizinyl and isochromanyl.
[1035] In another preferred embodiment relative to formula II, Rc
is the optionally substituted --C1-C10 alkyl groups as described
above.
[1036] Preferred compounds of the formula II include, amongst
others: ##STR5##
[1037] In another preferred embodiment, the invention provides
compounds of formula III: ##STR6## [1038] or a pharmaceutically
acceptable salt thereof wherein [1039] R.sub.1 represents phenyl
(C.sub.1-C.sub.6)alkyl where the phenyl is optionally substituted
with up to three groups independently selected from halogen,
hydroxy, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, amino,
nitro, trifluoromethyl, cyano, mono(C.sub.1-C.sub.2)alkylamino and
di(C.sub.1-C.sub.2)alkylamino; [1040] R.sub.a and R.sub.b
independently represent hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
mono- or di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6
alkyl sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, trifluoromethyl, mono(C.sub.1-C.sub.6)alkylaminocarbonyl,
or di(C.sub.1-C.sub.6)alkylaminocarbonyl and provided that not both
R.sub.a and R.sub.b are hydrogen simultaneously; [1041] R.sub.c
represents hydrogen, or C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl each of which is optionally
substituted with halogen, hydroxy, amino, cyano, or
trifluoromethyl; [1042] R.sub.d represents [1043] phenyl optionally
substituted with hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
mono- or di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6
alkyl sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl; or [1044] C.sub.1-C.sub.6 alkyl optionally substituted
with hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, cyano, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, or trifluoromethyl; and [1045] R.sub.20
represents hydrogen, C.sub.3-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, or trifluoromethyl. In accordance
with this preferred embodiment, R.sub.1 is benzyl where the phenyl
is optionally substituted. Also preferably, the phenyl is
substituted with one or two groups independently selected from
halogen, hydroxy, C.sub.1-C.sub.3 alkyl, amino, and
trifluoromethyl. In another preferred embodiment, phenyl is
substituted with two groups independently selected from halogen,
hydroxy, and trifluoromethyl. In an alternative preferred
embodiment, phenyl is disubstituted with halogen. Also preferably,
R.sub.1 is 3,5-difluorobenzyl. Preferably, R.sub.a and R.sub.b are
different and R.sub.b represents mono- or
di(C.sub.1-C.sub.6)alkylaminocarbonyl. Also preferably, R.sub.d is
phenyl optionally substituted with C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, amino, hydroxy, or halogen. In a further
preferred embodiment, R.sub.c is hydrogen or C.sub.1-C.sub.4 alkyl.
Also preferably, R.sub.c is C.sub.1-C.sub.3 alkyl. In yet another
preferred embodiment, R.sub.d is C.sub.1-C.sub.6 lower alkyl and
R.sub.20 is hydrogen.
[1046] In another preferred embodiment, the invention provides for
compounds of formula IV: ##STR7## where R.sub.a, R.sub.b, R.sub.1
R.sub.c R.sub.20 and R.sub.d are defined above for this preferred
embodiment. In another preferred embodiment, R.sub.1 is benzyl
where the phenyl is disubstituted with chloro or fluoro; R.sub.c is
C.sub.1-C.sub.3 alkyl; R.sub.d is C.sub.1-C.sub.6 lower alkyl;
R.sub.20 is hydrogen or C.sub.1-C.sub.6 alkyl; and R.sub.b is
di(C.sub.1-C.sub.6)alkylaminocarbonyl attached to the 3-position of
the phenyl group.
[1047] In another preferred embodiment, the invention provides
compounds of the formula V: ##STR8## [1048] or a pharmaceutically
acceptable salt thereof wherein [1049] R.sub.1 represents phenyl
(C.sub.3-C.sub.6)alkyl where the phenyl is optionally substituted
with up to three groups independently selected from halogen,
hydroxy, C.sub.1-C.sub.2 alkyl, C.sub.1-C.sub.2 alkoxy, amino,
nitro, trifluoromethyl, cyano, mono(C.sub.1-C.sub.2)alkylamino and
di(C.sub.1-C.sub.2)alkylamino; [1050] R.sub.a and R.sub.b
independently represent hydrogen, hydroxy, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
mono- or di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6
alkyl sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, trifluoromethyl, mono(C.sub.1-C.sub.6) alkylaminocarbonyl,
or di(C.sub.1-C.sub.6) alkylaminocarbonyl and provided that not
both R.sub.a and R.sub.b are hydrogen simultaneously; [1051]
R.sub.c represents hydrogen, or C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl each of which
is optionally substituted with halogen, hydroxy, amino, cyano, or
trifluoromethyl; [1052] R.sub.d represents [1053] phenyl optionally
substituted with hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
alkoxy, C.sub.3-C.sub.7 cycloalkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkyl, C.sub.3-C.sub.7
cycloalkyl(C.sub.1-C.sub.6)alkoxy, halogen, cyano, amino,
mono(C.sub.1-C.sub.6)alkylamino, di(C.sub.1-C.sub.6)alkylamino,
mono- or di(C.sub.1-C.sub.6)alkylaminosulfonyl, C.sub.1-C.sub.6
alkyl sulfonylamino, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl; or [1054] C.sub.1-C.sub.6 alkyl optionally substituted
with hydroxy, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 alkoxy,
halogen, cyano, amino, mono(C.sub.1-C.sub.6)alkylamino,
di(C.sub.1-C.sub.6)alkylamino, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, or trifluoromethyl; and [1055] R.sub.20
represents hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, or trifluoromethyl.
[1056] In accordance with this preferred embodiment, R.sub.1 is
benzyl where the phenyl is optionally substituted. Preferably, the
phenyl is substituted with one or two groups independently selected
from halogen, hydroxy, C.sub.1-C.sub.3 alkyl, amino, and
trifluoromethyl. Also preferably, phenyl is substituted with two
groups independently selected from halogen, hydroxy, and
trifluoromethyl. Also preferably, phenyl is disubstituted with
halogen. In another preferred embodiment, R.sub.1 is
3,5-difluorobenzyl. Also preferably, R.sub.a and R.sub.b are
different and R.sub.b represents
C.sub.1-C.sub.6)alkylsulfonylamino. Preferably, R.sub.d is phenyl
optionally substituted with C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, amino, hydroxy, or halogen. Prefereably, R.sub.c is
hydrogen or C.sub.1-C.sub.4 alkyl. Preferably, R.sub.c is
C.sub.1-C.sub.3 alkyl. Also preferably, R.sub.d is C.sub.1-C.sub.6
lower alkyl and R.sub.20 is hydrogen. Further in accordance with
this preferred embodiement, the invention provides compounds of the
formula VI: ##STR9## where R.sub.a, R.sub.b, R.sub.1 R.sub.c
R.sub.20 and R.sub.d are defined above for this preferred
embodiment. In another preferred embodiment, R.sub.1 is benzyl
where the phenyl is disubstituted with chloro or fluoro; R.sub.c is
C.sub.1-C.sub.3 alkyl; R.sub.d is C.sub.1-C.sub.6 lower alkyl;
R.sub.20 is hydrogen or C.sub.1-C.sub.6 alkyl; and R.sub.b is
alkylsulfonylamino attached to the 2-position of the thiazolyl
group.
[1057] Preferred compounds of the invention include: ##STR10##
##STR11## ##STR12## ##STR13## ##STR14## ##STR15## ##STR16##
##STR17## ##STR18## ##STR19## ##STR20## ##STR21## ##STR22##
##STR23## ##STR24## ##STR25## ##STR26## ##STR27## ##STR28##
##STR29## ##STR30## ##STR31## ##STR32## ##STR33## ##STR34##
##STR35## ##STR36## ##STR37## ##STR38## ##STR39## ##STR40##
##STR41## ##STR42## ##STR43## ##STR44## ##STR45## ##STR46##
##STR47## ##STR48## ##STR49## ##STR50## ##STR51## ##STR52##
##STR53## ##STR54## ##STR55##
[1058] In another embodiment, the invention provides a method of
treating a patient who has, or in preventing a patient from
getting, a disease or condition selected from the group consisting
of Alzheimer's disease, for helping prevent or delay the onset of
Alzheimer's disease, for treating patients with mild cognitive
impairment (MCI) and preventing or delaying the onset of
Alzheimer's disease in those who would progress from MCI to AD, for
treating Down's syndrome, for treating humans who have Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for
treating cerebral amyloid angiopathy and preventing its potential
consequences, i.e. single and recurrent lobar hemorrhages, for
treating other degenerative dementias, including dementias of mixed
vascular and degenerative origin, dementia associated with
Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, diffuse Lewy body type of Alzheimer's disease and who
is in need of such treatment which comprises administration of a
therapeutically effective amount of a compound selected from the
group consisting of an aza hydroxylated ethyl amine of the formula
II: ##STR56## or a pharmaceutically acceptable salt thereof, where
Rc is
[1059] (I) -C.sub.1-C.sub.10 alkyl optionally substituted with one,
two or three groups independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl,
--NR.sub.1-aR.sub.1-b, --OC.dbd.ONR.sub.1-aR.sub.1-b,
--S(.dbd.O).sub.0-2R.sub.1-a,
--NR.sub.1-aC.dbd.ONR.sub.1-aR.sub.1-b,
--C.dbd.ONR.sub.1-aR.sub.1-b, and --S(.dbd.O).sub.2
NR.sub.1-aR.sub.1-b wherein
[1060] R.sub.1-a and R.sub.1-b at each occurrence are independently
H or C.sub.1-C.sub.6 alkyl,
[1061] (II) --(CH.sub.2).sub.0-3--(C.sub.3-C.sub.8) cycloalkyl
where cycloalkyl can be optionally substituted with one, two or
three substituents independently selected from the group consisting
of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.6 alkoxy, --O-phenyl, --CO.sub.2H,
--CO.sub.2--(C.sub.1-C.sub.4 alkyl), and --NR.sub.1-aR.sub.1-b
[1062] (III) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-aryl where
R.sub.C-x and R.sub.C-y are independently selected from the group
consisting of --H, [1063] C.sub.1-C.sub.4 alkyl optionally
substituted with 1 or 2 --OH, [1064] C.sub.1-C.sub.4 alkoxy
optionally substituted with 1, 2, or 3 halogen, [1065]
--(CH.sub.2).sub.0-4--C.sub.3-C.sub.8 cycloalkyl; [1066]
C.sub.2-C.sub.6 alkenyl containing one or two double bonds, [1067]
C.sub.2-C.sub.6 alkynyl containing one or two triple bonds, and
phenyl, or [1068] R.sub.C-x and R.sub.C-y are taken together with
the carbon to which they are attached to form a carbocycle of
three, four, five, six or seven carbon atoms, where one carbon atom
is optionally replaced by a group selected from --O--, --S--,
--SO.sub.2--, --NR.sub.N-2-- and R.sub.C-aryl, wherein [1069]
R.sub.C-aryl is phenyl, which is optionally substituted with 1, 2,
or 3 groups that are independently: [1070] (1) C.sub.1-C.sub.6
alkyl, optionally substituted with one, two or three substituents
selected from the group consisting of C.sub.1-C.sub.3 alkyl,
halogen, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [1071] (2) --OH, [1072] (3)
--NO.sub.2, [1073] (4) halogen, [1074] (5) --CO.sub.2H, [1075] (6)
--C.ident.N, [1076] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where [1077]
R.sub.N-2 and R.sub.N-3 are independently selected from the group
consisting of: [1078] (a) --H, [1079] (b) --C.sub.1-C.sub.6 alkyl
optionally substituted with one substituent selected from the group
consisting of: [1080] (i) --OH, and [1081] (ii) --NH.sub.2, [1082]
(c) --C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --Br, --I, or OH, [1083]
(d) --C.sub.3-C.sub.7 cycloalkyl, [1084] (e) --(C.sub.1-C.sub.2
alkyl)-(C.sub.3-C.sub.7 cycloalkyl), [1085] (f) --(C.sub.1-C.sub.6
alkyl)-O-(C.sub.1-C.sub.3 alkyl), [1086] (g) --C.sub.2-C.sub.6
alkenyl [1087] (h) --C.sub.2-C.sub.6 alkynyl [1088] (i)
--C.sub.1-C.sub.6 alkyl chain with one double bond and one triple
bond, [1089] (j) --R.sub.1-aryl wherein R.sub.1-aryl at each
occurrence is independently phenyl, naphthyl, indanyl, indenyl,
dihydronaphthyl, or tetralinyl each of which is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[1090] (i) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy, [1091] (ii) C.sub.2-C.sub.6 alkenyl with
one or two double bonds, optionally substituted with one, two or
three substituents independently selected from the group consisting
of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [1092] (iii) C.sub.2-C.sub.6
alkynyl optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1093] (iv) --F, Cl, --Br and --I, [1094]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with 1, 2, or 3
--F, [1095] (vi) --NR.sub.N-2R.sub.N-3, [1096] (vii) --OH, [1097]
(viii) --C.ident.N, [1098] (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[1099] (x) --CO--(C.sub.1-C.sub.4 alkyl), [1100] (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [1101] (xii)
--CO--NR.sub.1-aR.sub.1-b, or [1102] (xiii)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), [1103] (k)
--R.sub.1-heteroaryl wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, [1104]
where the R.sub.1-heteroaryl group is optionally substituted with
1, 2, 3, or 4 groups that are independently: [1105] (i)
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, [1106] (ii)
C.sub.2-C.sub.6 alkenyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[1107] (iii) C.sub.2-C.sub.6 alkynyl optionally substituted with 1,
2, or 3 groups that are independently selected from the group
consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1108] (iv) --F,
--Cl, --Br and --I, [1109] (v) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three --F, [1110] (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [1111] (vii) --OH,
[1112] (viii) --C.ident.N, [1113] (ix)
(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[1114] (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6 alkyl), [1115]
(xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [1116]
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [1117] (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), [1118] (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and [1119] (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)--, [1120] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [1121] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [1122] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl) [1123] (11)
--(CH.sub.2).sub.0-4--CO--(CH.sub.2).sub.0-4(C.sub.3-C.sub.7
cycloalkyl), [1124] (12) --(CH.sub.2).sub.0-4--CO--R.sub.1-aryl,
[1125] (13) --(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [1126]
(14) --(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle wherein [1127]
R.sub.1-heterocycle at each occurrence is independently selected
from the group consisting of morpholinyl, thiomorpholinyl,
thiomorpholinyl S-oxide, thiomorpholinyl S,S-dioxide, piperazinyl,
homopiperazinyl, pyrrolidinyl, pyrrolinyl, tetrahydropyranyl,
piperidinyl, tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
[1128] where the R.sub.1-heterocycle group is bonded by any atom of
the parent R.sub.1-heterocycle group substituted by hydrogen such
that the new bond to the R.sub.1-heterocycle group replaces the
hydrogen atom and its bond, where heterocycle is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[1129] (a) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sub.1-aR.sub.1-b--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy, [1130] (b) C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b [1131] (c) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b [1132] (d) halogen, [1133] (e)
C.sub.1-C.sub.6 alkoxy, [1134] (f) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [1135] (g)
--NR.sub.N-2R.sub.N-3, [1136] (h) --OH, [1137] (i) --C.ident.N,
[1138] (j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.7 cycloalkyl),
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1139] (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl), [1140] (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, [1141] (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, [1142] (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and [1143]
(o) .dbd.O, [1144] (p)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- [1145] (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- [1146] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein [1147] R.sub.N-4 at
each occurrence is independently selected from the group consisting
of morpholinyl, thiomorpholinyl, pyrrolidinonyl, pyrrolyl,
pyrazolyl, thienyl, pyridyl N-oxide, piperazinyl, piperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl S-oxide,
homothiomorpholinyl S,S-dioxide, pyrrolinyl and pyrrolidinyl where
each group is optionally substituted with 1, 2, 3, or 4 groups that
are independently C.sub.1-C.sub.6 alkyl, [1148] (16)
--(CH.sub.2).sub.0-4--CO.sub.2--R.sub.N-5 where [1149] R.sub.N-5 at
each occurrence is independently selected from the group consisting
of: [1150] (a) C.sub.1-C.sub.6 alkyl, [1151] (b)
--(CH.sub.2).sub.0-2--(R.sub.1-aryl), [1152] (c) C.sub.2-C.sub.6
alkenyl, [1153] (d) C.sub.2-C.sub.6 alkynyl, [1154] (e)
C.sub.3-C.sub.7 cycloalkyl, and [1155] (f)
--(CH.sub.2).sub.0-4--(R.sub.1-heteroaryl), [1156] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3 [1157] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [1158] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), [1159]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.7 cycloalkyl),
[1160] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO.sub.2--R.sub.N-5, [1161] (22)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--N (R.sub.N-5).sub.2,
[1162] (23) --(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [1163]
(24) --(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2,
[1164] (25) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [1165] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [1166] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl) , [1167] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 where R.sub.100
is independently H or C.sub.1-C.sub.4 alkyl, [1168] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [1169] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [1170] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [1171] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [1172] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [1173] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl) wherein the alkyl
group is optionally substituted with one, two, three, four, or five
substituents independently selected from the group consisting of F,
Cl, Br, and I, [1174] (35) --(CH.sub.2).sub.0-4--(C.sub.3-C.sub.8
cycloalkyl), [1175] (36) C.sub.2-C.sub.6 alkenyl optionally
substituted with C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, [1176] (37) C.sub.2-C.sub.6 alkynyl
optionally substituted with C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br,
--I, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
or --NR.sub.1-aR.sub.1-b, and [1177] (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2;
[1178] (IV) --(CR.sub.C-xR.sub.C-y).sub.0-4--R.sub.C-heteroaryl
wherein R.sub.C-heteroaryl at each occurrence is independently
selected from the group consisting of pyridinyl, pyrimidinyl,
quinolinyl, benzothienyl, indolyl, indolinyl, pryidazinyl,
pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl, quinoxalinyl,
phthalazinyl, imidazolyl, isoxazolyl, pyrazolyl, oxazolyl,
thiazolyl, indolizinyl, indazolyl, benzoisothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, thienyl, pyrrolyl,
oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, oxazolopyridinyl,
isothiazolyl, naphthyridinyl, cinnolinyl, carbazolyl,
beta-carbolinyl, isochromanyl, chromanyl, tetrahydroisoquinolinyl,
isoindolinyl, isobenzotetrahydrofuranyl, isobenzotetrahydrothienyl,
isobenzothienyl, benzoxazolyl, pyridopyridinyl,
benzotetrahydrofuranyl, benzotetrahydrothienyl, purinyl,
benzodioxolyl, triazinyl, henoxazinyl, phenothiazinyl, pteridinyl,
benzothiazolyl, imidazopyridinyl, imidazothiazolyl,
dihydrobenzisoxazinyl, benzisoxazinyl, benzoxazinyl,
dihydrobenzisothiazinyl, benzopyranyl, benzothiopyranyl,
coumarinyl, isocoumarinyl, chromonyl, chromanonyl,
tetrahydroquinolinyl, dihydroquinolinyl, dihydroquinolinonyl,
dihydroisoquinolinonyl,dihydrocoumarinyl, dihydroisocoumarinyl,
isoindolinonyl, benzodioxanyl, benzoxazolinonyl, imidazopyrazolyl,
quinazolinonyl, pyrazopyridyl, benzooxadiazolyl,
dihydropyrimidinonyl, dihydrobenzofuranonyl, where the
R.sub.C-heteroaryl group is bonded by any atom of the parent
R.sub.C-heteroaryl group substituted by hydrogen such that the new
bond to the R.sub.C-heteroaryl group replaces the hydrogen atom and
its bond, where heteroaryl is optionally substituted 1, 2, 3, or 4
groups that are independently: [1179] (1) C.sub.1-C.sub.6 alkyl,
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1180] (2) --OH,
[1181] (3) --NO.sub.2, [1182] (4) --F, --Cl, --Br, --I, [1183] (5)
--CO--OH, [1184] (6) --C.ident.N, [1185] (V) C.sub.2-C.sub.10
alkenyl optionally substituted with one, two or three substituents
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.6 alkoxy, --O-phenyl, and --NR.sub.1-aR.sub.1-b,
[1186] (VI) C.sub.2-C.sub.10 alkynyl optionally substituted with
one, two or three substituents independently selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.6 alkoxy,
--O-phenyl, and --NR.sub.1-aR.sub.1-b, [1187] (VII)
--(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.6 alkyl)-OH, [1188]
(VIII) --CH.sub.2--NH--CH.sub.2--CH(--O--CH.sub.2--CH.sub.3).sub.2,
[1189] (IX)
--(CH.sub.2).sub.0-6--C(.dbd.NR.sub.1-a)(NR.sub.1-aR.sub.1-b);
where R.sub.N is
[1190] (I) R.sub.N-1--X.sub.N-- where X.sub.N is --CO--, and where
R.sub.N-1 is selected from the group consisting of: [1191] (A)
phenyl, which is optionally substituted with one, two or three of
the following substituents which can be the same or different and
are: [1192] (1) C.sub.1-C.sub.6 alkyl, optionally substituted with
one, two or three substituents selected from the group consisting
of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1193] wherein R.sub.1-a and R.sub.1-b at
each occurrence are independently H or C.sub.1-C.sub.6 alkyl,
[1194] (2) --OH, [1195] (3) --NO.sub.2, [1196] (4) --F, --Cl, --Br,
--I, [1197] (5) --CO.sub.2H, [1198] (6) --C.ident.N, [1199] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are the same or different and are selected from the group
consisting of: [1200] (a) --H, [1201] (b) --C.sub.1-C.sub.8 alkyl
optionally substituted with one substituent selected from the group
consisting of: [1202] (i) --OH, [1203] (ii) --NH.sub.2, [1204]
(iii) phenyl, [1205] (c) --C.sub.1-C.sub.8 alkyl optionally
substituted with 1, 2, or 3 groups that are independently --F,
--Cl, --Br, or --I, [1206] (d) --C.sub.3-C.sub.8 cycloalkyl, [1207]
(e) --(C.sub.1-C.sub.2 alkyl)-(C.sub.3-C.sub.8 cycloalkyl), [1208]
(f) --(C.sub.1-C.sub.6 alkyl)-O--(C.sub.1-C.sub.3 alkyl) [1209] (g)
--C.sub.2-C.sub.6 alkenyl, [1210] (h) --C.sub.2-C.sub.6 alkynyl,
[1211] (i) --C.sub.1-C.sub.6 alkyl chain with one double bond and
one triple bond, [1212] (j) --R.sub.1-aryl, wherein R.sub.1-aryl at
each occurrence is independently phenyl, naphthyl, indanyl,
indenyl, dihydronaphthyl, or tetralinyl each of which is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[1213] (i) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --NR.sub.1-aR.sub.1-b, --C.ident.N, --CF.sub.3, and
C.sub.1-C.sub.3 alkoxy, [1214] (ii) C.sub.2-C.sub.6 alkenyl with
one or two double bonds, optionally substituted with one, two or
three substituents independently selected from the group consisting
of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b, [1215] (iii) C.sub.2-C.sub.6
alkynyl optionally substituted with 1, 2, or 3 groups that are
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1216] (iv) --F, Cl, --Br and --I, [1217]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with 1, 2, or 3
--F, [1218] (vi) --NR.sub.N-2R.sub.N-3, [1219] (vii) --OH, [1220]
(viii) --C.ident.N, [1221] (ix) C.sub.3-C.sub.7 cycloalkyl,
optionally substituted with 1, 2, or 3 groups that are selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[1222] (x) --CO--(C.sub.1-C.sub.4 alkyl), [1223] (xi)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [1224] (xii)
--CO--NR.sub.1-aR.sub.1-b, or [1225] (xiii)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl) [1226] (k)
--R.sub.1-heteroaryl, wherein R.sub.1-heteroaryl at each occurrence
is independently selected from the group consisting of pyridinyl,
pyrimidinyl, quinolinyl, benzothienyl, indolyl, indolinyl,
pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl, quinazolinyl,
quinoxalinyl, phthalazinyI, imidazolyl, isoxazolyl, pyrazolyl,
oxazolyl, thiazolyl, indolizinyl, indazolyl, benzothiazolyl,
benzimidazolyl, benzofuranyl, furanyl, 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, and benzothiopyranyl S,S-dioxide, [1227]
where the R.sub.1-heteroaryl group is optionally substituted with
1, 2, 3, or 4 groups that are independently: [1228] (i)
C.sub.1-C.sub.6 alkyl optionally substituted with 1, 2, or 3 groups
independently selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --NR.sub.1-aR.sub.1-b,
--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3 alkoxy, [1229] (ii)
C.sub.2-C.sub.6 alkenyl optionally substituted with 1, 2, or 3
groups that are independently --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b,
[1230] (iii) C.sub.2-C.sub.6 alkynyl optionally substituted with 1,
2, or 3 groups that are independently --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, or
--NR.sub.1-aR.sub.1-b, [1231] (iv) --F, --Cl, --Br and --I, [1232]
(v) --C.sub.1-C.sub.6 alkoxy optionally substituted with one, two,
or three --F, [1233] (vi)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [1234] (vii) --OH,
[1235] (viii) --C.ident.N, [1236] (ix)
(CH.sub.2).sub.0-4--C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with 1, 2, or 3 groups that are independently selected
from the group consisting of --F, --Cl, --OH, --SH, --C.ident.N,
--CF.sub.3, C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b,
[1237] (x) (CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.6 alkyl) [1238]
(xi) (CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [1239]
(xii) (CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [1240] (xiii)
(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl) [1241] (xiv)
(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2--, and [1242] (xv)
(CH.sub.2).sub.0-4--N(R.sub.N-2) --C(O)--, [1243] (1)
--R.sub.1-heterocyle, wherein [1244] R.sub.1-heterocycle at each
occurrence is independently selected from the group consisting of
morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,
thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homothiomorpholinyl, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl,
dihydropyrazinyl, dihydropyridinyl, dihydropyrimidinyl,
dihydrofuryl, dihydropyranyl, tetrahydrothienyl S-oxide,
tetrahydrothienyl S,S-dioxide, and homothiomorpholinyl S-oxide,
[1245] where the R.sub.1-heterocycle group is bonded by any atom of
the parent R.sub.1-heterocycle group substituted by hydrogen such
that the new bond to the R.sub.1-heterocycle group replaces the
hydrogen atom and its bond, where heterocycle is optionally
substituted with 1, 2, 3, or 4 groups that are independently:
[1246] (a) C.sub.1-C.sub.6 alkyl optionally substituted with one,
two or three substituents independently selected from the group
consisting of C.sub.1-C.sub.3 alkyl, halogen, --OH, --SH,
--NR.sub.1-aR.sub.1-b--C.ident.N, --CF.sub.3, and C.sub.1-C.sub.3
alkoxy, [1247] (b) C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
independently selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b [1248] (c) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents independently selected from the group consisting of
--F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3
alkoxy, and --NR.sub.1-aR.sub.1-b [1249] (d) halogen, [1250] (e)
C.sub.1-C.sub.6 alkoxy, [1251] (f) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [1252] (g)
--NR.sub.N-2R.sub.N-3, [1253] (h) --OH, [1254] (i) --C.ident.N,
[1255] (j) (CH.sub.2).sub.0-4--(C.sub.3-C.sub.8 cycloalkyl),
optionally substituted with 1, 2, or 3 groups independently
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1256] (k)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.4 alkyl) [1257] (l)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.1-aR.sub.1-b, [1258] (m)
--(CH.sub.2).sub.0-4--CO--NR.sub.1-aR.sub.1-b, [1259] (n)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.6 alkyl), and [1260]
(O) .dbd.O, [1261] (p)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--SO.sub.2-- [1262] (q)
--(CH.sub.2).sub.0-4--N(R.sub.N-2)--C(O)-- [1263] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [1264] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [1265] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), [1266] (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), [1267] (12)
--(CH.sub.2).sub.0-4--O--R.sub.1-aryl, [1268] (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [1269] (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, [1270] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 wherein R.sub.N-4 is selected
from the group consisting of phenyl, morpholinyl, thiomorpholinyl,
piperazinyl, piperidinyl, homomorpholinyl, homothiomorpholinyl,
homothiomorpholinyl S-oxide, homothiomorpholinyl S,S-dioxide,
pyrrolinyl, thienyl, pyrazolyl, pyridyl N-oxide, oxazolyl,
thiazolyl, imidazolyl, and pyrrolidinyl where each group is
optionally substituted with one, two, three, or four groups that
are independently C.sub.1-C.sub.6 alkyl, [1271] (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 where R.sub.N-5 is selected
from the group consisting of: [1272] (a) C.sub.1-C.sub.6 alkyl,
[1273] (b) --(CH.sub.2).sub.0-2--(R.sub.1-aryl), [1274] (c)
C.sub.2-C.sub.6 alkenyl, [1275] (d) C.sub.2-C.sub.6 alkynyl, [1276]
(e) --(CH.sub.2).sub.0-2--C.sub.3-C.sub.8 cycloalkyl, [1277] (f)
--(CH.sub.2).sub.0-2--(R.sub.1-heteroaryl), and [1278] (g)
--(CH.sub.2).sub.0-2--(R.sub.1-heterocycle), [1279] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [1280] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [1281] (19)
--(CH.sub.2).sub.0-4--SO.sub.2(C.sub.1-C.sub.12 alkyl), [1282] (20)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl),
[1283] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, [1284] (22) --(CH.sub.2).sub.0-4--N(H
or R.sub.N-5)--CO--N(R.sub.N-5).sub.2, [1285] (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [1286] (24)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--CO--R.sub.N-2, [1287] (25)
--(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [1288] (26)
--(CH.sub.2).sub.0-4--R.sub.N-4, [1289] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [1290] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2 wherein [1291]
R.sub.100 at each occurrence is independently --H or
C.sub.1-C.sub.4 alkyl, [1292] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [1293] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [1294] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [1295] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [1296] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [1297] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), [1298]
(35) C.sub.3-C.sub.8 cycloalkyl, [1299] (36) C.sub.2-C.sub.6
alkenyl optionally substituted with C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [1300] (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [1301] (38)
--(CH.sub.2).sub.0-4--N(H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[1302] (39) --(CH.sub.2).sub.1-4--(C.sub.3-C.sub.8 cycloalkyl),
[1303] (B) --R.sub.N-heteroaryl where R.sub.N-heteroaryl is
selected from the group consisting of pyridinyl, indolyl,
indolinyl, isoindolyl, imidazolyl, isoxazolyl, oxazolyl, thiazolyl,
indolizinyl and isochromanyl, [1304] where the R.sub.N-heteroaryl
group is bonded by any atom of the parent R.sub.N-heteroaryl group
substituted by hydrogen such that the new bond to the
R.sub.N-heteroaryl group replaces the hydrogen atom and its bond,
where heteroaryl is optionally substituted with one, two, three, or
four of: [1305] (1) C.sub.1-C.sub.6 alkyl, optionally substituted
with one, two or three substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1306] (2) --OH, [1307] (3) --NO.sub.2,
[1308] (4) --F, --Cl, --Br, --I, [1309] (5) --CO.sub.2H, [1310] (6)
--C.ident.N, [1311] (7)
--(CH.sub.2).sub.0-4--CO--NR.sub.N-2R.sub.N-3, [1312] (8)
--(CH.sub.2).sub.0-4--CO--(C.sub.1-C.sub.12 alkyl), [1313] (9)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkenyl), [1314] (10)
--(CH.sub.2).sub.0-4--CO--(C.sub.2-C.sub.12 alkynyl), [1315] (11)
--(CH.sub.2).sub.0-4--CO--(C.sub.3-C.sub.8 cycloalkyl), [1316] (12)
--(CH.sub.2).sub.0-4--CO--R.sub.1-aryl, [1317] (13)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heteroaryl, [1318] (14)
--(CH.sub.2).sub.0-4--CO--R.sub.1-heterocycle, [1319] (15)
--(CH.sub.2).sub.0-4--CO--R.sub.N-4 [1320] (16)
--(CH.sub.2).sub.0-4--CO--O--R.sub.N-5 [1321] (17)
--(CH.sub.2).sub.0-4--SO.sub.2--NR.sub.N-2R.sub.N-3, [1322] (18)
--(CH.sub.2).sub.0-4--SO--(C.sub.1-C.sub.8 alkyl), [1323] (19)
--(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.1-C.sub.12 alkyl), [1324]
(20) --(CH.sub.2).sub.0-4--SO.sub.2--(C.sub.3-C.sub.8 cycloalkyl),
[1325] (21) --(CH.sub.2).sub.0-4--N(H or
R.sub.N-5)--CO--O--R.sub.N-5, [1326] (22) --(CH.sub.2).sub.0-4--N(H
or R.sub.N-5)--CO--N(R.sub.N-5).sub.2, [1327] (23)
--(CH.sub.2).sub.0-4--N--CS--N(R.sub.N-5).sub.2, [1328] (24)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--CO--R.sub.N-2, [1329]
(25) --(CH.sub.2).sub.0-4--NR.sub.N-2R.sub.N-3, [1330] (26)
--(CH
.sub.2).sub.0-4--R.sub.N-4, [1331] (27)
--(CH.sub.2).sub.0-4--O--CO--(C.sub.1-C.sub.6 alkyl), [1332] (28)
--(CH.sub.2).sub.0-4--O--P(O)--(OR.sub.100).sub.2, [1333] (29)
--(CH.sub.2).sub.0-4--O--CO--N(R.sub.N-5).sub.2, [1334] (30)
--(CH.sub.2).sub.0-4--O--CS--N(R.sub.N-5).sub.2, [1335] (31)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5), [1336] (32)
--(CH.sub.2).sub.0-4--O--(R.sub.N-5)--COOH, [1337] (33)
--(CH.sub.2).sub.0-4--S--(R.sub.N-5), [1338] (34)
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.6 alkyl optionally
substituted with one, two, three, four, or five of --F), [1339]
(35) C.sub.3-C.sub.8 cycloalkyl, [1340] (36) C.sub.2-C.sub.6
alkenyl optionally substituted with C.sub.1-C.sub.3 alkyl, --F,
--Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [1341] (37)
C.sub.2-C.sub.6 alkynyl optionally substituted with C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, or --NR.sub.1-aR.sub.1-b, [1342] (38)
--(CH.sub.2).sub.0-4--N(--H or R.sub.N-5)--SO.sub.2--R.sub.N-2,
[1343] (39) --(CH.sub.2).sub.1-4--C.sub.3-C.sub.8 cycloalkyl,
[1344] (C) R.sub.N-aryl--W--R.sub.N-aryl, [1345] (D)
R.sub.N-aryl--W--R.sub.N-heteroaryl, [1346] (E)
R.sub.N-aryl--W--R.sub.1-heterocycle, [1347] (F)
R.sub.N-heteroaryl--W--R.sub.N-aryl, [1348] (G)
R.sub.N-heteroaryl--W--R.sub.N-heteroaryl, [1349] (H)
R.sub.N-heteroaryl--W--R.sub.N-1-heterocycle, [1350] (I)
R.sub.N-heterocycle--W--R.sub.N-aryl, [1351] (J)
R.sub.N-heterocycle--W--R.sub.N-heteroaryl, [1352] (K)
R.sub.N-heterocycle--W--R.sub.N-1-heterocycle, [1353] where W is
[1354] (13) --(CH.sub.2).sub.1-4--, [1355] (14) --O--, [1356] (15)
--S(O).sub.0-2--, [1357] (16) --N(R.sub.N-5)--, [1358] (17) --CO--;
or [1359] (18) a bond;
[1360] (II) --CO--(C.sub.1-C.sub.6 alkyl)-M-(C.sub.1-C.sub.6
alkyl), where M is S, SO or SO.sub.2, and wherein each alkyl is
unsubstituted or substituted with one, two, or three of
substituents independently selected from the group consisting of:
[1361] (A) --NH--CO--(C.sub.1-C.sub.6 alkyl), [1362] (B)
--NH--CO--O--R.sub.N-8, [1363] (C) --NR.sub.N-2R.sub.N-3; where
R.sub.1 is
[1364] --(CH.sub.2).sub.n1-phenyl, where n.sub.1 is zero or one,
and which is optionally substituted with one, two, three or four of
the following substituents on the phenyl ring: [1365] (A)
C.sub.1-C.sub.6 alkyl optionally substituted with one, two or three
substituents selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1366] (B)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1367] (C)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1368] (D) --F,
Cl, --Br or --I, [1369] (F) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two or three of --F, [1370] (G)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined
below, [1371] (H) --OH, [1372] (I) --C.ident.N, [1373] (J)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1374] (K) --CO--(C.sub.1-C.sub.4 alkyl),
[1375] (L) --SO.sub.2--NR.sub.1-aR.sub.1-b, [1376] (M)
--CO--NR.sub.1-aR.sub.1-b, [1377] (N) --SO.sub.2--(C.sub.1-C.sub.4
alkyl); and where R.sub.2 is
[1378] (I) -(Z)-C.sub.1-C.sub.6 alkyl, where Z is a bond, --C(O),
--CO.sub.2-- or --SO.sub.2--, wherein the alkyl group is optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.7 alkyl
(optionally substituted with C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.3 alkoxy), --F, --Cl, --Br, --I, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy,
--NR.sub.1-aR.sub.1-b where R.sub.1-a and R.sub.1-b are
independently --H or C.sub.1-C.sub.6 alkyl, and
--OC.dbd.ONR.sub.1-aR.sub.1-b,
[1379] (II) -(Z)-CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6
alkyl),
[1380] (III)
-(Z)-CH.sub.2--CH.sub.2--S(O).sub.0-2--(C.sub.1-C.sub.6 alkyl),
[1381] (IV) -(Z)-C.sub.2-C.sub.6 alkenyl with one or two double
bonds, optionally substituted with one, two or three substituents
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b,
[1382] (V) -(Z)-C.sub.2-C.sub.6 alkynyl with one or two triple
bonds, optionally substituted with one, two or three substituents
selected from the group consisting of --F, --Cl, --OH, --SH,
--C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b,
[1383] (VI) -(Z)-(CH.sub.2).sub.n1--(R.sub.1-aryl), where Z is a
bond, CO, CO.sub.2 or SO.sub.2, where n.sub.1 is zero or one and
where R.sub.1-aryl is phenyl, 1-naphthyl, 2-naphthyl and indanyl,
indenyl, dihydronaphthalyl, or tetralinyl optionally substituted
with one, two, three or four of the following substituents on the
aryl ring: [1384] (A) C.sub.1-C.sub.6 alkyl optionally substituted
with one, two or three substituents selected from the group
consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1385] (B) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1386] (C) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1387] (D) --F, Cl, --Br or --I, [1388] (F)
--C.sub.1-C.sub.6 alkoxy optionally substituted with one, two or
three of --F, [1389] (G) --NR.sub.N-2R.sub.N-3 where R.sub.N-2 and
R.sub.N-3 are as defined below, [1390] (H) --OH, [1391] (I)
--C.ident.N, [1392] (J) C.sub.3-C.sub.7 cycloalkyl, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1393] (K)
--CO--(C.sub.1-C.sub.4 alkyl), [1394] (L)
--SO.sub.2--NR.sub.1-aR.sub.1-b, [1395] (M)
--CO--NR.sub.1-aR.sub.1-b, [1396] (N) --SO.sub.2--(C.sub.1-C.sub.4
alkyl),
[1397] (VII) -(Z)-(CH.sub.2).sub.n1--(R.sub.1-heteroaryl) where
n.sub.1 is as defined above and where R.sub.1-heteroaryl is
selected from the group consisting of:
[1398] pyridinyl, pyrimidinyl, quinolinyl, benzothienyl, indolyl,
indolinyl, pryidazinyl, pyrazinyl, isoindolyl, isoquinolyl,
quinazolinyl, quinoxalinyl, phthalazinyl, imidazolyl, isoxazolyl,
pyrazolyl, oxazolyl, thiazolyl, indolizinyl, indazolyl,
benzothiazolyl, benzimidazolyl, benzofuranyl, furanyl, 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, where the
R.sub.1-heteroaryl group is bonded to --(CH.sub.2).sub.n1-- by any
ring atom of the parent R.sub.N-heteroaryl group substituted by
hydrogen such that the new bond to the R.sub.1-heteroaryl group
replaces the hydrogen atom and its bond, where heteroaryl is
optionally substituted with one, two, three or four of: [1399] (1)
C.sub.1-C.sub.6 alkyl optionally substituted with one, two or three
substituents selected from the group consisting of C.sub.1-C.sub.3
alkyl, --F, --Cl, --Br, --I, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1400] (2)
C.sub.2-C.sub.6 alkenyl with one or two double bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1401] (3)
C.sub.2-C.sub.6 alkynyl with one or two triple bonds, optionally
substituted with one, two or three substituents selected from the
group consisting of --F, --Cl, --OH, --SH, --C.ident.N, --CF.sub.3,
C.sub.1-C.sub.3 alkoxy, and --NR.sub.1-aR.sub.1-b, [1402] (4) --F,
Cl, --Br or --I, [1403] (6) --C.sub.1-C.sub.6 alkoxy optionally
substituted with one, two, or three of --F, [1404] (7)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined
below, [1405] (8) --OH, [1406] (9) --C.ident.N, [1407] (10)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1408] (11) --CO--(C.sub.1-C.sub.4 alkyl)
[1409] (12) --SO.sub.2--NR.sub.1-aR.sub.1-b, [1410] (13)
--CO--NR.sub.1-aR.sub.1-b, or [1411] (14)
--SO.sub.2--(C.sub.1-C.sub.4 alkyl), with the proviso that when
n.sub.1 is zero R.sub.1-heteroaryl is not bonded to the carbon
chain by nitrogen, or
[1412] (VIII) -(Z)-(CH.sub.2).sub.n1--(R.sub.1-heterocycle) where
n.sub.1 is as defined above and R.sub.1-heterocycle is selected
from the group consisting of:
[1413] morpholinyl, thiomorpholinyl, thiomorpholinyl S-oxide,
thiomorpholinyl S,S-dioxide, piperazinyl, homopiperazinyl,
pyrrolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl,
tetrahydrofuranyl, tetrahydrothienyl, homopiperidinyl,
homomorpholinyl, homomorpholinyl S-oxide, homothiomorpholinyl
S,S-dioxide, oxazolidinonyl, dihydropyrazolyl, dihydropyrrolyl
dihydropyrazinyl dihydropyridinyl dihydropyrimidinyl, dihydrofuryl,
dihydropyranyl, tetrahydrothienyl S-oxide, tetrahydrothienyl
S,S-dioxide, homothiomorpholinyl S-oxide, where the
R.sub.1-heterocycle group is bonded by any atom of the parent
R.sub.1-heterocycle group substituted by hydrogen such that the new
bond to the R.sub.1-heterocycle group replaces the hydrogen atom
and its bond, where heterocycle is optionally substituted with one,
two, three or four: [1414] (1) C.sub.1-C.sub.6 alkyl optionally
substituted with one, two or three substituents selected from the
group consisting of C.sub.1-C.sub.3 alkyl, --F, --Cl, --Br, --I,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1415] (2) C.sub.2-C.sub.6 alkenyl with one
or two double bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1416] (3) C.sub.2-C.sub.6 alkynyl with one
or two triple bonds, optionally substituted with one, two or three
substituents selected from the group consisting of --F, --Cl, --OH,
--SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1417] (4) --F, Cl, --Br, or --I, [1418] (5)
C.sub.1-C.sub.6 alkoxy, [1419] (6) --C.sub.1-C.sub.6 alkoxy
optionally substituted with one, two, or three --F, [1420] (7)
--NR.sub.N-2R.sub.N-3 where R.sub.N-2 and R.sub.N-3 are as defined
below, [1421] (8) --OH, [1422] (9) --C.ident.N, [1423] (10)
C.sub.3-C.sub.7 cycloalkyl, optionally substituted with one, two or
three substituents selected from the group consisting of --F, --Cl,
--OH, --SH, --C.ident.N, --CF.sub.3, C.sub.1-C.sub.3 alkoxy, and
--NR.sub.1-aR.sub.1-b, [1424] (11) --CO--(C.sub.-C.sub.4 alkyl)
[1425] (12) --SO.sub.2--NR.sub.1-aR.sub.1-b, [1426] (13)
--CO--NR.sub.1-aR.sub.1-b, [1427] (14) --SO.sub.2--(C.sub.1-C.sub.4
alkyl), [1428] (15) .dbd.O, with the proviso that when n.sub.1 is
zero R.sub.1-heterocycle is not bonded to the carbon chain by
nitrogen; and where R.sub.20 is H or C.sub.1-6 alkyl or
alkenyl.
[1429] The compounds of the invention, and pharmaceutically
acceptable salts or esters thereof, are useful for treating humans
who have Alzheimer's disease, for helping prevent or delay the
onset of Alzheimer's disease, for treating patients with mild
cognitive impairment (MCI) and preventing or delaying the onset of
Alzheimer's disease in those who would progress from MCI to AD, for
treating Down's syndrome, for treating humans who have Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for
treating cerebral amyloid angiopathy and preventing its potential
consequences, i.e. single and recurrent lobar hemorrhages, for
treating other degenerative dementias, including dementias of mixed
vascular and degenerative origin, dementia associated with
Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, diffuse Lewy body type of Alzheimer's disease. It is
preferred that the disease is Alzheimer's disease.
[1430] The compounds of the invention are also useful to inhibit
beta-secretase and reduce or inhibit the formation of placque.
[1431] When treating these diseases, compounds of the invention can
either be used individually or together as is best for the
patient.
[1432] With regard to these diseases the term "treating" means that
compounds of the invention can be used in humans with existing
disease. The compounds of the invention will not necessarily cure
the patient who has the disease but will delay or slow the
progression of the disease thereby giving the individual a more
useful life span.
[1433] The term "preventing" means that if the compounds of the
invention are administered to those who do not now have the disease
but who would normally get the disease or be at increased risk for
the disease, they will not get the disease. In addition,
"preventing" also includes delaying the development of the disease
in an individual who will ultimately get the disease or would be at
risk for the disease. By delaying the onset of the disease,
compounds of the invention have prevented the individual from
getting the disease during the period in which the individual would
normally have gotten the disease or reduce the rate of development
of the disease or some of its effects but for the administration of
compounds of the invention up to the time the individual ultimately
gets the disease.
[1434] In treating or preventing the above diseases the compounds
of the invention are administered in 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.
[1435] In treating a patient with any of the diagnosed above
conditions a physician should begin administration of one or more
of the compounds of the invention immediately and continue
indefinitely.
[1436] In treating patients who do not at the have Alzheimer's
disease, but who are believed to be at substantial risk for getting
Alzheimer's disease in the future, the physician should 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 are at high risk
because of having the genetic marker APOE4 which is predictive for
Alzheimer's disease. In these situations, even though the patient
does not have the disease, the administration of the compounds of
the invention should be started before disease symptoms appear and
treatment continued indefinitely to prevent or delay them from
possibly getting the disease.
[1437] The compounds of the invention can be administered orally,
parenterally (IV, IM, depo-IM, SQ and depo-SQ), sublingually,
intranasally (inhalation), intrathecally, topically and rectally.
The invention here is the compounds of the invention. There is
nothing new about the routes of administration nor the dosage
forms. Dosage forms known to those skilled in the art are suitable
for delivery of the compounds of the invention.
[1438] When administered orally, the compounds of the 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 the solid dosage forms are used, it is preferred that they be
of the sustained release type so that the compounds of the
invention need to be administered only once or twice daily.
[1439] The oral dosage forms are administered to the patient one
thru four times daily. It is preferred that the compounds of the
invention be administered either three or fewer time, more
preferably once or twice daily. Hence, it is preferred that the
compounds of the invention 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 whatever dosage form is used, that it be designed so
as to protect the compounds of the invention 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 protect from the acidic stomach, are
also well known to those skilled in the art. When administered
orally the therapeutically effective amount is from about 0.1
mg/day to about 1,000 mg/day. It is preferred that the oral dosage
is from about 1 mg/day to about 100 mg/day. It is more preferred
that the oral dosage is from about 5 mg/day to about 50 mg/day. 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.
[1440] The compounds of the invention can be administered
parenterally, for example, by IV, IM, depo-IM, SC, or depo-SC. When
administered parenterally, a therapeutically effective amount of
about 0.5 to about 100 mg/day, preferably from about 5 to about 50
mg daily should be delivered. When a depot formulation is used for
injection once a month or once every two weeks, the dose should be
about 0.5 mg/day to about 50 mg/day, or a monthly dose of from
about 15 mg to about 1,500 mg. In part because of the forgetfulness
of the patients with Alzheimer's disease, it is preferred that the
parenteral dosage form be a depo formulation.
[1441] The compounds of the invention can be given sublingually.
When given sublingually, the compounds of the invention should be
given one thru four times daily in the same amount as for IM
administration.
[1442] The compounds of the invention 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 compounds of the invention for
intranasal administration is the same as for IM administration.
[1443] The compounds of the invention 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. The dosage of the compounds of the invention for
intrathecal administration is the same as for IM
administration.
[1444] The compounds of the invention can be administered
topically. When given by this route, the appropriate dosage form is
a cream, ointment., or patch. Because of the amount of the
compounds of the invention to be administered, the patch is
preferred. When administered topically, the dosage is from about
0.5 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 the
compounds of the invention be delivered as is known to those
skilled in the art. The compounds of the invention 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 0.5 mg to about 500 mg.
[1445] The compounds of the invention can be administered by
implants as is known to those skilled in the art. When
administering a compound of the invention by implant, the
therapeutically effective amount is the same as for depot
administration.
[1446] The compounds of the invention are used in the same manner
by the same routes of administration using the same pharmaceutical
dosage forms and at the same dosing schedule for treating patients
with MCI (mild cognitive impairment) and preventing or delaying the
onset of Alzheimer's disease in those who would progress from MCI
to AD, for treating Down's syndrome, for treating humans who have
Hereditary Cerebral Hemorrhage with Amyloidosis of the Dutch-Type,
for treating cerebral amyloid angiopathy and preventing its
potential consequences, i.e. single and recurrent lobar
hemorrhages, for treating other degenerative dementias, including
dementias of mixed vascular and degenerative origin, dementia
associated with Parkinson's disease, dementia associated with
progressive supranuclear palsy, dementia associated with cortical
basal degeneration, diffuse Lewy body type of Alzheimer's
disease.
[1447] The compounds of the invention can be used with each other
or with other agents used to treat or prevent the conditions listed
above. Such agents include gamma-secretase inhibitors, anti-amyloid
vaccines and pharmaceutical agents such as donepezil hydrochloride
(ARICEPT Tablets), tacrine hydrochloride (COGNEX Capsules) or other
acetylcholine esterase inhibitors and with direct or
indirectneurotropic agents of the future.
[1448] In addition, the compounds of the invention can also be used
with inhibitors of P-glycoproten (P-gp). The use of P-gp inhibitors
is 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
WO99/64001 and WO01/10387. The important thing is that the blood
level of the P-gp inhibitor be such that it exerts its effect in
inhibiting P-gp from decreasing brain blood levels of the compounds
of the invention. To that end the P-gp inhibitor and the compounds
of the invention can be administered at the same time, by the same
or different route of administration, or at different times. The
important thing is not the time of administration but having an
effective blood level of the P-gp inhibitor.
[1449] Suitable P-gp inhibitors include cyclosporin A, verapamil,
tamoxifen, quinidine, Vitamin E-TGPS, ritonavir, megestrol acetate,
progesterone, rapamycin, 10,1 1-methanodibenzosuberane,
phenothiazines, acridine derivatives such as GF120918, FK506,
VX-710, LY335979, PSC-833, GF-102,918 and other steroids. It is to
be understood that additional agents will be found that do the same
function and are also considered to be useful.
[1450] The P-gp inhibitors can be administered orally,
parenterally, (IV, IM, IM-depo, SQ, SQ-depo), topically,
sublingually, rectally, intranasally, intrathecally and by
implant.
[1451] The therapeutically effective amount of the P-gp inhibitors
is from about 0.1 to about 300 mg/kg/day, preferably about 0.1 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.
[1452] 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 and capsules as well as
liquid dosage forms such as solutions, suspensions and 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 thru 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 what ever dosage form is used, that it
be designed so as 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. In addition, capsules filled with
small spheres each coated to protect From the acidic stomach, are
also well known to those skilled in the art.
[1453] In addition, the P-gp inhibitors can be administered
parenterally. When administered parenterally they can be
administered IV, IM, depo-IM, SQ or depo-SQ. The P-gp inhibitors
can be given sublingually. When given sublingually, the P-gp
inhibitors should be given one thru four times daily in the same
amount as for IM administration.
[1454] 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.
[1455] 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.
[1456] The P-gp inhibitors can be given topically. When given by
this route ofadministration, 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.
[1457] The P-gp inhibitors can be administered rectally by
suppository as is known to those skilled in the art.
[1458] The P-gp inhibitors can be administered by implants' as is
known to those skilled in the art.
[1459] Route of administration and the dosage forms for
administering the P-gp inhibitors are known in the art. Given a
particular P-gp inhibitor, and a desired dosage form, one skilled
in the art would know how to prepare the appropriate dosage form
for the P-gp inhibitor.
[1460] 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 invention administered, the particular
condition being treated, the severity of the condition being
treated, the age, weight, general physical condition of the
particular patient, other medication the individual may be taking
as is well known to those skilled in the art.
[1461] The compounds of the invention are al-so useful to inhibit
beta-secretase and reduce or inhibit the formation of plaque.
Inhibition of APP Cleavage
[1462] The compounds of the 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 not wishing to be bound by a
particular theory, inhibition of beta-secretase activity is thought
to inhibit production of beta amyloid peptide (A-beta or Abeta).
Inhibitory activity is demonstrated in one of a variety of
inhibition assays, whereby cleavage of an APP substrate in the
presence of A-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 compound inhibitors of the invention are known. Representative
assay systems are described, for example, in U.S. Pat. Nos.
5,942,400, 5,744,346, as well as in the examples below.
[1463] The enzymatic activity of beta-secretase and the production
of Abeta can be analyzed in vitro or in vivo, using natural,
mutated, and/or synthetic APP substrates, natural, mutated, and/or
synthetic enzyme, and the test compound. The analysis may involve
primary or secondary cells expressing native, mutant, and/or
synthetic APP and enzyme, or may utilize transgenic animal models
expressing the substrate and enzyme. Detection of enzymatic
activity can be by analysis of one or more of the cleavage
products, for example, by immunoassay, flurometric or chromogenic
assay, HPLC, or other means of detection. Inhibitory compounds are
determined as those having the ability 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.
Beta-Secretase
[1464] Various forms of beta-secretase enzyme are known, and are
available and useful for assay of enzyme 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), Asp2, and memapsin 2, and has been
characterized, for example, in U.S. Pat. No. 5,744,346 and
published PCT patent applications WO98/22597, WO00/03819,
WO01/23533, and WO00/17369, as well as in literature publications
(Mol. Cell Neurosci. 14:419-427 (1999); Science 286:735-741 (1999);
Nature 402:533-537 (1999); Nature 40:537-540 (1999); and PNAS USA
97:1456-1460 (2000)). Synthetic forms of the enzyme have also been
described (WO98/22597 and WO00/17369). Beta-secretase can be
extracted and purified from human brain tissue and can be produced
in cells, for example mammalian cells expressing recombinant
enzyme.
[1465] Prefered compounds of the invention are effective to inhibit
50% of beta-secretase enzymatic activity at a concentration of less
than 50 micromolar, preferably at a concentration of 10 micromolar
or less, more preferably 1 micromolar or less, and most preferably
10 nanomolar or less.
APP Substrate
[1466] 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 in Nature 325:733-6 (1987), the 770 amino acid isotype
described Nature 331:530-532 (1981), and variants such as the
Swedish Mutation (KM670-1NL) (APP-SW), the London Mutation
(V7176F), and others. See, for example U.S. Pat. No. 5,766,846 and
also Nature Genet. 1:233-234 (1992), 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. Nos. 5,942,400 and
WO00/03819.
[1467] 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 forenzymatic assay, for example, having isolation and/or
detection properties. A useful moiety may be an antigenic epitope
for antibody binding, a label or other detection moiety, a binding
substrate, and the like.
Antibodies
[1468] Products characteristic of APP cleavage can be measured by
immunoassay using various antibodies, as described, for example, in
Neuro. Lett. 249:21-4 (1999) and in U.S. Pat. No. 5,612,486. Useful
antibodies to detect Abeta include, for example, the monoclonal
antibody 6E10 (Senetek, St. Louis, Mo.) that specifically
recognizes an epitope on amino acids 1-16 of the Abeta 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 beta-amyloid peptide, 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
[1469] 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
[1470] Exemplary assays that can be used to demonstrate the
inhibitory activity of the compounds of the invention are
described, for example, in WO00/17369, 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.
[1471] An APP substrate containing the beat-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 may
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.
[1472] Suitable incubation conditions for a cell-free in vitro
assay include, for example: approximately 200 nanomolar to 10
micromolar substrate, approximately 10 to 200 picomolar enzyme, and
approximately 0.1 nanomolar to 10 micromolar inhibitor compound, in
aqueous solution, at an approximate pH of 4-7, at approximately
37.degree. C., for a time period of approximately 10 minutes to 3
hours. 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.
[1473] 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
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
[1474] 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
invention can be used to demonstrate beta-secretase inhibitory
activity of the compound. Preferably, assay in the presence of a
useful inhibitory compound provides at least about 30%, most
preferably at least about 50% inhibition of the enzymatic activity,
as compared with a non-inhibited control.
[1475] In one 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 may 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.
[1476] Human cell lines that normally process Abeta from APP
provide a useful means to assay inhibitory activities of the
compounds of the 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.
[1477] 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 one or more cleavage products of the APP substrate.
For example, inhibition of beta-secretase activity against the
substrate APP would be expected to decrease release of specific
beta-secretase induced APP cleavage products such as Abeta.
[1478] 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 Abeta, 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.
[1479] 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, the amount of Abeta 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.
[1480] 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
[1481] Various animal models can be used to analyze beta-secretase
activity and/or processing of APP to release Abeta, 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 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 Nature 373:523 (1995)). Preferred are animals
that exhibit characteristics associated with the pathophysiology of
AD. Administration of the compound inhibitors of the invention to
the transgenic mice described herein provides an alternative method
for demonstrating the inhibitory activity of the compounds.
Administration of the compounds in a pharmaceutically effective
carrier and via an administrative route that reaches the target
tissue in an appropriate therapeutic amount is also preferred.
[1482] Inhibition of beta-secretase mediated cleavage of APP at the
beta-secretase cleavage site and of Abeta release can be analyzed
in these animals by measure of cleavage fragments in the animal's
body fluids such as cerebral fluid or tissues. Analysis of brain
tissues for Abeta deposits or plaques is preferred.
[1483] On contacting an APP substrate with A-beta-secretase enzyme
in the presence of an inhibitory compound of the invention and
under conditions sufficient to permit enzymatic mediated cleavage
of APP and/or release of Abeta from the substrate, the compounds of
the invention are effective to reduce beta-secretase-mediated
cleavage of APP at the beta-secretase cleavage site and/or
effective to reduce released amounts of Abeta. Where such
contacting is the administration of the inhibitory compounds of the
invention to an animal model, for example, as described above, the
compounds are effective to reduce Abeta deposition in brain tissues
of the animal, and to reduce the number and/or size of beta amyloid
plaques. Where such administration is to a human subject, the
compounds are effective to inhibit or slow the progression of
disease characterized by enhanced amounts of Abeta to slow the
progression of AD in the, and/or to prevent onset or development of
AD in a patient at risk for the disease.
[1484] 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.
DEFINITIONS AND CONVENTIONS
[1485] The definitions and explanations below are for the terms as
used throughout this entire document including both the
specification and the claims.
DEFINITIONS
[1486] Pharmaceutically acceptable refers to those properties
and/or substances which 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.
[1487] AD refers to Alzheimer's disease.
[1488] 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.
[1489] A-beta (or Abeta), amyloid beta peptide, is defined as any
peptide resulting from beta-secretase mediated cleavage of APP,
including 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.
[1490] Beta-secretase (beta-secretase, BACE1, Asp2, Memapsin 2) is
an aspartyl protease that mediates cleavage of APP at the
amino-terminal edge of Abeta. Human beta-secretase is described,
for example, in WO00/17369.
[1491] DMSO refers to dimethyl sulfoxide.
[1492] All temperatures are in degrees Centigrade.
[1493] HPLC refers to high pressure liquid chromatography.
[1494] BOC refers to 1,1-dimethylethoxy carbonyl or
t-butoxycarbonyl, --CO--O--C(CH.sub.3).sub.3.
[1495] Protecting group generally refers to any suitable protecting
groups, compatible with the synthetic routes for preparing the
compounds herein. Generally, suitable protecting groups are those
found in Protective Groups in Organic Synthesis, Greene, et. al.,
2.sup.nd ed., John Wiley & Sons, 1991; and 3.sup.rd ed., John
Wiley & Sones, 1999 More specific protecting groups are
.alpha.-methyl benzyl, t-butoxycarbonyl, benzyloxycarbonyl, formyl,
trityl, phthalimido, trichloroacetyl, 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-yloxycarbonyl, cyclopentanyloxycarbonyl,
1-methylcycoopentanyloxycarbonyl, cyclohexanyloxycarbonyl,
1-methylcyclohexanyloxycabonyl, 2-methylcyclohexanyloxycarbonyl,
2-(4-toluylsulfonyl)ethoxycarbonyl,
2-(methylsulfonyl)ethoxycarbonyl,
2-(triphenylphosphino)ethoxycarbonyl, fluorenylmethoxycarbonyl,
2-(trimethylsilyl)ethoxycarbonyl, allyloxycarbonyl,
1-(trimethylsilylmethyl)prop-l-enyloxycarbonyl,
5-benzisoxalylmethoxycarbonyl, 4-acetoxybenzyloxycarbonyl,
2,2,2-trichloroethoxycarbonyl, 2-ethynyl-2-propoxycarbonyl,
cyclopropylmethoxycarbonyl, 4-(decyloxyl)benzyloxycarbonyl,
isobrornyloxycarbonyl and 1-piperidyloxycarbonyl,
9-fluoroenylmethyl carbonate, --CH--CH.dbd.CH.sub.2 and
phenyl-C(.dbd.N--)--H.
[1496] Saline refers to an aqueous saturated sodium chloride
solution.
[1497] Chromatography (column and flash chromatography) refers to
purification/separation of compounds expressed as (support,
eluent). It is understood that the appropriate fractions are pooled
and concentrated to give the desired compound(s).
[1498] 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.
[1499] A therapeutically effective amount is defined as an amount
effective 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.
[1500] 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.
[1501] 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.
[1502] All patents and publications referred to herein are hereby
incorporated by reference for all purposes.
Conventions for Formulas and Definitions of Variables
[1503] The chemical formulas representing various compounds or
molecular fragments in the specification and claims may contain
variable substituents in addition to expressly defined structural
features. These variable substituents are identified by a letter or
a letter followed by a numerical subscript, for example, "Z.sub.1"
or "R.sub.1" where "i" is an integer. These variable substituents
are either monovalent or bivalent, that is, they represent a group
attached to the formula by one or two chemical bonds. For example,
a group Z.sub.1 would represent a bivalent variable if attached to
the formula CH.sub.3--C(=Z.sub.1)H. Groups R.sub.i and R.sub.j
would represent monovalent variable substituents if attached to the
formula CH.sub.3--CH.sub.2--C(R.sub.i) (R.sub.j)H.sub.2. When
chemical formulas are drawn in a linear fashion, such as those
above, variable substituents contained in parentheses are bonded to
the atom immediately to the left of the variable substituent
enclosed in parentheses. When two or more consecutive variable
substituents are enclosed in parentheses, each of the consecutive
variable substituents is bonded to the immediately preceding atom
to the left which is not enclosed in parentheses. Thus, in the
formula above, both R.sub.i and R.sub.j are bonded to the preceding
carbon atom. Also, for any molecule with an established system of
carbon atom numbering, such as steroids, these carbon atoms are
designated as C.sub.i, where "i" is the integer corresponding to
the carbon atom number. For example, C.sub.6 represents the 6
position or carbon atom number in the steroid nucleus as
traditionally designated by those skilled in the art of steroid
chemistry. Likewise the term "R.sub.6" represents a variable
substituent (either monovalent or bivalent) at the C.sub.6
position.
[1504] Chemical formulas or portions thereof drawn in a linear
fashion represent atoms in a linear chain. The symbol "--" in
general represents a bond between two atoms in the chain. Thus
CH.sub.3--O--CH.sub.2--CH(R.sub.i)--CH.sub.3 represents a
2-substituted-1-methoxypropane compound. In a similar fashion, the
symbol ".dbd." represents a double bond, e.g.,
CH.sub.2.dbd.C(R.sub.i)--O--CH.sub.3, and the symbol ".ident."
represents a triple bond, e.g.,
HC.ident.--C--CH(R.sub.i)--CH.sub.2--CH.sub.3. Carbonyl groups are
represented in either one of two ways: --CO-- or --C(.dbd.O)--,
with the former being preferred for simplicity.
[1505] Chemical formulas of cyclic (ring) compounds or molecular
fragments can be represented in a linear fashion. Thus, the
compound 4-chloro-2-methylpyridine can be represented in linear
fashion by N*.dbd.C(CH.sub.3)--CH.dbd.CCl--CH.dbd.C*H with the
convention that the atoms marked with an asterisk (*) are bonded to
each other resulting in the formation of a ring. Likewise, the
cyclic molecular fragment, 4-(ethyl)-1-piperazinyl can be
represented by
--N*--(CH.sub.2).sub.2--N(C.sub.2H.sub.5)--CH.sub.2--C*H.sub.2.
[1506] A rigid cyclic (ring) structure for any compounds herein
defines an orientation with respect to the plane of the ring for
substituents attached to each carbon atom of the rigid cyclic
compound. For saturated compounds which have two substituents
attached to a carbon atom which is part of a cyclic system,
--C(X.sub.1) (X.sub.2)-- the two substituents may be in either an
axial or equatorial position relative to the ring and may change
between axial/equatorial. However, the position of the two
substituents relative to the ring and each other remains fixed.
While either substituent at times may lie in the plane of the ring
(equatorial) rather than above or below the plane (axial) , one
substituent is always above the other. In chemical structural
formulas depicting such compounds, a substituent (X.sub.1) which is
"below" another substituent (X.sub.2) will be identified as being
in the alpha configuration and is identified by a broken, dashed or
dotted line attachment to the carbon atom, i.e., by the symbol " -
- - " or " . . . ". The corresponding substituent attached "above"
(X.sub.2) the other (X.sub.1) is identified as being in the beta
configuration and is indicated by an unbroken line attachment to
the carbon atom. When a variable substituent is bivalent, the
valences may be taken together or separately or both in the
definition of the variable. For example, a variable R.sub.i
attached to a carbon atom as --C(.dbd.R.sub.i)-- might be bivalent
and be defined as oxo or keto (thus forming a carbonyl group
(--CO--) or as two separately attached monovalent variable
substituents alpha-R.sub.i-j and beta-R.sub.i-k. When a bivalent
variable, R.sub.i, is defined to consist of two monovalent variable
substituents, the convention used to define the bivalent variable
is of the form "alpha-R.sub.i-:beta-R.sub.i-k" or some variant
thereof. In such a case both alpha-R.sub.i-j and beta-R.sub.i-k are
attached to the carbon atom to give --C(alpha-R.sub.i-j)
(beta-R.sub.i-k)--. For example, when the bivalent variable
R.sub.6, --C(.dbd.R.sub.6)-- is defined to consist of two
monovalent variable substituents, the two monovalent variable
substituents are alpha-R.sub.6-1:beta-R.sub.6-2, . . .
alpha-R.sub.6-9:beta-R.sub.6-10, etc, giving --C(alpha-R.sub.6-1)
(beta-R.sub.6.sub.2)--, . . . --C(alpha-R.sub.6-9)
(beta-R.sub.6-10)--, etc. Likewise, for the bivalent variable
R.sub.11, --C(.dbd.R.sub.11)--, two monovalent variable
substituents are alpha-R.sub.11-1:beta-R.sub.11-2. For a ring
substituent for which separate alpha and beta orientations do not
exist (e.g. due to the presence of a carbon double bond in the
ring), and for a substituent bonded to a carbon atom which is not
part of a ring the above convention is still used, but the alpha
and beta designations are omitted.
[1507] Just as a bivalent variable may be defined as two separate
monovalent variable substituents, two separate monovalent variable
substituents may be defined to be taken together to form a bivalent
variable. For example, in the formula
--C.sub.1(R.sub.i)H--C.sub.2(R.sub.j)H--(C.sub.1 and C.sub.2 define
arbitrarily a first and second carbon atom, respectively) R.sub.i
and R.sub.j may be defined to be taken together to form (1) a
second bond between C.sub.1 and C.sub.2 or (2) a bivalent group
such as oxa (--O--) and the formula thereby describes an epoxide.
When R.sub.i and R.sub.j are taken together to form a more complex
entity, such as the group --X--Y--, then the orientation of the
entity is such that C.sub.1 in the above formula is bonded to X and
C.sub.2 is bonded to Y. Thus, by convention the designation " . . .
R.sub.i and R.sub.j are taken together to form
--CH.sub.2--CH.sub.2--O--CO-- . . . " means a lactone in which the
carbonyl is bonded to C.sub.2. However, when designated " . . .
R.sub.j and R.sub.i are taken together to form
--CO--O--CH.sub.2--CH.sub.2-- the convention means a lactone in
which the carbonyl is bonded to C.sub.1.
[1508] The carbon atom content of variable substituents is
indicated in one of two ways. The first method uses a prefix to the
entire name of the variable such as "C.sub.1-C.sub.4", where both
"1" and "4" are integers representing the minimum and maximum
number of carbon atoms in the variable. The prefix is separated
from the variable by a space. For example,"C.sub.1-C.sub.4 alkyl"
represents alkyl of 1 through 4 carbon atoms, (including isomeric
forms thereof unless an express indication to the contrary is
given). Whenever this single prefix is given, the prefix indicates
the entire carbon atom content of the variable being defined. Thus
C.sub.2-C.sub.4 alkoxycarbonyl describes a group
CH.sub.3--(CH.sub.2).sub.n--O--CO-- where n is zero, one or two. By
the second method the carbon atom content of only each portion of
the definition is indicated separately by enclosing the
"C.sub.i-C.sub.j" designation in parentheses and placing it
immediately (no intervening space) before the portion of the
definition being defined. By this optional convention
(C.sub.1-C.sub.3)alkoxycarbonyl has the same meaning as
C.sub.2-C.sub.4 alkoxycarbonyl because the "C.sub.1-C.sub.3" refers
only to the carbon atom content of the alkoxy group. Similarly
while both C.sub.2-C.sub.6 alkoxyalkyl and
(C.sub.1-C.sub.C.sub.3)alkoxy(C.sub.1-C.sub.3)alkyl define
alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two
definitions differ since the former definition allows either the
alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while
the latter definition limits either of these groups to 3 carbon
atoms.
Modes of Preparation
[1509] Compounds of the invention can be prepared utilizing a
variety of known chemical transformations. In essence, the
preparation of the compounds of formula I may be achieved using
techniques and chemical processes analogous to those known in the
art; the choice of the specific route being dependent upon the
usual factors in pharmaceutical research institutions such as
availability and cost of starting materials, time and difficulties
in separation and purification of intermediates and final compounds
and such other factors well known and generally appreciated by
those of ordinary skill in the art. In fact, there will generally
be more than one process to prepare the compounds of the invention.
Those having skill in the art will recognize that the starting
materials may be varied and additional steps employed to produce
compounds encompassed by the present invention, as demonstrated by
the following examples.
[1510] The starting materials and various intermediates may be
obtained from commercial sources, prepared from commercially
available organic compounds, or prepared using well known synthetic
methods. In some cases, protection of reactive functionalities may
be necessary to achieve some of the transformations. In general,
the need for such protecting groups as well as the conditions
necessary to attach and remove such groups will be apparent to
those skilled in the art of organic synthesis.
[1511] Representative synthetic methodologies suitable for
preparing the compounds of the invention are disclosed in:
Tetrahedron Letters, 39, 4925-4928 (1998); Journal of Medicinal
Chemistry, 41, 3387-3401 (1998); Journal of Medicinal Chemistry,
39, 3203-3216 (1996); and/or Journal of the Chemical Society
Chemical Communications, 1052-1053 (1993).
[1512] Examples of syntheses for preparing compounds of the
invention are set forth below in Scheme 1, Scheme 2, Scheme 3 and
Scheme 4. Specific exemplary descriptions of the routes depicted in
Schemes 1-4 are found in the synthetic examples given for
Intermediates A-D, general compound couplings E-G and examples 1-5
below. ##STR57## As used herein, Pg means protecting group, which
is as defined herein; for exemplary synthesis of N-protected
a-amino aldehydes see: Chem. Rev. 1989, 89, 149. ##STR58##
##STR59##
[1513] The invention is illustrated further by the following
examples which are not to be construed as limiting the invention in
scope or spirit to the specific procedures described in them.
Intermediate Syntheses
A. 2-Methanesulfonylamino-thiazole-4-carboxylic acid
[1514] 2-Methanesulfonylamino-thiazole-4-carboxylic acid methyl
ester: To a well stirred solution of methyl
2-amino-thiazole-4-carboxylate hydrobromide (Justus Liebigs Ann.
Chem. 1951, 571, 44, Heterocycles 1997, 45, 1299) (13 g, 51 mmol)
and TEA (40 mL, 290 mmol) in DCM (130 mL) at rt was added
methanesulfonyl chloride (11 mL, 140 mmol) dropwise. After stirring
for 1 h, the reaction mixture was filtered and the filtrate
concentrated. The residue was re-suspended in ethyl acetate,
filtered and chromatographed on silica gel (ethyl acetate/ethanol,
97:3) to provide 2-methanesulfonylamino-thiazole-4-carboxylic acid
methyl ester (5.5 g). MS (ESI-) for
C.sub.6H.sub.8N.sub.2O.sub.4S.sub.2 m/z 234.9 (M-H).sup.-.
[1515] 2-Methanesulfonylamino-thiazole-4-carboxylic acid: A mixture
of 2-methanesulfonylamino-thiazole-4-carboxylic acid methyl ester
(5.5 g, 22 mmol) in 1M NaOH (50 mL) was stirred at rt 1 h. The
reaction mixture was extracted with ethyl acetate, concentrated and
chromatographed on silica gel (ethyl acetate/ethanol, 97:3) to
provide 2-methanesulfonylamino-thiazole-4-carboxylic acid (3.7 g)
as a solid. MS (ESI-) for C.sub.5H.sub.6N.sub.2O.sub.4S.sub.2 m/z
220.9 (M-H).sup.-.
B. tert-Butyl
2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate
[1516] N'-Ethylidene-hydrazinecarboxylic acid tert-butyl ester: A
solution of tert-butyl carbazate (50.0 g, 0.38 mole) and
acetaldehyde (17.5 g, 0.4 mole) in ethanol (250 mL) was refluxed
for 72 h. The solution was concentrated in vacuo and dissolved in
ethyl acetate. The solution was washed with water, dried (anhydrous
sodium sulfate) and concentrated to afford
N'-ethylidene-hydrazinecarboxylic acid tert-butyl ester (56 g) as a
light yellow oil that solidified on standing. MS (ESI+) for
C.sub.7H.sub.14N.sub.2O.sub.2 m/z 159.0 (M+H).sup.+.
[1517] N'-Ethylhydrazinecarboxylic acid tert-butyl ester: A slurry
of N'-ethylidene-hydrazinecarboxylic acid tert-butyl ester (5.0 g,
32 mmol), acetic acid (48 .mu.L) and PtO.sub.2 (250 mg) in ethanol
(50 mL) was shaken under a 40 psi pressure of H.sub.2 in a Parr
hydrogenator for 24 h. The mixture was filtered through Celite to
provide N'-ethylhydrazinecarboxylic acid tert-butyl ester (5 g) as
a clear oil. MS (ESI+) for C.sub.7H.sub.16N.sub.2O.sub.2 m/z 161.0
(M+H).sup.+.
[1518] tert-Butyl
2-((2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethy-
lhydrazinecarboxylate (J. Med. Chem. 1998, 41, 3387-3401): To a
well stirred solution of
[(1S)-1-(2S)-oxiranyl-2-phenylethyl]-carbamic acid phenylmethyl
ester (6.07 g, 20.4 mmol) in isopropanol (100 mL) was added
N'-ethylhydrazinecarboxylic acid tert-butyl ester (3.93 g, 24.5
mmol) and the reaction refluxed for 67 h. The reaction was
concentrated and chromatographed on silica gel (elution with a
gradiant from hexane to dichloromethane to 1% methanol saturated
with ammonia in dichloromethane) to give tert-butyl
2-((2R,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethy-
lhydrazinecarboxylate (7.9 g) as a white solid. MS (ESI+) for
C.sub.25H.sub.35N.sub.3O m/z 458.3 (M+H).sup.+.
[1519] tert-Butyl
2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate:
A solution of tert-butyl
2-((2R,3S)-3-([(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethy-
lhydrazinecarboxylate (3.11 g, 6.8 mmol) in methanol (50 mL) was
added to 10% Pd/C (0.32 g) and stirred in a hydrogen atmosphere (@
ambient pressure) for 5 h. The reaction was filtered through Celite
and the filtrate concentrated under reduced pressure to yield
tert-butyl
2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate
(2.2 g) as an oil. MS (ESI+) for C.sub.17H.sub.29N.sub.3O.sub.3 m/z
324.3 (M+H).sup.+.
C. tert-Butyl
2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate
[1520] tert-Butyl
2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethy-
lhydrazinecarboxylate: To a well stirred solution of
[(1S)-1-(2R)-oxiranyl-2-phenylethyl]-carbamic acid phenylmethyl
ester (312 mg, 1.0 mmol) in isopropanol (3 mL) was added
N'-ethylhydrazinecarboxylic acid tert-butyl ester (202 mg, 1.3
mmol) and the reaction refluxed for 24 h. The reaction was
concentrated to give crude tert-butyl
2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino]-2-hydroxy-4-phenylbutyl)-2-ethy-
lhydrazinecarboxylate (537 mg). MS (ESI+) for
C.sub.25H.sub.35N.sub.3O.sub.5 m/z 458.1 (M+H).sup.+.
[1521] tert-Butyl
2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate:
A solution of crude tert-butyl
2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-phenylbutyl)-2-ethy-
lhydrazinecarboxylate (502 mg, 1.1 mmol) in MeOH (10 mL) was added
to 10% Pd/C (5.2 mg) and stirred in a hydrogen atmosphere (@
ambient pressure) for 6 h. The reaction was filtered through Celite
and the filtrate concentrated under reduced pressure to yield crude
tert-butyl
2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate
(293 mg). MS (ESI+) for C.sub.17H.sub.29N.sub.3O.sub.3 m/z 324.2
(M+H).sup.+.
D. tert-Butyl
2-((2S,3S)-3-amino-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazin-
ecarboxylate
[1522] (Z)-2-Benzyloxycarbonylamino-3-phenyl-acrylate: A well
stirred solution of 3,5-difluorobenzaldehyde (1.92 g, 13.5 mmol)
and methyl benzyloxycarbonylamino-(dimethoxyphosphoryl)acetate
(5.37 g, 16.2 mmol) in dry THF (20 mL), under N.sub.2, was cooled
to 0.degree. C. and 1,1,3,3-tetramethylgaunidine (1.38 g, 16.2
mmol) added via syringe. The reaction was allowed to warm to rt and
stir for 6 h, quenched with saturated ammonium chloride and
extracted with ethyl acetate. After concentration, the residue was
chromatographed on silica gel (elution with 20% ethyl
acetate/heptane) to give methyl
(Z)-2-benzyloxycarbonylamino-3-phenyl-acrylate (3.55 g) as a white
solid. MS (ESI+) for C.sub.18H.sub.15F.sub.2NO.sub.4 m/z 348.2
(M+H).sup.+.
[1523] CBZ-L-3,5-Difluorophenylalanine Methyl Ester: A Parr
Hastelloy bomb was charged with
(Z)-2-benzyloxycarbonylamino-3-phenyl-acrylate (21 g, 48 mmol) in
degassed methanol (315 mL) and pressurized with H.sub.2 @ 80 psi.
After lh, (S)-EtDuPHOSRh(COD)BF.sub.4 (476 mg, 1.5 mol %) in
degassed methanol (15 mL) was added and the reaction stirred at rt
under 40 psi H.sub.2 for 16 h. The solution was filtered through
Celite, concentrated and chromatographed on silica gel (elution
with 20% ethyl acetate/heptane) to give 20 g of
CBZ-L-3,5-difluorophenylalanine methyl ester as a white solid. MS
(ESI+) for C.sub.18H.sub.17F.sub.2NO.sub.4 m/z 350.1
(M+H).sup.+.
[1524] [1S-(1-(3,5-Difluorobenzyl)-2-hydroxy-ethyl)]-carbamic acid
benzyl ester: To a well stirred solution of
L-3,5-difluorophenylalanine methyl ester (795 mg, 2.3 mmol) and
lithium chloride (97 mg, 2.3 mmol) in THF/ethanol (10 mL, 1:1),
under N.sub.2, was added solid sodium borohydride (86 mg, 2.3 mmol)
and the reaction stirred at rt overnight. The mixture was quenched
with saturated ammonium chloride, extracted with ethyl acetate and
the extracts combined, dried (anhydrous sodium sulfate) and
concentrated. The residue was chromatographed an silica gel
(elution with 20% ethyl acetate/heptane) to give
[1S-(1-(3,5-difluorobenzyl)-2-hydroxy-ethyl)]-carbamic acid benzyl
ester (660 mg) as a white solid. MS (ESI+) for
C.sub.17H.sub.17F.sub.2NO.sub.3 m/z 322.2 (M+H).sup.+.
[1525] [1S-(1-(3,5-difluorobenzyl)-2-oxo-ethyl)]-carbamic acid
benzyl ester: To a cold (-78.degree. C.) well-stirred solution of
oxalyl chloride (0.16 mL, 1.8 mmol) in methylene chloride (20 mL)
was added DMSO (0.13 mL, 1.8 mmol) followed by the slow addition of
[1S-(1-(3,5-difluoro-benzyl)-2-hydroxy-ethyl)]-carbamic acid benzyl
ester (1.5 mmol) as a solution in CH.sub.2Cl.sub.2 (10 mL). The
reaction mixture was stirred at -78.degree. C. for 10 minutes
followed by the addition of Et.sub.3N (0.63 mL, 4.5 mmol, 3.0
equiv). The mixture was stirred at -78.degree. C. until no starting
material was observed by TLC (2 h). The reaction mixture was then
washed with 10% citric acid (aq) and dried over MgSO.sub.4,
filtered and condensed. The white solid was purified by silica
chromatography (20% to 50% EtOAc/Heptane) to yield
[1S-(1-(3,5-difluorobenzyl)-2-oxo-ethyl)]-carbamic acid benzyl
ester (445 mg) as a white solid. MS (ESI+) for
C.sub.17H.sub.15F.sub.2NO.sub.3 m/z 320 (M+H).sup.+.
[1526] [1S-(1-(3,5-Difluorobenzyl)-2-propenyl)]-carbamic acid
benzyl ester: To a slurry of diethyl ether (5 mL) and Mg turnings
(0.17 g, 7.1 mmol) was added ClCH.sub.2Si(CH.sub.3).sub.3 (0.97 mL,
7.0 mmol) and the mixture was heated to reflux. After initiation
(0.5 h @ reflux), the reaction mixture was removed from heating and
stirred for an additional 1 h, then cooled to rt. To the cooled
solution was [1S-(1-(3,5-difluoro-benzyl)-2-oxo-ethyl)]-carbamic
acid benzyl ester (0.45 g, 1.4 mmol) as a solution in distilled THF
(10 mL). The reaction mixture was stirred at rt for 1 h, cooled to
0.degree. C. and BF.sub.3(OEt).sub.2 (0.97 mL, 7.0 mmol) added. The
reaction mixture was further stirred at rt for 16 h, quenched with.
10% NaOH (aq) (50 mL) and stirring continued for 1 h. The reaction
mixture was extracted with CH.sub.2Cl.sub.2, dried over MgSO.sub.4,
filtered and condensed to yield a clear oil. The oil was purified
by silica chromatography (20% to 50% EtOAc/heptane) to yield
[1S-(1-(3,5-difluorobenzyl)-2-propenyl)]-carbamic acid benzyl ester
(270 mg) as a white solid. MS (ESI+) for
C.sub.18H.sub.18F.sub.2NO.sub.2 m/z 318 (M+H).sup.+.
[1527] [(1S)-1-(2R) -oxiranyl-2-(3,5-difluorophenyl)ethyll-carbamic
acid phenylmethyl ester: To CH.sub.2Cl.sub.2 (20 mL) was added
[1S-(1-(3,5-difluoro-benzyl)-2-propenyl)]-carbamic acid benzyl
ester (270 mg, 0.85 mmol) followed by M-CPBA (77%, 458 mg, 1.0
mmol). The reaction mixture was stirred at rt for 24 h. The
reaction was diluted with CH.sub.2Cl.sub.2 and then washed with 10%
sodium thiosulfate (aq), dried over Na.sub.2SO.sub.4, filtered and
condensed. Preparative chromatography (5.times.50 cm Chiralcel OD,
30.degree. C., 70 ml/min. 25% IPA/75% heptane) provided
[(1S)-1-(2R) -oxiranyl-2-(3,5-difluorophenyl)ethyl]-carbamic acid
phenylmethyl ester. MS (ESI+) for C.sub.18H.sub.18F.sub.2NO.sub.3
m/z 334.2 (M+H).sup.+.
[1528] tert-Butyl
2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-(3,5-difluorophenyl-
)butyl)-2-ethylhydrazinecarboxylate: To a well stirred solution of
[(1S)-1-(2R)-oxiranyl-2-(3,5-difluorophenyl)ethyl]-carbamic acid
phenylmethyl ester (496 mg, 1.5 mmol) in isopropanol (4.25 mL) was
added N'-ethylhydrazinecarboxylic acid tert-butyl ester (575 mg,
3.6 mmol) and the reaction refluxed for 48 h. The reaction was
concentrated to provide crude tert-butyl
2-((2S,3S)-3-{[(benzyloxy)carbonyl]amino}-2-hydroxy-4-(3,5-difluorophenyl-
)butyl)-2-ethylhydrazine-carboxylate. MS (ESI+) for
C.sub.25H.sub.33F.sub.2N.sub.3O.sub.5 m/z 516.2 (M+Na).sup.+.
[1529] tert-Butyl
2-((2S,3S)-3-amino-2-hydroxy-4-(3,5-difluorophenyl)butyl)-2-ethylhydrazin-
ecarboxylate: A solution of crude tert-butyl
2-((2S,3S)-3-{[(benzyloxy)carbonyl]-amino}-2-hydroxy-4-(3,5-difluoropheny-
l)butyl)-2-ethylhydrazinecarboxylate (906 mg, 1.8 mmol) in MeOH (15
mL) was added to 10% Pd/C (95 mg) and stirred in a hydrogen
atmosphere (ambient pressure) for 4 h. The catalyst was filtered
off over Celite and the filtrate was concentrated under reduced
pressure to yield crude tert-butyl
2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazine-
carboxylate. MS (ESI+) for C.sub.17H.sub.27F.sub.2N.sub.3O.sub.3
m/z 360.2 (M+H).sup.+. ##STR60##
E. N-terminal acid coupling (R.sub.N)
[1530] Solutions of each acid (R.sub.N) were prepared (1.08 mmol)
in DMF (3 mL) (enough for 6 cartridges per acid). Solutions of
PyBOP (3.74 g, 7.2 mmol) and HOBT (0.96 g, 7.2 mmol) in DMF (24 mL)
were prepared. To each cartridge on a Bohdan block was added acid
solution (0.5 niL, 0.18 mmol) according to product layout (6
cartridges of each of the 8 acids). To each cartridge was added the
PyBOP/HOBT solution (0.5 mL, 0.078 g PYBOP, 0.15 mmol/0.02 g HOBT,
0.15 mmol) and DIEA (0.052 mL, 0.30 mmol). The Bohdan block was
agitated on a Bohdan shaker at 700-800 rpm for 1 h. A solution of
amine was prepared (2.30 g, 7.2 mmol) in 24 mL of CH.sub.2Cl.sub.2.
To each cartridge was added 0.5 mL of amine solution (0.48 g, 0.15
mmol). The Bohdan block was agitated on the Bohdan shaker at
700-800 rpm for 16 h. The reaction mixtures were drained into 48
well Robbin's blocks. Each cartridge was rinsed with 0.5 mL DMF
into another 48 well Robbin's block. The reaction mixtures were
concentrated in the Robbin's blocks under reduced pressure at
50.degree. C. for 6 h in a Jouan centrifugal evaporator. Products
were carried on crude to next reaction.
F. Deprotection (J. Org. Chem. 1998, 63, 3471)
[1531] Add Dowex 50Wx2-400 ion-exchange resin (.about.230 mg) to
each clean cartridge on a Bohdan block using an Argo Scoop. The
previous product was pipetted as a solution in 2 mL MeOH into each
cartridge. The Bohdan block was agitated on a Bohdan shaker at
50.degree. C. at 700-800 rpm for 4 h. Each cartridge was rinsed
with CH.sub.2Cl.sub.2 (2.times.2.5 mL) and MeOH (10.times.2.5 mL).
The products were eluted using 3.5M NH.sub.3 in MeOH (2.times.3 mL)
into 2 separate 48 well Robbin's blocks. Reaction mixtures were
concentrated in the Robbin's blocks under reduced pressure at
40.degree. C. for 4 h in a Jouan.
G. C-Terminal Acid Coupling (R.sub.2)
[1532] Solutions of each acid (R.sub.2) were prepared (1.80 mmol)
in DMF (2 mL) (enough for 8 cartridges per acid). A solution of
HATU (4.13 g, 10.8 mmol) in DMF (12 mL) was prepared. To each
cartridge on a Bohdan block was added acid solution (0.25 mL, 0.225
mmol) according to product layout (8 cartridges of each of the 6
acids). To each cartridge was added 0.25 mL of the HATU solution
(0.086 g, 0.225 mmol) and DIEA (0.163 mL, 0.94 mmol). The Bohdan
block was agitated on a Bohdan shaker at 700-800 rpm for 1 h.
Solution of the amines were prepared (0.15 mmol/mL) in DMF. To each
cartridge was added the amine solution (0.15 mmol,) according to
the product layout. The Bohdan block was agitated on the Bohdan
shaker at 700-800 rpm for 16 h. The reaction mixtures were drained
into 48 well Robbin's blocks. Each cartridge was rinsed with 0.5 mL
DMF into another 48 well Robbin's block. The reaction mixtures were
concentrated in the Robbin's blocks under reduced pressure at
50.degree. C. for 6 h in a Jouan. Products were dissolved in 2 mL
MeOH and each transferred to a Varian Mega BE-SCX (2 gm, 12 mL)
cartridge that had been presoaked with MeOH (5 mL). After products
were loaded onto SCX cartridges by gravity, each cartridge was
washed with MeOH (9.times.5 mL) using vacuum filtration. Final
products were eluted off by gravity using 3.5M NH.sub.3 in MeOH
(3.times.3 mL) into pre-tared vials.
EXAMPLES
Example 1
[1533]
N-[(1S,2R)-3-(2-benzoyl-1-ethylhydrazino)-1-benzyl-2-hydroxypropyl-
]-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide: Synthesized
as described above from tert-butyl
2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate,
benzoic acid and 2-methanesulfonylamino-thiazole-4-carboxylic acid.
MS (ESI+) for C.sub.24H.sub.29N.sub.5O.sub.5S.sub.2 m/z 532.7
(M+H).sup.+. ##STR61##
Example 2
[1534]
N-{(1S,2R)-1-benzyl-3-[1-ethyl-2-(4-methylpentanoyl)hydrazino]-2-h-
ydroxypropyl}-2-[(methylsulfonyl)amino]-1,3-thiazole-4-carboxamide:
Synthesized as described above from tert-butyl
2-((2R,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate,
4-methylpentanoic acid and
2-methanesulfonylamino-thiazole-4-carboxylic acid. MS (ESI+) for
C.sub.23H.sub.35N.sub.5O.sub.5S.sub.2 m/z 526.7 (M+H).sup.+.
##STR62##
Example 3
[1535]
N.sup.1-{(1S,2S)-1-benzyl-3-[1-ethyl-2-(4-methylpentanoyl)hydrazin-
o]-2-hydroxypropyl}-5-methyl-N.sup.3,N.sup.3-dipropylisophthalamide:
Synthesized as described above from tert-butyl
2-((2S,3S)-3-amino-2-hydroxy-4-phenylbutyl)-2-ethylhydrazinecarboxylate,
4-methylpentanoic acid and 5-methyl-N,N-dipropyl-isophthalamic acid
(WO 02/02512). MS (ESI+) for C.sub.33H.sub.50N.sub.4O.sub.4 m/z
567.3 (M+H).sup.+. ##STR63##
Example 4
[1536]
N.sup.1-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[1-ethyl-2-(4-methylpent-
anoyl)hydrazino]-2-hydroxypropyl}-5-methyl-N.sup.3,N.sup.3-dipropylisophth-
alamide: Synthesized as described above from tert-butyl
2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazine-
carboxylate, 3-methylpentanoic acid and
5-methyl-N,N-dipropyl-isophthalamic acid. MS (ESI+) for
C.sub.33H.sub.48F.sub.2N.sub.4O.sub.4 m/z 603.3 (M+H).sup.+.
##STR64##
Example 5
[1537]
N.sup.1-{(1S,2S)-1-(3,5-difluorobenzyl)-3-[1-ethyl-2-(4-methylbuta-
noyl)hydrazino]-2-hydroxypropyl}-5-methyl-N.sup.3,N.sup.3-dipropylisophtha-
lamide: Synthesized as described above from tert-butyl
2-((2S,3S)-3-amino-2-hydroxy-4-(3,5difluorophenyl)butyl)-2-ethylhydrazine-
carboxylate, 3-methylbutanoic acid and
5-methyl-N,N-dipropyl-isophthalamic acid. MS (ESI+) for
C.sub.32H.sub.46F.sub.2N.sub.4O.sub.4 m/z 589.3 (M+H).sup.+.
Example 6
[1538] The following compounds, as shown in Table 1 below, are
prepared essentially according to the procedures outlined in
Schemes 1-4 and according to examples 1-5: TABLE-US-00001 TABLE 1
##STR65## 1:A1 1, 1, 1, 1 ##STR66## 1:A2 1, 1, 1, 2 ##STR67## 1:A3
1, 1, 1, 3 ##STR68## 1:A4 1, 1, 1, 4 ##STR69## 1:A5 1, 1, 2, 1
##STR70## 1:A6 1, 1, 2, 2 ##STR71## 1:A7 1, 1, 2, 3 ##STR72## 1:A8
1, 1, 2, 4 ##STR73## 1:A9 1, 1, 3, 1 ##STR74## 1:A10 1, 1, 3, 2
##STR75## 1:A11 1, 1, 3, 3 ##STR76## 1:A12 1, 1, 3, 4 ##STR77##
1:B1 1, 1, 4, 1 ##STR78## 1:B2 1, 1, 4, 2 ##STR79## 1:B3 1, 1, 4, 3
##STR80## 1:B4 1, 1, 4, 4 ##STR81## 1:B5 1, 2, 1, 1 ##STR82## 1:B6
1, 2, 1, 2 ##STR83## 1:B7 1, 2, 1, 3 ##STR84## 1:B8 1, 2, 1, 4
##STR85## 1:B9 1, 2, 2, 1 ##STR86## 1:B10 1, 2, 3, 2 ##STR87##
1:B11 1, 2, 2, 3 ##STR88## 1:B12 1, 2, 3, 4 ##STR89## 1:C1 1, 2, 3,
1 ##STR90## 1:C2 1, 2, 3, 2 ##STR91## 1:C3 1, 2, 3, 3 ##STR92##
1:C4 1, 2, 3, 4 ##STR93## 1:C5 1, 2, 4, 1 ##STR94## 1:C6 1, 2, 4, 2
##STR95## 1:C7 1, 2, 4, 3 ##STR96## 1:C8 1, 2, 4, 4 ##STR97## 1:C9
1, 3, 1, 1 ##STR98## 1:C10 1, 3, 1, 2 ##STR99## 1:C11 1, 3, 1, 3
##STR100## 1:C12 1, 3, 1, 4 ##STR101## 1:D1 1, 3, 2, 1 ##STR102##
1:D2 1, 3, 2, 2 ##STR103## 1:D3 1, 3, 2, 3 ##STR104## 1:D4 1, 3, 2,
4 ##STR105## 1:D5 1, 3, 3, 1 ##STR106## 1:D6 1, 3, 3, 2 ##STR107##
1:D7 1, 3, 3, 3 ##STR108## 1:D6 1, 3, 3, 4 ##STR109## 1:D9 1, 3, 4,
1 ##STR110## 1:D10 1, 3, 4, 2 ##STR111## 1:D11 1, 3, 4, 3
##STR112## 1:D12 1, 3, 4, 4 ##STR113## 1:E1 1, 4, 1, 1 ##STR114##
1:E2 1, 4, 1, 2 ##STR115## 1:E3 1, 4, 1, 3 ##STR116## 1:E4 1, 4, 1,
4 ##STR117## 1:E5 1, 4, 2, 1 ##STR118## 1:E6 1, 4, 2, 2 ##STR119##
1:E7 1, 4, 2, 3 ##STR120## 1:E8 1, 4, 2, 4 ##STR121## 1:E9 1, 4, 3,
1 ##STR122## 1:E10 1, 4, 3, 2 ##STR123## 1:E11 1, 4, 3, 3
##STR124## 1:E12 1, 4, 3, 4 ##STR125## 1:F1 1, 4, 4, 1 ##STR126##
1:F2 1, 4, 4, 2 ##STR127## 1:F3 1, 4, 4, 3 ##STR128## 1:F4 1, 4, 4,
4 ##STR129## 1:F5 1, 5, 1, 1 ##STR130## 1:F6 1, 5, 1, 2 ##STR131##
1:F7 1, 5, 1, 3 ##STR132## 1:F8 1, 5, 1, 4 ##STR133## 1:F9 1, 5, 2,
1 ##STR134## 1:F10 1, 5, 2, 2 ##STR135## 1:F11 1, 5, 2, 3
##STR136## 1:F12 1, 5, 2, 4 ##STR137## 1:G1 1, 5, 3, 1 ##STR138##
1:G2 1, 5, 3, 2 ##STR139## 1:G3 1, 5, 3, 3 ##STR140## 1:G4 1, 5, 3,
4 ##STR141## 1:G5 1, 5, 4, 1 ##STR142## 1:G6 1, 5, 4, 2 ##STR143##
1:G7 1, 5, 4, 3 ##STR144## 1:G8 1, 5, 4, 4 ##STR145## 1:G9 1, 6, 1,
1 ##STR146##
1:G10 1, 6, 1, 2 ##STR147## 1:G11 1, 6, 1, 3 ##STR148## 1:G12 1, 6,
1, 4 ##STR149## 1:H1 1, 6, 2, 1 ##STR150## 1:H2 1, 6, 2, 2
##STR151## 1:H3 1, 6, 2, 3 ##STR152## 1:H4 1, 6, 2, 4 ##STR153##
1:H5 1, 6, 3, 1 ##STR154## 1:H6 1, 6, 3, 2 ##STR155## 1:H7 1, 6, 3,
3 ##STR156## 1:H8 1, 6, 3, 4 ##STR157## 1:H9 1, 6, 4, 1 ##STR158##
1:H10 1, 6, 4, 2 ##STR159## 1:H11 1, 6, 4, 3 ##STR160## 1:H12 1, 6,
4, 4 ##STR161## 2:A1 2, 1, 1, 1 ##STR162## 2:A2 2, 1, 1, 2
##STR163## 2:A3 2, 1, 1, 3 ##STR164## 2:A4 2, 1, 1, 4 ##STR165##
2:A5 2, 1, 2, 1 ##STR166## 2:A6 2, 1, 2, 2 ##STR167## 2:A7 2, 1, 2,
3 ##STR168## 2:A8 2, 1, 2, 4 ##STR169## 2:A9 2, 1, 3, 1 ##STR170##
2:A110 2, 1, 3, 2 ##STR171## 2:A11 2, 1, 3, 3 ##STR172## 2:A12 2,
1, 3, 4 ##STR173## 2:B1 2, 1, 4, 1 ##STR174## 2:B2 2, 1, 4, 2
##STR175## 2:B3 2, 1, 4, 3 ##STR176## 2:B4 2, 1, 4, 4 ##STR177##
2:B5 2, 2, 1, 1 ##STR178## 2:B6 2, 2, 1, 2 ##STR179## 2:B7 2, 2, 1,
3 ##STR180## 2:B8 2, 2, 1, 4 ##STR181## 2:B9 2, 2, 2, 1 ##STR182##
2:B10 2, 2, 2, 2 ##STR183## 2:B11 2, 2, 2, 3 ##STR184## 2:B12 2, 2,
2, 4 ##STR185## 2:C1 2, 2, 3, 1 ##STR186## 2:C2 2, 2, 3, 2
##STR187## 2:C3 2, 2, 3, 3 ##STR188## 2:C4 2, 2, 3, 4 ##STR189##
2:C5 2, 2, 4, 1 ##STR190## 2:C6 2, 2, 4, 2 ##STR191## 2:C7 2, 2, 4,
3 ##STR192## 2:C8 2, 2, 4, 4 ##STR193## 2:C9 2, 3, 1, 1 ##STR194##
2:C10 2, 3, 1, 2 ##STR195## 2:C11 2, 3, 1, 3 ##STR196## 2:C12 2, 3,
1, 4 ##STR197## 2:D1 2, 3, 2, 1 ##STR198## 2:D2 2, 3, 2, 2
##STR199## 2:D3 2, 3, 2, 3 ##STR200## 2:D4 2, 3, 2, 4 ##STR201##
2:D5 2, 3, 3, 1 ##STR202## 2:D6 2, 3, 3, 2 ##STR203## 2:D7 2, 3, 3,
3 ##STR204## 2:D8 2, 3, 3, 4 ##STR205## 2:D9 2, 3, 4, 1 ##STR206##
2:D10 2, 3, 4, 2 ##STR207## 2:D11 2, 3, 4, 3 ##STR208## 2:D12 2, 3,
4, 4 ##STR209## 2:E1 2, 4, 1, 1 ##STR210## 2:E2 2, 4, 1, 2
##STR211## 2:E3 2, 4, 1, 3 ##STR212## 2:E4 2, 4, 1, 4 ##STR213##
2:E5 2, 4, 2, 1 ##STR214## 2:E6 2, 4, 2, 2 ##STR215## 2:E7 2, 4, 2,
3 ##STR216## 2:E8 2, 4, 2, 4 ##STR217## 2:E9 2, 4, 3, 1 ##STR218##
2:E10 2, 4, 3, 2 ##STR219## 2:E11 2, 4, 3, 3 ##STR220## 2:E12 2, 4,
3, 4 ##STR221## 2:F1 2, 4, 4, 1 ##STR222## 2:F2 2, 4, 4, 2
##STR223## 2:F3 2, 4, 4, 3 ##STR224## 2:F4 2, 4, 4, 4 ##STR225##
2:F5 2, 5, 1, 1 ##STR226## 2:F6 2, 5, 1, 2 ##STR227## 2:F7 2, 5, 1,
3 ##STR228## 2:F8 2, 5, 1, 4 ##STR229## 2:F9 2, 5, 2, 1
##STR230## 2:F10 2, 5, 2, 2 ##STR231## 2:F11 2, 5, 2, 3 ##STR232##
2:F12 2, 5, 2, 4 ##STR233## 2:G1 2, 5, 3, 1 ##STR234## 2:G2 2, 5,
3, 2 ##STR235## 2:G3 2, 5, 3, 3 ##STR236## 2:G4 2, 5, 3, 4
##STR237## 2:G5 2, 5, 4, 1 ##STR238## 2:G6 2, 5, 4, 2 ##STR239##
2:G7 2, 5, 4, 3 ##STR240## 2:G8 2, 5, 4, 4 ##STR241## 2:G9 2, 6, 1,
1 ##STR242## 2:G10 2, 6, 1, 2 ##STR243## 2:G11 2, 6, 1, 3
##STR244## 2:G12 2, 6, 1, 4 ##STR245## 2:H1 2, 6, 2, 1 ##STR246##
2:H2 2, 6, 2, 2 ##STR247## 2:H12 2, 6, 4, 4 ##STR248## 3:A1 3, 1,
1, 1 ##STR249## 3:A2 3, 1, 1, 2 ##STR250## 3:A3 3, 1, 1, 3
##STR251## 3:A4 3, 1, 1, 4 ##STR252## 3:A5 3, 1, 2, 1 ##STR253##
3:A6 3, 1, 2, 2 ##STR254## 3:A7 3, 1, 2, 3 ##STR255## 3:A8 3, 1, 2,
4 ##STR256## 3:B8 3, 2, 1, 4 ##STR257## 3:B9 3, 2, 2, 1 ##STR258##
3:B10 3, 2, 2, 2 ##STR259## 3:B11 3, 2, 2, 3 ##STR260## 3:B12 3, 2,
2, 4 ##STR261## 3:C1 3, 2, 3, 1 ##STR262## 3:C2 3, 2, 3, 2
##STR263## 3:C3 3, 2, 3, 3 ##STR264## 3:C4 3, 2, 3, 4 ##STR265##
3:C5 3, 2, 4, 1 ##STR266## 3:C6 3, 2, 4, 2 ##STR267## 3:C7 3, 2, 4,
3 ##STR268## 3:C8 3, 2, 4, 4 ##STR269## 3:C9 3, 3, 1, 1 ##STR270##
3:C10 3, 3, 1, 2 ##STR271## 3:C11 3, 3, 1, 3 ##STR272## 3:C12 3, 3,
1, 4 ##STR273## 3:D1 3, 3, 2, 1 ##STR274## 3:D2 3, 3, 2, 2
##STR275## 3:D3 3, 3, 2, 3 ##STR276## 3:D4 3, 3, 2, 4 ##STR277##
3:D5 3, 3, 3, 1 ##STR278## 3:D6 3, 3, 3, 2 ##STR279## 3:D7 3, 3, 3,
3 ##STR280## 3:D8 3, 3, 3, 4 ##STR281## 3:D9 3, 3, 4, 1 ##STR282##
3:D10 3, 3, 4, 2 ##STR283## 3:D11 3, 3, 4, 3 ##STR284## 3:D12 3, 3,
4, 4 ##STR285## 3:E1 3, 4, 1, 1 ##STR286## 3:E2 3, 4, 1, 2
##STR287## 3:E3 3, 4, 1, 3 ##STR288## 3:E4 3, 4, 1, 4 ##STR289##
3:E5 3, 4, 2, 1 ##STR290## 3:E6 3, 4, 2, 2 ##STR291## 3:E7 3, 4, 2,
3 ##STR292## 3:E8 3, 4, 2, 1 ##STR293## 3:E9 3, 4, 3, 1 ##STR294##
3:E10 3, 4, 3, 2 ##STR295## 3:E11 3, 4, 3, 3 ##STR296## 3:E12 3, 4,
3, 4 ##STR297## 3:F1 3, 4, 4, 1 ##STR298## 3:F2 3, 4, 4, 2
##STR299## 3:F3 3, 4, 4, 3 ##STR300## 3:F4 3, 4, 4, 4 ##STR301##
3:F5 3, 5, 1, 1 ##STR302## 3:F6 3, 5, 1, 2 ##STR303## 3:F7 3, 5, 1,
3 ##STR304## 3:F8 3, 5, 1, 4 ##STR305## 3:F9 3, 5, 2, 1 ##STR306##
3:F10 3, 5, 2, 2 ##STR307## 3:F11 3, 5, 2, 3 ##STR308## 3:F12 3, 5,
2, 4 ##STR309## 3:G1 3, 5, 3, 1 ##STR310## 3:G2 3, 5, 3, 2
##STR311## 3:G3 3, 5, 3, 3 ##STR312## 3:G4 3, 5, 3, 4 ##STR313##
3:G5 3, 5, 4, 1
##STR314## 3:G6 3, 5, 4, 2 ##STR315## 3:G7 3, 5, 4, 3 ##STR316##
3:G8 3, 5, 4, 4 ##STR317## 3:G9 3, 6, 1, 1 ##STR318## 3:G10 3, 6,
1, 2 ##STR319## 3:G11 3, 6, 1, 3 ##STR320## 3:G12 3, 6, 1, 4
##STR321## 3:H1 3, 6, 2, 1 ##STR322## 3:H2 3, 6, 2, 2 ##STR323##
3:H3 3, 6, 2, 3 ##STR324## 3:H4 3, 6, 2, 4 ##STR325## 3:H5 3, 6, 3,
1 ##STR326## 3:H6 3, 6, 3, 2 ##STR327## 3:H7 3, 6, 3, 3 ##STR328##
3:H8 3, 6, 3, 4 ##STR329## 3:H9 3, 6, 4, 1 ##STR330## 3:H10 3, 6,
4, 2 ##STR331## 3:H11 3, 6, 4, 3 ##STR332## 3:H12 3, 6, 4, 4 Change
library "FDA581-2" With location, precursors ##STR333## 1:A1 1, 1,
1, 1 ##STR334## 1:A2 1, 1, 1, 2 ##STR335## 1:A3 1, 1, 1, 3
##STR336## 1:A4 1, 1, 1, 4 ##STR337## 1:A5 1, 1, 2, 1 ##STR338##
1:A6 1, 1, 2, 2 ##STR339## 1:A7 1, 1, 2, 3 ##STR340## 1:A8 1, 1, 2,
4 ##STR341## 1:A9 1, 1, 3, 1 ##STR342## 1:A10 1, 1, 3, 2 ##STR343##
1:A11 1, 1, 3, 3 ##STR344## 1:A12 1, 1, 3, 4 ##STR345## 1:B1 1, 1,
4, 1 ##STR346## 1:B2 1, 1, 4, 2 ##STR347## 1:B3 1, 1, 4, 3
##STR348## 1:B4 1, 1, 4, 4 ##STR349## 1:B5 1, 2, 1, 1 ##STR350##
1:B6 1, 2, 1, 2 ##STR351## 1:B7 1, 2, 1, 3 ##STR352## 1:B8 1, 2, 1,
4 ##STR353## 1:B9 1, 2, 2, 1 ##STR354## 1:B10 1, 2, 2, 2 ##STR355##
1:B11 1, 2, 2, 3 ##STR356## 1:B12 1, 2, 2, 4 ##STR357## 1:C1 1, 2,
3, 1 ##STR358## 1:C2 1, 2, 3, 2 ##STR359## 1:C3 1, 2, 3, 3
##STR360## 1:C4 1, 2, 3, 4 ##STR361## 1:C5 1, 2, 4, 1 ##STR362##
1:C6 1, 2, 4, 2 ##STR363## 1:C7 1, 2, 4, 3 ##STR364## 1:C8 1, 2, 4,
4 ##STR365## 1:C9 1, 3, 1, 1 ##STR366## 1:C10 1, 3, 1, 2 ##STR367##
1:C13 1, 3, 1, 3 ##STR368## 1:C12 1, 3, 1, 4 ##STR369## 1:D1 1, 3,
2, 1 ##STR370## 1:D2 1, 3, 2, 2 ##STR371## 1:D3 1, 3, 2, 3
##STR372## 1:D4 1, 3, 2, 4 ##STR373## 1:D5 1, 3, 3, 1 ##STR374##
1:D6 1, 3, 3, 2 ##STR375## 1:D7 1, 3, 3, 3 ##STR376## 1:D8 1, 3, 3,
4 ##STR377## 1:D9 1, 3, 4, 1 ##STR378## 1:D10 1, 3, 4, 2 ##STR379##
1:D11 1, 3, 4, 3 ##STR380## 1:D12 1, 3, 4, 4 ##STR381## 1:E1 1, 4,
1, 1 ##STR382## 1:E2 1, 4, 1, 2 ##STR383## 1:E3 1, 4, 1, 3
##STR384## 1:E4 1, 4, 1, 4 ##STR385## 1:E5 1, 4, 2, 1 ##STR386##
1:E6 1, 4, 2, 2 ##STR387## 1:E7 1, 4, 2, 3 ##STR388## 1:E8 1, 4, 2,
4 ##STR389## 1:E9 1, 4, 3, 1 ##STR390## 1:E10 1, 4, 3, 2 ##STR391##
1:E11 1, 4, 3, 3 ##STR392## 1:E12 1, 4, 3, 4 ##STR393## 1:F1 1, 4,
4, 1 ##STR394## 1:F2 1, 4, 4, 2 ##STR395## 1:F3 1, 4, 4, 3
##STR396## 1:F4 1, 4, 4, 4
##STR397## 1:F5 1, 5, 1, 1 ##STR398## 1:F6 1, 5, 1, 2 ##STR399##
1:F7 1, 5, 1, 3 ##STR400## 1:F8 1, 5, 1, 4 ##STR401## 1:F9 1, 5, 2,
1 ##STR402## 1:F10 1, 5, 2, 2 ##STR403## 1:F11 1, 5, 2, 3
##STR404## 1:F12 1, 5, 2, 4 ##STR405## 1:G1 1, 5, 3, 1 ##STR406##
1:G2 1, 5, 3, 2 ##STR407## 1:G3 1, 5, 3, 3 ##STR408## 1:G4 1, 5, 3,
4 ##STR409## 1:G5 1, 5, 4, 1 ##STR410## 1:G6 1, 5, 4, 2 ##STR411##
1:G7 1, 5, 4, 3 ##STR412## 1:G8 1, 5, 4, 4 ##STR413## 1:G9 1, 6, 1,
1 ##STR414## 1:G10 1, 6, 1, 2 ##STR415## 1:G11 1, 6, 1, 3
##STR416## 1:G12 1, 6, 1, 4 ##STR417## 1:H1 1, 6, 2, 1 ##STR418##
1:H2 1, 6, 2, 2 ##STR419## 1:H3 1, 6, 2, 3 ##STR420## 1:H4 1, 6, 2,
4 ##STR421## 1:H5 1, 6, 3, 1 ##STR422## 1:H6 1, 6, 3, 2 ##STR423##
1:H7 1, 6, 3, 3 ##STR424## 1:H8 1, 6, 3, 4 ##STR425## 1:H9 1, 6, 4,
1 ##STR426## 1:H10 1, 6, 4, 2 ##STR427## 1:H11 1, 6, 4, 3
##STR428## 1:H12 1, 6, 4, 4 ##STR429## 2:A1 2, 1, 1, 1 ##STR430##
2:A2 2, 1, 1, 2 ##STR431## 2:A3 2, 1, 1, 3 ##STR432## 2:A4 2, 1, 1,
4 ##STR433## 2:A5 2, 1, 2, 1 ##STR434## 2:A6 2, 1, 2, 2 ##STR435##
2:A7 2, 1, 2, 3 ##STR436## 2:A8 2, 1, 2, 4 ##STR437## 2:A9 2, 1, 3,
1 ##STR438## 2:A10 2, 1, 3, 2 ##STR439## 2:A11 2, 1, 3, 3
##STR440## 2:A12 2, 1, 3, 4 ##STR441## 2:B1 2, 1, 4, 1 ##STR442##
2:B2 2, 1, 4, 2 ##STR443## 2:B3 2, 1, 4, 3 ##STR444## 2:B4 2, 1, 4,
4 ##STR445## 2:B5 2, 2, 1, 1 ##STR446## 2:B6 2, 2, 1, 2 ##STR447##
2:B7 2, 2, 1, 3 ##STR448## 2:B8 2, 2, 1, 4 ##STR449## 2:B9 2, 2, 2,
1 ##STR450## 2:B10 2, 2, 2, 2 ##STR451## 2:B11 2, 2, 2, 3
##STR452## 2:B12 2, 2, 2, 4 ##STR453## 2:C1 2, 2, 3, 1 ##STR454##
2:C2 2, 2, 3, 2 ##STR455## 2:C3 2, 2, 3, 3 ##STR456## 2:C4 2, 2, 3,
4 ##STR457## 2:C5 2, 2, 4, 1 ##STR458## 2:C6 2, 2, 4, 2 ##STR459##
2:C7 2, 2, 4, 3 ##STR460## 2:C8 2, 2, 4, 4 ##STR461## 2:C9 2, 3, 1,
1 ##STR462## 2:C10 2, 3, 1, 2 ##STR463## 2:C11 2, 3, 1, 3
##STR464## 2:C12 2, 3, 1, 4 ##STR465## 2:D1 2, 3, 2, 1 ##STR466##
2:D2 2, 3, 2, 2 ##STR467## 2:D3 2, 3, 2, 3 ##STR468## 2:D4 2, 3, 2,
4 ##STR469## 2:D5 2, 3, 3, 1 ##STR470## 2:D6 2, 3, 3, 2 ##STR471##
2:D7 2, 3, 3, 3 ##STR472## 2:D8 2, 3, 3, 4 ##STR473## 2:D9 2, 3, 4,
1 ##STR474## 2:D10 2, 3, 4, 2 ##STR475## 2:D11 2, 3, 4, 3
##STR476## 2:D12 2, 3, 4, 4 ##STR477## 2:E1 2, 4, 1, 1 ##STR478##
2:E2 2, 4, 1, 2 ##STR479## 2:E3 2, 4, 1, 3 ##STR480##
2:E4 2, 4, 1, 4 ##STR481## 2:E5 2, 4, 2, 1 ##STR482## 2:E6 2, 4, 2,
2 ##STR483## 2:E7 2, 4, 2, 3 ##STR484## 2:E8 2, 4, 2, 4 ##STR485##
2:E9 2, 4, 3, 1 ##STR486## 2:E10 2, 4, 3, 2 ##STR487## 2:E11 2, 4,
3, 3 ##STR488## 2:E12 2, 4, 3, 4 ##STR489## 2:F1 2, 4, 4, 1
##STR490## 2:F2 2, 4, 4, 2 ##STR491## 2:F3 2, 4, 4, 3 ##STR492##
2:F4 2, 4, 4, 4 ##STR493## 2:F5 2, 5, 1, 1 ##STR494## 2:F6 2, 5, 1,
2 ##STR495## 2:F7 2, 5, 1, 3 ##STR496## 2:F8 2, 5, 1, 4 ##STR497##
2:F9 2, 5, 2, 1 ##STR498## 2:F10 2, 5, 2, 2 ##STR499## 2:F11 2, 5,
2, 3 ##STR500## 2:F12 2, 5, 2, 4 ##STR501## 2:G1 2, 5, 3, 1
##STR502## 2:G2 2, 5, 3, 2 ##STR503## 2:G3 2, 5, 3, 3 ##STR504##
2:G4 2, 5, 3, 4 ##STR505## 1:G5 2, 5, 4, 1 ##STR506## 2:G6 2, 5, 4,
2 ##STR507## 2:G7 2, 5, 4, 3 ##STR508## 2:G8 2, 5, 4, 4 ##STR509##
2:G9 2, 6, 1, 1 ##STR510## 2:G10 2, 6, 1, 2 ##STR511## 2:G11 2, 6,
1, 3 ##STR512## 2:G12 2, 6, 1, 4 ##STR513## 2:H1 2, 6, 2, 1
##STR514## 2:H2 2, 6, 2, 2 ##STR515## 2:H3 2, 6, 2, 3 ##STR516##
2:H4 2, 6, 2, 4 ##STR517## 2:H5 2, 6, 3, 1 ##STR518## 2:H6 2, 6, 3,
2 ##STR519## 2:H7 2, 6, 3, 3 ##STR520## 2:H8 2, 6, 3, 4 ##STR521##
2:H9 2, 6, 4, 1 ##STR522## 2:H10 2, 6, 4, 2 ##STR523## 2:H11 2, 6,
4, 3 ##STR524## 2:H12 2, 6, 4, 4 ##STR525## 3:A1 3, 1, 1, 1
##STR526## 3:A2 3, 1, 1, 2 ##STR527## 3:A3 3, 1, 1, 2 ##STR528##
3:A4 3, 1, 1, 4 ##STR529## 3:A5 3, 1, 2, 1 ##STR530## 3:A6 3, 1, 2,
2 ##STR531## 3:A7 3, 1, 2, 3 ##STR532## 3:A8 3, 1, 2, 4 ##STR533##
3:A9 3, 1, 3, 1 ##STR534## 3:A10 3, 1, 3, 2 ##STR535## 3:A11 3, 1,
3, 3 ##STR536## 3:A12 3, 1, 3, 4 ##STR537## 3:B1 3, 1, 4, 1
##STR538## 3:B2 3, 1, 4, 2 ##STR539## 3:B3 3, 1, 4, 3 ##STR540##
3:B4 3, 1, 4, 4 ##STR541## 3:B5 3, 2, 1, 1 ##STR542## 3:B6 3, 2, 1,
2 ##STR543## 3:B7 3, 2, 1, 3 ##STR544## 3:B8 3, 2, 1, 4 ##STR545##
3:B9 3, 2, 2, 1 ##STR546## 3:B10 3, 2, 2, 2 ##STR547## 3:B11 3, 2,
2, 3 ##STR548## 3:B12 3, 2, 2, 4 ##STR549## 3:C1 3, 2, 3, 1
##STR550## 3:C2 3, 2, 3, 2 ##STR551## 3:C3 3, 2, 3, 3 ##STR552##
3:C4 3, 2, 3, 4 ##STR553## 3:C5 3, 2, 4, 1 ##STR554## 3:C6 3, 2, 4,
2 ##STR555## 3:C7 3, 2, 4, 3 ##STR556## 3:C8 3, 2, 4, 4 ##STR557##
3:C9 3, 3, 1, 1 ##STR558## 3:C10 3, 3, 1, 2 ##STR559## 3:C11 3, 3,
1, 3 ##STR560## 3:C12 3, 3, 1, 4 ##STR561## 3:D1 3, 3, 2, 1
##STR562## 3:D2 3, 3, 2, 2 ##STR563## 3:D3 3, 3, 2, 3
##STR564## 3:D4 3, 3, 2, 4 ##STR565## 3:D6 3, 3, 3, 1 ##STR566##
3:D6 3, 3, 3, 2 ##STR567## 3:D7 3, 3, 3, 3 ##STR568## 3:D8 3, 3, 3,
4 ##STR569## 3:D9 3, 3, 4, 1 ##STR570## 3:D10 3, 3, 4, 2 ##STR571##
3:D11 3, 3, 4, 3 ##STR572## 3:D12 3, 3, 4, 4 ##STR573## 3:E1 3, 4,
1, 1 ##STR574## 3:E2 3, 4, 1, 2 ##STR575## 3:E3 3, 4, 1, 3
##STR576## 3:E4 3, 4, 1, 4 ##STR577## 3:E5 3, 4, 2, 1 ##STR578##
3:E6 3, 4, 2, 2 ##STR579## 3:E7 3, 4, 2, 3 ##STR580## 3:E8 3, 4, 2,
4 ##STR581## 3:E9 3, 4, 3, 1 ##STR582## 3:E10 3, 4, 3, 2 ##STR583##
3:E11 3, 4, 3, 3 ##STR584## 3:E12 3, 4, 3, 4 ##STR585## 3:F1 3, 4,
4, 1 ##STR586## 3:F2 3, 4, 4, 2 ##STR587## 3:F3 3, 4, 4, 3
##STR588## 3:F4 3, 4, 4, 4 ##STR589## 3:F5 3, 5, 1, 1 ##STR590##
3:F6 3, 5, 1, 2 ##STR591## 3:F7 3, 5, 1, 3 ##STR592## 3:F8 3, 5, 1,
4 ##STR593## 3:F9 3, 5, 2, 1 ##STR594## 3:F10 3, 5, 2, 2 ##STR595##
3:F11 3, 5, 2, 3 ##STR596## 3:F12 3, 5, 2, 4 ##STR597## 3:G1 3, 5,
3, 1 ##STR598## 3:G2 3, 5, 3, 2 ##STR599## 3:G3 3, 5, 3, 3
##STR600## 3:G4 3, 5, 3, 4 ##STR601## 3:G5 3, 5, 4, 1 ##STR602##
3:G5 3, 5, 4, 2 ##STR603## 3:G7 3, 5, 4, 3 ##STR604## 3:G8 3, 5, 4,
4 ##STR605## 3:G9 3, 6, 1, 1 ##STR606## 3:G10 3, 6, 1, 2 ##STR607##
3:G11 3, 6, 1, 3 ##STR608## 3:G12 3, 6, 1, 4 ##STR609## 3:H1 3, 6,
2, 1 ##STR610## 3:H2 3, 6, 2, 2 ##STR611## 3:H3 3, 6, 2, 3
##STR612## 3:H4 3, 6, 2, 4 ##STR613## 3:H5 3, 6, 3, 1 ##STR614##
3:H6 3, 6, 3, 2 ##STR615## 3:H7 3, 6, 3, 3 ##STR616## 3:H8 3, 6, 3,
4 ##STR617## 3:H9 3, 6, 4, 1 ##STR618## 3:H10 3, 6, 4, 2 ##STR619##
3:H11 3, 6, 4, 3 ##STR620## 3:H12 3, 6, 4, 4
[1539] The compounds of the invention may exist as geometric or
stereoisomers isomers as well as tautomers. Thus, the invention
includes all tautomers and geometric isomers, such as the E and Z
geometric isomers, as well as mixtures thereof. Furthermore, the
invention includes pure enantiomers and diasteriomers as well as
mixtures thereof, including racemic mixtures. The individual
geometric isomers, enantiomers, or diasteriomers may be prepared or
isolated by methods known in the art.
[1540] Compounds of the invention of designated stereochemistry may
be included in mixtures, including racemic mixtures, with other
enantiomers, diasteriomers, geometric isomers or tautomers.
Compounds of the invention with designated stereochemistry are
typically present in these mixtures in excess of 50 percent.
Preferably, compounds of the invention with designated
stereochemistry are present in these mixtures in excess of 80
percent. Most preferably, compounds of the invention with
designated stereochemistry are present in these mixtures in excess
of 90 percent.
[1541] Several of the compounds of formula (I) above are amines,
and as such form salts when reacted with acids. Pharmaceutically
acceptable salts are generally preferred over the corresponding
amines of the invention since they typically produce compounds
which are more water soluble, stable and/or more crystalline.
Pharmaceutically acceptable salts are 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.
The preferred pharmaceutically acceptable salts include salts of
the following acids acetic, aspartic, benzenesulfonic, benzoic,
bicarbonic, bisulfuric, bitartaric, butyric, calcium edetate,
camsylic, carbonic, chlorobenzoic, citric, edetic, edisylic,
estolic, esyl, esylic, formic, fumaric, gluceptic, gluconic,
glutamic, glycollylarsanilic, hexamic, hexylresorcinoic,
hydrabamic, hydrobromic, hydrochloric, hydroiodic,
hydroxynaphthoic, isethionic, lactic, lactobionic, maleic, malic,
malonic, mandelic, methanesulfonic, methylnitric, methylsulfuric,
mucic, muconic, napsylic, nitric, oxalic, p-nitromethanesulfonic,
pamoic, pantothenic, phosphoric, monohydrogen phosphoric,
dihydrogen phosphoric, phthalic, polygalactouronic, propionic,
salicylic, stearic, succinic, succinic, sulfamic, sulfanilic,
sulfonic, sulfuric, tannic, tartaric, teoclic and toluenesulfonic.
For other acceptable salts, see Int. J. Pharm., 33, 201-217 (1986)
and J. Pharm. Sci., 66 (1), 1, (1977).
[1542] The invention provides compounds, compositions, kits, and
methods for inhibiting beta-secretase enzyme activity and A beta
peptide production. Inhibition of beta-secretase enzyme activity
halts or reduces the production of A beta from APP and reduces or
eliminates the formation of beta-amyloid deposits in the brain.
METHODS OF THE INVENTION
[1543] As previously mentioned, compounds of the invention, and
pharmaceutically acceptable salts or esters thereof, are useful for
treating humans or animals suffering from a condition characterized
by a pathological form of beta-amyloid peptide, such as
beta-amyloid plaques, and for helping to prevent or delay the onset
of such a condition. For example, the compounds are useful for
treating Alzheimer's disease, for helping prevent or delay the
onset of Alzheimer's disease, for treating patients with MCI (mild
cognitive impairment) and preventing or delaying the onset of
Alzheimer's disease in those who would progress from MCI to AD, for
treating Down's syndrome, for treating humans who have Hereditary
Cerebral Hemorrhage with Amyloidosis of the Dutch-Type, for
treating cerebral amyloid angiopathy and preventing its potential
consequences, i.e. single and recurrent lobal hemorrhages, for
treating other degenerative dementias, including dementias of mixed
vascular and degenerative origin, dementia associated with
Parkinson's disease, dementia associated with progressive
supranuclear palsy, dementia associated with cortical basal
degeneration, and diffuse Lewy body type Alzheimer's disease. The
compounds and compositions of the invention are particularly useful
for treating or preventing Alzheimer's disease. When treating or
preventing these diseases, the compounds of the invention can
either be used individually or in combination, as is best for the
patient.
[1544] To prepare compositions, one or more compounds of the
invention are 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. The effective concentration is
sufficient for lessening or ameliorating at least one symptom of
the disease, disorder, or condition treated and may be empirically
determined.
[1545] 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. In addition, 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. The compounds may be
formulated as the sole pharmaceutically active ingredient in the
composition or may be combined with other active ingredients.
[1546] Where the compounds exhibit insufficient solubility, methods
for solubilizing may be used. Such methods are known and include,
but are not limited to, using cosolvents such as dimethylsulfoxide
(DMSO), using surfactants such as Tween.RTM., and dissolution in
aqueous sodium bicarbonate. Derivatives of the compounds, such as
salts or prodrugs may also be used in formulating effective
pharmaceutical compositions.
[1547] The concentration of the compound 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. Typically, the compositions are formulated for single
dosage administration.
[1548] The compounds of the invention 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, but not limited to,
microencapsulated delivery systems. 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. The
therapeutically effective concentration may be determined
empirically by testing the compounds in known in vitro and in vivo
model systems for the treated disorder.
[1549] The compounds and compositions of the invention can be
enclosed in multiple or single dose containers. The enclosed
compounds and compositions can be provided in kits, for example,
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 a second
therapeutic agent for co-administration. The inhibitor and second
therapeutic agent may be provided as separate component parts. A
kit may include a plurality of containers, each container holding
one or more unit dose of the compound of the invention. The
containers are preferably adapted for the desired mode of
administration, including, but not limited to tablets, gel
capsules, sustained-release capsules, 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.
[1550] The concentration of active compound in the drug composition
will depend on absorption, inactivation, and excretion rates of the
active compound, the dosage schedule, and amount administered as
well as other factors known to those of skill in the art.
[1551] The active ingredient may be administered at once, 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 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 to be further
understood that for any particular subject, specific dosage
regimens should 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.
[1552] If oral administration is desired, the compound should be
provided in a composition that protects it from the acidic
environment of the stomach. For example, the composition can be
formulated in an enteric coating that maintains its integrity in
the stomach and releases the active compound in the intestine. The
composition may also be formulated in combination with an antacid
or other such ingredient.
[1553] Oral compositions will generally include an inert diluent or
an edible carrier and may be compressed into tablets or enclosed in
gelatin capsules. For the purpose of oral therapeutic
administration, the active compound or compounds can be
incorporated with excipients and used in the form of tablets,
capsules, or troches. Pharmaceutically compatible binding agents
and adjuvant materials can be included as part of the
composition.
[1554] The tablets, pills, capsules, troches, and the like can
contain any of the following ingredients or compounds of a similar
nature: a binder such as, but not limited to, gum tragacanth,
acacia, corn starch, or gelatin; an excipient such as
microcrystalline cellulose, starch, or lactose; a disintegrating
agent such as, but not limited to, alginic acid and corn starch; a
lubricant such as, but not limited to, magnesium stearate; a
gildant, such as, but not limited to, colloidal silicon dioxide; a
sweetening agent such as sucrose or saccharin; and a flavoring
agent such as peppermint, methyl salicylate, or fruit
flavoring.
[1555] When the dosage unit form is a capsule, it can contain, in
addition to material of the above type, a liquid carrier such as a
fatty oil. In addition, dosage unit forms can contain various other
materials, which modify the physical form of the dosage unit, for
example, coatings of sugar and other enteric agents. The compounds
can also be administered 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 and
certain preservatives, dyes and colorings, and flavors.
[1556] 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.
[1557] Solutions or suspensions used for parenteral, intradermal,
subcutaneous, or topical application can include any of the
following components: a sterile diluent such as water for
injection, saline solution, fixed oil, a naturally occurring
vegetable oil such as sesame oil, coconut oil, peanut oil,
cottonseed oil, and the like, or a synthetic fatty vehicle such as
ethyl oleate, and the like, polyethylene glycol, glycerine,
propylene glycol, or other synthetic solvent; antimicrobial agents
such as benzyl alcohol and methyl parabens; antioxidants such as
ascorbic acid and sodium bisulfite; chelating agents such as
ethylenediaminetetraacetic acid (EDTA); buffers such as acetates,
citrates, and phosphates; and agents for the adjustment of tonicity
such as sodium chloride and dextrose. 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.
[1558] 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 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.
[1559] The active compounds may be prepared with carriers that
protect the compound against rapid elimination from the body, such
as time-release formulations or coatings. Such carriers include
controlled release formulations, such as, but not limited to,
implants and microencapsulated delivery systems, and 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 skilled in the art.
[1560] The compounds of the invention can be administered orally,
parenterally (IV, IM, depo-IM, SQ, and 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 the invention.
[1561] Compounds of the invention may be administered enterally or
parenterally. When administered orally, compounds of the 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 the solid dosage forms are used, it is preferred that
they be of the sustained release type so that the compounds of the
invention need to be administered only once or twice daily.
[1562] The oral dosage forms are administered to the patient 1, 2,
3, or 4 times daily. It is preferred that the compounds of the
invention be administered either three or fewer times, more
preferably once or twice daily. Hence, it is preferred that the
compounds of the invention be administered in oral dosage form. It
is preferred that whatever oral dosage form is used, that it be
designed so as to protect the compounds of the invention 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 protect from the acidic stomach,
are also well known to those skilled in the art.
[1563] 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 AD is from about 0.1 mg/day to about 1,000 mg/day.
It is preferred that the oral dosage is from about 1 mg/day to
about 100 mg/day. It is more preferred that the oral dosage is from
about 5 mg/day to about 50 mg/day. It is understood that while a
patient may be started at one dose, that dose may be varied over
time as the patient's condition changes.
[1564] Compounds of the invention may also be advantageously
delivered 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.
[1565] The compounds of the invention can be used in combination,
with each other or with other therapeutic agents or approaches used
to treat or prevent the conditions listed above. Such agents or
approaches include: acetylcholine esterase 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 and 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 (Emilieu, 2000, Arch. Neurol. 57:454), and other
neurotropic agents of the future.
[1566] 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 invention administered, the particular
condition being treated, the severity of the condition being
treated, the age, weight, general physical condition of the
particular patient, and other medication the individual may be
taking as is well known to administering physicians who are skilled
in this art.
[1567] The invention may be further understood with reference to
the following biological examples. These examples are intended to
be representative of specific embodiments of the invention, and are
not intended as limiting the scope of the invention.
Biology Examples
Biology Example A
Enzyme Inhibition Assay
[1568] The compounds of the 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 maltose binding protein
(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 WO00/47618.
[1569] 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 Leu 596 at the
substrate's APP-SW 751 mutation site.
Specific Assay Procedure:
[1570] Compounds are diluted in a 1:1 dilution series to a
six-point concentration curve (two wells per concentration) in one
96-plate row per compound tested. Each of the test compounds is
prepared in DMSO to make up a 10 millimolar stock solution. The
stock solution is serially diluted in DMSO to obtain a final
compound concentration of 200 micromolar at the high point of a
6-point dilution curve. Ten (10) microliters of each dilution is
added to each of two wells on row C of a corresponding V-bottom
plate to which 190 microliters of 52 millimolar NaOAc, 7.9% DMSO,
pH 4.5 are pre-added. The NaOAc diluted compound plate is spun down
to pellet precipitant and 20 microliters/well is transferred to a
corresponding flat-bottom plate to which 30 microliters of ice-cold
enzyme-substrate mixture (2.5 microliters MBP-C125SW substrate,
0.03 microliters enzyme and 24.5 microliters ice cold 0.09% TX100
per 30 microliters) is added. The final reaction mixture of 200
micromolar compound at the highest curve point is in 5% DMSO, 20
millimolar NaOAc, 0.06% TX100, at pH 4.5.
[1571] Warming the plates to 37 degrees C. starts the enzyme
reaction. After 90 minutes at 37 degrees C., 200 microliters/well
cold specimen diluent is added to stop the reaction and 20
microliters/well was transferred to a corresponding anti-MBP
antibody coated ELISA plate for capture, containing 80
microliters/well specimen diluent. This reaction is incubated
overnight at 4 degrees 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.
[1572] Relative compound inhibition potency is determined by
calculating the concentration of compound that showed a fifty
percent reduction in detected signal (IC.sub.50) compared to the
enzyme reaction signal in the control wells with no added compound.
In this assay, the compounds of the invention exhibited an
IC.sub.50 of less than 50 micromolar.
Biology Example B
Cell Free Inhibition Assay Utilizing a Synthetic APP Substrate
[1573] 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 of the invention. Useful substrates include
the following: TABLE-US-00002 Biotin-SEVNL-DAEFR [Oregon green] KK
[SEQ ID NO: 1] Biotin-SEVKM-DAEFR [Oregon green] KK [SEQ ID NO: 2]
Biotin-GLNIKTEEISEISY-EVEFRC [Oregon [SEQ ID NO: 3] green] KK
Biotin-ADRGLTTRPGSGLTNIKTEEISEVNL- [SEQ ID NO: 4] DAEF [Oregon
green] KK Biotin-FVNQHLCoxGSHLVEALY- [SEQ ID NO: 5]
LVCoxGERGFFYTPKA [Oregon green] KK
[1574] The enzyme (0.1 nanomolar) and test compounds (0.001-100
micromolar) are incubated in pre-blocked, low affinity, black
plates (384 well) at 37 degrees for 30 minutes. The reaction is
initiated by addition of 150 millimolar substrate to a final volume
of 30 microliter per well. The final assay conditions are:
0.001-100 micromolar compound inhibitor; 0.1 molar sodium acetate
(pH 4.5); 150 nanomolar substrate; 0.1 nanomolar soluble
beta-secretase; 0.001% Tween 20, and 2% DMSO. The assay mixture is
incubated for 3 hours at 37 degrees 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 minutes, fluorescence polarization is measured,
for example, using a LJL Acqurest (Ex485 nm/Em530 nm). 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,
compounds of the invention exhibited an IC.sub.50 of less than 50
micromolar.
Biology Example C
Beta-Secretase Inhibition: P26-P4' SW Assay
[1575] 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
WO00/47618. The P26-P4' SW substrate is a peptide of the sequence:
TABLE-US-00003 (biotin) CGGADRGLTTRPGSGLTNIKTEEISEVNLDAEF [SEQ ID
NO: 6]
[1576] The P26-P1 standard has the sequence: TABLE-US-00004
(biotin) CGGADRGLTTRPGSGLTNIKTEEISEVNL. [SEQ ID NO: 7]
[1577] Briefly, the biotin-coupled synthetic substrates are
incubated at a concentration of from about 0 to about 200
micromolar in this assay. When testing inhibitory compounds, a
substrate concentration of about 1.0 micromolar 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 to 2000 picomolar, after
dilution.
[1578] The reaction mixture also includes 20 millimolar sodium
acetate, pH 4.5, 0.06% Triton X100, and is incubated at 37 degrees
C. for about 1 to 3 hours. Samples are then diluted in assay buffer
(for example, 145.4 nanomolar sodium chloride, 9.51 millimolar
sodium phosphate, 7.7 millimolar sodium azide, 0.05% Triton X405, 6
g/liter bovine serum albumin, pH 7.4) to quench the reaction, then
diluted further for immunoassay of the cleavage products.
[1579] 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 hours at 4 degrees C.
After washing in TTBS buffer (150 millimolar sodium chloride, 25
millimolar Tris, 0.05% Tween 20, pH 7.5), the samples are incubated
with streptavidin-AP according to the manufacturer's instructions.
After a one hour incubation at room temperature, the samples are
washed in TTBS and incubated with fluorescent substrate solution A
(31.2 g/liter 2-amino-2-methyl-1-propanol, 30 mg/liter, 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.
Biology Example D
Assays using Synthetic Oligopeptide-Substrates
[1580] Synthetic oligopeptides are prepared that incorporate the
known cleavage site of beta-secretase, and optionally 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, herein incorporated by
reference. 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.
[1581] By way of example, one such peptide has the sequence
SEVNL-DAEF [SEQ ID NO: 8], and the cleavage site is between
residues 5 and 6. Another preferred substrate has the sequence
ADRGLTTRPGSGLTNIKTEEISEVNL-DAEF [SEQ ID NO: 9], and the cleavage
site is between residues 26 and 27.
[1582] 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 the compound inhibitor to
control results provides a measure of the compound's inhibitory
activity.
Biology Example E
Inhibition of Beta-Secretase Activity--Cellular Assay
[1583] 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 Lys651Met52 to
Asn651Leu652 (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.
[1584] The cells are incubated in the presence/absence of the
inhibitory compound (diluted in DMSO) at the desired concentration,
generally up to 10 micrograms/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.
Biology Example F
Inhibition of Beta-Secretase in Animal Models of AD
[1585] Various animal models can be used to screen for inhibition
of beta-secretase activity. Examples of animal models useful in the
invention include, but are not limited to, 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.
[1586] 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 compound 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 hours, the animals are sacrificed, and
brains removed for analysis.
[1587] Transgenic animals are administered an amount of the
compound inhibitor 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, animals are sacrificed and 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.
[1588] Animals administered the compound inhibitors of the
invention are expected to demonstrate reduced A beta in brain
tissues or cerebral fluids and reduced beta amyloid plaques in
brain tissue, as compared with non-treated controls.
Biology Example G
Inhibition of A Beta Production in Human Patients
[1589] Patients suffering from Alzheimer's Disease (AD) demonstrate
an increased amount of A beta in the brain. AD patients 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.
[1590] Patients administered the compound inhibitors are expected
to demonstrate slowing or stabilization of disease progression as
analyzed by changes in one or more of the following disease
parameters: A beta present in CSF or plasma; brain or hippocampal
volume; A beta deposits in the brain; amyloid plaque in the brain;
and scores for cognitive and memory function, as compared with
control, non-treated patients.
Biology Example H
Prevention of A Beta Production in Patients at Risk for AD
[1591] Patients predisposed or at risk for developing AD are
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 AD 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.
[1592] Patients administered the compound inhibitors are expected
to demonstrate slowing or stabilization of disease progression as
analyzed by changes in one or more of the following disease
parameters: A beta present in CSF or plasma; brain or hippocampal
volume; amyloid plaque in the brain; and scores for cognitive and
memory function, as compared with control, non-treated
patients.
[1593] 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.
[1594] 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.
[1595] All patents and publications referred to herein are hereby
incorporated by reference for all purposes.
[1596] The 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
invention.
* * * * *