U.S. patent application number 14/126763 was filed with the patent office on 2014-07-31 for therapeutically active compositions and their methods of use.
This patent application is currently assigned to AGIOS PHARMACEUTICALS, INC. The applicant listed for this patent is Sheldon Cao, Janeta Popovici-Muller, Francesco G. Salituro, Jeffrey O. Saunders, Xuefei Tan, Jeremy Travins, Shunqi Yan, Zhixiong Ye. Invention is credited to Sheldon Cao, Janeta Popovici-Muller, Francesco G. Salituro, Jeffrey O. Saunders, Xuefei Tan, Jeremy Travins, Shunqi Yan, Zhixiong Ye.
Application Number | 20140213580 14/126763 |
Document ID | / |
Family ID | 47330415 |
Filed Date | 2014-07-31 |
United States Patent
Application |
20140213580 |
Kind Code |
A1 |
Cao; Sheldon ; et
al. |
July 31, 2014 |
THERAPEUTICALLY ACTIVE COMPOSITIONS AND THEIR METHODS OF USE
Abstract
Provided are compounds with the following structure, formula (I)
pharmaceutically acceptable salts thereof, use of those compounds
for treating cancer and pharmaceutical compositions comprising
those compounds. ##STR00001##
Inventors: |
Cao; Sheldon; (San Diego,
CA) ; Popovici-Muller; Janeta; (Windham, NH) ;
Salituro; Francesco G.; (Marlborough, MA) ; Saunders;
Jeffrey O.; (Lincoln, MA) ; Tan; Xuefei;
(Shanghai, CN) ; Travins; Jeremy; (Southborough,
MA) ; Yan; Shunqi; (Irvine, CA) ; Ye;
Zhixiong; (West Windsor, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cao; Sheldon
Popovici-Muller; Janeta
Salituro; Francesco G.
Saunders; Jeffrey O.
Tan; Xuefei
Travins; Jeremy
Yan; Shunqi
Ye; Zhixiong |
San Diego
Windham
Marlborough
Lincoln
Shanghai
Southborough
Irvine
West Windsor |
CA
NH
MA
MA
MA
CA
NJ |
US
US
US
US
CN
US
US
US |
|
|
Assignee: |
AGIOS PHARMACEUTICALS, INC
Cambridge
MA
|
Family ID: |
47330415 |
Appl. No.: |
14/126763 |
Filed: |
June 18, 2012 |
PCT Filed: |
June 18, 2012 |
PCT NO: |
PCT/CN2012/000841 |
371 Date: |
March 10, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
61584210 |
Jan 6, 2012 |
|
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61509071 |
Jul 18, 2011 |
|
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Current U.S.
Class: |
514/218 ;
514/235.8; 514/249; 514/253.01; 514/253.04; 514/253.05; 514/253.06;
514/253.09; 514/253.1; 514/253.11; 514/253.12; 540/575; 544/121;
544/353; 544/357; 544/360; 544/362; 544/363; 544/364 |
Current CPC
Class: |
A61K 31/5377 20130101;
C07D 401/12 20130101; C07D 401/14 20130101; C07D 413/14 20130101;
A61K 31/496 20130101; C07D 405/12 20130101; C07F 9/65583 20130101;
A61K 31/4985 20130101; A61K 31/498 20130101; C07D 405/14 20130101;
C07D 417/14 20130101; A61K 31/506 20130101; C07D 498/04 20130101;
C07D 213/85 20130101; C07D 409/14 20130101; A61P 35/00 20180101;
A61P 35/02 20180101; C07D 487/04 20130101; A61K 31/501 20130101;
C07D 471/04 20130101; A61K 31/502 20130101; A61K 31/517 20130101;
C07D 401/04 20130101; C07F 9/650952 20130101; A61K 31/675
20130101 |
Class at
Publication: |
514/218 ;
514/235.8; 514/249; 514/253.01; 514/253.04; 514/253.05; 514/253.06;
514/253.09; 514/253.1; 514/253.11; 514/253.12; 540/575; 544/121;
544/353; 544/357; 544/360; 544/362; 544/363; 544/364 |
International
Class: |
C07D 401/04 20060101
C07D401/04; A61K 31/496 20060101 A61K031/496; C07D 401/14 20060101
C07D401/14; C07D 413/14 20060101 C07D413/14; C07D 213/85 20060101
C07D213/85; C07D 471/04 20060101 C07D471/04; C07D 405/14 20060101
C07D405/14; C07D 409/14 20060101 C07D409/14; C07D 417/14 20060101
C07D417/14; C07D 487/04 20060101 C07D487/04; A61K 31/4985 20060101
A61K031/4985; A61K 31/517 20060101 A61K031/517; A61K 31/501
20060101 A61K031/501; A61K 31/506 20060101 A61K031/506; A61K 31/502
20060101 A61K031/502; A61K 31/498 20060101 A61K031/498 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 17, 2011 |
CN |
201110172169.1 |
Claims
1. A compound of Structural Formula (I): ##STR00869## or a
pharmaceutically acceptable salt thereof, wherein: Y is
--N(R.sup.5)--, --N(R.sub.5)--CH.sub.2--, --CH.sub.2--N(R.sup.5)--
or --CH(R.sup.5)--; each R.sup.1a and R.sup.1b is independently
hydrogen, --C.sub.1-C.sub.4 alkyl, --N(R.sup.7)(C.sub.1-C.sub.4
alkylene)-N(R.sup.7)(C.sub.1-C.sub.4 alkyl), aryl, heteroaryl,
heterocyclyl, --C(O)N(R.sup.7)-aryl, --N(R.sup.7)C(O)-aryl,
--(C.sub.1-C.sub.4 alkylene)-aryl, --(C.sub.1-C.sub.4
alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4 alkylene)-aryl,
--O--(C.sub.0-C.sub.4 alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4
alkylene)-heterocyclyl, --O--(C.sub.0-C.sub.4
alkylene)-carbocyclyl, --N(R.sup.7)-aryl, or
--N(R.sup.7)-heteroaryl, --N(R.sup.9)-aryl,
--N(R.sup.9)-heteroaryl, --O--(C.sub.1-C.sub.4
alkeylene)-N(R.sup.7)C(O)O--(C.sub.1-C.sub.4 alkylene)-aryl,
--N(R.sup.9)--C(O)--(C.sub.2-C.sub.4 alkenyl) wherein: at least one
of R.sup.1a and R.sup.1b is not hydrogen or methyl; any alkylene
moiety present in R.sup.1a or R.sup.1b is optionally substituted
with OH or F; each R.sup.7 is independently selected from hydrogen
and C.sub.1-C.sub.4 alkyl; and any aryl, heteroaryl, or
heterocyclyl of R.sup.1a or R.sup.1b is optionally substituted with
one or more substituents selected from -G-L-M, halo, --NO.sub.2,
C.sub.1-C.sub.6 alkyl, --C.ident.N, .dbd.O, --CF.sub.3 and
--OCF.sub.3; G is a bond or a bivalent C.sub.1-C.sub.6 saturated or
unsaturated, straight or branched hydrocarbon chain wherein
optionally one, two or three methylene units of the hydrocarbon
chain are independently replaced by --NR.sup.8--, --O--, --C(O)--,
--OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR.sup.8)--, --N.dbd.N--, or --C(.dbd.N.sub.2)--; L is a
covalent bond or a bivalent C.sub.1-8 saturated or unsaturated,
straight or branched, hydrocarbon chain, wherein one, two, or three
methylene units of L are optionally and independently replaced by
cyclopropylene, --N(R.sup.8)C(O)--, --C(O)N(R.sup.8)--,
--N(R.sup.8)SO.sub.2--, SO.sub.2N(R.sup.8)--, --O--, --C(O)--,
--OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR.sup.8)--, --N.dbd.N--, or --C(.dbd.N.sub.2)--; M is E,
or a 3-10 membered monocyclic or bicyclic, saturated, partially
unsaturated, or aromatic ring having 0-3 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, and wherein said ring is
substituted with at 1-4 groups independently selected from -D-E,
oxo, NO.sub.2, halogen, CN, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl; D is a covalent bond or a
bivalent C.sub.1-C.sub.6 saturated or unsaturated, straight or
branched, hydrocarbon chain, wherein one or two methylene units of
D are optionally and independently replaced by --NR.sup.8--, --S--,
--O--, --C(O)--, --SO--, or --SO.sub.2--; E is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl, wherein said alkyl, alkenyl or alkynyl is optionally
substituted with oxo, halogen, or CN; and each R.sup.8 is
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, --C.sub.1-C.sub.6 alkoxy,
--S(O).sub.2--C.sub.2-C.sub.4 alkenyl, or an optionally substituted
group selected from phenyl, a 4-7 membered heterocyclyl having 1-2
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, or a 5-6 membered monocyclic heteroaryl ring having 1-4
heteroatoms independently selected from nitrogen, oxygen, or
sulfur; R.sup.2 is selected from phenyl, a 3-7 membered cycloalkyl,
C.sub.2-C.sub.4 alkyl, or CF.sub.3, wherein the phenyl or
cycloalkyl is optionally substituted with a substituent selected
from methyl or fluoro; each R.sup.3 is independently selected from
halo, --(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--C.sub.1-C.sub.4 fluoroalkyl, --C(O)--O--(C.sub.1-C.sub.4 alkyl),
-phenyl, -heteroaryl, C.sub.3-C.sub.7 cycloalkyl,
--CH.sub.2--N(C.sub.1-C.sub.4 alkyl).sub.2,
C(O)--N--(C.sub.1-C.sub.4 alkyl).sub.2,
--C(O)--NH--(C.sub.1-C.sub.4 alkyl), --C.sub.1-C.sub.4 alkyl
optionally substituted with one or more halo or --OH, or two
R.sup.3s are taken together to form a 3-8 saturated ring or a fused
phenyl wherein said saturated ring or fused phenyl is optionally
substituted with 1 to 2 methyl; R.sup.4 is selected from hydrogen,
--CN, halo, C.sub.1-C.sub.4 alkoxy, --CH.sub.2NH(C.sub.1-C.sub.4
alkyl), C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.4 fluoroalkyl, C(O)--N--(C.sub.1-C.sub.4
alkyl).sub.2, --C(O)--NH--(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkyl), --C(O)--OH,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), and a 5-membered heteroaryl;
R.sup.5 is selected from: --C(O)--(C.sub.1-C.sub.5 alkyl),
--C(O)--(C.sub.2-C.sub.6 alkenyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--(C.sub.1-C.sub.4 alkenylene)-Q,
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--O--(C.sub.0-C.sub.2 alkylene)-Q,
--C(O)--(C.sub.1-C.sub.2 alkylene)-O--(C.sub.0-C.sub.2 alkylene)-Q,
--C(O)--C(O)-Q, --S(O).sub.2-Q, --C(O)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4
alkyl), --C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.1-C.sub.6
alkyl), --C(O)--(C.sub.0-C.sub.2
alkylene)N(R.sup.6)--(C.sub.2-C.sub.6 alkynyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.2-C.sub.6
alkenyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-C(O)C(O)N(R)(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.2 alkylene)-S(O).sub.0-2-(C.sub.1-C.sub.4
alkyl), --S(O).sub.2--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-C(O)C(O)N(R.sup.6)(C.sub.1-C.sub.6 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-N(R.sup.6)S(O).sub.2--(C.sub.1-C.sub.6 alkyl), or
--C(O)--(C.sub.1-C.sub.4 alkylene)-N(R.sup.6)S(O).sub.2Q, wherein:
any alkylene moiety present in R.sup.5 is optionally substituted
with OCH.sub.3, OH or F; any terminal methyl moiety present in
R.sup.5 is optionally replaced with --CH.sub.2OH, CF.sub.3,
CH.sub.2F, --CH.sub.2Cl, C(O)CH.sub.3, C(O)CF.sub.3, CN,
--OCH.sub.3, --C(O)H, --OP(O)(OH).sub.2, --OP(O)(C.sub.1-C.sub.4
alkoxy).sub.2 or CO.sub.2H; each R.sup.6 is independently selected
from hydrogen and methyl; Q is selected from aryl, heteroaryl,
carbocyclyl and heterocyclyl, wherein Q is optionally substituted
with up to 3 substituents independently selected from
C.sub.1-C.sub.4 alkyl optionally substituted with OH,
C.sub.1-C.sub.4 alkoxy, --C(O)O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.1-C.sub.4 alkylene)-(C.sub.1-C.sub.4 alkoxy), --CN, --OH,
fluoro, chloro, and bromo; R.sup.9 is selected from aryl and
heteroaryl, wherein each aryl or heteroaryl is optionally
substituted with one or more substituents selected from -G-L-M,
halo, C.sub.1-C.sub.6 alkyl, --C.ident.N, .dbd.O, --CF.sub.3 and
--OCF.sub.3; and m is 0, 1, 2 or 3.
2. The compound of claim 1, wherein: Y is --N(R.sup.5)-- or
--CH(R.sup.5)--; each R.sup.1a and R.sup.1b is independently
hydrogen, --C.sub.1-C.sub.4 alkyl, --N(R.sup.7)(C.sub.1-C.sub.4
alkylene)-N(R.sup.7)(C.sub.1-C.sub.4 alkyl), aryl, heteroaryl,
heterocyclyl, --C(O)N(R.sup.7)-aryl, --N(R.sup.7)C(O)-aryl,
--(C.sub.1-C.sub.4 alkylene)-aryl, --(C.sub.1-C.sub.4
alkylene)-heteroaryl, --O--(C.sub.1-C.sub.4 alkylene)-aryl,
--O--(C.sub.1-C.sub.4 alkylene)-heteroaryl, --O--(C.sub.1-C.sub.4
alkylene)-heterocyclyl, --N(R.sup.7)-aryl, or
--N(R.sup.7)-heteroaryl, wherein: at least one of R.sup.1a and
R.sup.1b is not hydrogen or methyl; any alkylene moiety present in
R.sup.1a or R.sup.1b is optionally substituted with OH or F; each
R.sup.7 is independently selected from hydrogen and C.sub.1-C.sub.4
alkyl; and any aryl, heteroaryl, or hetercylyl of R.sup.1a or
R.sup.1b is optionally substituted with one or more substituents
selected from -G-L-M, halo, C.sub.1-C.sub.6 alkyl, --C.ident.N,
.dbd.O, --CF.sub.3 and --OCF.sub.3; G is a bond or a bivalent
C.sub.1-C.sub.6 saturated or unsaturated, straight or branched
hydrocarbon chain wherein optionally one, two or three methylene
units of the hydrocarbon chain are independently replaced by
--NR.sup.8--, --O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --SO--,
--SO.sub.2--, --C(.dbd.S)--, --C(.dbd.NR.sup.8)--, --N.dbd.N--, or
--C(.dbd.N.sub.2)--; L is a covalent bond or a bivalent C.sub.1-8
saturated or unsaturated, straight or branched, hydrocarbon chain,
wherein one, two, or three methylene units of L are optionally and
independently replaced by cyclopropylene, --N(R.sup.8)C(O)--,
--C(O)N(R.sup.8)--, --N(R.sup.8)SO.sub.2--, SO.sub.2N(R.sup.8)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--,
--C(.dbd.S)--, --C(.dbd.NR.sup.8)--, --N.dbd.N--, or
--C(.dbd.N.sub.2)--; M is E, or a 3-10 membered monocyclic or
bicyclic, saturated, partially unsaturated, or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, and wherein said ring is substituted with at 1-4 groups
independently selected from -D-E, oxo, NO.sub.2, halogen, CN,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl; D is a covalent bond or a bivalent C.sub.1-C.sub.6
saturated or unsaturated, straight or branched, hydrocarbon chain,
wherein one or two methylene units of D are optionally and
independently replaced by --NR.sup.8--, --S--, --O--, --C(O)--,
--SO--, or --SO.sub.2--; E is hydrogen, C.sub.1-C.sub.6 alkyl,
C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl, wherein said
alkyl, alkenyl or alkynyl is optionally substituted with oxo,
halogen, or CN; and each R.sup.8 is independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, or an optionally substituted group selected from phenyl, a
4-7 membered heterocyclyl having 1-2 heteroatoms independently
selected from nitrogen, oxygen, or sulfur, or a 5-6 membered
monocyclic heteroaryl ring having 1-4 heteroatoms independently
selected from nitrogen, oxygen, or sulfur; R.sup.2 is selected from
phenyl, a 3-7 membered cycloalkyl, and C.sub.2-C.sub.4 alkyl,
wherein the phenyl or cycloalkyl is optionally substituted with a
substituent selected from methyl or fluoro; each R.sup.3 is
independently selected from --C.sub.1-C.sub.4 alkyl,
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 fluoroalkyl,
--C(O)--O--(C.sub.1-C.sub.4 alkyl), -phenyl, -heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, --CH.sub.2--N(C.sub.1-C.sub.4
alkyl).sub.2, C(O)--N--(C.sub.1-C.sub.4 alkyl).sub.2, and
--C(O)--NH--(C.sub.1-C.sub.4 alkyl), or or two R.sup.3s are taken
together to form a 3-8 saturated ring or a fused phenyl wherein
said saturated ring or fused phenyl is optionally substituted with
1 to 2 methyl groups; R.sup.4 is selected from hydrogen, --CN,
halo, C.sub.1-C.sub.4 alkoxy, --CH.sub.2NH(C.sub.1-C.sub.4 alkyl),
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.4 fluoroalkyl, C(O)--N--(C.sub.1-C.sub.4
alkyl).sub.2, --C(O)--NH--(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkyl), --C(O)--OH,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), and a 5-membered heteroaryl;
R.sup.5 is selected from: --C(O)--(C.sub.1-C.sub.4alkyl),
--C(O)--(CH.sub.2).sub.0-2-Q,
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(CH.sub.2).sub.0-2-Q,
--C(O)--O--(CH.sub.2).sub.1-2-Q,
--C(O)--(CH.sub.2).sub.1-2--O--(CH.sub.2).sub.0-2-Q,
--C(O)--C(O)-Q, --S(O).sub.2-Q, --C(O)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4
alkyl), --C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(C.sub.1-C.sub.6 alkyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(C.sub.2-C.sub.6 alkynyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(C.sub.2-C.sub.6 alkenyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(CH.sub.2).sub.0-2--O--(C.sub.1-C-
.sub.4 alkyl), --C(O)--(CH.sub.2).sub.1-2--O--(C.sub.1-C.sub.4
alkyl), --C(O)--O--(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4
alkyl), --(CH.sub.2).sub.0-4--O--C(O)--(C.sub.1-C.sub.4 alkyl),
--(CH.sub.2).sub.0-4--C(O)--O--(C.sub.1-C.sub.4 alkyl),
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(CH.sub.2).sub.1-2--S--(C.sub.1-C.sub.4 alkyl),
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4
alkylene)-C(O)C(O)N(R.sup.6)(C.sub.1-C.sub.6 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-N(R.sup.6)S(O).sub.2--(C.sub.1-C.sub.6 alkyl), and
--C(O)--(C.sub.1-C.sub.4 alkylene)-N(R.sup.6)S(O).sub.2Q, wherein:
any alkylene moiety present in R.sup.5 is optionally substituted
with OH or F; any terminal methyl moiety present in R.sup.5 is
optionally replaced with --CH.sub.2OH, CF.sub.3, --CH.sub.2F,
--CH.sub.2Cl, C(O)CH.sub.3, or C(O)CF.sub.3; each R.sup.6 is
independently selected from hydrogen and methyl; Q is selected from
aryl, heteroaryl, carbocyclyl and heterocyclyl, wherein Q is
optionally substituted with up to 3 substituents independently
selected from C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy, --CN,
fluoro, chloro, and bromo; and m is 0, 1, 2 or 3.
3. The compound of claim 1, wherein R.sup.4 is selected from --CN
or C(O)--O--C.sub.1-C.sub.4 alkyl.
4. The compound of claim 1, wherein R.sup.4 is ##STR00870##
5. The compound of claim 1, wherein Y is --N(R.sup.5)--.
6. The compound of claim 6, wherein R.sup.5 is
--C(O)--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.2 alkyl),
--C(O)-Q, --C(O)--(C.sub.1-C.sub.5 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-Q, --C(O)--(C.sub.2-C.sub.4 alkenyl),
--C(O)O--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkenylene)-Q; wherein: any alkylene moiety present in R.sup.5 is
optionally substituted with OH; any terminal methyl moiety present
in R.sup.5 is optionally replaced with --OH, CF.sub.3, OCH.sub.3,
--C(O)H, OP(O)(C.sub.1-C.sub.4 alkoxy).sub.2, or --OP(O)(OH).sub.2
(or a salt of --OP(O)(OH).sub.2).
7. The compound of claim 6, wherein Q is cyclopropyl, cyclobutyl,
oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl,
dihydrofuranonyl, or cyclopentyl, wherein each member of Q is
optionally substituted with one substituent independently selected
from C.sub.1-C.sub.4 alkyl optionally substituted with OH,
C.sub.1-C.sub.4 alkoxy, alkylene)-(C.sub.1-C.sub.4 alkoxy), and
--OH.
8. The compound of claim 1, wherein R.sup.1a is H and R.sup.1b is
aryl, heteroaryl, heterocyclyl, alkylene)-aryl,
alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4 alkylene)-aryl,
--O--(C.sub.0-C.sub.4 alkylene)-heteroaryl, --N(R.sup.7)-aryl,
--N(R.sup.7)heteroaryl, --N(R.sup.9)-aryl, or
--N(R.sup.9)-heteroaryl; wherein said aryl or heteroaryl is
substituted with -G-L-M, CH.sub.3, or CN.
9. The compound of claim 8, wherein aryl associated with R.sup.1b
is phenyl.
10. The compound of claim 8, wherein heteroaryl is associated with
R.sup.1b pyridyl, pyrimidinyl, naphthyridinyl, quinolyl,
isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl,
benzothiazolyl, benzimidazolyl, pyrollopyridinyl,
pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl,
quinoxalinyl, quinazolinyl, pyridazinyl or pyrazolyl.
11. The compound of claim 8, wherein heterocyclyl is associated
with R.sup.1b benzodioxole, pyridazinone, benzoxazolone,
indolinone, N-methylindolinone, piperazinyl,
N-methylisoquinolinone, tetrahydropyridinyl, dihydropyrrolyl and
said phenyl, pyridyl, pyrimidinyl, naphthyridinyl, quinolyl,
isoquinolyl, isoxazolyl, benzoxazolyl, imidazopyrazinyl,
benzothiazolyl, benzimidazolyl, pyrollopyridinyl,
pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl,
quinoxalinyl, quinazolinyl, pyridazinyl, pyrazolyl, benzodioxole,
pyridazinone, benzoxazolone, indolinone, N-methylindolinone,
piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, or
dihydropyrrolyl
12. The compound of claim 9, wherein aryl, heteroaryl or
heterocyclyl associated with R.sup.1b is substituted with -G-L-M,
--CF.sub.3, --OCF.sub.3, halo (e.g., fluoro, chloro or bromo),
CH.sub.3, or CN.
13. The compound of claim 1, wherein R.sup.1a is methyl and
R.sup.1b is aryl, heteroaryl, heterocyclyl, --O--(C.sub.0-C.sub.4
alkylene)-aryl, or --O--(C.sub.0-C.sub.4 alkylene)-heteroaryl.
14. The compound of claim 13, wherein R.sup.1a is methyl and
R.sup.1b is aryl, heteroaryl, heterocyclyl, --O--(CH.sub.2)-aryl,
--O--CH(CH.sub.3)-aryl, --O--(CH.sub.2)-heteroaryl or
--O--CH(CH.sub.3)-heteroaryl.
15. The compound of claim 13, wherein aryl associated with R.sup.1b
is phenyl or naphthyl.
16. The compound of claim 13, wherein heteroaryl associated with
R.sup.1b is quinolinyl, pyrazolyl, isoquinolinyl, pyridyl,
pyrimidinyl, indolyl, or pyrazolyl.
17. The compound of claim 13, wherein heterocyclyl associated with
R.sup.1b is tetrahydropyridinyl and said phenyl, pyridyl,
pyrimidinyl, indolyl, or pyrazolyl.
18. The compound of claim 13, wherein aryl, heteroaryl or
heterocyclyl associated with R.sup.1b is substituted with -G-L-M,
halo, CH.sub.3, or CN.
19. The compound of claim 8, wherein -G-L-M: ##STR00871##
##STR00872## C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, tetrazolyl, morpholino, piperazinyl,
pyrrolidinone, pyrazolyl, benzyl, --(CH.sub.2).sub.1-4--SH,
--(CH.sub.2).sub.1-4--NH.sub.2, --NH.sub.2,
--(CH.sub.2).sub.1-4--OH, --N(H)C(O)OCH(CH.sub.3).sub.3,
--(CH.sub.2).sub.1-4--OCH.sub.3, --NH--(CH.sub.2).sub.1-4--OH,
--C(O)--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4 alkenyl),
--O--(CH.sub.2).sub.1-4--C(O)--O--(C.sub.1-C.sub.4 alkyl),
--C(O)NH.sub.2, --(CH.sub.2).sub.1-4C(O)CH.sub.3,
--N(CH.sub.3)(CH.sub.3), --NHC(O)(C.sub.2-C.sub.4 alkenyl),
--NHC(O)(C.sub.2-C.sub.4 alkyl), --SO.sub.2(CH.sub.2).sub.1-4,
--(CH.sub.2).sub.1-4--NHSO.sub.2Me, --NHSO.sub.2(CH.sub.2).sub.1-4,
--O--SO.sub.2CF.sub.3, --SO.sub.2NH--(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH--(C.sub.2-C.sub.4 alkenyl), SO.sub.2--NH.sub.2 or
--NHSO.sub.2Me
20. A pharmaceutical composition comprising a compound of claim 1,
and a pharmaceutically acceptable carrier.
21. The composition of claim 20, further comprising a second
therapeutic agent.
22. A method of treating a cancer characterized by the presence of
an IDH1 mutation, wherein the IDH1 mutation result in a new ability
of the enzyme to catalyze the NAPH-dependent reduction of
a-ketoglutarate to R(-)-2-hydroxyglutarate in a patient, comprising
the step of administering to the patient in need thereof a
composition of claim 20.
23. The method of claim 22, wherein the IDH1 mutation is an IDH1
R132H or IDH1 R132C mutation.
24. The method of claim 23, wherein the cancer is selected from
glioma (glioblastoma), acute myelogenous leukemia, sarcoma,
melanoma, non-small cell lung cancer and cholangiocarcinomas,
cholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes
(MDS), myeloproliferative neoplasm (MPN), or colon cancer.
25. The method of claim 22, further comprising administering to the
patient in need thereof a second therapeutic agent.
Description
CLAIM OF PRIORITY
[0001] This application claims priority from Chinese Patent
Application No. CN 201110172169.1, filed Jun. 17, 2011, U.S. Ser.
No. 61/509,071, filed Jul. 18, 2011 and U.S. Ser. No. 61/584,210,
filed Jan. 6, 2012, each of which is incorporated by reference in
its entirety.
BACKGROUND OF INVENTION
[0002] Isocitrate dehydrogenases (IDHs) catalyze the oxidative
decarboxylation of isocitrate to 2-oxoglutarate (i.e.,
.alpha.-ketoglutarate). These enzymes belong to two distinct
subclasses, one of which utilizes NAD(+) as the electron acceptor
and the other NADP(+). Five isocitrate dehydrogenases have been
reported: three NAD(+)-dependent isocitrate dehydrogenases, which
localize to the mitochondrial matrix, and two NADP(+)-dependent
isocitrate dehydrogenases, one of which is mitochondrial and the
other predominantly cytosolic. Each NADP(+)-dependent isozyme is a
homodimer.
[0003] IDH1 (isocitrate dehydrogenase 1 (NADP+), cytosolic) is also
known as IDH; IDP; IDCD; IDPC or PICD. The protein encoded by this
gene is the NADP(+)-dependent isocitrate dehydrogenase found in the
cytoplasm and peroxisomes. It contains the PTS-1 peroxisomal
targeting signal sequence. The presence of this enzyme in
peroxisomes suggests roles in the regeneration of NADPH for
intraperoxisomal reductions, such as the conversion of
2,4-dienoyl-CoAs to 3-enoyl-CoAs, as well as in peroxisomal
reactions that consume 2-oxoglutarate, namely the
alpha-hydroxylation of phytanic acid. The cytoplasmic enzyme serves
a significant role in cytoplasmic NADPH production.
[0004] The human IDH1 gene encodes a protein of 414 amino acids.
The nucleotide and amino acid sequences for human IDH1 can be found
as GenBank entries NM.sub.--005896.2 and NP.sub.--005887.2
respectively. The nucleotide and amino acid sequences for IDH1 are
also described in, e.g., Nekrutenko et al., Mol. Biol. Evol.
15:1674-1684 (1998); Geisbrecht et al., J. Biol. Chem.
274:30527-30533 (1999); Wiemann et al., Genome Res. 11:422-435
(2001); The MGC Project Team, Genome Res. 14:2121-2127(2004); Lubec
et al., Submitted (December 2008) to UniProtKB; Kullmann et al.,
Submitted (June 1996) to the EMBL/GenBank/DDBJ databases; and
Sjoeblom et al., Science 314:268-274 (2006).
[0005] Non-mutant, e.g., wild type, IDH1 catalyzes the oxidative
decarboxylation of isocitrate to a-ketoglutarate thereby reducing
NAD.sup.+ (NADP.sup.+) to NADP (NADPH), e.g., in the forward
reaction:
Isocitrate+NAD.sup.+(NADP.sup.+).fwdarw..alpha.-KG+CO.sub.2+NADH
(NADPH)+H.sup.+.
[0006] It has been discovered that mutations of IDH1 present in
certain cancer cells result in a new ability of the enzyme to
catalyze the NAPH-dependent reduction of .alpha.-ketoglutarate to
R(-)-2-hydroxyglutarate (2HG). 2HG is not formed by wild-type IDH1.
The production of 2HG is believed to contribute to the formation
and progression of cancer (Dang, L et al, Nature 2009,
462:739-44).
[0007] The inhibition of mutant IDH1 and its neoactivity is
therefore a potential therapeutic treatment for cancer.
Accordingly, there is an ongoing need for inhibitors of IDH1
mutants having alpha hydroxyl neoactivity.
SUMMARY OF INVENTION
[0008] Described herein are compounds of Structural Formula I:
##STR00002##
or a pharmaceutically acceptable salt thereof, wherein:
[0009] Y is --N(R.sup.5)--, --N(R.sub.5)--CH.sub.2--,
--CH.sub.2--N(R.sup.5)--, or --CH(R.sup.5)--;
[0010] each R.sup.1a and R.sup.1b is independently hydrogen,
--C.sub.1-C.sub.4 alkyl, --N(R.sup.7)(C.sub.1-C.sub.4
alkylene)-N(R.sup.7)(C.sub.1-C.sub.4 alkyl), aryl, heteroaryl,
heterocyclyl, --C(O)N(R.sup.7)-aryl, --N(R.sup.7)C(O)-aryl,
--(C.sub.1-C.sub.4 alkylene)-aryl, --(C.sub.1-C.sub.4
alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4 alkylene)-aryl,
--O--(C.sub.0-C.sub.4 alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4
alkylene)-heterocyclyl, --O--(C.sub.0-C.sub.4
alkylene)-carbocyclyl, --N(R.sup.7)-aryl, --N(R.sup.7)-heteroaryl,
--N(R.sup.9)-aryl, --N(R.sup.9)-heteroaryl, --O--(C.sub.1-C.sub.4
alkeylene)-N(R.sup.7)C(O)O--(C.sub.1-C.sub.4 alkylene)-aryl, or
--N(R.sup.9)--C(O)--(C.sub.2-C.sub.4 alkenyl) wherein:
[0011] at least one of R.sup.1a and R.sup.1b is not hydrogen or
methyl; any alkylene moiety present in R.sup.1a or R.sup.1 is
optionally substituted with OH or F;
[0012] each R.sup.7 is independently selected from hydrogen and
C.sub.1-C.sub.4 alkyl; and
[0013] any aryl, carbocyclyl, heteroaryl, or heterocyclyl of
R.sup.1a or R.sup.1b is optionally substituted with one or more
substituents selected from -G-L-M, halo, --NO.sub.2,
C.sub.1-C.sub.6 alkyl, --C.ident.N, .dbd.O, --CF.sub.3 and
--OCF.sub.3;
[0014] G is a bond or a bivalent C.sub.1-C.sub.6 saturated or
unsaturated, straight or branched hydrocarbon chain wherein
optionally one, two or three methylene units of the hydrocarbon
chain are independently replaced by --NR.sup.8--, --O--, --C(O)--,
--OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR.sup.8)--, --N.dbd.N--, or --C(.dbd.N.sub.2)--;
[0015] L is a covalent bond or a bivalent C.sub.1-8 saturated or
unsaturated, straight or branched, hydrocarbon chain, wherein one,
two, or three methylene units of L are optionally and independently
replaced by cyclopropylene, --NR.sup.8--, --N(R.sup.8)C(O)--,
--C(O)N(R.sup.8)--, --N(R.sup.8)SO.sub.2--, SO.sub.2N(R.sup.8)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--,
--C(.dbd.S)--, --C(.dbd.NR.sup.8)--, --N.dbd.N--, or
--C(.dbd.N.sub.2)--;
[0016] M is E, or a 3-10 membered monocyclic or bicyclic,
saturated, partially unsaturated, or aromatic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, and wherein said ring is substituted with at 1-4 groups
independently selected from -D-E, oxo, NO.sub.2, halogen, CN,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl;
[0017] D is a covalent bond or a bivalent C.sub.1-C.sub.6 saturated
or unsaturated, straight or branched, hydrocarbon chain, wherein
one or two methylene units of D are optionally and independently
replaced by --NR.sup.8--, --S--, --O--, --C(O)--, --SO--, or
--SO.sub.2--;
[0018] E is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, wherein said alkyl, alkenyl or
alkynyl is optionally substituted with oxo, halogen, or CN; and
[0019] each R.sup.8 is independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
--S(O).sub.2--C.sub.2-C.sub.4 alkenyl, --C.sub.1-C.sub.6 alkoxy, or
an optionally substituted group selected from phenyl, a 4-7
membered heterocyclyl having 1-2 heteroatoms independently selected
from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur;
[0020] R.sup.2 is selected from phenyl, a 3-7 membered cycloalkyl,
C.sub.2-C.sub.4 alkyl, or CF.sub.3, wherein the phenyl or
cycloalkyl is optionally substituted with a substituent selected
from methyl or fluoro;
[0021] each R.sup.3 is independently selected from halo,
--(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--C.sub.1-C.sub.4 fluoroalkyl, --C(O)--O--(C.sub.1-C.sub.4 alkyl),
-phenyl, -heteroaryl, C.sub.3-C.sub.7 cycloalkyl,
--CH.sub.2--N(C.sub.1-C.sub.4 alkyl).sub.2,
C(O)--N--(C.sub.1-C.sub.4 alkyl).sub.2,
--C(O)--NH--(C.sub.1-C.sub.4 alkyl), --C.sub.1-C.sub.4 alkyl
optionally substituted with one or more halo or --OH, or two
R.sup.3s are taken together to form a 3-8 saturated ring or a fused
phenyl wherein said saturated ring or fused phenyl is optionally
substituted with 1 to 2 methyl;
[0022] R.sup.4 is selected from hydrogen, --CN, halo,
C.sub.1-C.sub.4 alkoxy, --CH.sub.2NH(C.sub.1-C.sub.4 alkyl),
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.4 fluoroalkyl, C(O)--N--(C.sub.1-C.sub.4
alkyl).sub.2, --C(O)--NH--(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkyl), --C(O)--OH,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), and a 5-membered
heteroaryl;
[0023] R.sup.5 is selected from: --C(O)--(C.sub.1-C.sub.5 alkyl),
--C(O)--(C.sub.2-C.sub.6 alkenyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--(C.sub.1-C.sub.4 alkenylene)-Q,
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--O--(C.sub.0-C.sub.2 alkylene)-Q,
--C(O)--(C.sub.1-C.sub.2 alkylene)-O--(C.sub.0-C.sub.2 alkylene)-Q,
--C(O)--C(O)-Q, --S(O).sub.2-Q, --C(O)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4
alkyl), --C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.1-C.sub.6
alkyl), --C(O)--(C.sub.0-C.sub.2
alkylene)N(R.sup.6)--(C.sub.2-C.sub.6 alkynyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.2-C.sub.6
alkenyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-C(O)C(O)N(R)(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.2 alkylene)-S(O).sub.0-2-(C.sub.1-C.sub.4
alkyl), --S(O).sub.2--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-C(O)C(O)N(R.sup.6)(C.sub.1-C.sub.6 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-N(R.sup.6)S(O).sub.2--(C.sub.1-C.sub.6 alkyl), or
--C(O)--(C.sub.1-C.sub.4 alkylene)-N(R.sup.6)S(O).sub.2Q, wherein:
[0024] any alkylene moiety present in R.sup.5 is optionally
substituted with OCH.sub.3, OH or F; [0025] any terminal methyl
moiety present in R.sup.5 is optionally replaced with --CH.sub.2OH,
CF.sub.3, --CH.sub.2F, --CH.sub.2Cl, C(O)CH.sub.3, C(O)CF.sub.3,
CN, --OCH.sub.3, --C(O)H, --OP(O)(OH).sub.2,
--OP(O)(C.sub.1-C.sub.4 alkoxy).sub.2 or CO.sub.2H;
[0026] each R.sup.6 is independently selected from hydrogen and
methyl;
[0027] Q is selected from aryl, heteroaryl, carbocyclyl and
heterocyclyl, wherein Q is optionally substituted with up to 3
substituents independently selected from C.sub.1-C.sub.4 alkyl
optionally substituted with --OH, C.sub.1-C.sub.4 alkoxy,
--C(O)O--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4
alkylene)-(C.sub.1-C.sub.4 alkoxy), --CN, --OH, fluoro, chloro, and
bromo;
[0028] R.sup.9 is selected from aryl and heteroaryl, wherein each
aryl or heteroaryl is optionally substituted with one or more
substituents selected from -G-L-M, halo, C.sub.1-C.sub.6 alkyl,
--C.ident.N, .dbd.O, --CF.sub.3 and --OCF.sub.3; and
[0029] m is 0, 1, 2 or 3.
[0030] The compound of formula I inhibits mutant IDH1, particularly
mutant IDH1 having alpha hydroxyl neoactivity. Also described
herein are pharmaceutical compositions comprising a compound of
formula I or a salt thereof and methods of using such compositions
to treat cancers characterized by the presence of a mutant
IDH1.
DETAILED DESCRIPTION OF THE INVENTION
[0031] This invention is not limited in its application to the
details of construction and the arrangement of components set forth
in the following description or illustrated in the drawings. The
invention is capable of other embodiments and of being practiced or
of being carried out in various ways. Also, the phraseology and
terminology used herein is for the purpose of description and
should not be regarded as limiting. The use of "including,"
"comprising," or "having," "containing", "involving", and
variations thereof herein, is meant to encompass the items listed
thereafter and equivalents thereof as well as additional items.
DEFINITIONS
[0032] The term "halo" or "halogen" refers to any radical of
fluorine, chlorine, bromine or iodine.
[0033] The term "alkyl" refers to a hydrocarbon chain that may be a
straight chain or branched chain, containing the indicated number
of carbon atoms. For example, C.sub.1-C.sub.12 alkyl indicates that
the group may have from 1 to 12 (inclusive) carbon atoms in it. The
term "haloalkyl" refers to an alkyl in which one or more hydrogen
atoms are replaced by halo, and includes alkyl moieties in which
all hydrogens have been replaced by halo (e.g., perfluoroalkyl).
The terms "arylalkyl" or "aralkyl" refer to an alkyl moiety in
which an alkyl hydrogen atom is replaced by an aryl group. Aralkyl
includes groups in which more than one hydrogen atom has been
replaced by an aryl group. Examples of "arylalkyl" or "aralkyl"
include benzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl,
benzhydryl, and trityl groups.
[0034] The term "alkylene" refers to a divalent alkyl, e.g.,
--CH.sub.2--, --CH.sub.2CH.sub.2--, --CH.sub.2CH.sub.2CH.sub.2--
and --CH.sub.2CH(CH.sub.3)CH.sub.2--.
[0035] The term "alkenyl" refers to a straight or branched
hydrocarbon chain containing 2-12 carbon atoms and having one or
more double bonds. Examples of alkenyl groups include, but are not
limited to, allyl, propenyl, 2-butenyl, 3-hexenyl and 3-octenyl
groups. One of the double bond carbons may optionally be the point
of attachment of the alkenyl substituent.
[0036] The term "alkynyl" refers to a straight or branched
hydrocarbon chain containing 2-12 carbon atoms and characterized in
having one or more triple bonds. Examples of alkynyl groups
include, but are not limited to, ethynyl, propargyl, and 3-hexynyl.
One of the triple bond carbons may optionally be the point of
attachment of the alkynyl substituent.
[0037] The term "alkoxy" refers to an --O-alkyl radical. The term
"haloalkoxy" refers to an alkoxy in which one or more hydrogen
atoms are replaced by halo, and includes alkoxy moieties in which
all hydrogens have been replaced by halo (e.g.,
perfluoroalkoxy).
[0038] The term "aryl" refers to a fully aromatic monocyclic,
bicyclic, or tricyclic hydrocarbon ring system. Examples of aryl
moieties are phenyl, naphthyl, and anthracenyl. Unless otherwise
specified, any ring atom in an aryl can be substituted by one or
more substituents.
[0039] The term "carbocyclyl" refers to a non-aromatic, monocyclic,
bicyclic, or tricyclic hydrocarbon ring system. Carbocyclyl groups
include fully saturated ring systems (e.g., cycloalkyls), and
partially saturated ring systems.
[0040] The term "cycloalkyl" as employed herein includes saturated
cyclic, bicyclic, tricyclic, or polycyclic hydrocarbon groups
having 3 to 12 carbons. Any ring atom can be substituted (e.g., by
one or more substituents). Examples of cycloalkyl moieties include,
but are not limited to, cyclopropyl, cyclohexyl, methylcyclohexyl,
adamantyl, and norbornyl.
[0041] The term "heteroaryl" refers to a fully aromatic 5-8
membered monocyclic, 8-12 membered bicyclic, or 11-14 membered
tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said
heteroatoms selected from O, N, or S (or the oxidized forms such as
N.sup.+--O.sup.-, S(O) and S(O).sub.2).
[0042] The term "heterocyclyl" refers to a nonaromatic, 3-10
membered monocyclic, 8-12 membered bicyclic, or 11-14 membered
tricyclic ring system having 1-3 heteroatoms if monocyclic, 1-6
heteroatoms if bicyclic, or 1-9 heteroatoms if tricyclic, said
heteroatoms selected from O, N, or S (or the oxidized forms such as
N.sup.+--O.sup.-, S(O) and S(O).sub.2). The heteroatom may
optionally be the point of attachment of the heterocyclyl
substituent. Examples of heterocyclyl include, but are not limited
to, tetrahydropyranyl, tetrahydropyranyl, piperidinyl, morpholino,
pyrrolinyl, pyrimidinyl, and pyrrolidinyl. Heterocyclyl groups
include fully saturated ring systems, and partially saturated ring
systems.
[0043] Bicyclic and tricyclic ring systems containing one or more
heteroatoms and both aromatic and non-aromatic rings where the
point of attachment from the ring system to the rest of the
molecule is through a non-aromatic ring are considered to be
heterocyclyl groups. Bicyclic or tricyclic ring systems where an
aryl or a heteroaryl is fused to a carbocyclyl or heterocyclyl and
the point of attachment from the ring system to the rest of the
molecule is through an aromatic ring are considered to be aryl or
heteroaryl groups.
[0044] Aryl, heteroaryl, carbocyclyl (including cycloalkyl), and
heterocyclyl groups, either alone or a part of a group (e.g., the
aryl portion of an aralkyl group), are optionally substituted at
one or more substitutable atoms with, unless specified otherwise,
substituents independently selected from: halo, --CN,
C.sub.1-C.sub.4 alkyl, .dbd.O, --OR.sup.b, --OR.sup.b', --SR.sup.b,
--SR.sup.b', --(C.sub.1-C.sub.4 alkyl)-N(R.sup.b)(R.sup.b),
--(C.sub.1-C.sub.4 alkyl)-N(R.sup.b)(R.sup.b'),
--N(R.sup.b)(R.sup.b), --N(R)(R.sup.b'), --O--(C.sub.1-C.sub.4
alkyl)-N(R.sup.b)(R.sup.b), --O--(C.sub.1-C.sub.4
alkyl)-N(R.sup.b)(R.sup.b'), --(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl)-N(R.sup.b)(R.sup.b),
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4
alkyl)-N(R.sup.b)(R.sup.b'), --C(O)--N(R.sup.b)(R.sup.b),
--(C.sub.1-C.sub.4 alkyl)-C(O)--N(R.sup.b)(R.sup.b),
--(C.sub.1-C.sub.4 alkyl)-C(O)--N(R.sup.b)(R.sup.b'), --OR.sup.b',
R.sup.b', --C(O)(C.sub.1-C.sub.4 alkyl), --C(O)R.sup.b',
--C(O)N(R.sup.b')(R.sup.b), --N(R.sup.b)C(O)(R.sup.b),
--N(R.sup.b)C(O)(R.sup.b'), --N(R.sup.b)SO.sub.2(R.sup.b),
--SO.sub.2N(R.sup.b)(R.sup.b), --N(R.sup.b)SO.sub.2(R.sup.b'), and
--SO.sub.2N(R.sup.b)(R.sup.b'), wherein any alkyl substituent is
optionally further substituted with one or more of --OH,
--O--(C.sub.1-C.sub.4 alkyl), halo, --NH.sub.2,
--NH(C.sub.1-C.sub.4 alkyl), or --N(C.sub.1-C.sub.4
alkyl).sub.2;
[0045] each R.sup.b is independently selected from hydrogen, and
--C.sub.1-C.sub.4 alkyl; or
[0046] two R.sup.bs are taken together with the nitrogen atom to
which they are bound to form a 4- to 8-membered heterocyclyl
optionally comprising one additional heteroatom selected from N, S,
and O; and
[0047] each R.sup.b' is independently selected from C.sub.3-C.sub.7
carbocylyl, phenyl, heteroaryl, and heterocyclyl, wherein one or
more substitutable positions on said phenyl, cycloalkyl, heteroaryl
or heterocycle substituent is optionally further substituted with
one or more of --(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4
fluoroalkyl), --OH, --O--(C.sub.1-C.sub.4 alkyl),
--O--(C.sub.1-C.sub.4 fluoroalkyl), halo, --NH.sub.2,
--NH(C.sub.1-C.sub.4 alkyl), or --N(C.sub.1-C.sub.4
alkyl).sub.2.
[0048] Heterocyclyl groups, either alone or as part of a group, are
optionally substituted on one or more any substitutable nitrogen
atom with oxo, --C.sub.1-C.sub.4 alkyl, or fluoro-substituted
C.sub.1-C.sub.4 alkyl.
[0049] The term "substituted" refers to the replacement of a
hydrogen atom by another group.
[0050] As used herein, the term "elevated levels of 2HG" means 10%,
20% 30%, 50%, 75%, 100%, 200%, 500% or more 2HG then is present in
a subject that does not carry a mutant IDH1 allele. The term
"elevated levels of 2HG" may refer to the amount of 2HG within a
cell, within a tumor, within an organ comprising a tumor, or within
a bodily fluid.
[0051] The term "bodily fluid" includes one or more of amniotic
fluid surrounding a fetus, aqueous humour, blood (e.g., blood
plasma), serum, Cerebrospinal fluid, cerumen, chyme, Cowper's
fluid, female ejaculate, interstitial fluid, lymph, breast milk,
mucus (e.g., nasal drainage or phlegm), pleural fluid, pus, saliva,
sebum, semen, serum, sweat, tears, urine, vaginal secretion, or
vomit.
[0052] As used herein, the terms "inhibit" or "prevent" include
both complete and partial inhibition and prevention. An inhibitor
may completely or partially inhibit the intended target.
[0053] The term "treat" means decrease, suppress, attenuate,
diminish, arrest, or stabilize the development or progression of a
disease/disorder (e.g., a cancer), lessen the severity of the
disease/disorder (e.g., a cancer) or improve the symptoms
associated with the disease/disorder (e.g., a cancer).
[0054] As used herein, an amount of a compound effective to treat a
disorder, or a "therapeutically effective amount" refers to an
amount of the compound which is effective, upon single or multiple
dose administration to a subject, in treating a cell, or in curing,
alleviating, relieving or improving a subject with a disorder
beyond that expected in the absence of such treatment.
[0055] As used herein, the term "subject" is intended to include
human and non-human animals. Exemplary human subjects include a
human patient (referred to as a patient) having a disorder, e.g., a
disorder described herein or a normal subject. The term "non-human
animals" of the invention includes all vertebrates, e.g.,
non-mammals (such as chickens, amphibians, reptiles) and mammals,
such as non-human primates, domesticated and/or agriculturally
useful animals, e.g., sheep, dog, cat, cow, pig, etc.
Compounds
[0056] Provided is a compound of Structural Formula I:
##STR00003##
or a pharmaceutically acceptable salt thereof, wherein:
[0057] Y is --N(R.sup.5)--, --N(R.sub.5)--CH.sub.2--,
--CH.sub.2--N(R.sup.5)--, or --CH(R.sup.5)--;
[0058] each R.sup.1a and R.sup.1b is independently hydrogen,
--C.sub.1-C.sub.4 alkyl, --N(R.sup.7)(C.sub.1-C.sub.4
alkylene)-N(R.sup.7)(C.sub.1-C.sub.4 alkyl), aryl, heteroaryl,
heterocyclyl, --C(O)N(R.sup.7)-aryl, --N(R.sup.7)C(O)-aryl,
--(C.sub.1-C.sub.4 alkylene)-aryl, --(C.sub.1-C.sub.4
alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4 alkylene)-aryl,
--O--(C.sub.0-C.sub.4 alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4
alkylene)-heterocyclyl, --O--(C.sub.0-C.sub.4
alkylene)-carbocyclyl, --N(R.sup.7)-aryl, --N(R.sup.7)-heteroaryl,
--N(R.sup.9)-aryl, --N(R.sup.9)-heteroaryl, --O--(C.sub.1-C.sub.4
alkeylene)-N(R.sup.7)C(O)O--(C.sub.1-C.sub.4 alkylene)-aryl, or
--N(R.sup.9)--C(O)--(C.sub.2-C.sub.4 alkenyl) wherein:
[0059] at least one of R.sup.1a and R.sup.1b is not hydrogen or
methyl;
[0060] any alkylene moiety present in R.sup.1a or R.sup.1b is
optionally substituted with OH or F;
[0061] each R.sup.7 is independently selected from hydrogen and
C.sub.1-C.sub.4 alkyl; and
[0062] any aryl, carbocyclyl, heteroaryl, or heterocyclyl of
R.sup.1a or R.sup.1b is optionally substituted with one or more
substituents selected from -G-L-M, halo, --NO.sub.2,
C.sub.1-C.sub.6 alkyl, --C.ident.N, .dbd.O, --CF.sub.3 and
--OCF.sub.3;
[0063] G is a bond or a bivalent C.sub.1-C.sub.6 saturated or
unsaturated, straight or branched hydrocarbon chain wherein
optionally one, two or three methylene units of the hydrocarbon
chain are independently replaced by --NR.sup.8--, --O--, --C(O)--,
--OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR.sup.8)--, --N.dbd.N--, or --C(.dbd.N.sub.2)--;
[0064] L is a covalent bond or a bivalent C.sub.1-8 saturated or
unsaturated, straight or branched, hydrocarbon chain, wherein one,
two, or three methylene units of L are optionally and independently
replaced by cyclopropylene, --NR.sup.8--, --N(R.sup.8)C(O)--,
--C(O)N(R.sup.8)--, --N(R.sup.8)SO.sub.2--, SO.sub.2N(R.sup.8)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--,
--C(.dbd.S)--, --C(.dbd.NR.sup.8)--, --N.dbd.N--, or
--C(.dbd.N.sub.2)--;
[0065] M is E, or a 3-10 membered monocyclic or bicyclic,
saturated, partially unsaturated, or aromatic ring having 0-3
heteroatoms independently selected from nitrogen, oxygen, or
sulfur, and wherein said ring is substituted with at 1-4 groups
independently selected from -D-E, oxo, NO.sub.2, halogen, CN,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl;
[0066] D is a covalent bond or a bivalent C.sub.1-C.sub.6 saturated
or unsaturated, straight or branched, hydrocarbon chain, wherein
one or two methylene units of D are optionally and independently
replaced by --NR.sup.8--, --S--, --O--, --C(O)--, --SO--, or
--SO.sub.2--;
[0067] E is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, wherein said alkyl, alkenyl or
alkynyl is optionally substituted with oxo, halogen, or CN; and
[0068] each R.sup.8 is independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl,
--C.sub.1-C.sub.6 alkoxy, --S(O).sub.2--C.sub.2-C.sub.4 alkenyl, or
an optionally substituted group selected from phenyl, a 4-7
membered heterocyclyl having 1-2 heteroatoms independently selected
from nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur;
[0069] R.sup.2 is selected from phenyl, a 3-7 membered cycloalkyl,
C.sub.2-C.sub.4 alkyl, or CF.sub.3, wherein the phenyl or
cycloalkyl is optionally substituted with a substituent selected
from methyl or fluoro;
[0070] each R.sup.3 is independently selected from halo,
--(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--C.sub.1-C.sub.4 fluoroalkyl, --C(O)--O--(C.sub.1-C.sub.4 alkyl),
-phenyl, -heteroaryl, C.sub.3-C.sub.7 cycloalkyl,
--CH.sub.2--N(C.sub.1-C.sub.4 alkyl).sub.2,
C(O)--N--(C.sub.1-C.sub.4 alkyl).sub.2,
--C(O)--NH--(C.sub.1-C.sub.4 alkyl), --C.sub.1-C.sub.4 alkyl
optionally substituted with one or more halo or --OH, or two
R.sup.5 are taken together to form a 3-8 saturated ring or a fused
phenyl wherein said saturated ring or fused phenyl is optionally
substituted with 1 to 2 methyl;
[0071] R.sup.4 is selected from hydrogen, --CN, halo,
C.sub.1-C.sub.4 alkoxy, --CH.sub.2NH(C.sub.1-C.sub.4 alkyl),
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.4 fluoroalkyl, C(O)--N--(C.sub.1-C.sub.4
alkyl).sub.2, --C(O)--NH--(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkyl), --C(O)--OH,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), and a 5-membered
heteroaryl;
[0072] R.sup.5 is selected from: --C(O)--(C.sub.1-C.sub.5 alkyl),
--C(O)--(C.sub.2-C.sub.6 alkenyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--(C.sub.1-C.sub.4 alkenylene)-Q,
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--O--(C.sub.0-C.sub.2 alkylene)-Q,
--C(O)--(C.sub.1-C.sub.2 alkylene)-O--(C.sub.0-C.sub.2 alkylene)-Q,
--C(O)--C(O)-Q, --S(O).sub.2-Q, --C(O)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4
alkyl), --C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.1-C.sub.6
alkyl), --C(O)--(C.sub.0-C.sub.2
alkylene)N(R.sup.6)--(C.sub.2-C.sub.0 alkynyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.2-C.sub.6
alkenyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-C(O)C(O)N(R)(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.0-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.2 alkylene)-S(O).sub.0-2-(C.sub.1-C.sub.4
alkyl), --S(O).sub.2--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-C(O)C(O)N(R.sup.6)(C.sub.1-C.sub.6 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-N(R.sup.6)S(O).sub.2--(C.sub.1-C.sub.6 alkyl), or
--C(O)--(C.sub.1-C.sub.4 alkylene)-N(R.sup.6)S(O).sub.2Q, wherein:
[0073] any alkylene moiety present in R.sup.5 is optionally
substituted with OCH.sub.3, OH or F; [0074] any terminal methyl
moiety present in R.sup.5 is optionally replaced with --CH.sub.2OH,
[0075] CF.sub.3, --CH.sub.2F, --CH.sub.2Cl, C(O)CH.sub.3,
C(O)CF.sub.3, CN, --OCH.sub.3, --C(O)H, --OP(O)(O).sub.2,
--OP(O)(C.sub.1-C.sub.4 alkoxy).sub.2 or CO.sub.2H;
[0076] each R.sup.6 is independently selected from hydrogen and
methyl;
[0077] Q is selected from aryl, heteroaryl, carbocyclyl and
heterocyclyl, wherein Q is optionally substituted with up to 3
substituents independently selected from C.sub.1-C.sub.4 alkyl
optionally substituted with --OH, C.sub.1-C.sub.4 alkoxy,
--C(O)O--(C.sub.1-C.sub.4 alkyl), --(C.sub.1-C.sub.4
alkylene)-(C.sub.1-C.sub.4 alkoxy), --CN, --OH, fluoro, chloro, and
bromo;
[0078] R.sup.9 is selected from aryl, and heteroaryl, wherein each
aryl or heteroaryl is optionally substituted with one or more
substituents selected from -G-L-M, halo, C.sub.1-C.sub.6 alkyl,
--C.ident.N, .dbd.O, --CF.sub.3 and --OCF.sub.3; and
[0079] m is 0, 1, 2 or 3.
[0080] In some embodiments, provided is a compound of Structural
Formula I:
##STR00004##
or a pharmaceutically acceptable salt thereof, wherein:
[0081] Y is --N(R.sup.5)-- or --CH(R.sup.5)--;
[0082] each R.sup.1a and R.sup.1b is independently hydrogen,
--C.sub.1-C.sub.4 alkyl, --N(R.sup.7)(C.sub.1-C.sub.4
alkylene)-N(R.sup.7)(C.sub.1-C.sub.4 alkyl), aryl, heteroaryl,
heterocyclyl, --C(O)N(R.sup.7)-aryl, --N(R.sup.7)C(O)-aryl,
--(C.sub.1-C.sub.4 alkylene)-aryl, --(C.sub.1-C.sub.4
alkylene)-heteroaryl, --O--(C.sub.1-C.sub.4 alkylene)-aryl,
--O--(C.sub.1-C.sub.4 alkylene)-heteroaryl, --O--(C.sub.1-C.sub.4
alkylene)-heterocyclyl, --N(R.sup.7)-aryl, or
--N(R.sup.7)-heteroaryl, wherein: [0083] at least one of R.sup.1a
and R.sup.1b is not hydrogen or methyl; [0084] any alkylene moiety
present in R.sup.1a or R.sup.1b is optionally substituted with OH
or F; [0085] each R.sup.7 is independently selected from hydrogen
and C.sub.1-C.sub.4 alkyl; and [0086] any aryl, heteroaryl, or
hetercylyl of R.sup.1a or R.sup.1b is optionally substituted with
one or more substituents selected from -G-L-M, halo,
C.sub.1-C.sub.6 alkyl, --C.ident.N, .dbd.O, --CF.sub.3 and
--OCF.sub.3;
[0087] G is a bond or a bivalent C.sub.1-C.sub.6 saturated or
unsaturated, straight or branched hydrocarbon chain wherein
optionally one, two or three methylene units of the hydrocarbon
chain are independently replaced by --NR.sup.8--, --O--, --C(O)--,
--OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--, --C(.dbd.S)--,
--C(.dbd.NR.sup.8)--, --N.dbd.N--, or --C(.dbd.N.sub.2)--; [0088] L
is a covalent bond or a bivalent C.sub.1-8 saturated or
unsaturated, straight or branched, hydrocarbon chain, wherein one,
two, or three methylene units of L are optionally and independently
replaced by cyclopropylene, --NR.sup.8--, --N(R.sup.8)C(O)--,
--C(O)N(R.sup.8)--, --N(R.sup.8)SO.sub.2--, SO.sub.2N(R.sup.8)--,
--O--, --C(O)--, --OC(O)--, --C(O)O--, --S--, --SO--, --SO.sub.2--,
--C(.dbd.S)--, --C(.dbd.NR.sup.8)--, --N.dbd.N--, or
--C(.dbd.N.sub.2)--; M is E, or a 3-10 membered monocyclic or
bicyclic, saturated, partially unsaturated, or aromatic ring having
0-3 heteroatoms independently selected from nitrogen, oxygen, or
sulfur, and wherein said ring is substituted with at 1-4 groups
independently selected from -D-E, oxo, NO.sub.2, halogen, CN,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6
alkynyl;
[0089] D is a covalent bond or a bivalent C.sub.1-C.sub.6 saturated
or unsaturated, straight or branched, hydrocarbon chain, wherein
one or two methylene units of D are optionally and independently
replaced by --NR.sup.8--, --S--, --O--, --C(O)--, --SO--, or
--SO.sub.2--;
[0090] E is hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, wherein said alkyl, alkenyl or
alkynyl is optionally substituted with oxo, halogen, or CN; and
[0091] each R.sup.8 is independently hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or an
optionally substituted group selected from phenyl, a 4-7 membered
heterocyclyl having 1-2 heteroatoms independently selected from
nitrogen, oxygen, or sulfur, or a 5-6 membered monocyclic
heteroaryl ring having 1-4 heteroatoms independently selected from
nitrogen, oxygen, or sulfur;
[0092] R.sup.2 is selected from phenyl, a 3-7 membered cycloalkyl,
and C.sub.2-C.sub.4 alkyl, wherein the phenyl or cycloalkyl is
optionally substituted with a substituent selected from methyl or
fluoro;
[0093] each R.sup.3 is independently selected from
--C.sub.1-C.sub.4 alkyl, --(C.sub.1-C.sub.4
alkyl)-O--(C.sub.1-C.sub.4 alkyl), --C.sub.1-C.sub.4 fluoroalkyl,
--C(O)--O--(C.sub.1-C.sub.4 alkyl), -phenyl, -heteroaryl,
C.sub.3-C.sub.7 cycloalkyl, --CH.sub.2--N(C.sub.1-C.sub.4
alkyl).sub.2, C(O)--N--(C.sub.1-C.sub.4 alkyl).sub.2, and
--C(O)--NH--(C.sub.1-C.sub.4 alkyl), or
[0094] or two R.sup.3s are taken together to form a 3-8 saturated
ring or a fused phenyl wherein said saturated ring or fused phenyl
is optionally substituted with 1 to 2 methyl groups;
[0095] R.sup.4 is selected from hydrogen, --CN, halo,
C.sub.1-C.sub.4 alkoxy, --CH.sub.2NH(C.sub.1-C.sub.4 alkyl),
C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
--(C.sub.1-C.sub.4 alkyl)-O--(C.sub.1-C.sub.4 alkyl),
C.sub.1-C.sub.4 fluoroalkyl, C(O)--N--(C.sub.1-C.sub.4
alkyl).sub.2, --C(O)--NH--(C.sub.1-C.sub.4 alkyl),
--C(O)--O--(C.sub.1-C.sub.4 alkyl), --C(O)--OH,
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), and a 5-membered
heteroaryl;
[0096] R.sup.5 is selected from: --C(O)--(C.sub.1-C.sub.4alkyl),
--C(O)--(CH.sub.2).sub.0-2-Q,
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(CH.sub.2).sub.0-2-Q,
--C(O)--O--(CH.sub.2).sub.1-2-Q,
--C(O)--(CH.sub.2).sub.1-2--O--(CH.sub.2).sub.0-2-Q,
--C(O)--C(O)-Q, --S(O).sub.2-Q, --C(O)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4
alkyl), --C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--N(R.sup.6)--(C.sub.1-C.sub.4
alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(C.sub.1-C.sub.6 alkyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(C.sub.2-C.sub.6 alkynyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(C.sub.2-C.sub.6 alkenyl),
--C(O)--(CH.sub.2).sub.0-2--N(R.sup.6)--(CH.sub.2).sub.0-2--O--(C.sub.1-C-
.sub.4 alkyl), --C(O)--(CH.sub.2).sub.1-2--O--(C.sub.1-C.sub.4
alkyl), --C(O)--O--(C.sub.1-C.sub.4 alkylene)-O--(C.sub.1-C.sub.4
alkyl), --(CH.sub.2).sub.04--O--C(O)--(C.sub.1-C.sub.4 alkyl),
--(CH.sub.2).sub.0-4--C(O)--O--(C.sub.1-C.sub.4 alkyl),
--(CH.sub.2).sub.0-4--O--(C.sub.1-C.sub.4 alkyl),
--C(O)--(CH.sub.2).sub.1-2--S--(C.sub.1-C.sub.4 alkyl),
--S(O).sub.2--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4
alkylene)-C(O)C(O)N(R.sup.6)(C.sub.1-C.sub.6 alkyl),
--C(O)--(C.sub.1-C.sub.4
alkylene)-N(R.sup.6)S(O).sub.2--(C.sub.1-C.sub.6 alkyl), and
--C(O)--(C.sub.1-C.sub.4 alkylene)-N(R.sup.6)S(O).sub.2Q, wherein:
[0097] any alkylene moiety present in R.sup.5 is optionally
substituted with OH or F; [0098] any terminal methyl moiety present
in R.sup.5 is optionally replaced with --CH.sub.2OH, CF.sub.3,
--CH.sub.2F, --CH.sub.2Cl, C(O)CH.sub.3, or C(O)CF.sub.3;
[0099] each R.sup.6 is independently selected from hydrogen and
methyl;
[0100] Q is selected from aryl, heteroaryl, carbocyclyl and
heterocyclyl, wherein Q is optionally substituted with up to 3
substituents independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, --CN, fluoro, chloro, and bromo; and
[0101] m is 0, 1, 2 or 3.
[0102] In some embodiments, m is 0, 1 or 2; and each R.sup.3, if
present, is independently selected from methyl, ethyl, CF.sub.3,
isopropyl, cyclopropyl and phenyl. In some embodiments, R.sup.3 is
methyl or cyclopropyl. In some embodiments, R.sup.3 is methyl. In
some embodiments, R.sup.3 is cyclopropyl.
[0103] In some embodiments, m is 1. In some embodiments, m is
2.
[0104] In some embodiments, m is 1 and R.sup.3 is C.sub.3-7
cycloalkyl (e.g., cyclopropyl). In some embodiments, m is 1 and
R.sup.3 is C.sub.1-C.sub.4 (alkyl) (e.g., methyl or isopropyl). In
some embodiments, m is 1 and R.sup.3 is haloalkyl (e.g.,
C.sub.1-C.sub.4 fluoroalkyl, e.g., CF.sub.3). In some embodiments,
m is 2, one R.sup.3 is C.sub.1-4 alkyl (e.g., methyl) and the other
R.sup.3 is halo (e.g., fluoro).
[0105] In some embodiments, R.sup.4 is --CN or
--C(O)--O--(C.sub.1-C.sub.4 alkyl). In some embodiments, R.sup.4 is
CN.
[0106] In some embodiments, R.sup.4 is:
##STR00005##
In some embodiments, R.sup.4 is
##STR00006##
[0107] In some embodiments, Y is --N(R.sub.5)--CH.sub.2-- or
--CH.sub.2--N(R.sup.5)--; R.sup.5 is --C(O)-Q and Q is
cyclopropyl.
[0108] In some embodiments, Y is --N(R.sup.5)--; R.sup.5 is
--C(O)R.sup.10; and R.sup.10 is selected from heteroaryl, aryl,
--CH.sub.2-aryl, --CH.sub.2-heteroaryl, and
--(CH.sub.2).sub.2--O--CH.sub.3, wherein any aryl or heteroaryl
portion of R.sup.8 is optionally substituted with methyl.
[0109] In some embodiments, Y is --N(R.sup.5)--; R.sup.5 is
selected from selected from: --C(O)--(C.sub.1-C.sub.5 alkyl),
--C(O)--(C.sub.2-C.sub.6 alkenyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--(C.sub.1-C.sub.4 alkenylene)-Q,
--C(O)-(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--(C.sub.1-C.sub.2 alkylene)-O--(C.sub.0-C.sub.2
alkylene)-Q, --C(O)--(C.sub.1-C.sub.4
alkylene)-O--C(O)--(C.sub.1-C.sub.4 alkyl),
--C(O)--(C.sub.1-C.sub.4 alkylene)-C(O)--O--(C.sub.1-C.sub.4
alkyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-N(R.sup.6)--(C.sub.1-C.sub.6 alkyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)N(R.sup.6)--(C.sub.2-C.sub.6
alkynyl), --C(O)--(C.sub.0-C.sub.2
alkylene)-N(R.sup.6)--(C.sub.2-C.sub.6 alkenyl),
--C(O)--(C.sub.0-C.sub.2 alkylene)-N(R.sup.6)--(C.sub.0-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --(C.sub.0
alkylene)-C(O)O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-O--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-C(O)C(O)N(R)(C.sub.1-C.sub.4 alkyl), or
--C(O)--(C.sub.1-C.sub.4
alkylene)-C(O)C(O)N(R.sup.6)(C.sub.1-C.sub.6 alkyl), wherein:
[0110] any alkylene moiety present in R.sup.5 is optionally
substituted with OCH.sub.3, OH or F; [0111] any terminal methyl
moiety present in R.sup.5 is optionally replaced with --CH.sub.2OH,
CF.sub.3, --CH.sub.2F, --CH.sub.2Cl, C(O)CH.sub.3, C(O)CF.sub.3,
CN, --OCH.sub.3, --C(O)H, --OP(O)(OH).sub.2,
--OP(O)(C.sub.1-C.sub.4 alkoxy).sub.2 or CO.sub.2H;
[0112] each R.sup.6 is independently selected from hydrogen and
methyl; [0113] Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl,
azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl,
or cyclopentyl, wherein each member of Q is optionally substituted
with up to 3 substituents independently selected from
C.sub.1-C.sub.4 alkyl optionally substituted with OH,
C.sub.1-C.sub.4 alkoxy, --C(O)O--(C.sub.1-C.sub.4 alkyl),
--(C.sub.1-C.sub.4 alkylene)-(C.sub.1-C.sub.4 alkoxy), --CN, --OH,
fluoro, chloro, and bromo.
[0114] In some embodiments, Y is --N(R.sup.5)--; and R.sup.5 is
--C(O)--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.2 alkyl),
--C(O)-Q, --C(O)--(C.sub.1-C.sub.5 alkyl), --C(O)--(C.sub.1-C.sub.2
alkylene)-Q, --C(O)--(C.sub.2-C.sub.4 alkenyl),
--C(O)O--(C.sub.1-C.sub.4 alkyl), or --C(O)--(C.sub.1-C.sub.4
alkenylene)-Q; wherein: any alkylene moiety present in R.sup.5 is
optionally substituted with OH; any terminal methyl moiety present
in R.sup.5 is optionally replaced with --OH, CF.sub.3, OCH.sub.3,
--C(O)H, OP(O)(C.sub.1-C.sub.4 alkoxy).sub.2, or --OP(O)(OH).sub.2
(or a salt thereof, such as a sodium salt); Q is cyclopropyl,
cyclobutyl, oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl,
tetrahydrofuranyl, dihydrofuranonyl, or cyclopentyl, wherein each
member of Q is optionally substituted with one substituent
independently selected from C.sub.1-C.sub.4 alkyl optionally
substituted with OH, C.sub.1-C.sub.4 alkoxy, --(C.sub.1-C.sub.4
alkylene)-(C.sub.1-C.sub.4 alkoxy), and --OH.
[0115] In some embodiments, Y is --N(R.sup.5)--; and R.sup.5 is
--C(O)--(C.sub.1-C.sub.3 alkyl)-O--(C.sub.1-C.sub.2 alkyl). In some
embodiments, Y is --N(R.sup.5)--; and R.sup.5 is
--C(O)--(CH.sub.2).sub.2--OCH.sub.3. In some embodiments, Y is
--N(R.sup.5)-- and R.sup.5 is --C(O)--(C.sub.1-C.sub.3
alkyl)-CF.sub.3. In some embodiments, Y is --N(R.sup.5)-- and
R.sup.5 is --C(O)--CH.sub.2--CF.sub.3. In some embodiments, Y is
--N(R.sup.5)--; R.sup.5 is --C(O)-Q and Q is cyclopropyl, oxetanyl
or furanyl. In some embodiments, Y is --N(R.sup.5)-- and R.sup.5 is
--C(O)--CH.sub.2--CH.sub.2OH. In some embodiments, Y is
--N(R.sup.5)--; R.sup.5 is --C(O)-Q where Q is substituted with
C.sub.1-4 alkoxy. In some embodiments, Y is --N(R.sup.5)-- and
R.sup.5 is --C(O)-cyclopropyl substituted with C.sub.1-4 alkoxy
(e.g., ethoxy). In some embodiments, Y is --N(R.sup.5)-- and
R.sup.5 is --C(O)--OCH.sub.3. In some embodiments, Y is
--N(R.sup.5)-- and R.sup.5--C(O)-Q where Q is substituted with
(C.sub.1-4 alkylene)-OCH.sub.3. In some embodiments, Y is
--N(R.sup.5)-- and R.sup.5--C(O)-cyclopropyl substituted with
CH.sub.2OCH.sub.3. In some embodiments, Y is --N(R.sup.5)-- and
R.sup.5--C(O)-Q where Q is substituted with C.sub.1-4 alkyl wherein
alkyl is optionally substituted with --OH. In some embodiments, Y
is --N(R.sup.5)-- and R.sup.5--C(O)-cyclopropyl substituted with
CH.sub.2OH. In some embodiments, Y is --N(R.sup.5)--; R.sup.5 is
--C(O)-Q where Q is substituted with OH. In some embodiments, Y is
--N(R.sup.5)--; R.sup.5 is --C(O)-cyclopropyl substituted with OH.
In some embodiments, Y is --N(R.sup.5)--; R.sup.5 is
--C(O)--(C.sub.1-4 alkyl)-OH. In some embodiments, Y is
--N(R.sup.5)--; R.sup.5 is --C(O)--CH.sub.2C(OH)(CH.sub.3).sub.2.
In some embodiments, Y is --N(R.sup.5)--; R.sup.5 is
--C(O)--CH.sub.2CH(OH)CH.sub.3. In some embodiments, Y is
--N(R.sup.5)--; R.sup.5 is --C(O)--CH.sub.2CH.sub.2CH.sub.2OH. In
some embodiments, Y is --N(R.sup.5)--; R.sup.5 is
--C(O)--CH.sub.2CH.sub.2OH. In some embodiments, Y is
--N(R.sup.5)--; and R.sup.5 is --C(O)--(C.sub.1-C.sub.4 alkyl). In
some embodiments, Y is --N(R.sup.5)--; and R.sup.5 is
--C(O)--CH.sub.3. In some embodiments, Y is --N(R.sup.5)--; R.sup.5
is --C(O)--(C.sub.1-4 alkyl)-(OCH.sub.3).sub.2. In some
embodiments, Y is --N(R.sup.5)--; R.sup.5 is
--C(O)--CH.sub.2CH.sub.2C(H)(OCH.sub.3).sub.2. In some embodiments,
Y is --N(R.sup.5)--; R.sup.5 is --C(O)--(C.sub.1-4 alkyl)-C(O)H. In
some embodiments, Y is --N(R.sup.5)--; R.sup.5 is
--C(O)--CH.sub.2CH.sub.2C(O)H. In some embodiments, Y is
--N(R.sup.5)--; R.sup.5 is --C(O)--C(cyclopropyl)(OH). In some
embodiments, Y is --N(R.sup.5)--; R.sup.5 is --C(O)--(C.sub.1-4
alkyl)-C(O)OCH.sub.3. In some embodiments, Y is --N(R.sup.5)--;
R.sup.5 is --C(O)--CH.sub.2CH.sub.2C(O)OCH.sub.3. In some
embodiments, Y is --N(R.sup.5)-- and R.sup.5 is
--C(O)--(C.sub.0-C.sub.2 alkylene)-Q. In some embodiments, Y is
--N(R.sup.5)-- and R.sup.5 is --C(O)--(C.sub.0-C.sub.2 alkylene)-Q,
where Q is cyclopropyl, cyclobutyl, oxetanyl, furanyl,
azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl, dihydrofuranonyl,
or cyclopentyl. In some embodiments, Y is --N(R.sup.5)-- and
R.sup.5 is --C(O)--CH.sub.2-oxetanyl,
--C(O)--CH.sub.2-azetidinonyl, --C(O)--CH.sub.2-pyrrolidinonyl,
--C(O)--CH.sub.2-cyclobutyl, --C(O)--CH.sub.2-cyclopropyl,
--C(O)--CH.sub.2CH.sub.2-cyclopropyl,
--C(O)--CH.sub.2-tetrahydrofuranyl,
--C(O)--CH.sub.2-dihydrofuranone,
--C(O)--CH.sub.2CH.sub.2-oxetanyl,
--C(O)--CH.sub.2CH.sub.2-furanyl,
--C(O)--CH.sub.2-ietrahydrofuranyl,
--C(O)--CH.sub.2CH.sub.2-tetrahydrofuranyl or
--C(O)--CH.sub.2-cyclopentyl. In some embodiments, Y is
--N(R.sup.5)-- and R.sup.5 is --C(O)--(C.sub.2-C.sub.4 alkenyl)-OH.
In some embodiments, Y is --N(R.sup.5)-- and R.sup.5 is
--C(O)--CH.dbd.CH--CH.sub.2CH.sub.2OH. In some embodiments, Y is
--N(R.sup.5)-- and R.sup.5--(C.sub.0-C.sub.4
alkylene)-C(O)--O--(C.sub.1-C.sub.4 alkyl). In some embodiments, Y
is --N(R.sup.5)-- and R.sup.5--C(O)--O-(t-butyl). In some
embodiments, Y is --N(R.sup.5)-- and
R.sup.5--C(O)--(C.sub.1-C.sub.4 alkyl)-OP(O)(C.sub.1-C.sub.4
alkoxy).sub.2. In some embodiments, Y is --N(R.sup.5)-- and
R.sup.5--C(O)--CH.sub.2CH.sub.2CH.sub.2--OP(O)(t-butoxy).sub.2. In
some embodiments, Y is --N(R.sup.5)-- and
R.sup.5--C(O)--(C.sub.1-C.sub.4 alkyl)-OP(O)(OH).sub.2 or a salt
thereof, such as a sodium salt. In some embodiments, Y is
--N(R.sup.5)-- and
R.sup.5--C(O)--CH.sub.2CH.sub.2--OP(O)(t-butoxy).sub.2. In some
embodiments, Y is --N(R.sup.5)--; and R.sup.5 is
--C(O)--(C.sub.1-C.sub.5 alkyl). In some embodiments, Y is
--N(R.sup.5)--; and R.sup.5 is --C(O)-pentyl. In some embodiments,
Y is --N(R.sup.5)--; and R.sup.5--C(O)--(C.sub.1-C.sub.4
alkenylene)-Q. In some embodiments, Y is --N(R.sup.5)--; and
R.sup.5--C(O)--CH=cyclobutyl.
[0116] In some embodiments, one of R.sup.1a or R.sup.1b is selected
from hydrogen and methyl; and the other of R.sup.1a or R.sup.1b is
selected from isopropyl,
--N(CH.sub.3)--(CH.sub.2).sub.2--NH--CH.sub.3, aryl, heteroaryl,
--CH.sub.2-aryl, --CH.sub.2-heteroaryl, --O--CH.sub.2-aryl, and
--O--CH.sub.2-heteroaryl; wherein any aryl or heteroaryl of
R.sup.1a or R.sup.1b is optionally substituted with one or more
substituents independently selected from alkoxy, OH, halo,
C.sub.1-C.sub.6 alkyl, --CF.sub.3, CN, --OC(O)CH.sub.3, and
--OCF.sub.3.
[0117] In some embodiments, one of R.sup.1a or R.sup.1b is selected
from hydrogen and methyl; and the other of R.sup.1a or R.sup.1b is
selected from aryl, heteroaryl, heterocyclyl, --(C.sub.1-C.sub.4
alkylene)-aryl, --(C.sub.1-C.sub.4 alkylene)-heteroaryl,
--O--(C.sub.0-C.sub.4 alkylene)-aryl, --O--(C.sub.0-C.sub.4
alkylene)-heteroaryl, --N(R.sup.7)-aryl, --N(R.sup.7)heteroaryl,
--N(R.sup.9)-aryl, or --N(R.sup.9)-heteroaryl, wherein said aryl,
heterocyclyl, or heteroaryl is substituted with -G-L-M, CH.sub.3,
CN, alkoxy, OH, halo, C.sub.1-C.sub.6 alkyl, --CF.sub.3,
--OC(O)CH.sub.3, or --OCF.sub.3.
[0118] In some embodiments, one of R.sup.1a or R.sup.1b is selected
from hydrogen and methyl; and the other of R.sup.1a or R.sup.1b is
selected from aryl, heteroaryl, heterocyclyl, --(C.sub.1-C.sub.4
alkylene)-aryl, --(C.sub.1-C.sub.4 alkylene)-heteroaryl,
--O--(C.sub.0-C.sub.4 alkylene)-aryl, --O--(C.sub.0-C.sub.4
alkylene)-heteroaryl, --N(R.sup.7)-aryl, --N(R.sup.7)heteroaryl,
--N(R.sup.9)-aryl, or --N(R.sup.9)-heteroaryl, wherein said aryl or
heteroaryl is substituted with -G-L-M, CH.sub.3, or CN.
[0119] In some embodiments, R.sup.1a is H and R.sup.1b is aryl,
heteroaryl, heterocyclyl, --(C.sub.1-C.sub.4 alkylene)-aryl,
--(C.sub.1-C.sub.4 alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4
alkylene)-aryl, or --O--(C.sub.0-C.sub.4 alkylene)-heteroaryl,
--N(R.sup.7)-aryl, --N(R.sup.7)heteroaryl, --N(R.sup.9)-aryl,
--N(R.sup.9)-heteroaryl, wherein said aryl or heteroaryl is
substituted with -G-L-M, CH.sub.3, or CN. In some aspects of the
preceding embodiments, R.sup.1a is H and R.sup.1b is aryl,
heteroaryl, heterocyclyl, --CH.sub.2-aryl, --CH.sub.2-heteroaryl,
-D-aryl, --O-heteroaryl, --O--(CH.sub.2)-aryl,
--O--CH(CH.sub.3)-aryl, --O(CH)(C(CH.sub.3).sub.2)-aryl,
--O--CH(CH.sub.2CH.sub.3)-aryl, --NH-aryl, --NH-heteroaryl,
--N(CH.sub.3)-aryl, --N(CH.sub.3)-heteroaryl, --N(aryl)-aryl,
--N(heteroaryl)-heteroaryl, --O--(CH.sub.2)-heteroaryl or
--O--CH(CH.sub.3)-heteroaryl, wherein aryl is phenyl, heteroaryl is
pyridyl, pyrimidinyl, naphthyridinyl, quinolyl, isoquinolyl,
isoxazolyl, benzoxazolyl, imidazopyrazinyl, benzothiazolyl,
benzimidazolyl, pyrollopyridinyl, pyrazolopyridinyl, indolyl,
indazolyl, imidazopyridinyl, quinoxalinyl, quinazolinyl,
pyridazinyl or pyrazolyl, and heterocyclyl is benzodioxole,
pyridazinone, benzoxazolone, indolinone, N-methylindolinone,
piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl,
dihydropyrrolyl and said phenyl, pyridyl, pyrimidinyl,
naphthyridinyl, quinolyl, isoquinolyl, isoxazolyl, benzoxazolyl,
imidazopyrazinyl, benzothiazolyl, benzimidazolyl, pyrollopyridinyl,
pyrazolopyridinyl, indolyl, indazolyl, imidazopyridinyl,
quinoxalinyl, quinazolinyl, pyridazinyl, pyrazolyl, benzodioxole,
pyridazinone, benzoxazolone, indolinone, N-methylindolinone,
piperazinyl, N-methylisoquinolinone, tetrahydropyridinyl, or
dihydropyrrolyl is substituted with -G-L-M, --CF.sub.3,
--OCF.sub.3, halo (e.g., fluoro, chloro or bromo), CH.sub.3, or
CN.
[0120] In some embodiments, R.sup.1a is methyl and R.sup.1b is
aryl, heteroaryl, heterocyclyl, --O--(C.sub.0-C.sub.4
alkylene)-aryl, or --O--(C.sub.0-C.sub.4 alkylene)-heteroaryl,
wherein said aryl or heteroaryl is substituted with -G-L-M,
CH.sub.3, or CN. In some aspects of the preceding embodiments,
R.sup.1a is methyl or H and R.sup.1b is aryl, heteroaryl,
heterocyclyl, --O--(CH.sub.2)-aryl, --O--CH(CH.sub.3)-aryl,
--O--(CH.sub.2)-heteroaryl or --O--CH(CH.sub.3)-heteroaryl, wherein
aryl is phenyl or naphthyl and heteroaryl is quinolinyl, pyrazolyl,
isoquinolinyl, pyridyl, pyrimidinyl, indolyl, or pyrazolyl, and
heterocyclyl is tetrahydropyridinyl and said phenyl, pyridyl,
pyrimidinyl, indolyl, or pyrazolyl is substituted with -G-L-M, halo
(e.g., chloro or fluoro), CH.sub.3, or CN.
[0121] In some embodiments, -G-L-M is:
##STR00007## ##STR00008## ##STR00009##
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4
alkoxy, hydrogen, tetrazolyl, morpholino, piperazinyl,
pyrrolidinone, pyrazolyl, benzyl, --(CH.sub.2).sub.1-4--SH,
--(CH.sub.2).sub.1-4--NH.sub.2, --NH.sub.2,
--(CH.sub.2).sub.1-4--OH, --N(H)C(O)OCH(CH.sub.3).sub.3,
--(CH.sub.2).sub.1-4--OCH.sub.3, --NH--(CH.sub.2).sub.1-4--OH,
--C(O)--(C.sub.1-C.sub.4 alkyl), --C(O)--(C.sub.1-C.sub.4 alkenyl),
--O--(CH.sub.2).sub.1-4--C(O)--O--(C.sub.1-C.sub.4 alkyl),
--C(O)NH.sub.2, --(CH.sub.2).sub.1-4C(O)CH.sub.3,
--N(CH.sub.3)(CH.sub.3), --NHC(O)(C.sub.2-C.sub.4 alkenyl),
--NHC(O)(C.sub.2-C.sub.4 alkyl), --SO.sub.2(CH.sub.2).sub.1-4,
--(CH.sub.2).sub.1-4--NHSO.sub.2Me, --NHSO.sub.2(CH.sub.2).sub.1-4,
--O--SO.sub.2CF.sub.3, --SO.sub.2NH--(C.sub.1-C.sub.4 alkyl),
--SO.sub.2NH--(C.sub.2-C.sub.4 alkenyl), SO.sub.2--NH.sub.2 or
--NHSO.sub.2Me.
[0122] In some embodiments, R.sup.2 is selected from isopropyl,
cyclopropyl, cyclohexyl, and phenyl. In some embodiments, R.sup.2
is cyclopropyl. In some embodiments, R.sub.2 is isopropyl.
[0123] In some embodiments, R.sup.4 is CN; Y is --N(R.sup.5)--;
R.sup.5 is --C(O)R.sup.10; and the compound has Structural Formula
II:
##STR00010##
or a pharmaceutically acceptable salt thereof, wherein:
[0124] one of R.sup.1a or R.sup.1b is selected from hydrogen and
methyl;
[0125] the other of R.sup.1a or R.sup.1b is selected from aryl,
heteroaryl, heterocyclyl, --(C.sub.1-C.sub.4 alkylene)-aryl,
--(C.sub.1-C.sub.4 alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4
alkylene)-aryl, --O--(C.sub.0-C.sub.4 alkylene)-heteroaryl,
--N(R.sup.7)-aryl, --N(R.sup.7)heteroaryl, --N(R.sup.9)-aryl, or
--N(R.sup.9)-heteroaryl, wherein said aryl, heterocyclyl, or
heteroaryl is substituted with -G-L-M, CH.sub.3, CN, alkoxy, OH,
halo, C.sub.1-C.sub.6 alkyl, --CF.sub.3, --OC(O)CH.sub.3, or
--OCF.sub.3;
[0126] R.sup.2 is selected from isopropyl, cyclopropyl, cyclohexyl,
and phenyl;
[0127] each R.sup.3, if present, is selected from methyl, ethyl,
isopropyl, CF.sub.3, cyclopropyl and phenyl;
[0128] R.sup.10 is selected from --(C.sub.1-C.sub.3
alkyl)-O--(C.sub.1-C.sub.2 alkyl), Q, (C.sub.1-C.sub.5 alkyl),
C.sub.1-C.sub.2 alkylene)-Q, (C.sub.2-C.sub.4 alkenyl),
--O--(C.sub.1-C.sub.4 alkyl), or --(C.sub.1-C.sub.4 alkenylene)-Q;
wherein: any alkylene moiety present in R.sup.10 is optionally
substituted with OH; any terminal methyl moiety present in R.sup.10
is optionally replaced with --OH, CF.sub.3, OCH.sub.3, --C(O)H,
--OP(O)(C.sub.1-C.sub.4 alkoxy).sub.2, or --OP(O)(OH).sub.2 (or a
salt thereof, such as a sodium salt); Q is cyclopropyl, cyclobutyl,
oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl,
dihydrofuranonyl, or cyclopentyl, wherein each member of Q is
optionally substituted with one substituent independently selected
from C.sub.1-C.sub.4 alkyl optionally substituted with OH,
C.sub.1-C.sub.4 alkoxy, --(C.sub.1-C.sub.4
alkylene)-(C.sub.1-C.sub.4 alkoxy), and --OH; and
[0129] m is 0, 1, or 2.
[0130] In certain embodiments, m is 1; and the compound has
Structural Formula IIa:
##STR00011##
or a pharmaceutically acceptable salt thereof, wherein:
[0131] R.sup.1a is hydrogen or methyl;
[0132] R.sup.1b is selected from aryl, heteroaryl, heterocyclyl,
--(C.sub.1-C.sub.4 alkylene)-aryl, --(C.sub.1-C.sub.4
alkylene)-heteroaryl, --O--(C.sub.0-C.sub.4 alkylene)-aryl,
--O--(C.sub.0-C.sub.4 alkylene)-heteroaryl, --N(R.sup.7)-aryl,
--N(R.sup.7)heteroaryl, --N(R.sup.9)-aryl, or
--N(R.sup.9)-heteroaryl, wherein said aryl, heterocyclyl, or
heteroaryl is substituted with -G-L-M, CH.sub.3, CN, alkoxy, OH,
halo, C.sub.1-C.sub.6 alkyl, --CF.sub.3, --OC(O)CH.sub.3, or
--OCF.sub.3;
[0133] R.sup.2 is selected from isopropyl, cyclopropyl, cyclohexyl,
and phenyl;
[0134] each R.sup.3, if present, is selected from methyl,
isopropyl, and cyclopropyl;
[0135] R.sup.10 is selected from --(C.sub.1-C.sub.3
alkyl)-O--(C.sub.1-C.sub.2 alkyl), Q, (C.sub.1-C.sub.5 alkyl),
C.sub.1-C.sub.2 alkylene)-Q, (C.sub.2-C.sub.4 alkenyl),
--O--(C.sub.1-C.sub.4 alkyl), or --(C.sub.1-C.sub.4 alkenylene)-Q;
wherein: any alkylene moiety present in R.sup.10 is optionally
substituted with OH; any terminal methyl moiety present in R.sup.10
is optionally replaced with --OH, CF.sub.3, OCH.sub.3, --C(O)H,
--OP(O)(C.sub.1-C.sub.4 alkoxy).sub.2, or --OP(O)(OH).sub.2 (or a
salt thereof, such as a sodium salt); Q is cyclopropyl, cyclobutyl,
oxetanyl, furanyl, azetidinonyl, pyrrolidinonyl, tetrahydrofuranyl,
dihydrofuranonyl, or cyclopentyl, wherein each member of Q is
optionally substituted with one substituent independently selected
from C.sub.1-C.sub.4 alkyl optionally substituted with OH,
C.sub.1-C.sub.4 alkoxy, --(C.sub.1-C.sub.4
alkylene)-(C.sub.1-C.sub.4 alkoxy), and --OH; and
[0136] m is 0, 1, or 2.
[0137] In some embodiments, R.sup.4 is CN; Y is --N(R.sup.5)--;
R.sup.5 is --C(O)R.sup.10; and the compound has Structural Formula
II:
##STR00012##
or a pharmaceutically acceptable salt thereof, wherein:
[0138] one of R.sup.1a or R.sup.1b is selected from hydrogen and
methyl;
[0139] the other of R.sup.1a or R.sup.1b is selected from
isopropyl, --N(CH.sub.3)--(CH.sub.2).sub.2--NH--CH.sub.3, aryl,
heteroaryl, --CH.sub.2-aryl, --CH.sub.2-heteroaryl,
--O--CH.sub.2-aryl, and --O--CH.sub.2-heteroaryl; wherein any aryl
or heteroaryl portion of R.sup.1a or R.sup.1b is optionally
substituted with one or more substituents independently selected
from alkoxy, hydroxy, halo, C.sub.1-C.sub.6 alkyl, --CF.sub.3,
--OC(O)CH.sub.3, and --OCF.sub.3;
[0140] R.sup.2 is selected from isopropyl, cyclopropyl, cyclohexyl,
and phenyl;
[0141] each R.sup.3, if present, is selected from methyl, ethyl,
isopropyl, cyclopropyl and phenyl;
[0142] R.sup.10 is selected from heteroaryl, aryl, --CH.sub.2-aryl,
--CH.sub.2-heteroaryl, and --(CH.sub.2).sub.2--O--CH.sub.3, wherein
any aryl or heteroaryl portion of R.sup.10 is optionally
substituted with methyl; and
[0143] m is 0, 1, or 2.
[0144] In certain embodiments, m is 1; and the compound has
Structural Formula IIa:
##STR00013##
or a pharmaceutically acceptable salt thereof, wherein:
[0145] R.sup.1a is selected from hydrogen and methyl;
[0146] R.sup.1b is selected from aryl, and heteroaryl; wherein the
aryl or heteroaryl is optionally substituted with one or more
substituents independently selected from methoxy, fluoro, chloro,
methyl, --CF.sub.3, --OCF.sub.3;
[0147] R.sup.2 is selected from isopropyl and cyclopropyl;
[0148] R.sup.3 is selected from methyl, ethyl, isopropyl and
cyclopropyl; and
[0149] R.sup.10 is selected from --(CH.sub.2).sub.2--O--CH.sub.3,
furan-3-yl, 2-methylfuran-3-yl and thien-2-yl.
[0150] In some embodiments, R.sup.4 is CN; Y is --N(R.sup.5)--;
R.sup.5 is --C(O)R.sup.10; and the compound has Structural Formula
II:
##STR00014##
or a pharmaceutically acceptable salt thereof, wherein:
[0151] R.sup.1a is H;
[0152] R.sup.1b is aryl, heteroaryl, --O--(C.sub.1-C.sub.4
alkylene)-aryl, or --O--(C.sub.1-C.sub.4 alkylene)-heteroaryl,
wherein said aryl or heteroaryl is substituted with -G-L-M,
CH.sub.3, or CN;
[0153] R.sup.2 is selected from isopropyl, cyclopropyl, cyclohexyl,
and phenyl;
[0154] each R.sup.3, if present, is selected from methyl, ethyl,
isopropyl, cyclopropyl and phenyl;
[0155] R.sup.10 is selected from heteroaryl, aryl, --CH.sub.2-aryl,
--CH.sub.2-heteroaryl, and --(CH.sub.2).sub.2--O--CH.sub.3, wherein
any aryl or heteroaryl portion of R.sup.10 is optionally
substituted with methyl; and
[0156] m is 0, 1, or 2.
[0157] In certain embodiments, m is 1; and the compound has
Structural Formula IIa:
##STR00015##
or a pharmaceutically acceptable salt thereof, wherein:
[0158] R.sup.1a is H;
[0159] R.sup.1b is aryl, heteroaryl, --O--(CH.sub.2)-aryl,
--O--CH(CH.sub.3)-aryl, --O--(CH.sub.2)-heteroaryl or
--O--CH(CH.sub.3)-heteroaryl, wherein aryl is phenyl and heteroaryl
is pyridyl, pyrimidinyl, indolyl, or pyrazolyl, and said phenyl,
pyridyl, pyrimidinyl, indolyl or pyrazolyl is substituted with
-G-L-M, CH.sub.3, or CN;
[0160] R.sup.2 is selected from isopropyl and cyclopropyl;
[0161] R.sup.3 is selected from methyl, ethyl, isopropyl and
cyclopropyl; and
[0162] R.sup.10 is selected from --(CH.sub.2).sub.2--O--CH.sub.3,
furan-3-yl, 2-methylfuran-3-yl and thien-2-yl.
[0163] In another embodiment, the compound is selected from any one
of the compounds set forth in Table 1, below.
TABLE-US-00001 TABLE 1 Exemplary Compounds of Formula I. Cmpd No.
Structure 100 ##STR00016## 101 ##STR00017## 102 ##STR00018## 103
##STR00019## 104 ##STR00020## 105 ##STR00021## 106 ##STR00022## 107
##STR00023## 108 ##STR00024## 109 ##STR00025## 110 ##STR00026## 111
##STR00027## 113 ##STR00028## 114 ##STR00029## 115 ##STR00030## 116
##STR00031## 117 ##STR00032## 118 ##STR00033## 119 ##STR00034## 120
##STR00035## 121 ##STR00036## 122 ##STR00037## 123 ##STR00038## 124
##STR00039## 125 ##STR00040## 126 ##STR00041## 127 ##STR00042## 128
##STR00043## 129 ##STR00044## 130 ##STR00045## 131 ##STR00046## 132
##STR00047## 133 ##STR00048## 134 ##STR00049## 135 ##STR00050## 136
##STR00051## 137 ##STR00052## 138 ##STR00053## 139 ##STR00054## 140
##STR00055## 141 ##STR00056## 142 ##STR00057## 143 ##STR00058## 144
##STR00059## 145 ##STR00060## 146 ##STR00061## 147 ##STR00062## 148
##STR00063## 149 ##STR00064## 150 ##STR00065## 151 ##STR00066## 152
##STR00067## 153 ##STR00068## 154 ##STR00069## 155 ##STR00070## 156
##STR00071## 157 ##STR00072## 158 ##STR00073## 159 ##STR00074## 160
##STR00075## 161 ##STR00076## 162 ##STR00077## 163 ##STR00078## 164
##STR00079## 165 ##STR00080## 166 ##STR00081## 167 ##STR00082## 168
##STR00083## 169 ##STR00084## 170 ##STR00085## 171 ##STR00086## 172
##STR00087## 173 ##STR00088## 174 ##STR00089## 175 ##STR00090## 176
##STR00091## 177 ##STR00092## 178 ##STR00093## 179 ##STR00094## 180
##STR00095## 181 ##STR00096## 182 ##STR00097## 183 ##STR00098## 184
##STR00099## 185 ##STR00100## 187 ##STR00101## 188 ##STR00102## 189
##STR00103## 190 ##STR00104## 191 ##STR00105## 192 ##STR00106## 193
##STR00107## 195 ##STR00108## 196 ##STR00109## 197 ##STR00110## 198
##STR00111## 199 ##STR00112## 200 ##STR00113## 201 ##STR00114## 202
##STR00115## 203 ##STR00116## 204 ##STR00117## 205 ##STR00118## 206
##STR00119## 207 ##STR00120## 208 ##STR00121## 209 ##STR00122## 210
##STR00123## 211 ##STR00124## 212 ##STR00125## 213 ##STR00126## 214
##STR00127## 215 ##STR00128## 216 ##STR00129## 217 ##STR00130## 218
##STR00131## 219 ##STR00132## 220 ##STR00133## 221 ##STR00134## 222
##STR00135## 223 ##STR00136## 224 ##STR00137## 225 ##STR00138##
226 ##STR00139## 227 ##STR00140## 228 ##STR00141## 229 ##STR00142##
230 ##STR00143## 231 ##STR00144## 232 ##STR00145## 233 ##STR00146##
234 ##STR00147## 235 ##STR00148## 236 ##STR00149## 237 ##STR00150##
238 ##STR00151## 239 ##STR00152## 240 ##STR00153## 241 ##STR00154##
242 ##STR00155## 243 ##STR00156## 244 ##STR00157## 245 ##STR00158##
246 ##STR00159## 247 ##STR00160## 248 ##STR00161## 249 ##STR00162##
250 ##STR00163## 251 ##STR00164## 252 ##STR00165## 253 ##STR00166##
254 ##STR00167## 255 ##STR00168## 256 ##STR00169## 257 ##STR00170##
258 ##STR00171## 259 ##STR00172## 260 ##STR00173## 261 ##STR00174##
262 ##STR00175## 59 ##STR00176## 60 ##STR00177## 61
##STR00178##
[0164] In another embodiment, the compound is selected from any one
of the compounds set forth in Table 5, below.
TABLE-US-00002 TABLE 5 Exemplary Compounds of Formula I. Cpd #
Structure 263 ##STR00179## 264 ##STR00180## 265 ##STR00181## 266
##STR00182## 267 ##STR00183## 268 ##STR00184## 269 ##STR00185## 270
##STR00186## 271 ##STR00187## 272 ##STR00188## 273 ##STR00189## 274
##STR00190## 275 ##STR00191## 276 ##STR00192## 277 ##STR00193## 278
##STR00194## 279 ##STR00195## 280 ##STR00196## 281 ##STR00197## 282
##STR00198## 283 ##STR00199## 284 ##STR00200## 285 ##STR00201## 286
##STR00202## 287 ##STR00203## 288 ##STR00204## 289 ##STR00205## 290
##STR00206## 291 ##STR00207## 292 ##STR00208## 293 ##STR00209## 294
##STR00210## 295 ##STR00211## 296 ##STR00212## 297 ##STR00213## 298
##STR00214## 299 ##STR00215## 300 ##STR00216## 301 ##STR00217## 302
##STR00218## 303 ##STR00219## 304 ##STR00220## 305 ##STR00221## 306
##STR00222## 307 ##STR00223## 308 ##STR00224## 309 ##STR00225## 310
##STR00226## 311 ##STR00227## 312 ##STR00228## 313 ##STR00229## 314
##STR00230## 315 ##STR00231## 316 ##STR00232## 317 ##STR00233## 318
##STR00234## 319 ##STR00235## 320 ##STR00236## 321 ##STR00237## 322
##STR00238## 323 ##STR00239## 324 ##STR00240## 325 ##STR00241## 326
##STR00242## 327 ##STR00243## 328 ##STR00244## 329 ##STR00245## 330
##STR00246## 331 ##STR00247## 332 ##STR00248## 333 ##STR00249## 334
##STR00250## 335 ##STR00251## 336 ##STR00252## 337 ##STR00253## 338
##STR00254## 339 ##STR00255## 340 ##STR00256## 341 ##STR00257## 342
##STR00258## 343 ##STR00259## 344 ##STR00260## 345 ##STR00261## 346
##STR00262## 347 ##STR00263## 348 ##STR00264## 349 ##STR00265## 350
##STR00266## 351 ##STR00267## 352 ##STR00268## 353 ##STR00269## 354
##STR00270## 355 ##STR00271## 356 ##STR00272## 357 ##STR00273## 358
##STR00274## 359 ##STR00275## 360 ##STR00276## 361 ##STR00277## 362
##STR00278## 363 ##STR00279## 364 ##STR00280## 365 ##STR00281## 366
##STR00282## 367 ##STR00283## 368 ##STR00284## 369 ##STR00285## 370
##STR00286## 371 ##STR00287## 372 ##STR00288## 373 ##STR00289## 374
##STR00290## 375 ##STR00291## 376 ##STR00292## 377 ##STR00293## 378
##STR00294## 379 ##STR00295## 380 ##STR00296## 381 ##STR00297## 382
##STR00298## 383 ##STR00299## 384 ##STR00300##
385 ##STR00301## 386 ##STR00302## 387 ##STR00303## 388 ##STR00304##
389 ##STR00305## 390 ##STR00306## 391 ##STR00307## 392 ##STR00308##
393 ##STR00309## 394 ##STR00310## 395 ##STR00311## 396 ##STR00312##
397 ##STR00313## 398 ##STR00314## 399 ##STR00315## 400 ##STR00316##
401 ##STR00317## 402 ##STR00318## 403 ##STR00319## 404 ##STR00320##
405 ##STR00321## 406 ##STR00322## 407 ##STR00323## 408 ##STR00324##
409 ##STR00325## 410 ##STR00326## 411 ##STR00327## 412 ##STR00328##
413 ##STR00329## 414 ##STR00330## 415 ##STR00331## 416 ##STR00332##
417 ##STR00333## 418 ##STR00334## 419 ##STR00335## 420 ##STR00336##
421 ##STR00337## 422 ##STR00338## 423 ##STR00339## 424 ##STR00340##
425 ##STR00341## 426 ##STR00342## 427 ##STR00343## 428 ##STR00344##
429 ##STR00345## 430 ##STR00346## 431 ##STR00347## 432 ##STR00348##
433 ##STR00349## 434 ##STR00350## 435 ##STR00351## 436 ##STR00352##
437 ##STR00353## 438 ##STR00354## 439 ##STR00355## 440 ##STR00356##
441 ##STR00357## 442 ##STR00358## 443 ##STR00359## 444 ##STR00360##
445 ##STR00361## 446 ##STR00362## 447 ##STR00363## 448 ##STR00364##
449 ##STR00365## 450 ##STR00366## 451 ##STR00367## 452 ##STR00368##
453 ##STR00369## 454 ##STR00370## 455 ##STR00371## 456 ##STR00372##
457 ##STR00373## 458 ##STR00374## 459 ##STR00375## 460 ##STR00376##
461 ##STR00377## 462 ##STR00378## 463 ##STR00379## 464 ##STR00380##
465 ##STR00381## 466 ##STR00382## 467 ##STR00383## 470 ##STR00384##
471 ##STR00385## 472 ##STR00386## 473 ##STR00387## 474 ##STR00388##
475 ##STR00389## 476 ##STR00390## 477 ##STR00391## 478 ##STR00392##
479 ##STR00393## 480 ##STR00394## 481 ##STR00395## 482 ##STR00396##
483 ##STR00397## 484 ##STR00398## 485 ##STR00399## 486 ##STR00400##
487 ##STR00401## 488 ##STR00402## 489 ##STR00403## 490 ##STR00404##
493 ##STR00405## 494 ##STR00406## 495 ##STR00407## 496 ##STR00408##
497 ##STR00409## 498 ##STR00410## 499 ##STR00411## 500 ##STR00412##
501 ##STR00413## 502 ##STR00414## 503 ##STR00415## 504 ##STR00416##
505 ##STR00417## 506 ##STR00418## 507 ##STR00419## 508 ##STR00420##
509 ##STR00421## 510 ##STR00422## 511 ##STR00423## 512 ##STR00424##
513 ##STR00425## 514 ##STR00426##
515 ##STR00427## 516 ##STR00428## 517 ##STR00429## 518 ##STR00430##
519 ##STR00431## 520 ##STR00432## 521 ##STR00433## 522 ##STR00434##
523 ##STR00435## 524 ##STR00436## 525 ##STR00437## 526 ##STR00438##
527 ##STR00439## 528 ##STR00440## 529 ##STR00441## 530 ##STR00442##
531 ##STR00443## 532 ##STR00444## 533 ##STR00445## 534 ##STR00446##
535 ##STR00447## 536 ##STR00448## 537 ##STR00449## 538 ##STR00450##
539 ##STR00451## 540 ##STR00452## 541 ##STR00453## 542 ##STR00454##
543 ##STR00455## 544 ##STR00456## 546 ##STR00457## 547 ##STR00458##
548 ##STR00459## 549 ##STR00460## 550 ##STR00461## 551 ##STR00462##
552 ##STR00463## 553 ##STR00464## 554 ##STR00465## 555 ##STR00466##
556 ##STR00467## 557 ##STR00468## 558 ##STR00469## 559 ##STR00470##
560 ##STR00471## 561 ##STR00472## 562 ##STR00473## 563 ##STR00474##
564 ##STR00475## 565 ##STR00476## 566 ##STR00477## 567 ##STR00478##
568 ##STR00479## 569 ##STR00480## 570 ##STR00481## 571 ##STR00482##
572 ##STR00483## 573 ##STR00484## 574 ##STR00485## 575 ##STR00486##
576 ##STR00487## 577 ##STR00488## 578 ##STR00489## 579 ##STR00490##
580 ##STR00491## 581 ##STR00492## 582 ##STR00493## 583 ##STR00494##
584 ##STR00495## 585 ##STR00496## 586 ##STR00497## 587 ##STR00498##
588 ##STR00499## 589 ##STR00500## 590 ##STR00501## 591 ##STR00502##
592 ##STR00503## 593 ##STR00504## 594 ##STR00505## 595 ##STR00506##
596 ##STR00507## 597 ##STR00508## 598 ##STR00509## 599 ##STR00510##
600 ##STR00511## 601 ##STR00512## 602 ##STR00513## 603 ##STR00514##
604 ##STR00515## 605 ##STR00516## 606 ##STR00517## 607 ##STR00518##
608 ##STR00519## 609 ##STR00520## 610 ##STR00521## 611 ##STR00522##
612 ##STR00523## 613 ##STR00524## 614 ##STR00525## 615 ##STR00526##
616 ##STR00527## 617 ##STR00528## 618 ##STR00529## 619 ##STR00530##
620 ##STR00531## 621 ##STR00532## 622 ##STR00533## 623 ##STR00534##
624 ##STR00535## 625 ##STR00536## 626 ##STR00537## 627 ##STR00538##
628 ##STR00539## 629 ##STR00540## 630 ##STR00541## 631 ##STR00542##
632 ##STR00543## 633 ##STR00544## 634 ##STR00545## 635 ##STR00546##
636 ##STR00547## 637 ##STR00548## 638 ##STR00549## 639 ##STR00550##
640 ##STR00551##
641 ##STR00552## 642 ##STR00553## 643 ##STR00554## 644 ##STR00555##
645 ##STR00556## 646 ##STR00557## 647 ##STR00558## 648 ##STR00559##
649 ##STR00560## 650 ##STR00561## 651 ##STR00562## 652 ##STR00563##
653 ##STR00564## 654 ##STR00565## 655 ##STR00566## 656 ##STR00567##
657 ##STR00568## 658 ##STR00569## 659 ##STR00570## 660 ##STR00571##
661 ##STR00572## 662 ##STR00573## 663 ##STR00574## 664 ##STR00575##
665 ##STR00576## 666 ##STR00577## 667 ##STR00578## 668 ##STR00579##
669 ##STR00580## 670 ##STR00581## 671 ##STR00582## 672 ##STR00583##
673 ##STR00584## 674 ##STR00585## 675 ##STR00586## 676 ##STR00587##
677 ##STR00588## 678 ##STR00589## 679 ##STR00590## 680 ##STR00591##
681 ##STR00592## 682 ##STR00593## 683 ##STR00594## 684 ##STR00595##
685 ##STR00596## 686 ##STR00597## 687 ##STR00598## 688 ##STR00599##
689 ##STR00600## 690 ##STR00601## 691 ##STR00602## 692 ##STR00603##
693 ##STR00604## 694 ##STR00605## 695 ##STR00606## 696 ##STR00607##
697 ##STR00608## 698 ##STR00609## 699 ##STR00610## 700 ##STR00611##
701 ##STR00612## 702 ##STR00613## 703 ##STR00614## 704 ##STR00615##
705 ##STR00616## 706 ##STR00617## 707 708 ##STR00618## 709
##STR00619## 710 ##STR00620## 711 ##STR00621## 712 ##STR00622## 713
##STR00623## 714 ##STR00624## 715 ##STR00625## 716 ##STR00626## 717
##STR00627## 718 ##STR00628## 719 ##STR00629## 720 ##STR00630## 721
##STR00631## 722 ##STR00632## 723 ##STR00633## 724 ##STR00634## 725
##STR00635## 726 ##STR00636## 727 ##STR00637## 728 ##STR00638## 729
##STR00639## 730 ##STR00640## 731 ##STR00641## 732 ##STR00642## 733
##STR00643## 734 ##STR00644## 735 ##STR00645## 736 ##STR00646## 737
##STR00647## 738 ##STR00648## 739 ##STR00649## 740 ##STR00650## 741
##STR00651## 742 ##STR00652## 743 ##STR00653## 744 ##STR00654## 745
##STR00655## 746 ##STR00656## 747 ##STR00657## 748 ##STR00658## 749
##STR00659## 750 ##STR00660## 751 ##STR00661## 752 ##STR00662## 753
##STR00663## 754 ##STR00664## 755 ##STR00665## 756 ##STR00666## 757
##STR00667## 758 ##STR00668## 759 ##STR00669## 760 ##STR00670## 761
##STR00671## 762 ##STR00672## 763 ##STR00673## 764 ##STR00674## 765
##STR00675## 766 ##STR00676##
767 ##STR00677## 768 ##STR00678## 769 ##STR00679## 770 ##STR00680##
771 ##STR00681## 772 ##STR00682## 773 ##STR00683## 774 ##STR00684##
775 ##STR00685## 776 ##STR00686## 777 ##STR00687## 778 ##STR00688##
779 ##STR00689## 780 ##STR00690## 781 ##STR00691## 782 ##STR00692##
783 ##STR00693## 784 ##STR00694## 785 ##STR00695## 786 ##STR00696##
787 ##STR00697## 788 ##STR00698## 789 ##STR00699## 790 ##STR00700##
791 ##STR00701## 792 ##STR00702## 793 ##STR00703## 794 ##STR00704##
795 ##STR00705## 796 ##STR00706## 797 ##STR00707## 798 ##STR00708##
799 ##STR00709## 800 ##STR00710## 801 ##STR00711## 802 ##STR00712##
803 ##STR00713## 804 ##STR00714## 805 ##STR00715## 806 ##STR00716##
807 ##STR00717## 808 ##STR00718## 809 ##STR00719## 810 ##STR00720##
811 ##STR00721## 812 ##STR00722## 813 ##STR00723## 814 ##STR00724##
815 ##STR00725## 816 ##STR00726## 817 ##STR00727## 818 ##STR00728##
819 ##STR00729## 820 ##STR00730## 821 ##STR00731## 822 ##STR00732##
823 ##STR00733## 824 ##STR00734## 825 ##STR00735## 826 ##STR00736##
827 ##STR00737## 828 ##STR00738## 829 ##STR00739## 830
##STR00740##
[0165] The compounds of this invention may contain one or more
asymmetric centers and thus occur as racemates, racemic mixtures,
scalemic mixtures, and diastereomeric mixtures, as well as single
enantiomers or individual stereoisomers that are substantially free
from another possible enantiomer or stereoisomer. The term
"substantially free of other stereoisomers" as used herein means a
preparation enriched in a compound having a selected
stereochemistry at one or more selected stereocenters by at least
about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or
99%. The term "enriched" means that at least the designated
percentage of a preparation is the compound having a selected
stereochemistry at one or more selected stereocenters. Methods of
obtaining or synthesizing an individual enantiomer or stereoisomer
for a given compound are known in the art and may be applied as
practicable to final compounds or to starting material or
intermediates.
[0166] The compounds of Formula I, II and IIa may also comprise one
or more isotopic substitutions. For example, H may be in any
isotopic form, including .sup.1H, .sup.2H (D or deuterium), and
.sup.3H (T or tritium); C may be in any isotopic form, including
.sup.12C, .sup.13C, and .sup.14C; O may be in any isotopic form,
including .sup.16O and .sup.18O; and the like.
[0167] Unless otherwise indicated when a disclosed compound is
named or depicted by a structure without specifying the
stereochemistry and has one or more chiral centers, it is
understood to represent all possible stereoisomers of the
compound.
[0168] The compounds of this invention may also be represented in
multiple tautomeric forms, in such instances, the invention
expressly includes all tautomeric forms of the compounds described
herein, even though only a single tautomeric form may be
represented (e.g., alkylation of a ring system may result in
alkylation at multiple sites, the invention expressly includes all
such reaction products). All such isomeric forms of such compounds
are expressly included in the present invention. All crystal forms
of the compounds described herein are expressly included in the
present invention.
[0169] It may be convenient or desirable to prepare, purify, and/or
handle a corresponding salt of the active compound, for example, a
pharmaceutically-acceptable salt. Examples of pharmaceutically
acceptable salts are discussed in Berge et al., 1977,
"Pharmaceutically Acceptable Salts." J. Pharm. Sci. Vol. 66, pp.
1-19.
[0170] For example, if the compound is anionic, or has a functional
group which may be anionic (e.g., --COOH may be --COO), then a salt
may be formed with a suitable cation. Examples of suitable
inorganic cations include, but are not limited to, alkali metal
ions such as Na.sup.+ and K.sup.+, alkaline earth cations such as
Ca.sup.2+ and Mg.sup.2+, and other cations such as Al.sup.3+.
Examples of suitable organic cations include, but are not limited
to, ammonium ion (i.e., NH.sub.4.sup.+) and substituted ammonium
ions (e.g., NH.sub.3R.sup.+, NH.sub.2R.sup.2+, NHR.sup.3+,
NR.sup.+). Examples of some suitable substituted ammonium ions are
those derived from: ethylamine, diethylamine, dicyclohexylamine,
triethylamine, butylamine, ethylenediamine, ethanolamine,
diethanolamine, piperazine, benzylamine, phenylbenzylamine,
choline, meglumine, and tromethamine, as well as amino acids, such
as lysine and arginine. An example of a common quaternary ammonium
ion is N(CH.sub.3).sub.4.sup.+.
[0171] If the compound is cationic, or has a functional group that
may be cationic (e.g., --NH.sub.2 may be --NH.sub.3.sup.+), then a
salt may be formed with a suitable anion. Examples of suitable
inorganic anions include, but are not limited to, those derived
from the following inorganic acids: hydrochloric, hydrobromic,
hydroiodic, sulfuric, sulfurous, nitric, nitrous, phosphoric, and
phosphorous.
[0172] Examples of suitable organic anions include, but are not
limited to, those derived from the following organic acids:
2-acetyoxybenzoic, acetic, ascorbic, aspartic, benzoic,
camphorsulfonic, cinnamic, citric, edetic, ethanedisulfonic,
ethanesulfonic, fumaric, glucoheptonic, gluconic, glutamic,
glycolic, hydroxymaleic, hydroxynaphthalene carboxylic, isethionic,
lactic, lactobionic, lauric, maleic, malic, methanesulfonic, mucic,
oleic, oxalic, palmitic, pamoic, pantothenic, phenylacetic,
phenylsulfonic, propionic, pyruvic, salicylic, stearic, succinic,
sulfanilic, tartaric, toluenesulfonic, and valeric. Examples of
suitable polymeric organic anions include, but are not limited to,
those derived from the following polymeric acids: tannic acid,
carboxymethyl cellulose.
[0173] Unless otherwise specified, a reference to a particular
compound also includes salt forms thereof.
Compositions and Routes of Administration
[0174] The compounds utilized in the methods described herein may
be formulated together with a pharmaceutically acceptable carrier
or adjuvant into pharmaceutically acceptable compositions prior to
be administered to a subject. In another embodiment, such
pharmaceutically acceptable compositions further comprise
additional therapeutic agents in amounts effective for achieving a
modulation of disease or disease symptoms, including those
described herein.
[0175] The term "pharmaceutically acceptable carrier or adjuvant"
refers to a carrier or adjuvant that may be administered to a
subject, together with a compound of this invention, and which does
not destroy the pharmacological activity thereof and is nontoxic
when administered in doses sufficient to deliver a therapeutic
amount of the compound.
[0176] Pharmaceutically acceptable carriers, adjuvants and vehicles
that may be used in the pharmaceutical compositions of this
invention include, but are not limited to, ion exchangers, alumina,
aluminum stearate, lecithin, self-emulsifying drug delivery systems
(SEDDS) such as d-.alpha.-tocopherol polyethyleneglycol 1000
succinate, surfactants used in pharmaceutical dosage forms such as
Tweens or other similar polymeric delivery matrices, serum
proteins, such as human serum albumin, buffer substances such as
phosphates, glycine, sorbic acid, potassium sorbate, partial
glyceride mixtures of saturated vegetable fatty acids, water, salts
or electrolytes, such as protamine sulfate, disodium hydrogen
phosphate, potassium hydrogen phosphate, sodium chloride, zinc
salts, colloidal silica, magnesium trisilicate, polyvinyl
pyrrolidone, cellulose-based substances, polyethylene glycol,
sodium carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers, polyethylene glycol
and wool fat. Cyclodextrins such as .alpha.-, .beta.-, and
.gamma.-cyclodextrin, or chemically modified derivatives such as
hydroxyalkylcyclodextrins, including 2- and
3-hydroxypropyl-.beta.-cyclodextrins, or other solubilized
derivatives may also be advantageously used to enhance delivery of
compounds of the formulae described herein.
[0177] The pharmaceutical compositions of this invention may be
administered orally, parenterally, by inhalation spray, topically,
rectally, nasally, buccally, vCompound AGInally or via an implanted
reservoir, preferably by oral administration or administration by
injection. The pharmaceutical compositions of this invention may
contain any conventional non-toxic pharmaceutically-acceptable
carriers, adjuvants or vehicles. In some cases, the pH of the
formulation may be adjusted with pharmaceutically acceptable acids,
bases or buffers to enhance the stability of the formulated
compound or its delivery form. The term parenteral as used herein
includes subcutaneous, intracutaneous, intravenous, intramuscular,
intraarticular, intraarterial, intrasynovial, intrasternal,
intrathecal, intralesional and intracranial injection or infusion
techniques.
[0178] The pharmaceutical compositions may be in the form of a
sterile injectable preparation, for example, as a sterile
injectable aqueous or oleCompound AGlnous suspension. This
suspension may be formulated according to techniques known in the
art using suitable dispersing or wetting agents (such as, for
example, Tween 80) and suspending agents. The sterile injectable
preparation may also be a sterile injectable solution or suspension
in a non-toxic parenterally acceptable diluent or solvent, for
example, as a solution in 1,3-butanediol. Among the acceptable
vehicles and solvents that may be employed are mannitol, water,
Ringer's solution and isotonic sodium chloride solution. In
addition, sterile, fixed oils are conventionally employed as a
solvent or suspending medium. For this purpose, any bland fixed oil
may be employed including synthetic mono- or diglycerides. Fatty
acids, such as oleic acid and its glyceride derivatives are useful
in the preparation of injectables, as are natural
pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil solutions
or suspensions may also contain a long-chain alcohol diluent or
dispersant, or carboxymethyl cellulose or similar dispersing agents
which are commonly used in the formulation of pharmaceutically
acceptable dosage forms such as emulsions and or suspensions. Other
commonly used surfactants such as Tweens or Spans and/or other
similar emulsifying agents or bioavailability enhancers which are
commonly used in the manufacture of pharmaceutically acceptable
solid, liquid, or other dosage forms may also be used for the
purposes of formulation.
[0179] The pharmaceutical compositions of this invention may be
orally administered in any orally acceptable dosage form including,
but not limited to, capsules, tablets, emulsions and aqueous
suspensions, dispersions and solutions. In the case of tablets for
oral use, carriers which are commonly used include lactose and corn
starch. Lubricating agents, such as magnesium stearate, are also
typically added. For oral administration in a capsule form, useful
diluents include lactose and dried corn starch. When aqueous
suspensions and/or emulsions are administered orally, the active
ingredient may be suspended or dissolved in an oily phase is
combined with emulsifying and/or suspending agents. If desired,
certain sweetening and/or flavoring and/or coloring agents may be
added.
[0180] The pharmaceutical compositions of this invention may also
be administered in the form of suppositories for rectal
administration. These compositions can be prepared by mixing a
compound of this invention with a suitable non-irritating excipient
which is solid at room temperature but liquid at the rectal
temperature and therefore will melt in the rectum to release the
active components. Such materials include, but are not limited to,
cocoa butter, beeswax and polyethylene glycols.
[0181] Topical administration of the pharmaceutical compositions of
this invention is useful when the desired treatment involves areas
or organs readily accessible by topical application. For
application topically to the skin, the pharmaceutical composition
should be formulated with a suitable ointment containing the active
components suspended or dissolved in a carrier. Carriers for
topical administration of the compounds of this invention include,
but are not limited to, mineral oil, liquid petroleum, white
petroleum, propylene glycol, polyoxyethylene polyoxypropylene
compound, emulsifying wax and water. Alternatively, the
pharmaceutical composition can be formulated with a suitable lotion
or cream containing the active compound suspended or dissolved in a
carrier with suitable emulsifying agents. Suitable carriers
include, but are not limited to, mineral oil, sorbitan
monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol,
2-octyldodecanol, benzyl alcohol and water. The pharmaceutical
compositions of this invention may also be topically applied to the
lower intestinal tract by rectal suppository formulation or in a
suitable enema formulation. Topically-transdermal patches are also
included in this invention.
[0182] The pharmaceutical compositions of this invention may be
administered by nasal aerosol or inhalation. Such compositions are
prepared according to techniques well-known in the art of
pharmaceutical formulation and may be prepared as solutions in
saline, employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability, fluorocarbons,
and/or other solubilizing or dispersing agents known in the art.
When the compositions of this invention comprise a combination of a
compound of the formulae described herein and one or more
additional therapeutic or prophylactic agents, both the compound
and the additional agent should be present at dosage levels of
between about 1 to 100%, and more preferably between about 5 to 95%
of the dosage normally administered in a monotherapy regimen. The
additional agents may be administered separately, as part of a
multiple dose regimen, from the compounds of this invention.
Alternatively, those agents may be part of a single dosage form,
mixed together with the compounds of this invention in a single
composition.
[0183] The compounds described herein can, for example, be
administered by injection, intravenously, intraarterially,
subdermally, intraperitoneally, intramuscularly, or subcutaneously;
or orally, buccally, nasally, transmucosally, topically, in an
ophthalmic preparation, or by inhalation, with a dosage ranging
from about 0.5 to about 100 mg/kg of body weight, alternatively
dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or
according to the requirements of the particular drug. The methods
herein contemplate administration of an effective amount of
compound or compound composition to achieve the desired or stated
effect. Typically, the pharmaceutical compositions of this
invention will be administered from about 1 to about 6 times per
day or alternatively, as a continuous infusion. Such administration
can be used as a chronic or acute therapy. The amount of active
ingredient that may be combined with the carrier materials to
produce a single dosage form will vary depending upon the host
treated and the particular mode of administration. A typical
preparation will contain from about 5% to about 95% active compound
(w/w). Alternatively, such preparations contain from about 20% to
about 80% active compound.
[0184] Lower or higher doses than those recited above may be
required. Specific dosage and treatment regimens for any particular
subject will depend upon a variety of factors, including the
activity of the specific compound employed, the age, body weight,
general health status, sex, diet, time of administration, rate of
excretion, drug combination, the severity and course of the
disease, condition or symptoms, the subject's disposition to the
disease, condition or symptoms, and the judgment of the treating
physician.
[0185] Upon improvement of a subject's condition, a maintenance
dose of a compound, composition or combination of this invention
may be administered, if necessary. Subsequently, the dosage or
frequency of administration, or both, may be reduced, as a function
of the symptoms, to a level at which the improved condition is
retained when the symptoms have been alleviated to the desired
level. Subjects may, however, require intermittent treatment on a
long-term basis upon any recurrence of disease symptoms.
[0186] The pharmaceutical compositions described above comprising a
compound of Structural Formula I, II or IIa or a compound described
in any one of the embodiments herein, may further comprise another
therapeutic agent useful for treating cancer.
Methods of Use
[0187] Provided is a method for inhibiting a mutant IDH1 activity
comprising contacting a subject in need thereof a compound of
Structural Formula I, II or IIa, a compound described in any one of
the embodiments herein, or a pharmaceutically acceptable salt
thereof. In one embodiment, the cancer to be treated is
characterized by a mutant allele of IDH1 wherein the IDH1 mutation
result in a new ability of the enzyme to catalyze the
NAPH-dependent reduction of .alpha.-ketoglutarate to
R(-)-2-hydroxyglutarate in a subject. In one aspect of this
embodiment, the mutant IDH1 has an R132X mutation. In one aspect of
this embodiment, the R132X mutation is selected from R132H, R132C,
R132L, R132V, R132S and R132G. In another aspect, the R132X
mutation is R132H or R132C. In yet another aspect, the R132X
mutation is R132H.
[0188] Also provided are methods of treating a cancer characterized
by the presence of a mutant allele of IDH1 comprising the step of
administering to subject in need thereof (a) a compound of
Structural Formula I, II or IIa, a compound described in any one of
the embodiments herein, or a pharmaceutically acceptable salt
thereof, or (b) a pharmaceutical composition comprising (a) and a
pharmaceutically acceptable carrier.
[0189] In one embodiment, the cancer to be treated is characterized
by a mutant allele of IDH1 wherein the IDH1 mutation result in a
new ability of the enzyme to catalyze the NAPH-dependent reduction
of .alpha.-ketoglutarate to R(-)-2-hydroxyglutarate in a patient.
In one aspect of this embodiment, the IDH1 mutation is an R132X
mutation. In another aspect of this embodiment, the R132X mutation
is selected from R132H, R132C, R132L, R132V, R132S and R132G. In
another aspect, the R132X mutation is R132H or R132C. A cancer can
be analyzed by sequencing cell samples to determine the presence
and specific nature of (e.g., the changed amino acid present at) a
mutation at amino acid 132 of IDH1.
[0190] Without being bound by theory, applicants believe that
mutant alleles of IDH1 wherein the IDH1 mutation result in a new
ability of the enzyme to catalyze the NAPH-dependent reduction of
.alpha.-ketoglutarate to R(-)-2-hydroxyglutarate, and in particular
R132H mutations of IDH1, characterize a subset of all types of
cancers, without regard to their cellular nature or location in the
body. Thus, the compounds and methods of this invention are useful
to treat any type of cancer that is characterized by the presence
of a mutant allele of IDH1 imparting such activity and in
particular an IDH1 R132H or R132C mutation.
[0191] In one aspect of this embodiment, the efficacy of cancer
treatment is monitored by measuring the levels of 2HG in the
subject. Typically levels of 2HG are measured prior to treatment,
wherein an elevated level is indicative of the use of the compound
of Formula I to treat the cancer. Once the elevated levels are
established, the level of 2HG is determined during the course of
and/or following termination of treatment to establish efficacy. In
certain embodiments, the level of 2HG is only determined during the
course of and/or following termination of treatment. A reduction of
2HG levels during the course of treatment and following treatment
is indicative of efficacy. Similarly, a determination that 2HG
levels are not elevated during the course of or following treatment
is also indicative of efficacy. Typically, the these 2HG
measurements will be utilized together with other well-known
determinations of efficacy of cancer treatment, such as reduction
in number and size of tumors and/or other cancer-associated
lesions, improvement in the general health of the subject, and
alterations in other biomarkers that are associated with cancer
treatment efficacy.
[0192] 2HG can be detected in a sample by LC/MS. The sample is
mixed 80:20 with methanol, and centrifuged at 3,000 rpm for 20
minutes at 4 degrees Celsius. The resulting supernatant can be
collected and stored at -80 degrees Celsius prior to LC-MS/MS to
assess 2-hydroxyglutarate levels. A variety of different liquid
chromatography (LC) separation methods can be used. Each method can
be coupled by negative electrospray ionization (ESI, -3.0 kV) to
triple-quadrupole mass spectrometers operating in multiple reaction
monitoring (MRM) mode, with MS parameters optimized on infused
metabolite standard solutions. Metabolites can be separated by
reversed phase chromatography using 10 mM tributyl-amine as an ion
pairing agent in the aqueous mobile phase, according to a variant
of a previously reported method (Luo et al. J Chromatogr A 1147,
153-64, 2007). One method allows resolution of TCA metabolites:
t=0, 50% B; t=5, 95% B; t=7, 95% B; t=8, 0% B, where B refers to an
organic mobile phase of 100% methanol. Another method is specific
for 2-hydroxyglutarate, running a fast linear gradient from 50%-95%
B (buffers as defined above) over 5 minutes. A Synergi Hydro-RP,
100 mm.times.2 mm, 2.1 .mu.m particle size (Phenomonex) can be used
as the column, as described above. Metabolites can be quantified by
comparison of peak areas with pure metabolite standards at known
concentration. Metabolite flux studies from .sup.13C-glutamine can
be performed as described, e.g., in Munger et al. Nat Biotechnol
26, 1179-86, 2008.
[0193] In one embodiment 2HG is directly evaluated.
[0194] In another embodiment a derivative of 2HG formed in process
of performing the analytic method is evaluated. By way of example
such a derivative can be a derivative formed in MS analysis.
Derivatives can include a salt adduct, e.g., a Na adduct, a
hydration variant, or a hydration variant which is also a salt
adduct, e.g., a Na adduct, e.g., as formed in MS analysis.
[0195] In another embodiment a metabolic derivative of 2HG is
evaluated. Examples include species that build up or are elevated,
or reduced, as a result of the presence of 2HG, such as glutarate
or glutamate that will be correlated to 2HG, e.g., R-2HG.
[0196] Exemplary 2HG derivatives include dehydrated derivatives
such as the compounds provided below or a salt adduct thereof:
##STR00741##
[0197] In one embodiment the cancer is a tumor wherein at least 30,
40, 50, 60, 70, 80 or 90% of the tumor cells carry an IDH1
mutation, and in particular an IDH1 R132H or R132C mutation, at the
time of diagnosis or treatment.
[0198] IDH1 R132X mutations are known to occur in certain types of
cancers as indicated in Table 2, below.
TABLE-US-00003 TABLE 2 IDH mutations associated with certain
cancers IDH1 R132X Cancer Type Mutation Tumor Type brain tumors
R132H primary tumor R132C primary tumor R132S primary tumor R132G
primary tumor R132L primary tumor R132V primary tumor fibrosarcoma
R132C HT1080 fibrosarcoma cell line Acute Myeloid Leukemia R132H
primary tumor (AML) R132G primary tumor R132C primary tumor
Prostate cancer R132H primary tumor R132C primary tumor Acute
lymphoblastic leukemia R132C primary tumor (ALL) paragangliomas
R132C primary tumor
[0199] IDH1 R132H mutations have been identified in glioblastoma,
acute myelogenous leukemia, sarcoma, melanoma, non-small cell lung
cancer, cholangiocarcinomas, chondrosarcoma, myelodysplastic
syndromes (MDS), myeloproliferative neoplasm (MPN), colon cancer,
and angio-immunoblastic non-Hodgkin's lymphoma (NHL). Accordingly,
in one embodiment, the methods described herein are used to treat
glioma (glioblastoma), acute myelogenous leukemia, sarcoma,
melanoma, non-small cell lung cancer (NSCLC) or
eholangiocarcinomas, chondrosarcoma, myelodysplastic syndromes
(MDS), myeloproliferative neoplasm (MPN) or colon cancer in a
patient.
[0200] Accordingly in one embodiment, the cancer is a cancer
selected from any one of the cancer types listed in Table 2, and
the IDH R132X mutation is one or more of the IDH1 R132X mutations
listed in Table 2 for that particular cancer type.
[0201] Treatment methods described herein can additionally comprise
various evaluation steps prior to and/or following treatment with a
compound of Structural Formula I, II or IIa or a compound described
in any one of the embodiments described herein.
[0202] In one embodiment, prior to and/or after treatment with a
compound of Structural Formula I, II or IIa or a compound described
in any one of the embodiments described herein, the method further
comprises the step of evaluating the growth, size, weight,
invasiveness, stage and/or other phenotype of the cancer.
[0203] In one embodiment, prior to and/or after treatment with a
compound of formula I or I-a or a compound described in any one of
the embodiments described herein, the method further comprises the
step of evaluating the IDH1 genotype of the cancer. This may be
achieved by ordinary methods in the art, such as DNA sequencing,
immuno analysis, and/or evaluation of the presence, distribution or
level of 2HG.
[0204] In one embodiment, prior to and/or after treatment with a
compound of formula I or I-a or a compound described in any one of
the embodiments described herein, the method further comprises the
step of determining the 2HG level in the subject. This may be
achieved by pectroscopic analysis, e.g., magnetic resonance-based
analysis, e.g., MRI and/or MRS measurement, sample analysis of
bodily fluid, such as serum or spinal cord fluid analysis, or by
analysis of surgical material, e.g., by mass-spectroscopy.
Combination Therapies
[0205] In some embodiments, the methods described herein comprise
the additional step of co-administering to a subject in need
thereof a second therapy e.g., an additional cancer therapeutic
agent or an additional cancer treatment. Exemplary additional
cancer therapeutic agents include for example, chemotherapy,
targeted therapy, antibody therapies, immunotherapy, and hormonal
therapy. Additional cancer treatments include, for example:
surgery, and radiation therapy. Examples of each of these
treatments are provided below.
[0206] The term "co-administering" as used herein with respect to
an additional cancer therapeutic agents means that the additional
cancer therapeutic agent may be administered together with a
compound of this invention as part of a single dosage form (such as
a composition of this invention comprising a compound of the
invention and an second therapeutic agent as described above) or as
separate, multiple dosage forms. Alternatively, the additional
cancer therapeutic agent may be administered prior to,
consecutively with, or following the administration of a compound
of this invention. In such combination therapy treatment, both the
compounds of this invention and the second therapeutic agent(s) are
administered by conventional methods. The administration of a
composition of this invention, comprising both a compound of the
invention and a second therapeutic agent, to a subject does not
preclude the separate administration of that same therapeutic
agent, any other second therapeutic agent or any compound of this
invention to said subject at another time during a course of
treatment. The term "co-administering" as used herein with respect
to an additional cancer treatment means that the additional cancer
treatment may occur prior to, consecutively with, concurrently with
or following the administration of a compound of this
invention.
[0207] In some embodiments, the additional cancer therapeutic agent
is a chemotherapy agent. Examples of chemotherapeutic agents used
in cancer therapy include, for example, antimetabolites (e.g.,
folic acid, purine, and pyrimidine derivatives), alkylating agents
(e.g., nitrogen mustards, nitrosoureas, platinum, alkyl sulfonates,
hydrazines, triazenes, aziridines, spindle poison, cytotoxic
agents, topoisomerase inhibitors and others) and hypomethylating
agents (e.g., decitabine (5-aza-deoxycytidine), zebularine,
isothiocyanates, azacitidine (5-azacytidine),
5-fluoro-2'-deoxycytidine, 5,6-dihydro-5-azacytidine and others).
Exemplary agents include Aclarubicin, Actinomycin, Alitretinoin,
Altretamine, Aminopterin, Aminolevulinic acid, Amrubicin,
Amsacrine, Anagrelide, Arsenic trioxide, AsparCompound AGlnase,
Atrasentan, Belotecan, Bexarotene, bendamustine, Bleomycin,
Bortezomib, Busulfan, Camptothecin, Capecitabine, Carboplatin,
Carboquone, Carmofur, Carmustine, Celecoxib, Chlorambucil,
Chlormethine, Cisplatin, Cladribine, Clofarabine, Crisantaspase,
Cyclophosphamide, Cytarabine, Dacarbazine, Dactinomycin,
Daunorubicin, Decitabine, Demecolcine, Docetaxel, Doxorubicin,
Efaproxiral, Elesclomol, Elsamitrucin, Enocitabine, Epirubicin,
Estramustine, Etoglucid, Etoposide, Floxuridine, Fludarabine,
Fluorouracil (5FU), Fotemustine, Gemcitabine, Gliadel implants,
Hydroxycarbamide, Hydroxyurea, Idarubicin, Ifosfamide, Irinotecan,
Irofulven, Ixabepilone, Larotaxel, Leucovorin, Liposomal
doxorubicin, Liposomal daunorubicin, Lonidamine, Lomustine,
Lucanthone, Mannosulfan, Masoprocol, Melphalan, Mercaptopurine,
Mesna, Methotrexate, Methyl aminolevulinate, Mitobronitol,
Mitoguazone, Mitotane, Mitomycin, Mitoxantrone, Nedaplatin,
Nimustine, Oblimersen, Omacetaxine, Ortataxel, Oxaliplatin,
Paclitaxel, Pegaspargase, Pemetrexed, Pentostatin, Pirarubicin,
Pixantrone, Plicamycin, Porfimer sodium, Prednimustine,
Procarbazine, Raltitrexed, Ranimustine, Rubitecan, Sapacitabine,
Semustine, Sitimagene ceradenovec, Strataplatin, Streptozocin,
Talaporfin, Tegafur-uracil, Temoporfin, Temozolomide, Teniposide,
Tesetaxel, Testolactone, Tetranitrate, Thiotepa, Tiazofurine,
Tioguanine, Tipifarnib, Topotecan, Trabectedin, Triaziquone,
Triethylenemelamine, Triplatin, Tretinoin, Treosulfan,
Trofosfamide, Uramustine, Valrubicin, Verteporfin, Vinblastine,
Vincristine, Vindesine, Vinflunine, Vinorelbine, Vorinostat,
Zorubicin, and other cytostatic or cytotoxic agents described
herein.
[0208] Because some drugs work better together than alone, two or
more drugs are often given at the same time. Often, two or more
chemotherapy agents are used as combination chemotherapy.
[0209] In some embodiments, the additional cancer therapeutic agent
is a differentiation agent. Such differentiation agent includes
retinoids (such as all-trans-retinoic acid (ATRA), 9-cis retinoic
acid, 13-cis-retinoic acid (13-cRA) and 4-hydroxy-phenretinamide
(4-HPR)); arsenic trioxide; histone deacetylase inhibitors HDACs
(such as azacytidine (Vidaza) and butyrates (e.g., sodium
phenylbutyrate)); hybrid polar compounds (such as hexamethylene
bisacetamide ((HMBA)); vitamin D; and cytokines (such as
colony-stimulating factors including G-CSF and GM-CSF, and
interferons).
[0210] In some embodiments the additional cancer therapeutic agent
is a targeted therapy agent. Targeted therapy constitutes the use
of agents specific for the deregulated proteins of cancer cells.
Small molecule targeted therapy drugs are generally inhibitors of
enzymatic domains on mutated, overexpressed, or otherwise critical
proteins within the cancer cell. Prominent examples are the
tyrosine kinase inhibitors such as Axitinib, Bosutinib, Cediranib,
aasatinib, erlotinib, imatinib, gefitinib, lapatinib, Lestaurtinib,
Nilotinib, Semaxanib, Sorafenib, Sunitinib, and Vandetanib, and
also cyclin-dependent kinase inhibitors such as Alvocidib and
Seliciclib. Monoclonal antibody therapy is another strategy in
which the therapeutic agent is an antibody which specifically binds
to a protein on the surface of the cancer cells. Examples include
the anti-HER2/neu antibody trastuzumab (HERCEPTIN.RTM.) typically
used in breast cancer, and the anti-CD20 antibody rituximab and
Tositumomab typically used in a variety of B-cell malignancies.
Other exemplary antibodies include Cetuximab, Panitumumab,
Trastuzumab, Alemtuzumab, Bevacizumab, Edrecolomab, and Gemtuzumab.
Exemplary fusion proteins include Aflibercept and Denileukin
diftitox. In some embodiments, the targeted therapy can be used in
combination with a compound described herein, e.g., a biguanide
such as metformin or phenformin, preferably phenformin.
[0211] Targeted therapy can also involve small peptides as "homing
devices" which can bind to cell surface receptors or affected
extracellular matrix surrounding the tumor. Radionuclides which are
attached to these peptides (e.g., RGDs) eventually kill the cancer
cell if the nuclide decays in the vicinity of the cell. An example
of such therapy includes BEXXAR.RTM..
[0212] In some embodiments, the additional cancer therapeutic agent
is an immunotherapy agent. Cancer immunotherapy refers to a diverse
set of therapeutic strategies designed to induce the subject's own
immune system to fight the tumor. Contemporary methods for
generating an immune response against tumors include intravesicular
BCG immunotherapy for superficial bladder cancer, and use of
interferons and other cytokines to induce an immune response in
renal cell carcinoma and melanoma subjects.
[0213] Allogeneic hematopoietic stem cell transplantation can be
considered a form of immunotherapy, since the donor's immune cells
will often attack the tumor in a graft-versus-tumor effect. In some
embodiments, the immunotherapy agents can be used in combination
with a compound or composition described herein.
[0214] In some embodiments, the additional cancer therapeutic agent
is a hormonal therapy agent. The growth of some cancers can be
inhibited by providing or blocking certain hormones. Common
examples of hormone-sensitive tumors include certain types of
breast and prostate cancers. Removing or blocking estrogen or
testosterone is often an important additional treatment. In certain
cancers, administration of hormone agonists, such as progestogens
may be therapeutically beneficial. In some embodiments, the
hormonal therapy agents can be used in combination with a compound
or a composition described herein.
[0215] Other possible additional therapeutic modalities include
imatinib, gene therapy, peptide and dendritic cell vaccines,
synthetic chlorotoxins, and radiolabeled drugs and antibodies.
EXAMPLES
TABLE-US-00004 [0216] ABBREVIATIONS anhy.--anhydrous aq.--aqueous
min--minute(s) mL--milliliter mmol--millimole(s) mol--mole(s)
MS--mass spectrometry NMR--nuclear magnetic resonance TLC--thin
layer chromatography HPLC--high-performance liquid chromatography
Hz--hertz .delta.--chemical shift J--coupling constant s--singlet
d--doublet t--triplet q--quartet m--multiplet br--broad qd--quartet
of doublets dquin--doublet of quintets dd--doublet of doublets
dt--doublet of triplets CHCl.sub.3--chloroform DCM--dichloromethane
DMF--dimethylformamide Et.sub.2O--diethyl ether EtOH--ethyl alcohol
EtOAc--ethyl acetate MeOH--methyl alcohol MeCN--acetonitrile
PE--petroleum ether THF--tetrahydrofuran AcOH--acetic acid
HCl--hydrochloric acid H.sub.2SO.sub.4--sulfuric acid
NH.sub.4Cl--ammonium chloride KOH--potassium hydroxide NaOH--sodium
hydroxide K.sub.2CO.sub.3--potassium carbonate
Na.sub.2CO.sub.3--sodium carbonate TFA--trifluoroacetic acid
Na.sub.2SO.sub.4--sodium sulfate NaBH.sub.4--sodium borohydride
NaHCO.sub.3--sodium bicarbonate LiHMDS--lithium
hexamethyldisilylamide NaHMDS--sodium hexamethyldisilylamide
LAH--lithium aluminum hydride NaBH.sub.4--sodium borohydride
LDA--lithium diisopropylamide Et.sub.3N--triethylamine
DMAP--4-(dimethylamino)pyridine DIPEA--N,N-diisopropylethylamine
NH.sub.4OH--ammonium hydroxide
EDCI--1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
HOBt--1-hydroxybenzotriazole
HATU--O-(7-azabenzotriazol-1-yl)-N,N,N',N',-tetra-methyluronium
BINAP--2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl
[0217] In the following examples, reagents were purchased from
commercial sources (including Alfa, Acros, Sigma Aldrich, TCI and
Shanghai Chemical Reagent Company), and used without further
purification. Flash chromatography was performed on an Ez Purifier
III using a column with silica gel particles of 200-300 mesh.
Analytical and preparative thin layer chromatography plates (TLC)
were HSGF 254 (0.15-0.2 mm thickness, Shanghai Anbang Company,
China). Nuclear magnetic resonance (NMR) spectra were obtained on a
Brucker AMX-400 NMR (Brucker, Switzerland). Chemical shifts were
reported in parts per million (ppm, .delta.) downfield from
tetramethylsilane. Mass spectra were run with electrospray
ionization (ESI) from a Waters LCT TOF Mass Spectrometer (Waters,
USA). HPLC chromatographs were recorded on an Compound AGIlent 1200
Liquid Chromatography (Compound AGIlent, USA, column: Ultimate 4.6
mm.times.50 mm, 5 .mu.m, mobile phase A: 0.1% formic acid in water;
mobile phase B: acetonitrile). Microwave reactions were run on an
Initiator 2.5 Microwave Synthesizer (Biotage, Sweden).
[0218] For exemplary compounds disclosed in this section, the
specification of a stereoisomer (e.g., an (R) or (S) stereoisomer)
indicates a preparation of that compound such that the compound is
enriched at the specified stereocenter by at least about 90%, 95%,
96%, 97%, 98%, or 99%.
Example 1
Preparation of
(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-
nicotinonitrile
[0219]
(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-
-1-yl)nicotinonitrile (7, wherein R.sup.1a is hydrogen; m is 1;
R.sup.3 is 3-methyl; and R.sup.8 is methoxyethyl) was prepared
according to general Scheme 1, below.
##STR00742##
Step A: 1-(dimethylamino)-4-methylpent-1-en-3-one (2)
[0220] To a solution of commerically available 3-methylbutan-2-one
(1; 8.613 g, 100 mmol) in 150 mL of anhydrous DMF was added
commercially available 1,1-dimethoxy-N,N-dimethylmethanamine (29.80
g, 250 mmol). The resulting mixture was stirred at 100.degree. C.
overnight. After removal of DMF and excess of acetal, 14 g of title
compound was obtained as a crude product and used in subsequent
reaction without further purification. .sup.1H NMR (CHLOROFORM-d)
.delta. 7.57 (d, J=12.8 Hz, 1H), 5.05 (d, J=12.5 Hz, 1H), 2.80-3.10
(m, 6H), 2.56 (dt, J=13.7, 6.8 Hz, 1H), 1.06-1.14 (m, 6H).
Step B: 6-isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrile
(3)
[0221] 8.8 g of 1-(dimethylamino)-4-methylpent-1-en-3-one (2; 62
mmol) and 5.3 g of commercially available cyanoacetamide (62 mmol)
in 24 mL of H.sub.2O was treated with a premixed buffer solution of
0.7 mL of acetic acid, 1.8 mL of H.sub.2O, and enough piperidine to
make the buffer solution basic. The resulting solution was refluxed
for 2 hrs and LC-MS showed the formation of desired product. After
cooling to room temperature, the mixture was acidified with glacial
acetic acid, and a brown yellowish precipitate was formed. The
filter cake was washed with H.sub.2O and air-dried to give 6.5 g of
title compound. MS (ES) M+H expected 163.1, found 163.0. .sup.1H
NMR (DMSO-d.sub.6) .delta. 12.51 (br. s., 1H), 7.96-8.18 (m, 1H),
6.24 (d, J=7.5 Hz, 1H), 2.83 (spt, J=6.9 Hz, 1H), 1.19 (s, 29H),
1.17 (s, 3H).
Step C:
5-bromo-6-isopropyl-2-oxo-1,2-dihydropyridine-3-carbonitrile
(4)
[0222] To a solution of 2-hydroxy-6-isopropylnicotinonitrile (3;
3.0 g, 19 mmol) in 50 mL of DCE was added NBS (5 g, 28 mmol) at
room temperature. The reaction mixture was then heated at reflux
for 3 hours. After LC-MS showed the completion of reaction, the
mixture was cooled to room temperature and poured into water and
extracted with methylene chloride. The combined organic layer was
dried over anhy. Na.sub.2SO.sub.4 and concentrated in vacuo. Column
chromatography (4% MeOH/DCM) afforded 3.9 g of title compound as a
brown solid. MS (ES) M+H expected 241.0, found 240.9. .sup.1H NMR
(DMSO-d.sub.6) .delta. 12.58 (br. s., 1H), 8.38 (s, 1H), 3.25-3.32
(m, 1H), 1.23 (s, 3H), 1.21 (s, 3H).
Step D: 5-bromo-3-cyano-6-isopropylpyridin-2-yl
trifluoromethanesulfonate (5)
[0223] To a solution of
5-bromo-2-hydroxy-6-isopropylnicotinonitrile (4; 2.0 g, 8 mmol) in
20 mL of methylene chloride was added DMAP (100 mg, 0.8 mmol), and
triethylamine (1.01 g, 10 mmol). The mixture was cooled to
0.degree. C. in an ice-water bath, and trifluoromethanesulfonic
anhydride (2.82 g, 10 mmol) was added dropwise by syringe. The
resulting reaction mixture was stirred at 0.degree. C. for 30 min
before it was allowed to warm to room temperature and stirred for
additional 2 hours. After TLC showed the complete conversion of
starting material to product, the reaction mixture was concentrated
and purified by column chromatography (20% EtOAc/petroleum ether)
to afford 2.8 g of title compound. .sup.1H NMR (CHLOROFORM-d)
.delta. 8.22 (s, 1H), 3.57 (spt, J=6.7 Hz, 1H), 1.28 (d, J=6.8 Hz,
6H).
Step E:
(R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(6)
[0224] A mixture of the above triflate 5 (1.68 g, 4.5 mmol),
(R)-2-methylpiperazine (770 mg, 6.77 mmol), and triethylamine (1.9
mL, 13.5 mmol) suspended in 5 mL of MeCN was subjected to microwave
reaction at 175.degree. C. for 45 min. After the mixture was
concentrated in vacuo, the residue was purified by column
chromatography (10% DCM/MeOH) to afford 0.91 g of title compound as
a light yellowish solid. MS (ES) M+H expected 323.1, found 323.0.
.sup.1H NMR (CHLOROFORM-d) S 7.79 (s, 1H), 4.35-4.40 (m, 0.5H),
4.32-4.35 (m, 1H), 4.30 (t, J=2.4 Hz, 0.5H), 3.37-3.45 (m, 1H),
3.08-3.13 (m, 0.5H), 3.05-3.08 (m, 1H), 3.04 (d, J=2.5 Hz, 0.5H),
2.96-3.01 (m, 1H), 2.89-2.96 (m, 1H), 2.65-2.74 (m, 1H), 1.21 (dd,
J=6.8, 0.8 Hz, 6H), 1.13 (d, J=6.3 Hz, 3H).
Step F:
(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazi-
n-1-yl)nicotinonitrile (7)
[0225] To a 25 mL of round-bottom flask was added
(R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(6; 680 mg, 2.1 mmol), 3-methoxypropanoic acid (438 mg, 4.2 mmol),
HATU (1.6 g, 4.2 mmol), DIPEA (1.1 mL, 6.31 mmol) and 5 mL of
methylene chloride. The resulting reaction mixture was stirred at
room temperature for 4 hours until TLC showed the completion of the
reaction. After washing with Satd. NaHCO.sub.3, brine, the combined
organic layer was dried over anhy. Na.sub.2SO.sub.4 and
concentrated in vacuo. Column chromatography purification (20%
EtOAc/petroleum ether) afforded 550 mg of title compound as a light
yellowish solid. MS (ES) M+H expected 409.1, found 409.0. .sup.1H
NMR (CHLOROFORM-d) .delta. 7.83 (s, 1H), 4.90 (br. s., 0.5H), 4.52
(d, J=12.3 Hz, 0.5H), 4.19-4.39 (m, 3H), 3.76-3.85 (m, 0.5H), 3.73
(t, J=6.4 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.25-3.35 (m,
1H), 3.02-3.20 (m, 1H), 2.63-2.80 (m, 1H), 2.51-2.61 (m, 1H), 1.35
(d, J=7.0 Hz, 1.5H), 1.25 (d, J=6.3 Hz, 1.5H), 1.21-1.23 (m, 3H),
1.19-1.21 (m, 3H)
[0226] Other intermediates 7 were prepared by similar steps
according to Scheme 1 and either: (1) replacing
(R)-2-methylpiperazine in Step E with an alternately substituted or
unsubstituted piperazine; and/or (2) replacing 3-methoxypropanoic
acid in Step F with an alternate acid.
Example 2
Preparation of
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile
[0227]
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)nicotinonitrile (17; wherein R.sup.1a is hydrogen; R.sup.2
is cyclopropyl; m is 1; R.sup.3 is 3-methyl; and R.sup.8 is
methoxyethyl) was prepared according to general Scheme 2,
below.
##STR00743##
Step L: 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one (12)
[0228] To a solution of commercially available
1-cyclopropylethanone (11; 8.584 g, 100 mmol) in 200 mL of
anhydrous DMF was added 1,1-dimethoxy-N,N-dimethylmethanamine
(29.80 g, 250 mmol). The resulting mixture was stirred at
100.degree. C. overnight. After removal of DMF and excess of
acetal, 13.9 g of title Compound was obtained as a crude product
and used in subsequent reaction without further purification.
.sup.1H NMR (CHLOROFORM-d) .delta. 7.56 (d, J=12.8 Hz, 1H), 5.20
(d, J=12.5 Hz, 1H), 2.78-3.08 (m, 6H), 1.79 (tt, J=7.9, 4.5 Hz,
1H), 0.94-1.04 (m, 2H), 0.67-0.80 (m, 2H).
Step M: 6-cyclopropyl-2-hydroxynicotinonitrile (13)
[0229] 3.532 g of 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one 12
and 2.032 g of cyanoacetamide in 10 mL of H.sub.2O was treated with
a premixed buffer solution of 0.33 mL of acetic acid, 0.82 mL of
H.sub.2O, and enough amount of piperidine to make solution basic.
The resulting solution was refluxed for 2 hrs and LC-MS showed the
formation of desired product 13. After cooling to room temperature,
the mixture was acidified with glacial acetic acid, and a brown
yellowish precipitated was formed. The thick brown slurry was
filtered and filter cake was washed with H.sub.2O and air-dried to
give 1.30 g of title compound. MS (ES) M+H expected 161.1, found
161.0. .sup.1H NMR (CHLOROFORM-d) .delta. 13.60 (br. s., 1H), 7.77
(d, J=7.8 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 1.96-2.12 (m, 1H),
1.29-1.36 (m, 2H), 1.04-1.11 (m, 2H).
Step N: 5-bromo-6-cyclopropyl-2-hydroxynicotinonitrile (14)
[0230] To a solution of 6-cyclopropyl-2-hydroxynicotinonitrile (13;
0.32 g, 2.0 mmol) in 5 mL of DCE was added NBS (0.534 g, 3.0 mmol)
at room temperature. The reaction mixture was heated at reflux for
3 hours. After LC-MS showed completion of reaction, the reaction
mixture was cooled to room temperature and poured into water. After
extraction with methylene chloride (3.times.5 mL), the combined
organic layer was dried over anhy. Na.sub.2SO.sub.4 and
concentrated in vacuo. Column chromatography (4% MeOH/DCM) afforded
0.45 g of 14. MS (ES) M+H expected 239.0, found 238.9. .sup.1H NMR
(CHLOROFORM-d) .delta. 8.49-8.72 (br. s., 1H), 7.93 (s, 1H),
2.23-2.34 (m, 1H), 1.36-1.42 (m, 2H), 1.29-1.36 (m, 2H).
Step O: 5-bromo-3-cyano-6-cyclopropylpyridin-2-yl
trifluoromethanesulfonate (15)
[0231] To a 5-bromo-6-cyclopropyl-2-hydroxynicotinonitrile (14;
0.45 g, 1.882 mmol) in 10 mL of methylene chloride was added DMAP
(23.2 mg, 0.19 mmol), and triethylamine (0.247 g, 2.45 mmol). The
mixture was cooled to 0.degree. C. in an ice-water bath, and
trifluoromethanesulfonic anhydride (0.69 g, 2.45 mmol) was added
dropwise via syringe. The resulting reaction mixture was stirred at
0.degree. C. for 30 min before it was allowed to warm to room
temperature and stirred for additional 2 hours. After TLC showed
the complete conversion of starting material to product, the
reaction mixture was concentrated and purified by column
chromatography (20% ethyl acetate/petroleum ether) to afford 537 mg
of 15. .sup.1H NMR (CHLOROFORM-d) .delta. 8.14-8.19 (m, 1H),
2.55-2.66 (m, 1H), 1.30 (dt, J=7.8, 3.1 Hz, 2H), 1.21-1.27 (m,
2H).
Step P:
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitril-
e (16)
[0232] A mixture of above triflate 15 (1.68 g, 4.6 mmol),
(R)-2-methylpiperazine (790 mg, 6.9 mmol), and triethylamine (1.9
mL, 13.8 mmol) suspended in 5 mL of MeCN was subjected to microwave
reaction at 175.degree. C. for 60 min. After the mixture was
concentrated under reduced pressure, the residue was extracted
between ethyl acetate and water. The combined organic layer was
then washed with aq. NaHCO.sub.3, brine, dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo to give 1.26 g of crude
16. MS (ES) M+H expected 321.1, found 321.2. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.78 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14
(m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, J=12.9,
10.2 Hz, 1H), 2.42-2.52 (m, 1H), 1.16 (d, J=6.3 Hz, 3H), 1.08 (s,
2H), 1.07 (d, J=3.8 Hz, 2H).
Step Q:
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)nicotinonitrile (17)
[0233] To a 25 mL of round-bottom flask was added
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(16; 1.26 g, 3.9 mmol), 3-methoxypropanoic acid (0.74 mL, 7.8
mmol), HATU (2.98 g, 7.8 mmol), DIPEA (2 mL, 11.76 mmol) and 10 mL
of methylene chloride. The resulting reaction mixture was stirred
at room temperature overnight until TLC showed the completion of
the reaction. Reaction mixture was with Satd. NaHCO.sub.3 and
brine. The combined organic layer was then dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Column chromatography
purification (30% EtOAc/petroleum ether) afforded 1.28 g of title
compound as a white solid. MS (ES) M+H expected 407.1, found 407.0.
.sup.1H NMR (CHLOROFORM-d) .delta. 7.78-7.85 (m, 1H), 4.82-4.92 (m,
0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.18-4.21 (m, 2H), 4.07-4.16 (m,
1H), 3.75-3.82 (m, 0.5H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 0.5H),
3.36 (s, 3H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m,
1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz,
1.5H), 1.25 (d, J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s,
2H).
[0234] Other intermediates 17 were similarly prepared according to
Scheme 2 by either: (1) replacing (R)-2-methylpiperazine in Step P
with an alternately substituted or unsubstituted piperazine; and/or
(2) replacing 3-methoxypropanoic acid in Step Q with an alternate
acid.
Example 3
Preparation of
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)-4-methylnicotinonitrile
[0235]
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)-4-methylnicotinonitrile (28; wherein R.sup.1a is methyl;
R.sup.2 is cyclopropyl; m is 1; R.sup.3 is 3-methyl; and R.sup.8 is
methoxyethyl) was prepared according to general Scheme 3,
below.
##STR00744##
Step Aa: 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (24)
[0236] To a suspension of ammonium acetate (140 g, 1.82 mol) in 400
mL of EtOH was added successively commercially available
1-cyclopropylethanone (22; 22.5 mL, 22.7 mmol), acetaldehyde (21;
10 g, 22.7 mmol), and ethyl cyanoacetate (23; 24.2 mL, 22.7 mmol).
The resulting mixture was stirred at reflux temperature for 2 hrs
and subsequently at room temperature overnight. After the LC-MS
showed the formation of the desired product, the solvent was
removed under reduced pressure. Flash column Chromatography (10%
MeOH/DCM) afforded 1.3 g of 24 as a white solid. MS (ES) M+H
expected 175.1, found 175.1. .sup.1H NMR (DMSO-d6) .delta. 12.36
(br. s., 1H), 5.93 (s, 1H), 2.26 (s, 3H), 1.81-1.91 (m, 1H),
1.06-1.14 (m, 2H), 0.91-0.95 (m, 2H).
Step Bb: 5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile
(25)
[0237] To a solution of
6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (24; 2.6 g, 15
mmol) in 10 mL of DCE was added NBS (4 g, 22.5 mmol) at room
temperature. The reaction mixture was then heated at reflux for 3
hours. After LC-MS showed the completion of reaction, the mixture
was cooled to room temperature and poured into water and extracted
with methylene chloride. The combined organic layer was dried over
anhy. Na.sub.2SO.sub.4 and concentrated in vacuo. Column
chromatography (4% MeOH/DCM) afforded 4 g of 25 as a brown solid.
MS (ES) M+H expected 253.0, found 253.0. .sup.1H NMR (CHLOROFORM-d)
.delta. 2.68 (s, 3H), 1.79-1.88 (m, 1H), 1.03-1.09 (m, 2H),
0.93-1.01 (m, 2H).
Step Cc: 5-bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yl
trifluoromethanesulfonate (26)
[0238] To a solution of
5-bromo-2-hydroxy-6-isopropylnicotinonitrile (25; 4.0 g, 14.6 mmol)
in 20 mL of methylene chloride was added DMAP (178 mg, 1.46 mmol),
and triethylamine (2.5 mL, 17.5 mmol). The mixture was cooled to
0.degree. C. in an ice-water bath, and trifluoromethanesulfonic
anhydride (3.7 mL, 21.9 mmol) was added dropwise by syringe. The
resulting reaction mixture was stirred at 0.degree. C. for 30 min
then allowed to warm to room temperature and stirred overnight.
After TLC showed the complete conversion of starting material to
product, the reaction mixture was concentrated and purified by
column chromatography (20% EtOAc/petroleum ether) to afford 1.66 g
of 26. .sup.1H NMR (CHLOROFORM-d) .delta. 2.70 (s, 3H), 2.16-2.20
(m, 1H), 1.23-1.25 (m, 2H), 1.19-1.22 (m, 2H).
Step Dd:
(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nico-
tinonitrile (27)
[0239] A mixture of above triflate 26 (1.66 g, 4.3 mmol),
(R)-2-methylpiperazine (738 mg, 6.46 mmol), and triethylamine (1.8
mL, 12.9 mmol) suspended in 5 mL of MeCN was subjected to microwave
reaction at 150.degree. C. for 1 hour. After removal of solvent
under reduced pressure, the residue was extracted between EtOAc and
water. The organic layer was then washed with satd. aq. NaHCO.sub.3
and brine, dried over anhy. Na.sub.2SO.sub.4 and concentrated in
vacuo. Flash column chromatography (10% DCM/MeOH) afforded 330 mg
of 27 as a light yellowish solid. MS (ES) M+H expected 335.1, found
335.2. .sup.1H NMR (CHLOROFORM-d) .delta. 4.08-4.16 (m, 0.5H),
4.05-4.08 (m, 1H), 4.01-4.04 (m, 0.5H), 2.99-3.08 (m, 1H), 2.97 (d,
J=8.8 Hz, 2H), 2.88-2.95 (m, 1H), 2.58-2.65 (m, 1H), 2.55-2.57 (m,
3H), 1.77 (br. s., 1H), 1.12 (s, 1.5H), 1.10 (s, 1.5H), 1.05-1.09
(m, 2H), 1.00-1.05 (m, 2H).
Step Ee:
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)-4-methylnicotinonitrile (28)
[0240] To a 50 mL of round-bottom flask was added
(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitr-
ile (27; 1.12 g, 3.34 mmol), 3-methoxypropanoic acid (0.63 mL, 6.68
mmol), HATU (2.54 g, 6.68 mmol), DIPEA (3.8 g, 10 mmol) and 10 mL
of methylene chloride. The resulting reaction mixture was stirred
at room temperature overnight until TLC showed the completion of
the reaction. After washing the reaction mixture with Satd.
NaHCO.sub.3, brine, the organic layer was dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Flash column
chromatography (20% EtOAc/petroleum ether) afforded 1.7 g of 28 as
a yellowish solid. MS (ES) M+H expected 421.1, found 421.3. .sup.1H
NMR (CHLOROFORM-d) .delta. 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz,
0.5H), 4.22 (br. s., 0.5H), 3.95-4.13 (m, 2H), 3.78 (br. s., 0.5H),
3.74 (t, J=5.9 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.38 (s, 3H),
3.07-3.24 (m, 1.5H), 2.90-3.06 (m, 1H), 2.65-2.79 (m, 1H), 2.60 (s,
3H), 2.52-2.63 (m, 1H), 2.17-2.21 (m, 1H), 1.37 (d, J=6.5 Hz,
1.5H), 1.27 (d, J=6.3 Hz, 1.5H), 1.09 (s, 2H), 1.05-1.08 (m,
2H).
[0241] Other intermediates 28 were similarly prepared according to
Scheme 3 by either: (1) replacing (R)-2-methylpiperazine in Step Dd
with an alternately substituted or unsubstituted piperazine; and/or
(2) replacing 3-methoxypropanoic acid in Step Ee with an alternate
acid.
Example 4
Preparation of
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(t-
rifluoromethyl)phenyl)-nicotinonitrile (Compound 189)
[0242] A mixture of bromide 7 from Example 1 (26 mg, 0.06 mmol),
4-(trifluoromethyl)phenylboronic acid (17 mg, 0.089 mmol),
Pd(PPh.sub.3).sub.4 (3 mg, 0.003 mmol), and K.sub.2CO.sub.3 (16 mg,
0.119 mmol) suspended in 1 mL of DMF was subjected to microwave
reaction at 150.degree. C. for 45 min. After the reaction, the
reaction mixture was concentrated in vacuo, and the residue was
purified by column chromatography to afford 19 mg of Compound 189
as yellowish oil. MS (ES) M+H expected 475.2, found 475.1. .sup.1H
NMR (CHLOROFORM-d) .delta. 7.70 (d, J=8.0 Hz, 2H), 7.60 (s, 1H),
7.38 (d, J=8.0 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d, J=11.0 Hz,
0.5H), 4.44 (d, J=12.3 Hz, 1H), 4.32-4.39 (m, 1H), 4.28 (br. s.,
0.5H), 3.83 (d, J=13.3 Hz, 0.5H), 3.68-3.79 (m, 2H), 3.53-3.64 (m,
0.5H), 3.38 (s, 3H), 3.36 (br. s., 0.5H), 3.33 (br. s., 0.5H),
3.10-3.28 (m, 1.5H), 3.07 (dt, J=13.3, 1 Hz, 1H), 2.65-2.80 (m,
1H), 2.52-2.65 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.3
Hz, 1.5H), 1.16 (d, J=6.5 Hz, 6H).
[0243] Other Compounds of Formula II listed below, wherein R.sup.1b
is aryl or heteroaryl; and R.sup.2 is isopropyl or cyclopropyl were
similarly prepared using any of intermediates 7 (Scheme 1), 17
(Scheme 2), or 28 (Scheme 3) as starting material.
(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(4-(trif-
luoromethyl)phenyl)nicotinonitrile (Compound 185)
[0244] .sup.1H NMR (CHLOROFORM-d) .delta. 7.70 (d, J=8.0 Hz, 2H),
7.61 (s, 1H), 7.47-7.56 (m, 1H), 7.38 (d, J=7.8 Hz, 1H), 7.07 (d,
J=3.5 Hz, 1H), 6.48-6.55 (m, 1H), 4.86-4.96 (m, 1H), 4.43-4.59 (m,
2H), 4.38 (dt, J=13.3, 2.0 Hz, 1H), 3.56 (br. s., 1H), 3.46 (dd,
J=13.3, 3.8 Hz, 1H), 3.28 (td, J=12.4, 3.4 Hz, 1H), 3.07 (quin,
J=6.7 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.16 (dd, J=6.7, 1.6 Hz,
6H). LC-MS: m/z 483.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(4-(trif-
luoromethyl)phenyl)nicotinonitrile (Compound 187)
[0245] .sup.1H NMR (CHLOROFORM-d) .delta. 7.76 (s, 1H), 7.70 (d,
J=8.0 Hz, 2H), 7.61 (s, 1H), 7.44-7.49 (m, 1H), 7.38 (d, J=8.0 Hz,
2H), 6.56-6.63 (m, 1H), 4.75 (br. s., 1H), 4.45 (d, J=13.1 Hz, 1H),
4.35-4.42 (m, 2H), 3.42-3.64 (m, 1H), 3.31-3.41 (m, 1H), 3.18 (td,
J=12.5, 3.5 Hz, 1H), 3.07 (dt, J=13.2, 6.6 Hz, 1H), 1.44 (d, J=6.8
Hz, 3H), 1.16 (dd, J=6.7, 1.9 Hz, 6H). LC-MS: m/z 483.2
(M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-(-
4-(trifluoromethyl)phenyl)nicotinonitrile (Compound 188)
[0246] .sup.1H NMR (CHLOROFORM-d) .delta. 7.69 (d, J=8.3 Hz, 2H),
7.59 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.22 (dd, J=5.1, 1.1 Hz, 1H),
6.95-7.00 (m, 1H), 6.89-6.95 (m, 1H), 4.95 (br. s., 0.5H), 4.59 (d,
J=12.8 Hz, 0.5H), 4.19-4.48 (m, 3H), 3.89-4.06 (m, 2H), 3.82 (d,
J=13.6 Hz, 0.5H), 3.57 (t, J=11.3 Hz, 0.5H), 3.20-3.38 (m, 1H),
3.08-3.20 (m, 1H), 3.00-3.08 (m, 1H), 1.35 (d, J=6.5 Hz, 1.5H),
1.31 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 513.1
(M+H).sup.+.
(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-m-tolyln-
icotinonitrile (Compound 190)
[0247] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.51 (d,
J=1.0 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H),
7.01-7.09 (m, 3H), 6.51 (dd, J=3.3, 1.8 Hz, 1H), 4.90 (br. s., 1H),
4.52 (d, J=13.3 Hz, 1H), 4.42 (d, J=13.8 Hz, 1H), 4.30-4.37 (m,
1H), 3.56 (br. s., 1H), 3.41 (dd, J=13.2, 3.6 Hz, 1H), 3.24 (td,
J=12.4, 3.3 Hz, 1H), 3.15 (dt, J=13.3, 6.7 Hz, 1H), 2.40 (s, 3H),
1.48 (d, J=6.5 Hz, 3H), 1.15 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z
429.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-m-tolyln-
icotinonitrile (Compound 191)
[0248] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (s, 1H), 7.61 (s,
1H), 7.46 (t, J=1.6 Hz, 1H), 7.31 (t, J=7.8 Hz, 1H), 7.20 (d, J=7.8
Hz, 1H), 7.00-7.08 (m, 2H), 6.59 (d, J=1.0 Hz, 1H), 4.74 (br. s.,
1H), 4.20-4.50 (m, 3H), 3.41-3.61 (m, 1H), 3.32 (dd, J=13.1, 3.0
Hz, 1H), 3.08-3.19 (m, 2H), 2.40 (s, 3H), 1.45 (d, J=6.8 Hz, 3H),
1.08-1.19 (m, 6H). LC-MS: m/z 429.1 (M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-m-
-tolylnicotinonitrile (Compound 192)
[0249] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.28-7.35
(m, 1H), 7.16-7.25 (m, 2H), 7.00-7.07 (m, 2H), 6.89-6.99 (m, 2H),
4.94 (br. s., 0.5H), 4.58 (d, J=13.3 Hz, 0.5H), 4.33-4.43 (m, 1H),
4.19-4.33 (m, 2H), 3.90-4.05 (m, 2H), 3.80 (d, J=13.3 Hz, 0.5H),
3.51-3.63 (m, 0.5H), 3.17-3.33 (m, 1H), 3.10-3.17 (m, 1H),
2.99-3.10 (m, 1H), 2.40 (s, 3H), 1.36 (d, J=6.3 Hz, 1.5H), 1.32 (d,
J=6.8 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 459.1
(M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-m-toly-
lnicotinonitrile (Compound 193)
[0250] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.31 (t,
J=7.9 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.01-7.08 (m, 2H), 4.93 (br.
s., 0.5H), 4.56 (d, J=13.1 Hz, 0.5H), 4.30-4.44 (m, 2H), 4.19-4.30
(m, 1H), 3.81 (d, J=13.6 Hz, 0.5H), 3.71-3.78 (m, 2H), 3.52-3.65
(m, 0.5H), 3.38 (s, 3H), 3.24-3.36 (m, 1H), 3.10-3.23 (m, 2H),
2.65-2.80 (m, 1H), 2.54-2.64 (m, 1H), 2.40 (s, 3H), 1.41 (d, J=6.5
Hz, 1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS:
m/z 421.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-isopropylpiperazin-1-yl)-6-isopropyl-5-(4-(t-
rifluoromethyl)phenyl)nicotinonitrile (Compound 195)
[0251] .sup.1H NMR (CHLOROFORM-d) .delta. 7.67-7.84 (m, 3H),
7.57-7.64 (m, 1H), 7.45-7.53 (m, 1H), 7.38 (d, J=8.0 Hz, 2H), 6.58
(s, 1H), 4.84 (d, J=13.6 Hz, 1H), 4.49-4.69 (m, 2H), 3.81-4.22 (m,
1H), 3.22-3.57 (br. s., 3H), 3.07 (dt, J=13.3, 6.7 Hz, 1H),
2.19-2.38 (m, 1H), 1.18 (d, J=6.8 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H),
0.88-1.05 (m, 6H). LC-MS: m/z 511.1 (M+H).sup.+.
(R)-6-isopropyl-2-(3-isopropyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)--
5-(4-(trifluoromethyl)phenyl)-nicotinonitrile (Compound 196)
[0252] .sup.1H NMR (CHLOROFORM-d) .delta. 7.64-7.75 (m, 2H),
7.55-7.62 (m, 1H), 7.37-7.46 (d, J=8.5 Hz, 2H), 7.22 (ddd, J=4.8,
3.2, 1.3 Hz, 1H), 6.87-7.02 (m, 2H), 4.68-4.82 (m, 1.5H), 4.35-4.54
(m, 1.5H), 3.81-4.11 (m, 3H), 3.63 (d, J=10.3 Hz, 0.5H), 3.37-3.53
(m, 0.5H), 3.08-3.20 (m, 1H), 2.96-3.08 (m, 2H), 2.18-2.32 (m,
0.5H), 2.04-2.17 (m, 0.5H), 1.17 (dd, J=6.7, 3.6 Hz, 3H), 1.13 (d,
J=6.5 Hz, 3H), 1.08 (dd, J=11.0, 6.5 Hz, 3H), 0.87-0.93 (m, 1.5H),
0.85 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 541.1 (M+H).sup.+.
(R)-6-isopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(4--
(trifluoromethyl)phenyl)nicotinonitrile (Compound 197)
[0253] .sup.1H NMR (CHLOROFORM-d) .delta. 7.66-7.76 (m, 2H), 7.59
(d, J=2.3 Hz, 1H), 7.38 (d, J=8.0 Hz, 2H), 4.68-4.84 (m, 1.5H),
4.47-4.5 (s, 1.5H), 3.88 (d, J=13.6 Hz, 0.5H), 3.69-3.82 (m, 2H),
3.61 (d, J=10.3 Hz, 0.5H), 3.42-3.52 (m, 0.5H), 3.38 (d, J=2.8 Hz,
3H), 3.12-3.27 (m, 2H), 3.02-3.12 (m, 1H), 2.90-3.02 (m, 0.5H),
2.53-2.83 (m, 2H), 2.17-2.30 (m, 0.5H), 1.98-2.16 (m, 0.5H), 1.18
(d, J=6.5 Hz, 3H), 1.14 (d, J=6.8 Hz, 3H), 1.08 (dd, J=6.5, 2.8 Hz,
3H), 0.91 (d, J=6.8 Hz, 1.5H), 0.85 (d, J=6.8 Hz, 1.5H). LC-MS: m/z
407.4 (M+H).sup.+.
(R)-5-(4-fluorophenyl)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl-
)piperazin-1-yl)nicotinonitrile (Compound 199)
[0254] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.29 (d,
J=2.0 Hz, 1H), 7.17-7.24 (m, 2H), 7.08-7.16 (m, 2H), 6.38 (d, J=1.8
Hz, 1H), 4.68 (br. s., 1H), 4.41 (d, J=13.1 Hz, 1H), 4.36 (d,
J=13.1 Hz, 1H), 4.20-4.28 (d, J=13.6 Hz, 1H), 3.39-3.59 (m, 1H),
3.25-3.37 (m, 1H), 3.03-3.18 (m, 2H), 2.41 (s, 3H), 1.41 (d, J=6.5
Hz, 3H), 1.14 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z 447.2
(M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5--
m-tolylnicotinonitrile (Compound 200)
[0255] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.29 (d,
J=2.0 Hz, 2H), 7.17-7.24 (m, 1H), 7.08-7.16 (m, 2H), 6.38 (d, J=1.8
Hz, 1H), 4.68 (br. s., 1H), 4.41 (d, J=13.1 Hz, 1H), 4.36 (d,
J=13.1 Hz, 1H), 4.20-4.28 (d, J=13.6 Hz, 1H), 3.39-3.59 (m, 4H),
3.25-3.37 (m, 4H), 3.03-3.18 (m, 8H), 2.41 (s, 11H), 1.41 (d, J=6.5
Hz, 11H), 1.14 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z 443.3
(M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5--
(4-(trifluoromethyl)phenyl)-nicotinonitrile (Compound 201)
[0256] .sup.1H NMR (CHLOROFORM-d) .delta. 7.70 (d, J=8.0 Hz, 2H),
7.57-7.64 (m, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.27-7.32 (m, 1H),
6.35-6.42 (m, 1H), 4.68 (br. s., 1H), 4.34-4.53 (m, 2H), 4.20-4.34
(m, 1H), 3.48 (d, J=4.8 Hz, 1H), 3.28-3.40 (m, 1H), 3.16 (td,
J=12.6, 3.4 Hz, 1H), 3.00-3.11 (m, 1H), 2.41 (s, 3H), 1.38-1.48 (m,
3H), 1.16 (dd, J=6.8, 2.3 Hz, 6H). LC-MS: m/z 497.2
(M+H).sup.+.
(R)-6-isopropyl-5-(4-isopropylphenyl)-2-(3-methyl-4-(2-methylfuran-3-carbo-
nyl)piperazin-1-yl)nicotinonitrile (Compound 202)
[0257] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58-7.65 (m, 1H), 7.28
(d, J=8.3 Hz, 3H), 7.11-7.20 (m, 2H), 6.37 (d, J=2.0 Hz, 1H),
4.59-4.68 (br. s., 1H), 4.30-4.43 (m, 2H), 4.19 (br. s., 1H),
3.40-3.54 (m, 1H), 3.30 (dd, J=12.8, 3.0 Hz, 1H), 3.14-3.22 (m,
1H), 3.06-3.14 (m, 1H), 2.96 (spt, J=6.9 Hz, 1H), 2.41 (s, 3H),
1.39-1.45 (m, 3H), 1.30 (d, J=7.0 Hz, 6H), 1.15 (dd, J=6.8, 3.0 Hz,
6H). LC-MS: m/z 471.3 (M+H).sup.+.
(R)-5-(furan-3-yl)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)pip-
erazin-1-yl)nicotinonitrile (Compound 203)
[0258] .sup.1H NMR (CHLOROFORM-d) .delta. 7.64 (s, 1H), 7.49-7.53
(m, 1H), 7.43-7.47 (m, 1H), 7.29 (d, J=1.8 Hz, 1H), 6.45 (d, J=0.8
Hz, 1H), 6.36 (d, J=1.8 Hz, 1H), 4.68 (br. s., 1H), 4.39 (d, J=13.1
Hz, 1H), 4.34 (d, J=13.1 Hz, 1H), 4.18-4.26 (br. s., 1H), 3.38-3.56
(m, 1H), 3.22-3.35 (m, 2H), 3.11 (td, J=12.6, 3.4 Hz, 1H),
2.36-2.47 (m, 3H), 1.39 (d, J=6.5 Hz, 3H), 1.18 (dd, J=6.7, 1.6 Hz,
6H). LC-MS: m/z 419.2 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-5-(furan-3-yl)-6-isopr-
opylnicotinonitrile (Compound 204)
[0259] .sup.1H NMR (CHLOROFORM-d) .delta. 7.72-7.77 (m, 1H), 7.64
(s, 1H), 7.50 (t, J=1.8 Hz, 1H), 7.44-7.47 (m, 2H), 6.58 (dd,
J=1.8, 0.8 Hz, 1H), 6.45 (dd, J=1.8, 0.8 Hz, 1H), 5.30 (s, 1H),
4.73 (br. s., 1H), 4.38 (s, 1H), 4.41 (s, 1H), 4.31 (t, J=2.1 Hz,
1H), 4.35 (t, J=2.0 Hz, 1H), 3.48 (br. s., 1H), 3.32 (dd, J=9.9,
3.1 Hz, 1H), 3.24-3.30 (m, 1H), 3.14 (td, J=12.5, 3.5 Hz, 1H), 1.42
(d, J=7.0 Hz, 3H), 1.19 (dd, J=6.8, 1.0 Hz, 6H). LC-MS: m/z 405.2
(M+H).sup.+.
(R)-5-(furan-3-yl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-
-1-yl)nicotinonitrile (Compound 205)
[0260] .sup.1H NMR (CHLOROFORM-d) .delta. 7.63 (s, 1H), 7.50 (t,
J=1.8 Hz, 1H), 7.42-7.47 (m, 1H), 6.44 (dd, J=1.8, 0.8 Hz, 1H),
4.92 (br. s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.38 (dd, J=12.2,
2.1 Hz, 1H), 4.17-4.35 (m, 2H), 3.80 (d, J=13.1 Hz, 0.5H), 3.74 (t,
J=6.5 Hz, 2H), 3.51-3.62 (m, 0.5H), 3.36-3.39 (m, 3H), 3.23-3.35
(m, 2H), 3.06-3.17 (m, 1H), 2.64-2.80 (m, 1H), 2.51-2.63 (m, 1H),
1.38 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.0 Hz, 1.5H), 1.19 (d, J=6.8
Hz, 6H). LC-MS: m/z 397.2 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(4-isopr-
opylphenyl)nicotinonitrile (Compound 206)
[0261] .sup.1H NMR (CHLOROFORM-d) .delta. 7.72-7.77 (m, 1H), 7.61
(s, 1H), 7.46 (t, J=1.6 Hz, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.12-7.19
(m, 2H), 6.59 (dd, J=1.8, 0.8 Hz, 1H), 4.74 (br. s., 1H), 4.39 (d,
J=13.3 Hz, 1H), 4.33 (dt, J=13.2, 1.9 Hz, 2H), 3.49 (br. s., 1H),
3.32 (dd, J=13.2, 3.4 Hz, 1H), 3.08-3.23 (m, 2H), 2.96 (dt, J=13.8,
6.9 Hz, 1H), 1.45 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.0 Hz, 6H), 1.15
(dd, J=6.5, 2.3 Hz, 6H). LC-MS: m/z 457.2 (M+H).sup.+.
(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)nicotinonitrile (Compound 207)
[0262] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.17-7.24
(m, 2H), 7.08-7.16 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.0
Hz, 0.5H), 4.40 (dd, J=12.2, 1.9 Hz, 1H), 4.19-4.35 (m, 2H), 3.82
(d, J=12.5 Hz, 0.5H), 3.69-3.78 (m, 2H), 3.53-3.63 (m, 0.5H), 3.38
(s, 3H), 3.26-3.35 (m, 1H), 3.13-3.22 (m, 1H), 3.03-3.12 (m, 1H),
2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 1.40 (d, J=6.3 Hz, 1.5H),
1.30 (d, J=6.5 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 425.2
(M+H).sup.+.
(R)-6-isopropyl-5-(4-isopropylphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpi-
perazin-1-yl)nicotinonitrile (Compound 208)
[0263] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59-7.65 (m, 1H),
7.29-7.33 (m, 2H), 7.14-7.22 (m, 2H), 4.95 (br. s., 0.5H), 4.58 (d,
J=13.1 Hz, 0.5H), 4.37-4.44 (m, 1H), 4.22-4.37 (m, 2H), 3.83 (d,
J=13.3 Hz, 0.5H), 3.70-3.80 (m, 2H), 3.55-3.67 (m, 0.5H), 3.40 (s,
3H), 3.33 (t, J=12.3 Hz, 1H), 3.15-3.25 (m, 2H), 2.98 (quin, J=6.9
Hz, 1H), 2.67-2.83 (m, 1H), 2.55-2.67 (m, 1H), 1.43 (d, J=5.8 Hz,
1.5H), 1.34 (m, 1.5H), 1.32 (d, J=7.0 Hz, 6H), 1.17 (d, J=6.8 Hz,
6H). LC-MS: m/z 449.2 (M+H).sup.+.
(R)-5-(benzofuran-2-yl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 209)
[0264] .sup.1H NMR (CHLOROFORM-d) .delta. 8.12 (s, 1H), 7.61 (dd,
J=7.7, 0.9 Hz, 1H), 7.48-7.56 (m, 1H), 7.32 (td, J=7.7, 1.5 Hz,
1H), 7.24-7.29 (m, 1H), 6.78-6.88 (m, 1H), 4.93 (br. s., 0.5H),
4.38-4.64 (m, 2H), 4.27 (br. s., 0.5H), 3.83 (d, J=12.8 Hz, 1H),
3.75 (br. s., 2H), 3.55 (quin, J=6.7 Hz, 2H), 3.38 (s, 3H),
3.08-3.29 (m, 2H), 2.66-2.83 (m, 1H), 2.60 (br. s., 1H), 1.38 (d,
J=6.0 Hz, 1.5H), 1.33 (br. s., 1.5H), 1.28 (d, J=6.5 Hz, 6H).
LC-MS: m/z 447.1 (M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyrim-
idin-5-yl)nicotinonitrile (Compound 210)
[0265] .sup.1H NMR (CHLOROFORM-d) .delta. 9.23-9.28 (m, 1H), 8.69
(s, 2H), 7.62 (s, 1H), 4.94 (br. s., 0.5H), 4.56 (d, J=9.5 Hz,
0.5H), 4.37-4.53 (m, 2H), 4.29 (br. s., 0.5H), 3.84 (d, J=13.3 Hz,
0.5H), 3.68-3.79 (m, 2H), 3.52-3.64 (m, 0.5H), 3.40-3.46 (m, 0.5H),
3.38 (s, 3H), 3.20-3.32 (m, 1H), 3.16 (d, J=9.5 Hz, 1H), 2.93-3.04
(m, 1H), 2.65-2.78 (m, 1H), 2.52-2.64 (m, 1H), 1.39 (d, J=6.5 Hz,
1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 1.19 (dd, J=6.7, 1.1 Hz, 6H).
LC-MS: m/z 409.2 (M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(napht-
halen-2-yl)nicotinonitrile (Compound 211)
[0266] .sup.1H NMR (CHLOROFORM-d) .delta. 7.83-7.97 (m, 3H),
7.66-7.77 (m, 2H), 7.49-7.60 (m, 2H), 7.36 (dd, J=8.4, 1.6 Hz, 1H),
4.94 (br. s., 0.5H), 4.57 (d, J=12.8 Hz, 0.5H), 4.42 (d, J=12.8 Hz,
1H), 4.30-4.38 (m, 1H), 4.27 (br. s., 1H), 3.83 (d, J=13.3 Hz,
0.5H), 3.69-3.79 (m, 2H), 3.54-3.65 (m, 0.5H), 3.39 (s, 3H),
3.29-3.38 (m, 1H), 3.18-3.24 (m, 1H), 3.06-3.17 (m, 1H), 2.66-2.83
(m, 1H), 2.52-2.65 (m, 1H), 1.42 (d, J=7.3 Hz, 1.5H), 1.32 (d,
J=6.5 Hz, 1.5H), 1.17 (d, J=6.8 Hz, 6H). LC-MS: m/z 457.1
(M+H).sup.+.
(R)-6-isopropyl-5-(3-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 212)
[0267] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 7.34 (t,
J=7.9 Hz, 1H), 6.92 (dd, J=8.3, 1.8 Hz, 1H), 6.82 (d, J=7.5 Hz,
1H), 6.74-6.79 (m, 1H), 4.93 (br. s., 0.5H), 4.56 (d, J=12.8 Hz,
0.5H), 4.39 (d, J=13.6 Hz, 1H), 4.21-4.34 (m, 2H), 3.84 (s, 3H),
3.79 (d, J=8.0 Hz, 0.5H), 3.70-3.77 (m, 2H), 3.53-3.64 (m, 0.5H),
3.38 (s, 3H), 3.26-3.36 (m, 1H), 3.12-3.22 (m, 2H), 2.65-2.80 (m,
1H), 2.52-2.64 (m, 1H), 1.41 (d, J=1.5 Hz, 4H), 1.31 (d, J=6.5 Hz,
1.5H), 1.10-1.19 (m, 6H). LC-MS: m/z 437.1 (M+H).sup.+.
(R)-2-isopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,4'-bip-
yridine-5-carbonitrile (Compound 213)
[0268] .sup.1H NMR (CHLOROFORM-d) .delta. 8.69 (d, J=5.3 Hz, 2H),
7.61 (s, 1H), 7.22 (d, J=5.5 Hz, 2H), 4.93 (br. s., 0.5H), 4.56 (d,
J=9.8 Hz, 0.5H), 4.34-4.51 (m, 2H), 4.28 (br. s., 1H), 3.83 (d,
J=13.3 Hz, 0.5H), 3.68-3.79 (m, 2H), 3.58 (t, J=11.0 Hz, 0.5H),
3.38 (s, 3H), 3.14-3.28 (m, 2H), 3.03-3.14 (m, 1H), 2.65-2.83 (m,
1H), 2.52-2.65 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H), 1.29 (d, J=6.5
Hz, 1.5H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z 408.1
(M+H).sup.+.
(R)-6-isopropyl-5-(4-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 214)
[0269] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.11-7.20
(m, 2H), 6.92-7.01 (m, 2H), 4.92 (br. s., 0.5H), 4.56 (d, J=12.8
Hz, 0.5H), 4.37 (d, J=12.5 Hz, 1H), 4.29 (d, J=13.1 Hz, 2H), 3.86
(s, 3H), 3.81 (d, J=13.6 Hz, 0.5H), 3.75 (br. s., 2H), 3.53-3.64
(m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=13.2 Hz, 1H), 3.11-3.20 (m,
2H), 2.66-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.41 (d, J=6.0 Hz,
1.5H), 1.31 (d, J=5.8 Hz, 1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z
437.3 (M+H).sup.+.
(R)-5-(4-chlorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)nicotinonitrile (Compound 215)
[0270] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.38-7.43
(m, 2H), 7.14-7.20 (m, 2H), 4.93 (br. s., 0.5H), 4.55 (d, J=12.5
Hz, 0.5H), 4.40 (d, J=12.8 Hz, 1H), 4.21-4.36 (m, 2H), 3.82 (d,
J=13.6 Hz, 0.5H), 3.69-3.78 (m, 2H), 3.53-3.63 (m, 0.5H), 3.38 (s,
3H), 3.27-3.37 (m, 1H), 3.11-3.23 (m, 1H), 3.02-3.11 (m, 1H),
2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H),
1.30 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.5 Hz, 6H). LC-MS: m/z 441.1
(M+H).sup.+.
5-(4-ethylphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin--
1-yl)nicotinonitrile (Compound 216)
[0271] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.27 (s,
1H), 7.25 (s, 1H), 7.15 (d, J=8.0 Hz, 2H), 4.93 (br. s., 0.5H),
4.56 (d, J=12.5 Hz, 0.5H), 4.38 (d, J=12.3 Hz, 1H), 4.30 (d, J=12.3
Hz, 2H), 3.81 (d, J=13.3 Hz, 0.5H), 3.75 (br. s., 2H), 3.51-3.64
(m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=13.6 Hz, 1H), 3.12-3.22 (m,
2H), 3.10 (d, J=14.3 Hz, 0.5H), 2.77 (br. s., 0.5H), 2.71 (q, J=7.5
Hz, 2H), 2.61 (br. s., 1H), 1.41 (d, J=6.0 Hz, 1.5H), 1.32 (br. s.,
1.5H), 1.29 (t, J=7.5 Hz, 3H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z
435.3 (M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(napht-
halen-1-yl)nicotinonitrile (Compound 217)
[0272] .sup.1H NMR (CHLOROFORM-d) .delta. 7.92 (t, J=7.4 Hz, 2H),
7.63 (s, 1H), 7.49-7.57 (m, 2H), 7.39-7.47 (m, 2H), 7.27-7.34 (m,
1H), 4.96 (br. s., 0.5H), 4.59 (d, J=12.5 Hz, 0.5H), 4.45 (d,
J=13.3 Hz, 1H), 4.32-4.41 (m, 1H), 4.30 (br. s., 1H), 3.85 (d,
J=13.6 Hz, 0.5H), 3.70-3.81 (m, 2H), 3.55-3.67 (m, 0.5H), 3.39 (s,
3H), 3.07-3.27 (m, 2H), 2.67-2.76 (m, 2H), 2.53-2.66 (m, 1H), 1.45
(d, J=5.5 Hz, 1.5H), 1.36 (d, J=6.5 Hz, 1.5H), 1.06 (d, J=6.5 Hz,
6H). LC-MS: m/z 457.3 (M+H).sup.+.
(R)-5-(3-chlorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)nicotinonitrile (Compound 218)
[0273] .sup.1H NMR (CHLOROFORM-d) .delta. 7.56-7.61 (m, 1H),
7.35-7.39 (m, 2H), 7.21-7.25 (m, 1H), 7.11-7.14 (m, 1H), 4.93 (br.
s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H), 4.42 (d, J=12.5 Hz, 1H),
4.29-4.37 (m, 1H), 4.26 (br. s., 1H), 3.82 (d, J=13.6 Hz, 0.5H),
3.68-3.78 (m, 2H), 3.53-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.37 (m,
1H), 3.12-3.24 (m, 1H), 3.04-3.12 (m, 1H), 2.65-2.80 (m, 1H),
2.50-2.64 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.5 Hz,
1.5H), 1.15 (d, J=6.5 Hz, 6H). LC-MS: m/z 441.2 (M+H).sup.+.
(R)-5-(3,4-dimethylphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)nicotinonitrile (Compound 220)
[0274] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.18 (d,
J=7.5 Hz, 1H), 7.00 (s, 1H), 6.97 (dd, J=7.7, 1.6 Hz, 1H), 4.93
(br. s., 0.5H), 4.55 (d, J=13.1 Hz, 0.5H), 4.32-4.42 (m, 1H), 4.29
(d, J=12.8 Hz, 1H), 3.78-3.85 (m, 0.5H), 3.71-3.77 (m, 2H),
3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.24-3.35 (m, 1H), 3.17 (dt,
J=13.3, 6.7 Hz, 2H), 3.01-3.12 (m, 1H), 2.65-2.80 (m, 1H),
2.53-2.63 (m, 1H), 2.31 (d, J=3.0 Hz, 6H), 1.40 (d, J=6.5 Hz,
1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.14 (d, J=6.5 Hz, 6H). LC-MS: m/z
435.4 (M+H).sup.+.
(R)-5-(3-fluoro-4-methylphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-me-
thylpiperazin-1-yl)nicotinonitrile (Compound 221)
[0275] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.23 (t,
J=8.0 Hz, 1H), 6.90-6.95 (m, 1H), 6.89 (dd, J=5.8, 1.3 Hz, 1H),
4.93 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.21-4.45 (m, 3H),
3.81 (d, J=13.3 Hz, 0.5H), 3.70-3.77 (m, 2H), 3.52-3.63 (m, 0.5H),
3.38 (s, 3H), 3.26-3.37 (m, 1H), 3.10-3.18 (m, 2H), 2.65-2.80 (m,
1H), 2.53-2.63 (m, 1H), 2.33 (d, J=1.5 Hz, 3H), 1.40 (d, J=6.5 Hz,
1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z
439.4 (M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-phenyl-
nicotinonitrile (Compound 222)
[0276] .sup.1H NMR (CHLOROFORM-d) .delta. 7.56-7.61 (m, 1H),
7.35-7.39 (m, 3H), 7.21-7.25 (m, 2H), 4.93 (br. s., 0.5H), 4.55 (d,
J=11.8 Hz, 0.5H), 4.42 (d, J=12.5 Hz, 1H), 4.29-4.37 (m, 1H), 4.26
(br. s., 1H), 3.82 (d, J=13.6 Hz, 0.5H), 3.68-3.78 (m, 2H),
3.53-3.65 (m, 0.5H), 3.38 (s, 3H), 3.28-3.37 (m, 1H), 3.12-3.24 (m,
1H), 3.04-3.12 (m, 1H), 2.65-2.80 (m, 1H), 2.50-2.64 (m, 1H), 1.40
(d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.15 (d, J=6.5 Hz,
6H). LC-MS: m/z 407.4 (M+H).sup.+.
(R)-5-(3,4-dimethoxyphenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methyl-
piperazin-1-yl)nicotinonitrile (Compound 223)
[0277] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 6.92 (d,
J=8.3 Hz, 1H), 6.78 (dd, J=8.2, 1.9 Hz, 1H), 6.73 (d, J=2.0 Hz,
1H), 4.88-4.96 (m, 0.5H), 4.55 (d, J=13.1 Hz, 0.5H), 4.18-4.46 (m,
3H), 3.93 (s, 3H), 3.89 (s, 3H), 3.78-3.86 (m, 0.5H), 3.71-3.78 (m,
2H), 3.52-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t, J=10.8 Hz, 1H),
3.10-3.22 (m, 2H), 2.65-2.80 (m, 1H), 2.52-2.64 (m, 1H), 1.33 (s,
1.5H), 1.28 (s, 1.5H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z 467.3
(M+H).sup.+.
(R)-5-(benzo[d][1,3]-dioxol-5-yl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile (Compound 224)
[0278] .sup.1H NMR (CHLOROFORM-d) .delta. 7.57 (s, 1H), 6.83-6.90
(m, 1H), 6.64-6.73 (m, 2H), 6.02 (s, 2H), 4.92 (br. s., 0.5H), 4.55
(d, J=12.5 Hz, 0.5H), 4.20-4.43 (m, 3H), 3.81 (d, J=12.8 Hz, 0.5H),
3.74 (t, J=6.3 Hz, 2H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H),
3.25-3.36 (m, 1H), 3.10-3.22 (m, 2H), 2.64-2.80 (m, 1H), 2.52-2.64
(m, 1H), 1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.14
(d, J=6.8 Hz, 6H). LC-MS: m/z 451.3 (M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(tr-
ifluoromethoxy)phenyl)nicotinonitrile (Compound 230)
[0279] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58-7.63 (m, 1H),
7.42-7.51 (m, 1H), 7.22-7.26 (m, 1H), 7.18 (dd, J=7.8, 1.3 Hz, 1H),
7.11 (s, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz, 0.5H),
4.27-4.46 (m, 3H), 3.78-3.88 (m, 0.5H), 3.75 (t, J=6.4 Hz, 2H),
3.50-3.64 (m, 0.5H), 3.38 (s, 3H), 3.29-3.36 (m, 1H), 3.13-3.24 (m,
1H), 3.07 (dt, J=13.3, 6.7 Hz, 1H), 2.65-2.81 (m, 1H), 2.52-2.64
(m, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.3 Hz, 1.5H), 1.16
(d, J=6.5 Hz, 6H). LC-MS: m/z 491.3 (M+H).sup.+.
(R)-5-(3-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)nicotinonitrile (Compound 231)
[0280] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.39 (td,
J=8.0, 6.1 Hz, 1H), 7.05-7.13 (m, 1H), 7.02 (d, J=7.8 Hz, 1H), 6.95
(dt, J=9.4, 2.1 Hz, 1H), 4.93 (br. s., 0.5H), 4.55 (d, J=11.8 Hz,
0.5H), 4.26-4.45 (m, 3H), 3.82 (d, J=13.1 Hz, 0.5H), 3.75 (t, J=6.1
Hz, 2H), 3.51-3.64 (m, 0.5H), 3.38 (s, 3H), 3.27-3.35 (m, 1H),
3.16-3.23 (m, 1H), 3.09-3.14 (m, 1H), 2.65-2.81 (m, 1H), 2.60 (t,
J=5.9 Hz, 1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H),
1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 443.3 (M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(tr-
ifluoromethoxy)phenyl)nicotinonitrile (Compound 232)
[0281] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.27 (s,
4H), 4.93 (br. s., 0.5H), 4.49-4.61 (m, 9.5H), 4.26-4.47 (m, 3H),
3.82 (d, J=13.6 Hz, 0.5H), 3.72-3.77 (m, 2H), 3.51-3.65 (m, 0.5H),
3.38 (s, 3H), 3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H), 3.08 (dt,
J=13.3, 6.7 Hz, 1H), 2.65-2.80 (m, 1H), 2.60 (t, J=5.9 Hz, 1H),
1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.16 (d, J=6.5
Hz, 6H). LC-MS: m/z 491.3 (M+H).sup.+.
(R)-5-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-6-isopropyl-2-(4-(3-methoxypro-
panoyl)-3-methylpiperazin-1-yl)nicotinonitrile (Compound 233)
[0282] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.27 (s,
4H), 4.93 (br. s., 0.5H), 4.49-4.61 (m, 0.5H), 4.26-4.47 (m, 3H),
3.82 (d, J=13.6 Hz, 0.5H), 3.72-3.77 (m, 2H), 3.51-3.65 (m, 0.5H),
3.38 (s, 3H), 3.28-3.36 (m, 1H), 3.13-3.23 (m, 1H), 3.08 (dt,
J=13.3, 6.7 Hz, 1H), 2.65-2.80 (m, 1H), 2.60 (t, J=5.9 Hz, 1H),
1.40 (d, J=6.0 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.16 (d, J=6.5
Hz, 6H). LC-MS: m/z 465.3 (M+H).sup.+.
(R)-6-isopropyl-5-(isoquinolin-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)nicotinonitrile (Compound 234)
[0283] .sup.1H NMR (CHLOROFORM-d) .delta. 9.33 (s, 1H), 8.37 (s,
1H), 8.06-8.16 (m, 1H), 7.64-7.69 (m, 2H), 7.45-7.50 (m, 2H), 4.96
(br. s., 0.5H), 4.58 (br. s., 0.5H), 4.31-4.54 (m, 3H), 3.86 (d,
J=12.5 Hz, 0.5H), 3.76 (t, J=6.4 Hz, 2H), 3.56-3.67 (m, 0.5H), 3.42
(d, J=3.8 Hz, 1H), 3.36-3.40 (m, 3H), 3.08-3.33 (m, 1H), 2.65-2.78
(m, 2H), 2.54-2.64 (m, 1H), 1.44 (d, J=4.5 Hz, 1.5H), 1.35 (d,
J=6.0 Hz, 1.5H), 1.05-1.11 (m, 6H). LC-MS: m/z 458.2
(M+H).sup.+.
(R)-6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)nicotinonitrile (Compound 219)
[0284] .sup.1H NMR (CHLOROFORM-d) .delta. 7.57 (s, 1H), 7.31-7.39
(m, 2H), 7.27 (s, 1H), 7.10-7.18 (m, 2H), 4.90 (br. s., 0.5H), 4.53
(d, J=13.6 Hz, 0.5H), 4.07-4.33 (m, 3H), 3.77-3.84 (m, 0.5H),
3.71-3.76 (m, 2H), 3.48-3.60 (m, 0.5H), 3.36-3.41 (m, 3H), 3.25 (t,
J=10.4 Hz, 1H), 3.06-3.18 (m, 1H), 2.63-2.79 (m, 1H), 2.51-2.62 (m,
1H), 1.95-2.07 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8
Hz, 1.5H), 1.12-1.18 (m, 2H), 0.91-0.97 (m, 2H). LC-MS: m/z 423.3
(M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-m-to-
lylnicotinonitrile (Compound 225)
[0285] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.30-7.36
(m, 1H), 7.14-7.22 (m, 3H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1
Hz, 0.5H), 3.80-4.36 (m, 3H), 3.80 (br. s., 0.5H), 3.74 (t, J=6.3
Hz, 2H), 3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.19-3.29 (m, 1H),
3.07-3.17 (m, 1H), 2.63-2.80 (m, 1H), 2.53-2.62 (m, 1H), 2.41 (s,
3H), 2.03-2.13 (m, 1H), 1.39 (d, J=5.8 Hz, 1.5H), 1.29 (d, J=6.5
Hz, 1.5H), 1.11-1.17 (m, 2H), 0.89-0.97 (m, 2H). LC-MS: m/z 419.3
(M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(-
trifluoromethyl)phenyl)nicotinonitrile (Compound 226)
[0286] .sup.1H NMR (CHLOROFORM-d) .delta. 7.71 (d, J=8.0 Hz, 2H),
7.60 (s, 1H), 7.52 (d, J=8.0 Hz, 2H), 4.82-4.95 (m, 0.5H), 4.53 (d,
J=12.8 Hz, 0.5H), 4.17-4.39 (m, 3H), 3.80 (d, J=13.6 Hz, 0.5H),
3.74 (t, J=6.3 Hz, 2H), 3.49-3.62 (m, 0.5H), 3.37 (s, 3H),
3.24-3.33 (m, 1H), 3.03-3.15 (m, 1H), 2.63-2.80 (m, 1H), 2.51-2.62
(m, 1H), 1.93-2.02 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.28 (d,
J=3.5 Hz, 1.5H), 1.14-1.20 (m, 2H), 0.93-0.99 (m, 2H). LC-MS: m/z
473.3 (M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4-(-
trifluoromethoxy)phenyl)nicotinonitrile (Compound 227)
[0287] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.41-7.44
(m, 1H), 7.38-7.41 (m, 1H), 7.30 (s, 1H), 7.28 (s, 1H), 4.90 (br.
s., 0.5H), 4.53 (d, J=11.5 Hz, 0.5H), 4.12-4.34 (m, 3H), 3.81 (br.
s., 0.5H), 3.74 (t, J=6.3 Hz, 2H), 3.55 (t, J=11.4 Hz, 0.5H), 3.37
(s, 3H), 3.26 (br. s., 1H), 3.11 (br. s., 1H), 2.63-2.78 (m, 1H),
2.58 (d, J=5.8 Hz, 1H), 1.95-2.05 (m, 1H), 1.38 (d, J=5.8 Hz,
1.5H), 1.28 (d, J=5.8 Hz, 1.5H), 1.13-1.18 (m, 2H), 0.93-0.99 (m,
2H). LC-MS: m/z 489.2 (M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(-
trifluoromethoxy)phenyl)-nicotinonitrile (Compound 228)
[0288] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.48 (t,
J=7.9 Hz, 1H), 7.33 (d, J=7.8 Hz, 1H), 7.27 (br. s., 1H), 7.21-7.26
(m, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 4.17-4.36
(m, 3H), 3.77-3.86 (m, 0.5H), 3.74 (t, J=6.1 Hz, 2H), 3.51-3.62 (m,
0.5H), 3.37 (s, 3H), 3.28 (t, J=8.9 Hz, 1H), 3.12 (d, J=10.8 Hz,
1H), 2.64-2.80 (m, 1H), 2.52-2.63 (m, 1H), 1.96-2.04 (m, 1H),
1.35-1.42 (m, 1.5H), 1.28 (d, J=5.5 Hz, 1.5H), 1.14-1.20 (m, 2H),
0.93-1.01 (m, 2H). LC-MS: m/z 489.2 (M+H).sup.+.
(R)-6-cyclopropyl-5-(3-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)nicotinonitrile (Compound 229)
[0289] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.41 (td,
J=7.8, 6.1 Hz, 1H), 7.14-7.19 (m, 1H), 7.04-7.13 (m, 2H), 4.90 (br.
s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.12-4.34 (m, 3H), 3.77-3.85
(m, 0.5H), 3.74 (t, J=6.1 Hz, 2H), 3.48-3.61 (m, 0.5H), 3.37 (s,
3H), 3.26 (t, J=9.4 Hz, 1H), 3.06-3.16 (m, 1H), 2.64-2.79 (m, 1H),
2.51-2.62 (m, 1H), 1.99-2.08 (m, 1H), 1.38 (d, J=6.0 Hz, 1.5H),
1.28 (d, J=6.5 Hz, 1.5H), 1.12-1.19 (m, 2H), 0.93-0.99 (m, 2H).
LC-MS: m/z 423.3 (M+H).sup.+.
(R)-6-cyclopropyl-5-(3-fluoro-4-methylphenyl)-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile (Compound 235)
[0290] .sup.1H NMR (CHLOROFORM-d) .delta. 7.57 (s, 1H), 7.21-7.26
(m, 1H), 7.06 (s, 1H), 7.01-7.05 (m, 1H), 4.89 (br. s., 0.5H), 4.52
(d, J=12.8 Hz, 0.5H), 4.11-4.33 (m, 3H), 3.80 (br. s., 0.5H), 3.74
(t, J=6.3 Hz, 2H), 3.49-3.60 (m, 0.5H), 3.36-3.41 (m, 3H), 3.25 (t,
J=9.8 Hz, 1H), 3.03-3.15 (m, 1H), 2.63-2.79 (m, 1H), 2.51-2.61 (m,
1H), 2.32 (d, J=1.5 Hz, 3H), 2.01-2.09 (m, 1H), 1.38 (d, J=6.0 Hz,
1.5H), 1.26-1.30 (m, 1.5H), 1.12-1.17 (m, 2H), 0.92-0.97 (m, 2H).
LC-MS: m/z 437.3 (M+H).sup.+.
(R)-6-cyclopropyl-5-(3-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpi-
perazin-1-yl)nicotinonitrile (Compound 236)
[0291] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.32-7.38
(m, 1H), 6.94-6.99 (m, 1H), 6.87-6.94 (m, 2H), 4.90 (br. s., 0.5H),
4.53 (d, J=13.1 Hz, 0.5H), 4.18-4.26 (m, J=12.7 Hz, 3H), 3.84 (s,
3H), 3.81 (d, J=5.5 Hz, 0.5H), 3.74 (t, J=6.1 Hz, 2H), 3.55 (t,
J=11.0 Hz, 0.5H), 3.37 (s, 3H), 3.25 (t, J=10.2 Hz, 1H), 3.03-3.15
(m, 1H), 2.63-2.79 (m, 1H), 2.51-2.62 (m, 1H), 2.05-2.15 (m, 1H),
1.39 (d, J=6.0 Hz, 1.5H), 1.29 (d, J=6.3 Hz, 1.5H), 1.11-1.18 (m,
2H), 0.91-0.96 (m, 2H). LC-MS: m/z 435.3 (M+H).sup.+.
(R)-6-cyclopropyl-5-(3,4-dimethoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-meth-
ylpiperazin-1-yl)nicotinonitrile (Compound 237)
[0292] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 6.92-6.95
(m, 2H), 6.88 (s, 1H), 4.89 (br. s., 0.5H), 4.53 (d, J=14.1 Hz,
0.5H), 4.16-4.30 (m, 3H), 3.93 (s, 3H), 3.90 (s, 3H), 3.78-3.84 (m,
0.5H), 3.71-3.77 (m, 2H), 3.55 (br. s., 0.5H), 3.37 (s, 1H), 3.24
(br. s., 1H), 3.03-3.09 (m., 1H), 2.66-2.79 (m, 1H), 2.59 (br. s.,
1H), 2.08-2.15 (m, 1.5H), 1.38 (br. s., 1.5H), 1.13-1.17 (m, 2H),
0.93 (dd, J=8.0, 3.3 Hz, 2H). LC-MS: m/z 465.1 (M+H).sup.+.
(R)-6-cyclopropyl-5-(isoquinolin-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)nicotinonitrile (Compound 242)
[0293] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.47 (dd, J=5.0, 3.0 Hz,
1H), 7.17 (dd, J=2.8, 1.3 Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H),
4.91 (br. s., 0.5H), 4.55 (d, J=10.8 Hz, 0.5H), 3.98-4.27 (m, 3H),
3.75 (q, J=6.0 Hz, 2.5H), 3.53-3.63 (m, 0.5H), 3.40 (s, 3H),
3.11-3.25 (m, 1H), 2.94-3.06 (m, 1H), 2.69-2.81 (m, 1H), 2.67 (d,
J=7.3 Hz, 1H), 2.25 (s, 3H), 1.71-1.78 (m, 1H), 1.42 (d, J=6.5 Hz,
1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.06-1.08 (m, 2H), 0.83-0.88 (m,
2H). LC-MS: m/z 456.2 (M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(thi-
ophen-3-yl)nicotinonitrile (Compound 246)
[0294] .sup.1H NMR (CHLOROFORM-d) .delta. 7.64 (s, 1H), 7.41 (dd,
J=4.8, 3.0 Hz, 1H), 7.29 (dd, J=3.0, 1.3 Hz, 1H), 7.18 (dd, J=5.0,
1.3 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H),
4.14-4.32 (m, 2.5H), 3.67-3.84 (m, 2.5H), 3.55 (br. s., 0.5H),
3.18-3.34 (m, 1H), 2.96-3.18 (m, 1.5H), 2.50-2.71 (m, 2H),
2.12-2.23 (m, 1H), 1.34-1.41 (m, 1.5H), 1.24-1.30 (m, 1.5H),
1.12-1.18 (m, 2H), 0.92-1.02 (m, 2H). LC-MS: m/z 411.3
(M+H).sup.+.
(R)-5-(benzo[b]thiophen-2-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-me-
thylpiperazin-1-yl)nicotinonitrile (Compound 247)
[0295] .sup.1H NMR (CHLOROFORM-d) .delta. 7.82-7.87 (m, 1H),
7.78-7.82 (m, 1H), 7.77 (s, 1H), 7.33-7.42 (m, 2H), 7.32 (s, 1H),
4.90 (br. s., 0.5H), 4.52 (d, J=12.8 Hz, 0.5H), 4.24-4.39 (m, 3H),
3.70-3.80 (m, 2.5H), 3.35-3.41 (m, 3H), 3.29 (t, J=9.8 Hz, 1H),
3.03-3.20 (m, 1.5H), 2.63-2.78 (m, 1H), 2.52-2.63 (m, 1H),
2.34-2.44 (m, 1H), 1.37 (d, J=6.0 Hz, 1.5H), 1.23-1.29 (m, 1.5H),
1.15-1.21 (m, 2H), 0.95-1.06 (m, 2H). LC-MS: m/z 461.3
(M+H).sup.+.
(R)-5-(3-chloro-4-fluorophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile (Compound 248)
[0296] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.45 (dd,
J=6.9, 1.9 Hz, 1H), 7.22-7.28 (m, 2H), 4.92 (br. s., 0.5H), 4.54
(d, J=12.8 Hz, 0.5H), 4.16-4.37 (m, 3H), 3.70-3.81 (m, 2.5H),
3.50-3.64 (m, 0.5H), 3.37-3.42 (m, 3H), 3.28 (t, J=10.2 Hz, 1H),
3.12 (d, J=11.0 Hz, 1H), 2.65-2.87 (m, 1H), 2.55-2.65 (m, 1H),
1.94-2.05 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=4.0 Hz,
1.5H), 1.14-1.21 (m, 2H), 0.94-1.03 (m, 2H). LC-MS: m/z 457.3
(M+H).sup.+.
(R)-6-cyclopropyl-5-(2-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)nicotinonitrile (Compound 249)
[0297] .sup.1H NMR (CHLOROFORM-d) .delta. 7.62 (s, 1H), 7.37-7.45
(m, 1H), 7.30-7.36 (m, 1H), 7.22-7.27 (m, 1H), 7.19 (t, J=9.0 Hz,
1H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.19-4.37 (m,
3H), 3.78-3.86 (m, 0.5H), 3.70-3.78 (m, 2H), 3.51-3.61 (m, 0.5H),
3.39 (s, 3H), 3.27 (t, J=12.5 Hz, 1H), 3.02-3.16 (m, 1H), 2.65-2.82
(m, 1H), 2.54-2.64 (m, 1H), 1.83-1.90 (m, 1H), 1.41 (d, J=6.3 Hz,
1.5H), 1.30 (d, J=6.8 Hz, 1.5H), 1.12-1.19 (m, 2H), 0.92-0.98 (m,
2H). LC-MS: m/z 423.3 (M+H).sup.+.
(R)-6-cyclopropyl-5-(2,4-difluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)nicotinonitrile (Compound 250)
[0298] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.26-7.35
(m, 1H), 6.91-7.04 (m, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3
Hz, 0.5H), 4.18-4.37 (m, 3H), 3.78-3.85 (m, 0.5H), 3.71-3.78 (m,
2H), 3.51-3.62 (m, 0.5H), 3.39 (s, 3H), 3.23-3.33 (m, 1H), 3.14 (d,
J=10.5 Hz, 1H), 2.65-2.80 (m, 1H), 2.53-2.63 (m, 1H), 1.77-1.85 (m,
1H), 1.40 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.5 Hz, 1.5H), 1.11-1.19
(m, 2H), 0.96 (dd, J=7.8, 3.0 Hz, 2H). LC-MS: m/z 441.3
(M+H).sup.+.
(R)-2-cyclopropyl-6-methoxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1--
yl)-3,3'-bipyridine-5-carbonitrile (Compound 252)
[0299] .sup.1H NMR (CHLOROFORM-d) .delta. 8.18 (d, J=2.3 Hz, 1H),
7.60 (dd, J=8.5, 2.5 Hz, 1H), 7.56 (s, 1H), 6.83 (d, J=8.5 Hz, 1H),
4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz, 0.5H), 4.15-4.36 (m, 3H),
3.96-4.02 (m, 3H), 3.76-3.86 (m, 0.5H), 3.74 (t, J=6.3 Hz, 2H),
3.53-3.61 (m, 0.5H), 3.37 (s, 3H), 3.21-3.31 (m, 1H), 3.12 (d,
J=11.3 Hz, 1H), 2.63-2.80 (m, 1H), 2.51-2.62 (m, 1H), 1.93-2.04 (m,
1H), 1.38 (d, J=6.0 Hz, 1.5H), 1.28 (d, J=6.3 Hz, 1.5H), 1.12-1.19
(m, 2H), 0.92-1.00 (m, 2H). LC-MS: m/z 436.2 (M+H).sup.+.
(R)-6-cyclopropyl-5-(1H-indol-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 253)
[0300] .sup.1H NMR (CHLOROFORM-d) .delta. 8.28 (br. s., 1H), 7.66
(s, 1H), 7.63 (s, 1H), 7.46 (d, J=8.3 Hz, 1H), 7.29 (t, J=2.8 Hz,
1H), 7.20 (dd, J=8.3, 1.8 Hz, 1H), 6.60 (t, J=2.1 Hz, 1H), 4.91
(br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.12-4.33 (m, 3H), 3.81
(br. s., 0.5H), 3.75 (t, J=6.4 Hz, 2H), 3.51-3.63 (m, 0.5H), 3.38
(s, 3H), 3.22 (d, J=14.1 Hz, 1H), 3.01-3.17 (m, 1H), 2.66-2.81 (m,
1H), 2.62 (t, J=5.8 Hz, 1H), 2.11-2.21 (m, 1H), 1.41 (d, J=5.5 Hz,
1.5H), 1.31 (d, J=6.3 Hz, 1.5H), 1.11-1.17 (m, 2H), 0.87-0.94 (m,
2H). LC-MS: m/z 444.3 (M+H).sup.+.
(R)-6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)-4-methylnicotinonitrile (Compound 241)
[0301] .sup.1H NMR (CHLOROFORM-d) .delta. 7.17 (s, 2H), 7.16 (d,
J=1.8 Hz, 2H), 4.90 (br. s., 0.51H), 4.53 (d, J=13.3 Hz, 0.5H),
4.03-4.22 (m, 3H), 3.79 (br. s., 0.5H), 3.74 (t, J=6.3 Hz, 2H),
3.52-3.63 (m, 0.5H), 3.38 (s, 3H), 3.16-3.25 (m, 1H), 2.92-3.08 (m,
1H), 2.64-2.79 (m, 1H), 2.51-2.63 (m, 1H), 2.18 (s, 3H), 1.56-1.63
(m, 1H), 1.41 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H),
1.03-1.09 (m, 2H), 0.79-0.84 (m, 2H). LC-MS: m/z 437.2
(M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-5-m-tolylnicotinonitrile (Compound 243)
[0302] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.36 (t, J=7.5 Hz, 1H),
7.22 (d, J=7.5 Hz, 1H), 6.97-7.04 (m, 2H), 4.92 (br. s., 0.5H),
4.55 (d, J=12.3 Hz, 0.5H), 4.24 (br. s., 0.5H), 4.03-4.19 (m, 2H),
3.76 (s, 0.5H), 3.75 (s, 2H), 3.55-3.64 (m, 0.5H), 3.40 (s, 3H),
3.11-3.26 (m, 1H), 2.93-3.08 (m, 1H), 2.68-2.80 (m, 1H), 2.61 (d,
J=11.0 Hz, 1H), 2.42 (s, 3H), 2.20 (s, 3H), 1.62-1.71 (m, 1H), 1.43
(d, J=6.5 Hz, 1.5H), 1.34 (d, J=6.0 Hz, 1.5H), 1.01-1.11 (m, 2H),
0.80-0.85 (m, 2H). LC-MS: m/z 433.3 (M+H).sup.+.
(R)-6-cyclopropyl-5-(3-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpi-
perazin-1-yl)-4-methylnicotinonitrile (Compound 251)
[0303] .sup.1H NMR (CHLOROFORM-d) .delta. 7.37 (t, J=7.8 Hz, 1H),
6.93 (dd, J=8.3, 2.5 Hz, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.74 (s, 1H),
4.90 (br. s., 0.5H), 4.53 (d, J=12.8 Hz, 0.5H), 3.96-4.21 (m, 3H),
3.83 (s, 3H), 3.71-3.77 (m, 2H), 3.52-3.63 (m, 1H), 3.37 (s, 3H),
3.09-3.25 (m, 1H), 2.89-3.04 (m, 1H), 2.63-2.79 (m, 1H), 2.59 (br.
s., 1H), 2.16-2.29 (m, 3H), 1.63-1.72 (m, 1H), 1.41 (d, J=6.3 Hz,
1.5H), 1.29-1.33 (m, 1.5H), 1.06 (d, J=7.3 Hz, 2H), 0.78-0.84 (m,
2H). LC-MS: m/z 449.3 (M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-5-(4-(trifluoromethoxy)-phenyl)nicotinonitrile (Compound
255)
[0304] .sup.1H NMR (CHLOROFORM-d) .delta. 7.31-7.36 (m, J=8.0 Hz,
2H), 7.23-7.28 (m, J=8.3 Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d,
J=13.8 Hz, 0.5H), 4.01-4.22 (m, 2.5H), 3.69-3.85 (m, 2.5H),
3.53-3.67 (m, 0.5H), 3.36-3.43 (m, 3H), 3.12-3.28 (m, 1.5H),
2.94-3.12 (m, 1H), 2.66-2.83 (m, 1H), 2.61 (br. s., 1H), 2.16-2.22
(m, 3H), 1.54-1.65 (m, 1H), 1.39-1.46 (m, 1.5H), 1.32 (d, J=6.3 Hz,
1.5H), 1.03-1.12 (m, 2H), 0.80-0.89 (m, 2H). LC-MS: m/z 503.3
(M+H).sup.+.
6-cyclopropyl-5-(2,4-difluorophenyl)-2-((R)-4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)-4-methyl-nicotinonitrile (Compound 256)
[0305] .sup.1H NMR (CHLOROFORM-d) .delta. 7.16-7.25 (m, 1H),
6.93-7.07 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H),
4.03-4.30 (m, 2.5H), 3.71-3.86 (m, 2.5H), 3.51-3.67 (m, 0.5H), 3.40
(s, 3H), 3.12-3.30 (m, 1.5H), 2.95-3.11 (m, 1H), 2.73 (td, J=15.3,
7.3 Hz, 1H), 2.54-2.64 (m, 1H), 2.18-2.25 (m, 3H), 1.53-1.61 (m,
1H), 1.39-1.47 (m, 1.5H), 1.32 (t, J=5.8 Hz, 1.5H), 1.03-1.17 (m,
2H), 0.82-0.93 (m, 2H). LC-MS: m/z 455.4 (M+H).sup.+.
(R)-6-cyclopropyl-5-(3-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)-4-methylnicotinonitrile (Compound 257)
[0306] .sup.1H NMR (CHLOROFORM-d) .delta. 7.41-7.51 (m, 1H), 7.12
(td, J=8.5, 2.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.95 (d, J=9.0 Hz,
1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.04-4.22 (m,
2.5H), 3.72-3.84 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.40 (s, 3H),
3.12-3.29 (m, 1.5H), 2.93-3.11 (m, 1H), 2.66-2.83 (m, 1H), 2.61 (d,
J=6.3 Hz, 1H), 2.16-2.25 (m, 3H), 1.57-1.64 (m, 1H), 1.43 (d, J=6.5
Hz, 1.5H), 1.33 (d, J=6.8 Hz, 1.5H), 1.08 (t, J=4.6 Hz, 2H),
0.80-0.91 (m, 2H). LC-MS: m/z 437.4 (M+H).sup.+.
(R)-6-cyclopropyl-5-(3-fluoro-4-methylphenyl)-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)-4-methylnicotinonitrile (Compound 258)
[0307] .sup.1H NMR (CHLOROFORM-d) .delta. 7.23-7.33 (m, 2H), 6.89
(s, 1H), 6.87 (d, J=3.5 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d,
J=13.3 Hz, 0.5H), 4.23 (br. s., 1H), 4.01-4.21 (m, 1.5H), 3.70-3.84
(m, 2.5H), 3.50-3.66 (m, 0.5H), 3.39 (s, 3H), 3.10-3.28 (m, 1.5H),
2.92-3.09 (m, 1H), 2.65-2.81 (m, 1H), 2.53-2.64 (m, 1H), 2.32-2.39
(m, 3H), 2.20 (s, 3H), 1.60-1.70 (m, 1H), 1.39-1.47 (m, 1.5H),
1.30-1.35 (m, 1.5H), 1.07 (t, J=4.6 Hz, 2H), 0.83 (dt, J=7.5, 3.5
Hz, 2H). LC-MS: m/z 451.4 (M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-5-(napthalen-2-yl)nicotinonitrile (Compound 259)
[0308] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.96 (d, J=8.5 Hz, 1H),
7.91-7.95 (m, 1H), 7.88 (dd, J=6.1, 3.4 Hz, 1H), 7.71 (s, 1H),
7.53-7.59 (m, 2H), 7.34 (dd, J=8.4, 1.4 Hz, 1H), 4.94 (br. s.,
0.5H), 4.57 (d, J=13.3 Hz, 0.5H), 4.05-4.32 (m, 3H), 3.83 (br. s.,
0.5H), 3.77 (t, J=6.3 Hz, 2H), 3.56-3.67 (m, 0.5H), 3.41 (s, 3H),
3.17-3.29 (m, 1H), 2.96-3.12 (m, 1H), 2.67-2.83 (m, 1H), 2.55-2.65
(m, 1H), 2.23 (s, 3H), 1.63-1.71 (m, 1H), 1.45 (d, J=5.8 Hz, 1.5H),
1.35 (d, J=5.5 Hz, 1.5H), 1.05-1.14 (m, 2H), 0.77-0.83 (m, 2H).
LC-MS: m/z 469.4 (M+H).sup.+.
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-3,4'-bipyridine-5-carbonitrile (Compound 260)
[0309] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.87 (br. s., 2H), 7.86
(br. s., 2H), 4.94 (br. s., 0.5H), 4.71 (s, 0.5H), 4.31-4.35 (s,
3H), 3.82 (br. s., 0.5H), 3.71-3.79 (m, 2H), 3.58 (br. s., 0.5H),
3.40 (s, 3H), 3.21 (br. s., 1H), 3.14 (br. s., 1H), 2.68 (br. s.,
1H), 2.61 (br. s., 1H), 2.04 (br. s., 1H), 1.45 (d, J=5.8 Hz,
1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.05-1.14 (m, 2H), 0.77-0.83 (m,
2H). LC-MS: m/z 420.5 (M+H).sup.+.
(R)-5-(benzo[d][1,3]dioxol-5-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-
-methylpiperazin-1-yl)-4-methylnicotinonitrile (Compound 261)
[0310] .sup.1H NMR (DMSO-d.sub.6) .delta. 6.91 (d, J=8.0 Hz, 1H),
6.62-6.71 (m, 2H), 6.03-6.10 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d,
J=13.6 Hz, 0.5H), 4.03-4.24 (m, 3H), 3.80 (br. s., 0.5H), 3.76 (t,
J=6.1 Hz, 2H), 3.59 (t, J=11.7 Hz, 0.5H), 3.39 (s, 3H), 3.18-3.25
(m, 1H), 2.92-3.08 (m, 1H), 2.65-2.80 (m, 1H), 2.54-2.65 (m, 1H),
2.22 (s, 3H), 1.68-1.77 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.33 (d,
J=6.5 Hz, 1.5H), 1.06 (t, J=5.3 Hz, 2H), 0.84 (t, J=6.1 Hz, 2H)
LC-MS: m/z 463.3 (M+H).sup.+.
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-5-(thiophen-3-yl)nicotinonitrile (Compound 262)
[0311] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.47 (dd, J=5.0, 3.0 Hz,
1H), 7.17 (dd, J=2.8, 1.3 Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H),
4.91 (br. s., 0.5H), 4.55 (d, J=10.8 Hz, 0.5H), 3.98-4.27 (m, 3H),
3.75 (q, J=6.0 Hz, 2.5H), 3.53-3.63 (m, 0.5H), 3.40 (s, 3H),
3.11-3.25 (m, 1H), 2.94-3.06 (m, 1H), 2.69-2.81 (m, 1H), 2.67 (d,
J=7.3 Hz, 1H), 2.25 (s, 3H), 1.71-1.78 (m, 1H), 1.42 (d, J=6.5 Hz,
1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.06-1.08 (m, 2H), 0.83-0.88 (m,
2H). LC-MS: m/z 425.3 (M+H).sup.+.
Example 5
Preparation of
(R)-5-benzyl-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl-
)nicotinonitrile (Compound 239)
[0312] A mixture of the bromide 7 from Example 1 (20 mg, 0.049
mmol) and PdCl.sub.2(dppf) CH.sub.2Cl.sub.2 (4 mg, 0.005 mmol) in 1
mL of dry THF was stirred at room temperature for 5 min under
nitrogen atmosphere. Benzyl zinc bromide (2 mL of 0.5M solution in
THF, 0.098 mmol) was then added via a transfer needle, and the
resulting reaction mixture was then refluxed for 4 h before the
volatile was evaporated under reduced pressure. The black solid was
applied to the top of a flash silica gel column, which was eluted
with CH.sub.2Cl.sub.2 and then 8:1 CH.sub.2Cl.sub.2-EtOAc to obtain
5.1 mg of Compound 239 as a reddish solid. MS (ES) M+H expected
421.3, found 421.2. .sup.1H NMR (CHLOROFORM-d) .delta. 7.43 (s,
1H), 7.28-7.36 (m, 2H), 7.19-7.25 (m, 1H), 7.08 (d, J=7.0 Hz, 2H),
4.90 (br. s., 0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.16-4.36 (m, 3H),
3.91 (s, 2H), 3.79 (br. s., 0.5H), 3.73 (t, J=6.5 Hz, 2H),
3.51-3.61 (m, 0.5H), 3.37 (s, 3H), 3.22-3.30 (m, 1H), 3.12-3.21 (m,
1H), 2.63-2.78 (m, 1H), 2.51-2.61 (m, 1H), 1.38 (d, J=5.8 Hz,
1.5H), 1.28-1.32 (m, 1.5H), 1.12 (d, J=6.5 Hz, 6H). Other Compounds
of Formula II listed below, wherein R.sup.1b is alkyl,
--CH.sub.2-aryl or --CH.sub.2-heteroaryl; and R.sup.2 is isopropyl
or cyclopropyl were similarly prepared using any of intermediates 7
(Scheme 1), 17 (Scheme 2), or 28 (Scheme 3) as starting
material.
(R)-5-benzyl-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)-4-methylnicotinonitrile (Compound 245)
[0313] .sup.1H NMR (CHLOROFORM-d) .delta. 7.29-7.35 (m, 2H), 7.24
(d, J=7.5 Hz, 1H), 7.09 (d, J=7.3 Hz, 2H), 4.91 (br. s., 0.5H),
4.54 (d, J=14.1 Hz, 0.5H), 4.22 (br. s., 0.5H), 4.16 (s, 2H), 4.09
(d, J=15.6 Hz, 1.5H), 3.97-4.05 (m, 1H), 3.69-3.82 (m, 2H),
3.53-3.63 (m, 1H), 3.36-3.42 (m, 3H), 3.15 (t, J=13.9 Hz, 1H),
2.90-3.05 (m, 1H), 2.66-2.81 (m, 1H), 2.54-2.63 (m, 1H), 2.40 (s,
3H), 2.04 (dd, J=8.0, 4.8 Hz, 1H), 1.42 (d, J=6.8 Hz, 1.5H), 1.35
(br. s., 1.5H), 1.07-1.15 (m, 2H), 0.90-0.92 (m, 2H). LC-MS: m/z
433.3 (M+H).sup.+.
Example 6
Preparation of
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(me-
thyl(2-(methylamino)ethyl)amino)nicotinonitrile (Compound 238)
[0314]
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-
-5-(methyl(2-(methylamino)ethyl)amino)nicotinonitrile (Compound
238) was prepared by mixing bromide 7 (30 mg, 0.074 mmol), CuI (0.7
mg, 0.004 mmol), K.sub.2CO.sub.3 (20 mg, 0.147 mmol), and N1,
N2-dimethylethane-1,2-diamine (3.25 mg, 0.035 mmol) in a 5 mL
microwave tube capped with a rubber septum. The tube was placed
under vacuum and refilled with nitrogen three times. Piperidine (19
mg, 0.22 mmol) and DMSO (1 mL) were added to the tube and the
rubber septum was quickly replaced with microwave tube cap. The
reaction was heated in an oil bath at 120.degree. C. overnight
before it was cooled, diluted with EtOAc, and filtered through a
pad of Celite. The EtOAc was removed on a rotary evaporator.
Compound 238 was obtained in 10 mg of quantity via preparative TLC
(DCM: MeOH/10:1) separation. MS (ES) M+H expected 417.3, found
417.5. .sup.1H NMR (CHLOROFORM-d) .delta. 7.56 (s, 1H), 4.91 (br.
s., 0.5H), 4.53 (d, J=12.3 Hz, 6.5H), 4.02-4.31 (m, 3H), 3.67-3.83
(m, 3H), 3.47-3.64 (m, 2H), 3.34-3.41 (m, 3H), 3.16-3.30 (m, 1H),
2.93-3.13 (m, 4H), 2.74-2.84 (m, 2H), 2.61 (s, 3H), 2.53 (s, 3H),
1.39 (d, J=5.8 Hz, 1.5H), 1.30-1.34 (m, 1.5H), 1.17 (d, J=6.5 Hz,
6H).
Example 7
Preparation of
(R)-5-amino-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-
nicotinonitrile
[0315]
(R)-5-amino-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-
-1-yl)nicotinonitrile was prepared according to Scheme 4.
##STR00745##
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,-
5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (30)
[0316] To a solution of
(R)-5-bromo-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-
nicotinonitrile (7; 747 mg, 1.8 mmol) in DMF (8 mL) was added
4,4,4',4',5,5,5',5'-octamethyl-2, T-bi(1,3,2 dioxaborolane) (563
mg, 2.2 mmol) and KOAc (538 mg, 5.5 mmol). The resulting mixture
was stirred at room temperature for 5 min before addition of
PdCl.sub.2(dppf). CH.sub.2Cl.sub.2 (45 mg, 0.03 mmol). After
flushing with nitrogen, the reaction mixture was heated at
85.degree. C. for 18 hours. LC-MS analysis indicated starting
material still present, the temperature was raised to 120.degree.
C. and stirred overnight. After cooling, the reaction mixture was
diluted with water, and extracted with methylene chloride. The
organic layer was then washed with brine, dried over anhy.
Na.sub.2SO.sub.4, and concentrated in vacuo. Column chromatography
(25% EtOAc/petroleum ether) afforded 334 mg of 30 as a white solid.
MS (ES) M+H expected 457.3, found 457.4. .sup.1H NMR (CHLOROFORM-d)
.delta. 8.16 (s, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=12.3 Hz,
0.5H), 4.19-4.39 (m, 3H), 3.76-3.85 (m, 0.5H), 3.73 (t, J=6.4 Hz,
2H), 3.50-3.61 (m, 0.5H), 3.37 (s, 3H), 3.25-3.35 (m, 1H),
3.02-3.20 (m, 1H), 2.63-2.80 (m, 1H), 2.51-2.61 (m, 1H), 1.45 (d,
J=7.0 Hz, 1.5H), 1.35 (d, J=6.3 Hz, 1.5H), 1.34 (s, 12H), 1.19-1.21
(dd, J=6.8, 2.0 Hz, 3H), 1.23-1.25 (d, J=6.8 Hz, 3H).
(R)-5-azido-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)n-
icotinonitrile (31)
[0317] To a solution of above boronate 30 (10 mg, 0.022 mmol) and
Cu(OAc).sub.2.H.sub.2O (0.5 mg, 0.0025 mmol) in MeOH (0.2 mL) was
added slowly NaN.sub.3 (2.4 mg, 0.037 mmol) with stirring. After
the addition, the reaction mixture was heated to 50.degree. C. and
stirred overnight. After cooling and dilution with water, the
reaction mixture was extracted with methylene chloride. The organic
layer was then washed with brine, dried over anhy.
Na.sub.2SO.sub.4, and concentrated in vacuo. Column chromatography
(25% ethyl acetate/petroleum ether) afforded 3.7 mg of 31 as a
yellowish solid. MS (ES) M+H expected 372.2, found 372.3.
--(R)-5-amino-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl-
)nicotinonitrile (32)
[0318] To a solution of above azide 31 (10 mg, 0.027 mmol) in 1 mL
of MeOH was added 10% Pd/C (0.5 mg). The resulting mixture was
purged with hydrogen and stirred at room temperature for 1 h under
hydrogen atmosphere. After LC-MS analysis showed the formation of
desired product, the reaction mixture was filtered, the filtrate
was concentrated in vacuo. Column chromatography (25%
EtOAc/petroleum ether) afforded 9 mg of 32 as a pink solid. MS (ES)
M+H expected 346.2, found 346.1. .sup.1H NMR (CHLOROFORM-d) .delta.
7.25 (s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1 Hz, 0.5H), 4.20
(br. s., 1H), 3.95-4.07 (m, 1H), 3.93 (br. s., 1H), 3.75 (br. s.,
0.5H), 3.73 (t, J=6.4 Hz, 2H), 3.52-3.63 (m, 0.5H), 3.37 (s, 3H),
3.02-3.21 (m, 2H), 2.88-3.02 (m, 1H), 2.62-2.78 (m, 1H), 2.59 (t,
J=5.8 Hz, 1H), 1.41 (d, J=5.8 Hz, 1.5H), 1.31-1.32 (m, 1.5H), 1.26
(s, 6H).
Example 8
Preparation of
(R)-5-(benzyloxy)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-
-1-yl)nicotinonitrile (Compound 254)
[0319] Compound 254 was prepared according to general Scheme 5,
below:
##STR00746##
wherein R.sup.c is --CH.sub.2-aryl or --CH.sub.2-heteroaryl.
Step K-1:
(R)-5-hydroxy-6-isopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)p-
iperazin-1-yl)nicotinonitrile
[0320] To a solution of boronate 30 from Example 7 (30 mg, 0.066
mmol) in 15 mL of THF, at room temperature, was added aq. NaOH
solution (2.86 g, 0.07 mmol). After stirring for 5 min, a solution
of 30% of H.sub.2O.sub.2 (2.43 mg, 0.07 mmol) was added. The
reaction mixture was allowed to stir at room temperature for
additional 30 min before it was adjusted to neutral pH and
concentrated in vacuo. Column chromatography (50% EtOAc/petroleum
ether) afforded 21 mg of 33. MS (ES) M+H expected 347.2, found
347.3. .sup.1H NMR (METHANOL-d.sub.4) .delta. 7.26 (s, 1H), 4.82
(br. s., 0.5H), 4.47 (d, J=13.1 Hz, 0.5H), 4.39 (br. s., 0.5H),
3.95 (d, J=13.1 Hz, 0.5H), 3.79-3.92 (m, 2H), 3.55-3.74 (m, 3H),
3.36 (s, 3H), 3.10-3.23 (m, 1H), 2.95-3.10 (m, 1H), 2.81-2.93 (m,
1H), 2.71-2.81 (m, 1H), 2.59-2.69 (m, 1H), 1.45 (d, J=6.8 Hz,
1.5H), 1.36 (br. s., 1.5H), 1.23 (d, J=6.8 Hz, 6H).
Step K-2:
(R)-5-(benzyloxy)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methyl-
piperazin-1-yl)nicotinonitrile (Compound 254)
[0321] To a solution of
(R)-5-hydroxy-6-isopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin--
1-yl)nicotinonitrile (33; 15 mg, 0.043 mmol) in 1 mL of THF was
added 60% NaH (2.1 mg, 0.052 mmol) at 0.degree. C. After stirring
at room temperature for 30 min, benzyl bromide (8.9 mg, 0.052 mmol)
was then added. The reaction mixture was stirred at 0.degree. C.
for 30 min and then at room temperature overnight. After the
reaction mixture was concentrated, preparative TLC separation of
the crude (50% ethyl acetate/petroleum ether) afforded 6.5 mg of
Compound 254 as a yellowish solid. MS (ES) M+H expected 437.3,
found 437.4. .sup.1H NMR (CHLOROFORM-d) .delta. 7.33-7.43 (m, 5H),
7.23 (s, 1H), 5.02 (s, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3
Hz, 0.5H), 4.21 (br. s., 0.5H), 4.02-4.09 (m, 1H), 3.90-4.02 (m,
1H), 3.65-3.85 (m, 3H), 3.51-3.61 (m, 0.5H), 3.42-3.51 (m, 1H),
3.37 (s, 3H), 3.09-3.23 (m, 1H), 2.91-3.07 (m, 1H), 2.63-2.78 (m,
1H), 2.51-2.62 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5
Hz, 1.5H), 1.20 (d, J=6.8 Hz, 6H).
[0322] Other Compounds of Formula II listed below, wherein R.sup.1b
is --O--CH.sub.2-aryl or --O--CH.sub.2-heteroaryl; and R.sup.2 is
isopropyl or cyclopropyl were similarly prepared according to
Scheme 5 by replacing
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,4,-
5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile 30 with
alternate boronates prepared from any of intermediates 7 (Scheme
1), 17 (Scheme 2), or 28 (Scheme 3) using similar procedures set
forth in Example 7 to prepare 30.
(R)-5-(benzyloxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazi-
n-1-yl)nicotinonitrile (Compound 254)
[0323] 1H NMR (CHLOROFORM-d) .delta. 7.33-7.43 (m, 5H), 7.23 (s,
1H), 5.02 (s, 2H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H),
4.21 (br. s., 0.5H), 4.02-4.09 (m, 1H), 3.90-4.02 (m, 1H),
3.65-3.85 (m, 3H), 3.51-3.61 (m, 0.5H), 3.42-3.51 (m, 1H), 3.37 (s,
3H), 3.09-3.23 (m, 1H), 2.91-3.07 (m, 1H), 2.63-2.78 (m, 1H),
2.51-2.62 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.31 (d, J=6.5 Hz,
1.5H), 1.20 (d, J=6.8 Hz, 6H). LC-MS: m/z 437.4 (M+H).sup.+.
Example 9
Preparation of
(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5-
-phenylnicotinonitrile (Compound 164)
[0324] Compound 164 (45, wherein m is 1; R.sup.3 is 3-methyl; and
R.sup.8 is 2-methylfuran-3-yl) was prepared according to the
general scheme set forth below in general Scheme 6.
##STR00747##
Step R: 1-(dimethylamino)-4-methyl-2-phenylpent-1-en-3-one (41)
[0325] To a solution of 3-methyl-1-phenylbutan-2-one (40; 3.38 g,
20 mmol) in 40 mL of anhydrous DMF was added
1,1-dimethoxy-N,N-dimethylmethanamine (5.958 g, 50 mmol). The
resulting mixture was stirred at 100.degree. C. overnight. After
removal of DMF and excess of acetal, 4.3 g of 41 was obtained as a
crude product and used in subsequent reaction without further
purification. MS (ES) M+H expected 218.2, found 218.0.
Step S: 2-hydroxy-6-isopropyl-5-phenylnicotinonitrile (42)
[0326] To a 20 mL of anhydrous DMF solution containing 960 mg of
sodium hydride (22 mmol, 60% dispersion in mineral oil) was added
dropwise a solution of crude
1-(dimethylamino)-4-methyl-2-phenylpent-1-en-3-one (41; 4.3 g, 20
mmol DMF solution), cyano acetamide (1.72 g, 20 mmol), and 2 mL of
MeOH in 35 mL of DMF. After the addition was completed, the
resulting mixture was stirred at 80.degree. C. overnight. After
removal of DMF under reduced pressure, the residue was re-dissolved
in methylene chloride and washed with water, and brine. The organic
layer was then dried over anhy. Na.sub.2SO.sub.4 and concentrated
in vacuo. Flash column chromatography (1:10 ethyl acetate/petroleum
ether) afforded 3.84 g of 42 as a white solid. MS (ES) M+H expected
239.1, found 239.0. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.03 (s,
1H), 7.43-7.50 (m, 2H), 7.37-7.43 (m, 1H), 7.30-7.33 (m, 1H), 7.29
(s, 1H), 2.85-2.97 (m, 1H), 1.21 (s, 3H), 1.20 (s, 3H).
Step T. 2-chloro-6-isopropyl-5-phenylnicotinonitrile (43)
[0327] A mixture of 2-hydroxy-6-isopropyl-5-phenylnicotinonitrile
(42; 2.3 g, 10 mmol), 5 mL of phosphoryl trichloride and one drop
of DMF were heated to reflux overnight until LC-MS indicated the
complete conversion to the product. After evaporation of excess of
phosphoryl trichloride under reduced pressure, the residue was
re-dissolved in methylene chloride and neutralized carefully with
satd. aq. NaHCO.sub.3 and washed subsequently with 1N HCl and
brine. The combined organic layer was dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Flash column
chromatography (1:5 ethyl acetate/petroleum ether) afforded 2.4 g
of 43 as a yellowish solid. MS (ES) M+H expected 257.1, found
257.0. .sup.1H NMR (CHLOROFORM-d) .delta. 7.76-7.82 (m, 1H),
7.43-7.54 (m, 3H), 7.28 (br. s., 1H), 7.22-7.26 (m, 1H), 3.20 (spt,
J=6.7 Hz, 1H), 1.22 (s, 3H), 1.20 (s, 3H).
Step U:
(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-5-phenylnicotinonitrile
(44)
[0328] A mixture of above chloride 43 (192.5 mg, 0.75 mmol),
(R)-2-methylpiperazine (187.8 mg, 1.875 mmol), and triethylamine
(0.261 mL, 1.875 mmol) suspended in 2 mL of acetonitrile was
subjected to microwave reaction at 175.degree. C. for 45 min. After
the reaction mixture was concentrated in vacuo, the residue was
purified by flash column chromatography to give 184 mg of 44 as
yellowish oil. MS (ES) M+H expected 321.2, found 321.1. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.56-7.66 (m, 1H), 7.34-7.51 (m, 3H),
7.19-7.28 (m, 2H), 4.31-4.59 (m, 2H), 3.11-3.27 (m, 3H), 3.01-3.11
(m, 2H), 2.84 (dd, J=12.8, 10.3 Hz, 1H), 1.22 (d, J=6.3 Hz, 3H),
1.15 (dd, J=6.7, 1.1 Hz, 6H).
Step V:
(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin--
1-yl)-5-phenylnicotinonitrile (Compound 164)
[0329] In a 5-mL of amber glass vial was placed
(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-5-phenyl-nicotinonitrile
(50 mg, 0.156 mmol), 2-methylfuran-3-carboxylic acid (39 mg, 0.312
mmol), EDCI (60 mg, 0.312 mmol), HOBt (42 mg, 0.312 mmol),
triethylamine (40 mg, 0.312 mmol) and 2 mL of methylene chloride.
The resulting reaction mixture was stirred at room temperature
overnight. The mixture was quenched with 1 N HCl aqueous solution,
extracted with EtOAc three times. The combined organic layer was
washed with satd. NaHCO.sub.3 and brine, dried over anhy.
Na.sub.2SO.sub.4, and concentrated in vacuo. The crude product was
purified by preparative TLC (EtOAc: petroleum ether/100:20) to
afford 28 mg of the title compound as a white solid. MS (ES) M+H
expected 429.2, found 429.1. .sup.1H NMR (METHANOL-d.sub.4) .delta.
7.59-7.67 (m, 1H), 7.37-7.50 (m, 3H), 7.31 (d, J=2.0 Hz, 1H),
7.21-7.28 (m, 2H), 6.39 (d, J=2.0 Hz, 1H), 4.70 (br. s., 1H),
4.29-4.50 (m, 2H), 4.23 (br. s., 1H), 3.49 (br. s., 1H), 3.33 (dd,
J=12.9, 3.1 Hz, 1H), 3.08-3.23 (m, 2H), 2.40-2.47 (m, 3H), 1.43 (d,
J=6.8 Hz, 3H), 1.16 (dd, J=6.8, 2.8 Hz, 6H).
[0330] Other Compounds of Formula II listed below, wherein R.sup.1a
is hydrogen; R.sup.1b is optionally substituted phenyl; were
similarly prepared according to Scheme 6 by replacing one or more
of: (1) methyl-1-phenylbutan-2-one (40) with an alternate phenyl
ketone as starting material; (2) (R)-2-methylpiperazine with an
alternate piperazine in Step U; and (3) 2-methylfuran-3-carboxylic
acid with an alternate acid in Step V.
2-(4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile
(Compound 109)
[0331] .sup.1H NMR (CHLOROFORM-d) .delta. 7.65 (s, 1H), 7.53-7.58
(m, 1H), 7.38-7.49 (m, 3H), 7.24-7.28 (m, 2H), 7.10 (d, J=3.3 Hz,
1H), 6.54 (dd, J=3.3, 1.8 Hz, 1H), 4.03 (br. s., 4H), 3.89 (dd,
J=6.4, 3.6 Hz, 4H), 3.17 (dt, J=13.4, 6.7 Hz, 1H), 1.18 (d, J=6.5
Hz, 6H). LC-MS: m/z 401.1 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylnicoti-
nonitrile (Compound 119)
[0332] .sup.1H NMR (CHLOROFORM-d) .delta. 7.62-7.69 (m, 1H), 7.54
(d, J=0.8 Hz, 1H), 7.40-7.47 (m, 3H), 7.23-7.28 (m, 2H), 7.08 (d,
J=3.5 Hz, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 4.93 (br. s., 1H),
4.54 (d, J=12.8 Hz, 1H), 4.45 (d, J=12.3 Hz, 1H), 4.37 (d, J=13.3
Hz, 1H), 3.58 (br. s., 1H), 3.44 (dd, J=13.3, 3.8 Hz, 1H), 3.27
(td, J=12.4, 3.4 Hz, 1H), 3.16 (dt, J=13.3, 6.7 Hz, 1H), 1.50 (d,
J=6.8 Hz, 3H), 1.17 (dd, J=6.7, 1.9 Hz, 6H). LC-MS: m/z 414.9
(M+H).sup.+.
2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylnicoti-
nonitrile (Compound 120)
[0333] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.64 (s,
1H), 7.40-7.51 (m, 4H), 7.24-7.28 (m, 2H), 6.61 (d, J=1.3 Hz, 1H),
4.76 (br. s., 1H), 4.33-4.52 (m, 3H), 3.51 (s, 1H), 3.35 (dd,
J=13.2, 3.1 Hz, 1H), 3.12-3.22 (m, 2H), 1.47 (d, J=6.8 Hz, 3H),
1.17 (dd, J=6.5, 2.0 Hz, 6H). LC-MS: m/z 414.9 (M+H).sup.+.
2-(4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonitrile
(Compound 124)
[0334] .sup.1H NMR (CHLOROFORM-d) .delta. 7.76-7.81 (m, 1H), 7.65
(s, 1H), 7.36-7.51 (m, 4H), 7.23-7.28 (m, 2H), 6.62 (dd, J=1.9, 0.9
Hz, 1H), 3.91 (br. s., 4H), 3.84 (br. s., 4H), 3.17 (dt, J=13.4,
6.6 Hz, 1H), 1.17 (d, J=6.8 Hz, 6H). LC-MS: m/z 401.1
(M+H).sup.+.
2-(4-(1H-indole-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnicotinonit-
rile (Compound 125)
[0335] .sup.1H NMR (CHLOROFORM-d) .delta. 8.97 (br. s., 1H),
7.74-7.81 (m, 1H), 7.64 (s, 1H), 7.53 (br. s., 1H), 7.38-7.50 (m,
4H), 7.28-7.31 (m, 1H), 7.24-7.28 (m, 3H), 3.94 (br. s., 4H), 3.85
(br. s., 4H), 3.16 (dt, J=13.2, 6.6 Hz, 1H), 1.17 (d, J=6.5 Hz,
6H). LC-MS: m/z 450.2 (M+H).sup.+.
6-isopropyl-5-phenyl-2-(4-(2-phenylacetyl)piperazin-1-yl)nicotinonitrile
(Compound 126)
[0336] .sup.1H NMR (CHLOROFORM-d) .delta. 7.62 (s, 1H), 7.41-7.47
(m, 3H), 7.38-7.41 (m, 1H), 7.37 (s, 1H), 7.34-7.36 (m, 1H), 7.32
(s, 1H), 7.30 (s, 1H), 7.25 (d, J=1.5 Hz, 1H), 7.24 (s, 1H),
3.84-3.89 (m, 2H), 3.83 (s, 2H), 3.73-3.78 (m, 2H), 3.64-3.68 (m,
2H), 3.58-3.63 (m, 2H), 3.15 (dt, J=13.3, 6.7 Hz, 1H), 1.15 (d,
J=6.5 Hz, 6H). LC-MS: m/z 425.1 (M+H).sup.+.
6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-5-phenylnicotino-
nitrile (Compound 139)
[0337] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 7.37-7.51
(m, 4H), 7.33-7.37 (m, 2H), 7.29-7.33 (m, 2H), 7.22-7.27 (m, 2H),
4.62 (d, J=13.6 Hz, 0.5H), 4.42 (d, J=12.5 Hz, 0.5H), 4.19-4.35 (m,
2H), 3.81 (br. s., 1H), 3.76 (d, J=13.1 Hz, 0.5H), 3.49 (t, J=12.0
Hz, 0.5H), 2.91-3.29 (m, 3H), 1.31 (br. s., 3H), 1.15 (d, J=6.8 Hz,
6H). LC-MS: m/z 439.2 (M+H).sup.+.
2-((3S,5R)-3,5-dimethyl-4-(2-phenylacetyl)piperazin-1-yl)-6-isopropyl-5-ph-
enylnicotinonitrile (Compound 140)
[0338] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61-7.64 (m, 1H),
7.41-7.48 (m, 3H), 7.38-7.41 (m, 1H), 7.37 (s, 1H), 7.34-7.36 (m,
1H), 7.32 (s, 1H), 7.30 (s, 1H), 7.27 (d, J=1.8 Hz, 1H), 7.23-7.26
(m, 1H), 4.90 (br. s., 1H), 4.46 (br. s., 2H), 4.20 (br. s., 1H),
3.82 (s, 2H), 3.12-3.22 (m, 2H), 3.11 (br. s., 1H), 1.43 (d, J=7.0
Hz, 6H), 1.16 (d, J=6.8 Hz, 6H). LC-MS: m/z 453.1 (M+H).sup.+.
2-((3S,5R)-4-(furan-3-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-isopropyl-5--
phenylnicotinonitrile (Compound 141)
[0339] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (dd, J=1.5, 0.8 Hz,
1H), 7.65 (s, 1H), 7.47-7.49 (m, 1H), 7.45-7.47 (m, 1H), 7.44 (s,
1H), 7.40-7.43 (m, 1H), 7.24-7.28 (m, 2H), 6.65 (dd, J=1.9, 0.9 Hz,
1H), 4.71 (br. s., 2H), 4.47 (s, 1H), 4.50 (s, 1H), 3.27 (dd,
J=12.9, 4.1 Hz, 2H), 3.18 (dt, J=13.3, 6.7 Hz, 1H), 1.55 (d, J=7.0
Hz, 6H), 1.18 (d, J=6.5 Hz, 6H). LC-MS: m/z 429.2 (M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-5-phenylnico-
tinonitrile (Compound 143)
[0340] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 7.39-7.47
(m, 3H), 7.34-7.39 (m, 2H), 7.29-7.33 (m, 2H), 7.22-7.28 (m, 3H),
4.98 (br. s., 0.5H), 4.62 (d, J=13.8 Hz, 0.5H), 4.42 (d, J=12.0 Hz,
0.5H), 4.15-4.35 (m, 2H), 3.81 (br. s., 2H), 3.72-3.79 (m, 0.5H),
3.49 (t, J=11.3 Hz, 0.5H), 3.29 (d, J=10.0 Hz, 0.5H), 3.04-3.21 (m,
2.5H), 2.88-3.01 (m, 0.5H), 1.27-1.34 (m, 3H), 1.15 (d, J=6.5 Hz,
6H). LC-MS: m/z 439.2 (M+H).sup.+.
(S)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylni-
cotinonitrile (Compound 144)
[0341] .sup.1H NMR (CHLOROFORM-d) .delta. 7.74-7.80 (m, 1H), 7.64
(s, 1H), 7.36-7.52 (m, 4H), 7.27 (dd, J=7.9, 6.4 Hz, 2H), 6.59-6.64
(m, 1H), 4.76 (br. s., 1H), 4.20-4.50 (m, 3H), 3.51 (br. s., 1H),
3.35 (dd, J=13.3, 3.3 Hz, 1H), 3.06-3.24 (m, 2H), 1.47 (d, J=6.8
Hz, 3H), 1.17 (dd, J=6.5, 2.0 Hz, 6H). LC-MS: m/z 415.2
(M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-5-phenylnico-
tinonitrile (Compound 145)
[0342] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 7.29-7.47
(m, 7H), 7.22-7.28 (m, 3H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.6
Hz, 0.5H), 4.42 (d, J=12.8 Hz, 0.5H), 4.15-4.37 (m, 2H), 3.80-3.85
(m, 2H), 3.76 (d, J=12.8 Hz, 0.5H), 3.49 (t, J=11.2 Hz, 0.5H),
3.25-3.37 (m, 0.5H), 3.02-3.23 (m, 2.5H), 2.88-3.01 (m, 0.5H),
1.26-1.35 (m, 3H), 1.15 (d, J=6.8 Hz, 6H). LC-MS: m/z 439.2
(M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-phenylni-
cotinonitrile (Compound 150)
[0343] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (dd, J=1.5, 1.0 Hz,
1H), 7.63-7.66 (m, 1H), 7.38-7.50 (m, 4H), 7.23-7.28 (m, 2H), 6.61
(dd, J=1.8, 0.8 Hz, 1H), 4.76 (br. s., 1H), 4.30-4.51 (m, 3H), 3.52
(br. s., 1H), 3.35 (dd, J=13.2, 3.6 Hz, 1H), 3.06-3.24 (m, 2H),
1.47 (d, J=6.8 Hz, 3H), 1.17 (dd, J=6.8, 2.0 Hz, 6H). LC-MS: m/z
415.1 (M+H).sup.+.
2-(4-(furan-3-carbonyl)-3-phenylpiperazin-1-yl)-6-isopropyl-5-phenylnicoti-
nonitrile (Compound 153)
[0344] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59-7.74 (m, 1H), 7.56
(s, 1H), 7.33-7.50 (m, 8H), 7.29 (d, J=7.3 Hz, 1H), 7.17-7.25 (m,
2H), 6.54 (br. s., 1H), 5.74 (br. s., 1H), 4.79 (br. s., 1H), 4.51
(br. s., 1H), 4.33 (d, J=9.5 Hz, 1H), 3.95 (d, J=11.5 Hz, 1H), 3.58
(br. s., 2H), 3.12 (spt, J=6.6 Hz, 1H), 1.08-1.18 (m, 6H). LC-MS:
m/z 477.1 (M+H).sup.+.
2-(4-(furan-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-5-phenylnicoti-
nonitrile (Compound 159)
[0345] .sup.1H NMR (CHLOROFORM-d) .delta. 7.72 (br. s., 1H),
7.48-7.60 (m, 5H), 7.46 (br. s., 3H), 7.40 (br. s., 2H), 7.27 (br.
s., 1H), 7.20 (d, J=6.8 Hz, 1H), 6.77 (s, 1H), 6.59 (s, 1H),
5.14-5.37 (m, 1H), 4.25 (br. s., 2H), 3.87 (br. s., 3H), 3.64 (br.
s., 1H), 2.81-2.95 (m, 1H), 1.16 (d, J=6.5 Hz, 3H), 1.06 (d, J=6.3
Hz, 3H). LC-MS: m/z 477.2 (M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-p-
henylnicotinonitrile (Compound 165)
[0346] .sup.1H NMR (METHANOL-d.sub.4) .delta. 7.62 (s, 1H),
7.35-7.57 (m, 3H), 7.21-7.28 (m, 3H), 6.87-7.11 (m, 2H), 4.60 (d,
J=13.3 Hz, 1H), 4.29-4.37 (m, 2H), 3.98 (s, 2H), 3.59 (t, J=11.4
Hz, 1H), 3.04-3.27 (m, 4H), 1.36 (dd, J=15.2, 5.9 Hz, 3H), 1.16 (d,
J=6.5 Hz, 6H). LC-MS: m/z 445.0 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-5-phenylnicoti-
nonitrile (Compound 166)
[0347] .sup.1H NMR (CHLOROFORM-d) .delta. 7.54-7.56 (m, 2H), 7.52
(br. s., 3H), 7.43 (br. s., 2H), 7.24-7.30 (m, 3H), 7.20 (d, J=7.3
Hz, 1H), 7.08 (d, J=3.3 Hz, 1H), 6.77 (s, 1H), 6.52 (br. s., 1H),
5.31-5.37 (br. s., 1H), 4.40 (br. s., 1H), 4.32 (br. s., 1H),
3.85-4.03 (m, 2H), 3.79 (d, J=13.1 Hz, 1H), 3.68 (d, J=4.8 Hz, 1H),
2.87 (dt, J=13.4, 6.8 Hz, 1H), 1.15 (d, J=6.8 Hz, 3H), 1.06 (d,
J=6.5 Hz, 3H). LC-MS: m/z 477.2 (M+H).sup.+.
2-(4-(1H-indole-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-5-phenylni-
cotinonitrile (Compound 168)
[0348] .sup.1H NMR (CHLOROFORM-d) .delta. 9.09 (br. s., 1H), 7.76
(br. s., 1H), 7.51 (s, 2H), 7.55 (s, 3H), 7.39 (br. s., 3H), 7.29
(s, 2H), 7.33 (s, 1H), 7.24 (br. s., 3H), 6.77 (br. s., 1H), 5.29
(br. s., 1H), 4.30 (d, J=11.5 Hz, 1H), 4.18 (br. s., 1H), 3.93 (br.
s., 3H), 3.64 (br. s., 1H), 2.89 (br. s., 1H), 1.16 (d, J=5.8 Hz,
3H), 1.07 (d, J=5.8 Hz, 3H). LC-MS: m/z 526.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-isopropylpiperazin-1-yl)-6-isopropyl-5-pheny-
lnicotinonitrile (Compound 170)
[0349] .sup.1H NMR (CHLOROFORM-d) .delta. 7.74 (br. s., 1H), 7.61
(s, 1H), 7.47 (t, J=1.6 Hz, 1H), 7.35-7.46 (m, 3H), 7.20-7.26 (m,
2H), 6.58 (s, 1H), 4.79 (d, J=12.8 Hz, 1H), 4.54-4.68 (br. s., 1H),
4.45 (br. s., 1H), 3.8-4.07 (m, 1H), 3.56-3.74 (m, 1H), 3.19 (br.
s., 1H), 3.06-3.18 (m, 3H), 1.52-1.59 (m, 3H), 1.40-1.48 (m, 3H),
1.17 (d, J=6.8 Hz, 3H), 1.13 (d, J=6.8 Hz, 3H). LC-MS: m/z 443.1
(M+H).sup.+.
(R)-2-(3-ethyl-4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnic-
otinonitrile (Compound 171)
[0350] .sup.1H NMR (CHLOROFORM-d) .delta. 7.74 (s, 1H), 7.58-7.65
(m, 1H), 7.35-7.50 (m, 4H), 7.20-7.26 (m, 2H), 6.58 (dd, J=1.8, 0.8
Hz, 1H), 5.02 (s, 1H), 4.69 (br. s., 1H), 4.50 (d, J=13.1 Hz, 1H),
4.41 (d, J=12.3 Hz, 1H), 4.23-4.31 (br. s., 1H), 3.46-3.86 (m, 2H),
3.27 (dd, J=13.3, 3.3 Hz, 1H), 3.10-3.21 (m, 2H), 1.79-1.96 (m,
2H), 1.54 (d, J=6.5 Hz, 1.5H), 1.45 (d, J=6.5 Hz, 1.5H), 1.15 (dd,
J=6.8, 3.5 Hz, 6H). LC-MS: m/z 429.1 (M+H).sup.+.
(R)-2-(3-ethyl-4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropyl-5-phenylnic-
otinonitrile (Compound 172)
[0351] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59-7.64 (m, 1H), 7.51
(dd, J=1.8, 0.8 Hz, 1H), 7.36-7.46 (m, 3H), 7.21-7.26 (m, 2H),
7.02-7.10 (m, 1H), 6.51 (dd, J=3.5, 1.8 Hz, 1H), 4.71 (br. s., 1H),
4.38-4.60 (m, 3H), 3.50 (br. s., 1H), 3.35 (dd, J=13.3, 3.5 Hz,
1H), 3.22 (td, J=12.5, 3.4 Hz, 1H), 3.08-3.18 (m, 1H), 1.90-2.06
(m, 1H), 1.83 (dquin, J=14.2, 7.2 Hz, 1H), 1.15 (dd, J=6.7, 3.1 Hz,
6H), 0.97 (t, J=7.4 Hz, 3H). LC-MS: m/z 429.1 (M+H).sup.+.
(R)-2-(3-ethyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-6-isopropyl-5-p-
henylnicotinonitrile (Compound 173)
[0352] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58-7.66 (m, 1H),
7.35-7.47 (m, 3H), 7.29 (d, J=2.0 Hz, 1H), 7.21-7.26 (m, 2H),
6.32-6.41 (m, 1H), 4.59-4.80 (m, 1H), 4.50 (d, J=13.1 Hz, 1H), 4.42
(br. s., 1H), 3.91-3.97 (br. s., 1H), 3.45-3.65 (m, 1H), 3.27 (dd,
J=13.1, 3.3 Hz, 1H), 3.05-3.19 (m, 2H), 2.41 (s, 3H), 1.86-1.95 (m,
1H), 1.79 (dt, J=14.1, 7.0 Hz, 1H), 1.15 (dd, J=6.8, 2.0 Hz, 6H),
0.87-0.99 (m, 3H). LC-MS: m/z 443.1 (M+H).sup.+.
(R)-2-(3-ethyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-6-isopropyl-5-ph-
enylnicotinonitrile (Compound 174)
[0353] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.35-7.49
(m, 3H), 7.17-7.25 (m, 3H), 6.92-6.99 (m, 2H), 4.75 (br. s., 0.5H),
4.59-4.71 (m, 0.5H), 4.30-4.50 (m, 2H), 3.79-4.07 (m, 3H),
3.46-3.56 (m, 0.5H), 3.17-3.30 (m, 0.5H), 2.97-3.17 (m, 3H),
1.78-1.89 (m, 1H), 1.69-1.78 (m, 1H), 1.10-1.16 (m, 6H), 0.90-0.97
(m, 3H). LC-MS: m/z 459.1 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-5,6-diphenylnicotinonitril-
e (Compound 117)
[0354] Compound 117 was synthesized was synthesized was synthesized
using 1,2-diphenylethanone as starting material.
[0355] .sup.1H NMR (CHLOROFORM-d) .delta. 7.87 (s, 1H), 7.53 (dd,
J=1.5, 0.8 Hz, 1H), 7.37-7.44 (m, 2H), 7.27-7.35 (m, 6H), 7.12-7.19
(m, 2H), 7.06-7.12 (m, 1H), 6.53 (dd, J=3.4, 1.9 Hz, 1H), 4.94 (br.
s., 1H), 4.53 (t, J=11.7 Hz, 2H), 4.36-4.46 (m, 1H), 3.62 (br. s.,
1H), 3.44-3.54 (m, 1H), 3.26-3.37 (m, 1H), 1.52 (d, J=6.5 Hz, 3H).
LC-MS: m/z 448.9 (M+H).sup.+.
2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-5,6-diphenylnicotinonitril-
e (Compound 118)
[0356] Compound 118 was synthesized using 1,2-diphenylethanone as
starting material.
[0357] .sup.1H NMR (CHLOROFORM-d) .delta. 7.88 (s, 1H), 7.77 (s,
1H), 7.48 (s, 1H), 7.38 (d, J=8.0 Hz, 2H), 7.27-7.33 (m, 6H),
7.13-7.16 (m, 2H), 6.61 (s, 1H), 4.71-4.79 (br. s., 1H), 4.47-4.50
(s, 1H), 4.38 (s, 1H), 4.41 (s, 1H), 3.48-3.64 (m, 1H), 3.38-3.42
(m, 1H), 3.21 (td, J=12.4, 3.0 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H).
LC-MS: m/z 448.9 (M+H).sup.+.
2-(4-(furan-3-carbonyl)piperazin-1-yl)-5,6-diphenylnicotinonitrile
(Compound 122)
[0358] Compound 122 was synthesized using 1,2-diphenylethanone as
starting material.
[0359] .sup.1H NMR (CHLOROFORM-d) .delta. 7.88 (s, 1H), 7.78 (s,
1H), 7.47-7.51 (m, 1H), 7.37-7.42 (m, 2H), 7.27-7.35 (m, 6H), 7.15
(dd, J=6.5, 3.0 Hz, 2H), 6.62 (s, 1H), 3.92 (br. s., 4H), 3.89 (br.
s., 4H). LC-MS: m/z 435.1 (M+H).sup.+.
5,6-diphenyl-2-(4-(2-phenylacetyl)piperazin-1-yl)nicotinonitrile
(Compound 123)
[0360] Compound 123 was synthesized using 1,2-diphenylethanone as
starting material. .sup.1H NMR (CHLOROFORM-d) .delta. 7.85 (s, 1H),
7.34-7.39 (m, 4H), 7.28-7.33 (m, 8H), 7.22-7.26 (m, 1H), 7.13 (dd,
J=6.5, 3.0 Hz, 2H), 3.85-3.91 (m, 2H), 3.79-3.84 (m, 4H), 3.66 (s,
4H). LC-MS: m/z 459.1 (M+H).sup.+.
(R)-5-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-i-
sopropylnicotinonitrile (Compound 161)
[0361] Compound 161 was synthesized using
1-(3-fluorophenyl)-3-methylbutan-2-one as starting material.
[0362] .sup.1H NMR (CHLOROFORM-d) .delta. 7.73-7.79 (m, 1H), 7.61
(s, 1H), 7.47 (t, J=1.6 Hz, 1H), 7.35-7.44 (m, 1H), 7.06-7.13 (m,
1H), 7.00-7.04 (m, 1H), 6.96 (dt, J=9.3, 2.1 Hz, 1H), 6.54-6.63 (m,
1H), 4.61-4.90 (m, 1H), 4.41 (s, 0.5H), 4.44 (s, 0.5H), 4.19-4.39
(m, 2H), 3.42-3.49 (br. s., 1H), 3.34 (dd, J=13.2, 3.1 Hz, 1H),
3.14-3.23 (m, 1H), 3.06-3.14 (m, 1H), 1.44 (d, J=6.8 Hz, 3H), 1.15
(dd, J=6.8, 1.8 Hz, 6H). LC-MS: m/z 433.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(2-metho-
xyphenyl)nicotinonitrile (Compound 175)
[0363] Compound 175 was synthesized using
1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
[0364] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (s, 1H), 7.56 (s,
1H), 7.46 (t, J=1.5 Hz, 1H), 7.34-7.41 (m, 1H), 7.06-7.12 (m, 1H),
7.01 (t, J=7.3 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.55-6.62 (m, 1H),
4.74 (br. s., 1H), 4.18-4.46 (m, 3H), 3.77 (s, 3H), 3.49 (br. s.,
1H), 3.31 (dd, J=13.2, 3.1 Hz, 1H), 3.14 (td, J=12.5, 3.0 Hz, 1H),
2.86 (quin, J=6.7 Hz, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.15 (br. s.,
3H), 1.04 (br. s., 3H). LC-MS: m/z 445.2 (M+H).sup.+.
(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-(2-metho-
xyphenyl)nicotinonitrile (Compound 176)
[0365] Compound 176 was synthesized using
1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
[0366] .sup.1H NMR (CHLOROFORM-d) .delta. 7.56 (s, 1H), 7.50-7.53
(m, 1H), 7.34-7.41 (m, 1H), 7.07-7.13 (m, 1H), 7.03-7.06 (m, 1H),
6.99-7.02 (m, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.51 (dd, J=3.3, 1.8 Hz,
1H), 4.90 (br. s., 1H), 4.51 (d, J=13.6 Hz, 1H), 4.41 (d, J=13.8
Hz, 1H), 4.34 (d, J=13.3 Hz, 1H), 3.77 (s, 3H), 3.57 (d, J=10.5 Hz,
1H), 3.39 (dd, J=13.1, 3.5 Hz, 1H), 3.23 (td, J=12.4, 3.1 Hz, 1H),
2.86 (dt, J=13.3, 6.7 Hz, 1H), 1.49 (d, J=6.5 Hz, 3H), 1.16 (br.
s., 3H), 1.05 (br. s., 3H). LC-MS: m/z 445.2 (M+H).sup.+.
(R)-6-isopropyl-5-(2-methoxyphenyl)-2-(3-methyl-4-(2-(thiophen-2-acetyl)pi-
perazin-1-yl)nicotinonitrile (Compound 177)
[0367] Compound 177 was synthesized using
1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
[0368] .sup.1H NMR (CHLOROFORM-d) .delta. 7.54 (s, 1H), 7.33-7.41
(m, 1H), 7.20-7.24 (m, 1H), 7.05-7.11 (m, 1H), 6.98-7.04 (m, 1H),
6.89-6.98 (m, 3H), 4.94 (br. s., 0.5H), 4.58 (d, J=12.8 Hz, 0.2H),
4.17-4.46 (m, 3H), 3.91-4.04 (m, 2H), 3.76 (s, 3H), 3.56 (t, J=11.2
Hz, 0.5H), 3.27 (d, J=12.8 Hz, 0.5H), 3.13-3.23 (m, 1H), 2.98-3.11
(m, 1H), 2.85 (dt, J=13.3, 6.7 Hz, 1H), 1.33-1.39 (m, 3H), 1.15
(br. s., 3H), 1.04 (br. s., 3H). LC-MS: m/z 475.2 (M+H).sup.+.
(R)-6-isopropyl-5-(2-methoxyphenyl)-2-(3-methyl-4-(2-methylfuran-3-carbony-
l)piperazin-1-yl)nicotino-nitrile (Compound 178)
[0369] Compound 178 was synthesized using
1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
[0370] .sup.1H NMR (CHLOROFORM-d) .delta. 7.52-7.59 (m, 1H),
7.34-7.41 (m, 1H), 7.29 (d, J=1.8 Hz, 1H), 7.08 (dd, J=7.3, 1.8 Hz,
1H), 7.01 (t, J=7.2 Hz, 1H), 6.96 (d, J=8.3 Hz, 1H), 6.38 (d, J=1.8
Hz, 1H), 4.69 (br. s., 1H), 4.29-4.43 (m, 2H), 4.00-4.29 (m, 1H),
3.77 (s, 3H), 3.46 (br. s., 1H), 3.24-3.39 (m, 1H), 3.11 (td,
J=12.5, 3.0 Hz, 1H), 2.86 (spt, J=6.6 Hz, 1H), 2.41 (s, 3H), 1.43
(d, J=6.8 Hz, 3H), 1.12-1.19 (m, 3H), 1.04 (br. s., 3H). LC-MS: m/z
459.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-p-tolyln-
icotinonitrile (Compound 179)
[0371] Compound 179 was synthesized using
3-methyl-1-p-tolylbutan-2-one as starting material.
[0372] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (s, 1H), 7.60 (s,
1H), 7.44-7.49 (m, 1H), 7.24 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.0 Hz,
2H), 6.55-6.62 (m, 1H), 4.74 (br. s., 1H), 4.20-4.49 (m, 3H),
3.38-3.57 (m, 1H), 3.31 (dd, J=13.1, 3.0 Hz, 1H), 3.07-3.22 (m,
2H), 2.37-2.46 (m, 3H), 1.45 (d, J=6.8 Hz, 3H), 1.07-1.20 (m, 6H).
LC-MS: m/z 429.1 (M+H).sup.+.
(R)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-5-p-tolyln-
icotinonitrile (Compound 180)
[0373] Compound 180 was synthesized using
3-methyl-1-p-tolylbutan-2-one as starting material.
[0374] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.50-7.53
(m, 1H), 7.24 (d, J=7.8 Hz, 2H), 7.13 (d, J=8.0 Hz, 2H), 7.05 (d,
J=3.5 Hz, 1H), 6.46-6.55 (m, 1H), 4.90 (br. s., 1H), 4.51 (d,
J=13.6 Hz, 1H), 4.42 (d, J=14.1 Hz, 1H), 4.33 (dt, J=13.3, 2.0 Hz,
1H), 3.57 (d, J=10.3 Hz, 1H), 3.40 (dd, J=13.2, 3.6 Hz, 1H),
3.18-3.30 (m, 1H), 3.09-3.18 (m, 1H), 2.41 (s, 3H), 1.48 (d, J=6.8
Hz, 3H), 1.07-1.20 (m, 6H). LC-MS: m/z 429.2 (M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-(thiophen-2-yl)acetyl)piperazin-1-yl)-5-p-
-tolylnicotinonitrile (Compound 181)
[0375] Compound 181 was synthesized using
3-methyl-1-p-tolylbutan-2-one as starting material.
[0376] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (s, 1H), 7.20-7.25
(m, 3H), 7.12 (d, J=7.8 Hz, 2H), 6.88-7.00 (m, 2H), 4.94 (br. s.,
0.5H), 4.58 (d, J=13.1 Hz, 0.5H), 4.32-4.43 (m, 1H), 4.27 (s, 1H),
4.30 (s, 1H), 3.91-4.05 (m, 2H), 3.80 (d, J=13.6 Hz, 0.5H),
3.51-3.63 (m, 0.5H), 3.20-3.33 (m, 1H), 3.11-3.20 (m, 1H),
2.98-3.10 (m, 1H), 2.41 (s, 3H), 1.36 (d, J=6.3 Hz, 1.5H), 1.32 (d,
J=6.8 Hz, 1.5H), 1.13 (d, J=6.5 Hz, 6H). LC-MS: m/z 459.1
(M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-methylfuran-3-carbonyl)piperazin-1-yl)-5--
p-tolylnicotinonitrile (Compound 182)
[0377] Compound 182 was synthesized using
3-methyl-1-p-tolylbutan-2-one as starting material.
[0378] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.28-7.32
(m, 1H), 7.24 (d, J=8.0 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 6.36-6.41
(m, 1H), 4.69 (br. s., 1H), 4.38 (d, J=13.3 Hz, 1H), 4.33 (d,
J=13.1 Hz, 1H), 4.23 (d, J=12.0 Hz, 1H), 3.46 (br. s., 1H),
3.26-3.34 (m, 1H), 3.13-3.21 (m, 1H), 3.05-3.13 (m, 1H), 2.41 (s,
6H), 1.41 (d, J=6.8 Hz, 3H), 1.14 (dd, J=6.7, 3.4 Hz, 6H). LC-MS:
m/z 443.2 (M+H).sup.+.
(R)-6-isopropyl-5-(2-methoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 183)
[0379] Compound 183 was synthesized using
1-(2-methoxyphenyl)-3-methylbutan-2-one as starting material.
[0380] .sup.1H NMR (CHLOROFORM-d) .delta. 7.55 (s, 1H), 7.34-7.42
(m, 1H), 7.05-7.12 (m, 1H), 6.99-7.05 (m, 1H), 6.96 (d, J=8.3 Hz,
1H), 4.93 (br. s., 0.5H), 4.55 (d, J=13.1 Hz, 0.5H), 4.19-4.43 (m,
3H), 3.82 (d, J=7.5 Hz, 0.5H), 3.76 (s, 3H), 3.70-3.76 (m, 2H),
3.54-3.64 (m, 0.5H), 3.38 (s, 3H), 3.30 (t, J=13.3 Hz, 1H),
3.02-3.22 (m, 1H), 2.82-2.92 (m, 1H), 2.66-2.80 (m, 1H), 2.53-2.65
(m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.16
(br. s., 3H), 1.05 (br. s., 3H). LC-MS: m/z 437.1 (M+H).sup.+.
(S)-5-(2-ethoxyphenyl)-2-(4-(furan-2-carbonyl)-2-methylpiperazin-1-yl)-6-i-
sopropylnicotinonitrile (Compound 184)
[0381] Compound 184 was synthesized using
1-(2-ethoxyphenyl)-3-methylbutan-2-one as starting material.
[0382] .sup.1H NMR (CHLOROFORM-d) .delta. 7.55 (s, 1H), 7.48-7.53
(m, 1H), 7.31-7.38 (m, 1H), 7.05-7.11 (m, 2H), 6.96-7.02 (m, 1H),
6.94 (d, J=8.3 Hz, 1H), 6.45-6.56 (m, 1H), 4.77 (br. s., 1H), 4.53
(d, J=11.3 Hz, 1H), 4.36 (d, J=13.3 Hz, 1H), 4.23-4.33 (m, 1H),
4.02 (q, J=6.8 Hz, 2H), 3.38-3.67 (m, 3H), 2.84-2.97 (m, 1H), 1.36
(d, J=6.8 Hz, 3H), 1.27-1.30 (m, 3H), 1.24-1.27 (m, 6H). LC-MS: m/z
459.1 (M+H).sup.+.
(R)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-p-toly-
lnicotinonitrile (Compound 198)
[0383] Compound 198 was synthesized using
3-methyl-1-p-tolylbutan-2-one as starting material.
[0384] .sup.1H NMR (CHLOROFORM-d) .delta. 7.59 (s, 1H), 7.23 (d,
J=7.8 Hz, 2H), 7.12 (d, J=8.0 Hz, 2H), 4.92 (br. s., 0.5H), 4.55
(d, J=12.8 Hz, 0.5H), 4.21-4.42 (m, 3H), 3.81 (d, J=13.8 Hz, 0.5H),
3.69-3.77 (m, 62H), 3.53-3.64 (m, 0.5H), 3.38 (s, 3H), 3.31 (t,
J=12.3 Hz, 1H), 3.11-3.19 (m, 2H), 2.65-2.81 (m, 1H), 2.54-2.63 (m,
1H), 2.41 (s, 3H), 1.40 (d, J=6.3 Hz, 1.5H), 1.31 (d, J=6.5 Hz,
1.5H), 1.14 (d, J=6.8 Hz, 6H). LC-MS: m/z 421.1 (M+H).sup.+.
(R)-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5,6-diphenylnicotino-
nitrile (Compound 240)
[0385] Compound 240 was synthesized using 1,2-diphenylethanone as
starting material. .sup.1H NMR (CHLOROFORM-d) .delta. 7.84 (s, 1H),
7.33-7.40 (m, 2H), 7.26-7.33 (m, 4H), 7.20-7.25 (m, 2H), 7.08-7.16
(m, 2H), 4.94 (br. s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.38-4.49
(m, 1H), 4.23-4.38 (m, 2H), 3.77-3.90 (m, 1H), 3.74 (t, J=6.0 Hz,
2H), 3.54-3.64 (m, 0.5H), 3.37 (s, 3H), 3.34 (d, J=6.3 Hz, 0.5H),
3.19-3.26 (m, 1H), 3.06-3.19 (m, 1H), 2.66-2.78 (m, 1H), 2.55-2.63
(m, 1H), 1.39-1.46 (m, 1.5H), 1.33 (d, J=6.0 Hz, 1.5H). LC-MS: m/z
441.3 (M+H).sup.+.
Example 10
Preparation of
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenyln-
icotinonitrile (Compound 130)
[0386] Compound 130 (55, wherein m is 1, R.sup.3 is methyl; and
R.sup.8 is furan-3-yl) was synthesized according to general Scheme
7.
##STR00748##
Step W: 2-hydroxy-6-isopropyl-4-phenylnicotinonitrile (52)
[0387] To a suspension of ammonium acetate (31.46 g, 0.4 mol) in
200 mL of EtOH was added successively the 3-methyl-2-butanone (51;
5.38 mL, 50 mmol), benzaldehyde (50; 5.21 g, 50 mmol), and ethyl
cyanoacetate (23; 5.6 mL, 50 mmol). The resulting mixture was
stirred at reflux temperature for 3 hrs and subsequently at room
temperature overnight. After the LC-MS showed the formation of the
desired product, the precipitate formed was filtered and washed
with EtOH (10 mL.times.3 times) and hexane (10 mL.times.3 times).
After air-drying, 2.18 g of 52 was obtained as a white solid. MS
(ES) M+H expected 239.1, found 239.0. .sup.1H NMR (CHLOROFORM-d)
.delta. 7.61-7.70 (m, 2H), 7.51-7.58 (m, 3H), 6.33 (s, 1H), 3.06
(dt, J=13.8, 6.9 Hz, 1H), 1.42 (d, J=7.0 Hz, 6H).
Step X: 2-chloro-6-isopropyl-4-phenylnicotinonitrile (53)
[0388] A mixture of 2-hydroxy-6-isopropyl-4-phenylnicotinonitrile
52; (0.702 g, 2.94 mmol), 7 mL of phosphoryl trichloride and one
drop of DMF were heated to reflux overnight until LC-MS indicated
the complete conversion to the product. After evaporation of excess
of phosphoryl trichloride under reduced pressure, the residue was
re-dissolved in methylene chloride and neutralized carefully with
satd. aq. NaHCO.sub.3 and washed subsequently with 1N HCl and
brine. The combined organic layer was dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Flash column
chromatography (1:5 ethyl acetate/petroleum ether) afforded 717 mg
of 53 as a yellowish solid. MS (ES) M+H expected 257.1, found
257.0. .sup.1H NMR (CHLOROFORM-d) .delta. 7.52-7.64 (m, 5H), 7.26
(s, 1H), 3.09-3.21 (m, 1H), 1.37 (d, J=7.0 Hz, 6H).
Step Y:
(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-4-phenylnicotinonitrile
(54)
[0389] A mixture of above chloride 53 (192.6 mg, 0.75 mmol),
(R)-2-methylpiperazine (150 mg, 1.5 mmol), and triethylamine (0.21
mL, 1.5 mmol) suspended in 1.5 mL of acetonitrile was subjected to
microwave reaction at 175.degree. C. for 45 min. After the reaction
mixture was concentrated in vacuo, the residue was purified by
flash column chromatography to give 197 mg of 54 as yellowish oil.
MS (ES) M+H expected 321.2, found 321.1. .sup.1H NMR (CHLOROFORM-d)
.delta. 7.54-7.60 (m, 2H), 7.47-7.53 (m, 3H), 6.71 (s, 1H),
4.21-4.35 (m, 2H), 3.03-3.18 (m, 4H), 2.99 (dt, J=13.8, 6.9 Hz,
1H), 2.78 (dd, J=12.7, 10.2 Hz, 1H), 1.30 (d, J=7.0 Hz, 6H),
1.15-1.20 (m, 3H).
Step Z:
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4--
phenylnicotinonitrile (Compound 130)
[0390] In a 5-mL of amber glass vial was placed
(R)-6-isopropyl-2-(3-methylpiperazin-1-yl)-4-phenyl-nicotinonitrile
(54; 32 mg, 0.1 mmol), furan-3-carboxylic acid (22.4 mg, 0.312
mmol), EDCI (38.2 mg, 0.2 mmol), HOBt (27 mg, 0.2 mmol),
triethylamine (35 .mu.L, 0.2 mmol) and 1.5 mL of methylene
chloride. The resulting reaction mixture was stirred at room
temperature overnight. The mixture was quenched with 1 N HCl
aqueous solution, extracted with EtOAc three times. The combined
organic layer was washed with satd. NaHCO.sub.3 and brine, dried
over anhy. Na.sub.2SO.sub.4, and concentrated in vacuo. The crude
product was purified by preparative TLC (EtOAc: petroleum
ether/20:100) to afford 23 mg of Compound 130 as a light yellowish
solid. MS (ES) M+H expected 415.2, found 415.1. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.55-7.58 (m, 2H), 7.50-7.53
(m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H), 6.60-6.62 (m, 1H),
4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d, J=13.1 Hz,
1H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6 Hz, 1H), 3.17 (td,
J=12.5, 3.5 Hz, 1H), 3.01 (spt, J=6.9 Hz, 1H), 1.47 (d, J=6.8 Hz,
3H), 1.31 (d, J=6.8 Hz, 6H).
[0391] Other Compounds of Formula II listed below, wherein R.sup.1a
is optionally substituted phenyl; and R.sup.1b is hydrogen; were
similarly prepared by general Scheme 7 replacing one or more of:
(1) 3-methyl-2-butanone (51) with an alternate ketone as starting
material; (2) benzaldehyde (50) with an alternate aldehyde as
starting material; (3) (R)-2-methylpiperazine with an alternate
piperazine in Step Y; and (4) 2-methylfuran-3-carboxylic acid with
an alternate acid in Step Z. In addition, a compound wherein
R.sup.1a is isopropyl; R.sup.1b is hydrogen and R.sup.2 is phenyl
was also prepared by the same method of general Scheme 7.
2-(4-benzoylpiperazin-1-yl)-6-isopropyl-4-phenylnicotinonitrile
(Compound 100)
[0392] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.54-7.59 (m, 2H),
7.50-7.54 (m, 3H), 7.47 (s, 5H), 6.80 (s, 1H), 4.01 (br. s., 2H),
3.74-3.89 (m, 3H), 3.66 (br. s., 3H), 3.01 (quin, J=6.8 Hz, 1H),
1.32 (s, 3H), 1.30 (s, 3H). LC-MS: m/z 411.1 (M+H).sup.+.
2-((3S,5R)-4-benzoyl-3,5-dimethylpiperazin-1-yl)-6-isopropyl-4-phenylnicot-
inonitrile (Compound 101)
[0393] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.53-7.58 (m, 2H),
7.49-7.53 (m, 3H), 7.40-7.47 (m, 5H), 6.79 (s, 1H), 4.54 (br. s.,
2H), 4.24 (s, 1H), 4.27 (s, 1H), 3.28 (dd, J=13.1, 4.3 Hz, 2H),
3.01 (dt, J=13.6, 6.9 Hz, 1H), 1.52 (d, J=6.8 Hz, 6H), 1.31 (d,
J=7.0 Hz, 6H). LC-MS: m/z 439.1 (M+H).sup.+.
2-((3S,5R)-4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-isopropyl-4--
phenylnicotinonitrile (Compound 102)
[0394] .sup.1H NMR (CHLOROFORM-d) .delta. 7.54-7.61 (m, 2H),
7.45-7.54 (m, 4H), 7.08 (d, J=3.5 Hz, 1H), 6.78 (s, 1H), 6.52 (dd,
J=3.5, 1.8 Hz, 1H), 4.90 (br. s., 2H), 4.30 (s, 1H), 4.34 (s, 1H),
3.32 (dd, J=12.9, 4.4 Hz, 2H), 3.01 (quin, J=6.9 Hz, 1H), 1.60 (d,
J=7.0 Hz, 6H), 1.31 (d, J=7.0 Hz, 6H). LC-MS: m/z 429.1
(M+H).sup.+.
2-(4-(furan-2-carbonyl)piperazin-1-yl)-4-isopropyl-6-phenylnicotinonitrile
(Compound 103)
[0395] Compound 103 was synthesized using isobutyraldehyde and
acetophenone as starting materials.
[0396] .sup.1H NMR (DMSO-d.sub.6) .delta. 8.02-8.08 (m, 2H),
7.50-7.56 (m, 2H), 7.46-7.50 (m, 2H), 7.30 (s, 1H), 7.08 (dd,
J=3.4, 0.6 Hz, 1H), 6.53 (dd, J=3.3, 1.8 Hz, 1H), 4.05 (br. s.,
4H), 3.79-3.85 (m, 4H), 3.40 (dt, J=13.7, 6.8 Hz, 1H), 1.38 (d,
J=6.8 Hz, 6H). LC-MS: m/z 400.8 (M+H).sup.+.
2-(4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nico-
tinonitrile (Compound 104)
[0397] Compound 104 was synthesized using 2-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0398] .sup.1H NMR (CHLOROFORM-d) .delta. 7.51-7.57 (m, 1H),
7.43-7.51 (m, 1H), 7.23-7.28 (m, 1H), 7.03-7.11 (m, 3H), 6.75 (s,
1H), 6.53 (dd, J=3.0, 1.5 Hz, 1H), 4.02 (br. s., 4H), 3.89 (s, 3H),
3.74-3.82 (m, 4H), 3.00 (dt, J=13.8, 6.9 Hz, 1H), 1.31 (d, J=6.8
Hz, 6H). LC-MS: m/z 430.9 (M+H).sup.+.
2-(4-benzoylpiperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nicotinonitrile
(Compound 105)
[0399] Compound 105 was synthesized using 2-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0400] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.43-7.50 (m, 6H), 7.25
(dd, J=7.4, 1.6 Hz, 1H), 7.07-7.10 (m, 1H), 7.02-7.06 (m, 1H), 6.75
(s, 1H), 3.99 (br. s., 2H), 3.87 (s, 3H), 3.78 (br. s., 2H), 3.64
(br. s., 4H), 2.99 (dt, J=13.8, 6.9 Hz, 1H), 1.31 (s, 3H), 1.29 (s,
3H). LC-MS: m/z 440.8 (M+H).sup.+.
2-(4-(1H-indole-3-carbonyl)piperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)-
nicotinonitrile (Compound 106)
[0401] Compound 106 was synthesized using 2-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0402] .sup.1H NMR (CHLOROFORM-d) .delta. 9.02 (br. s., 1H),
7.73-7.80 (m, 1H), 7.41-7.51 (m, 3H), 7.21-7.28 (m, 3H), 7.01-7.11
(m, 2H), 6.75 (s, 1H), 3.94 (br. s., 4H), 3.87 (s, 3H), 3.75 (br.
s., 4H), 3.02 (dt, J=13.7, 6.8 Hz, 1H), 1.31 (d, J=6.8 Hz, 6H).
LC-MS: m/z 480 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicoti-
nonitrile (Compound 107)
[0403] .sup.1H NMR (CHLOROFORM-d) .delta. 7.55-7.60 (m, 2H),
7.48-7.54 (m, 4H), 7.06 (dd, J=3.5, 0.8 Hz, 1H), 6.77 (s, 1H), 6.52
(dd, J=3.5, 1.8 Hz, 1H), 4.91 (br. s., 1H), 4.52 (d, J=13.6 Hz,
1H), 4.29-4.36 (m, 1H), 4.23 (dt, J=13.1, 2.1 Hz, 1H), 3.62 (br.
s., 1H), 3.43 (dd, J=13.1, 3.8 Hz, 1H), 3.26 (td, J=12.4, 3.5 Hz,
1H), 3.00 (quin, J=6.9 Hz, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.31 (d,
J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-4-isopropyl-6-phenylnicoti-
nonitrile (Compound 108)
[0404] Compound 108 was synthesized using benzaldehyde and
3-methylbutan-2-one as starting materials.
[0405] .sup.1H NMR (CHLOROFORM-d) .delta. 8.00-8.08 (m, 2H),
7.50-7.57 (m, 2H), 7.45-7.50 (m, 2H), 7.29 (s, 1H), 7.07 (dd,
J=3.5, 0.5 Hz, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.94 (br. s.,
1H), 4.54 (d, J=13.3 Hz, 1H), 4.34 (dd, J=12.5, 2.3 Hz, 1H), 4.24
(dt, J=13.1, 2.1 Hz, 1H), 3.65 (br. s., 1H), 3.41-3.46 (m, 1H),
3.38-3.41 (m, 1H), 3.25 (td, J=12.4, 3.3 Hz, 1H), 1.53 (d, J=6.8
Hz, 3H), 1.38 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1 (M+H).sup.+.
2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylnicoti-
nonitrile (Compound 110)
[0406] .sup.1H NMR (CHLOROFORM-d) .delta. 8.00-8.06 (m, 2H), 7.77
(s, 1H), 7.50 (br. s., 1H), 7.48 (d, J=4.3 Hz, 3H), 7.30 (s, 1H),
6.61 (s, 1H), 4.78 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22
(d, J=13.1 Hz, 1H), 3.58 (br. s., 1H), 3.40 (quin, J=6.9 Hz, 1H),
3.33 (dd, J=12.9, 3.1 Hz, 1H), 3.17 (td, J=12.4, 3.3 Hz, 1H), 1.50
(d, J=6.8 Hz, 3H), 1.38 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.0
(M+H).sup.+.
2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-isopropyl-6-phenylnicoti-
nonitrile (Compound III)
[0407] Compound III was synthesized using benzaldehyde and
3-methylbutan-2-one as starting materials.
[0408] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.53-7.61
(m, 2H), 7.49-7.53 (m, 3H), 7.47 (s, 1H), 6.79 (s, 4H), 6.61 (s,
1H), 4.71-4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H), 4.22 (d,
J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.34 (dd, J=13.1, 3.3 Hz, 1H),
3.17 (td, J=12.5, 3.4 Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.47
(d, J=6.8 Hz, 3H), 1.29 (d, J=7.3 Hz, 6H). LC-MS: m/z 414.9
(M+H).sup.+.
2-(4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropyl-4-(2-methoxyphenyl)nico-
tinonitrile (Compound 113)
[0409] Compound 113 was synthesized using 2-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0410] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.42-7.53
(m, 2H), 7.25 (dd, J=7.5, 1.5 Hz, 1H), 7.02-7.13 (m, 2H), 6.76 (s,
1H), 6.59-6.66 (m, 1H), 3.90 (br. s., 4H), 3.88 (s, 3H), 3.73 (br.
s., 4H), 3.00 (dt, J=13.7, 6.8 Hz, 1H), 1.30 (d, J=6.8 Hz, 6H).
LC-MS: m/z 431.0 (M+H).sup.+.
4-(3-fluorophenyl)-2-(4-(furan-2-carbonyl)piperazin-1-yl)-6-isopropylnicot-
inonitrile (Compound 114)
[0411] Compound 114 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0412] .sup.1H NMR (CHLOROFORM-d) .delta. 7.42-7.56 (m, 2H), 7.36
(dq, J=7.7, 0.9 Hz, 1H), 7.17-7.27 (m, 2H), 7.09 (dd, J=3.4, 0.9
Hz, 1H), 6.76 (s, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 4.03 (br. s.,
4H), 3.83 (dd, J=6.3, 4.0 Hz, 4H), 2.95-3.10 (m, 1H), 1.31 (d,
J=6.8 Hz, 6H). LC-MS: m/z 419.1 (M+H).sup.+.
4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)piperazin-1-yl)-6-isopropylnicot-
inonitrile (Compound 115)
[0413] Compound 115 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0414] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77-7.80 (m, 1H),
7.45-7.53 (m, 2H), 7.36 (dt, J=7.7, 1.2 Hz, 1H), 7.17-7.28 (m, 2H),
6.77 (s, 1H), 6.62 (dd, J=1.9, 0.6 Hz, 1H), 3.92 (br. s., 4H), 3.77
(br. s., 4H), 2.92-3.10 (m, 1H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z
419.0 (M+H).sup.+.
2-(4-(1H-indole-3-carbonyl)piperazin-1-yl)-4-(3-fluorophenyl)-6-isopropyln-
icotinonitrile (Compound 116)
[0415] Compound 116 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0416] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (d, J=7.0 Hz, 1H),
7.40-7.63 (m, 3H), 7.36 (d, J=7.8 Hz, 1H), 7.17-7.28 (m, 3H), 6.77
(s, 1H), 3.94 (br. s., 4H), 3.79 (br. s., 4H), 3.67 (s, 1H),
3.02-3.13 (m, 1H), 1.32 (d, J=6.8 Hz, 6H). LC-MS: m/z 468.1
(M+H).sup.+.
6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-4-phenylnicotino-
nitrile (Compound 121)
[0417] .sup.1H NMR (CHLOROFORM-d) .delta. 7.48-7.58 (m, 5H),
7.33-7.39 (m, 3H), 7.30 (d, J=1.5 Hz, 1H), 7.25-7.28 (m, 1H), 6.75
(s, 1H), 4.71 (s, 1H), 4.27 (br. s., 1H), 4.09-4.20 (m, 2H), 3.80
(br. s., 2H), 3.52 (s, 1H), 3.19-3.26 (s, 1H), 3.06-3.15 (m, 1H),
2.98 (dt, J=13.7, 6.8 Hz, 1H), 1.40 (s, 3H), 1.30 (d, J=4.5 Hz,
19H). LC-MS: m/z 439.2 (M+H).sup.+.
4-(3-fluorophenyl)-2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopr-
opylnicotinonitrile (Compound 127)
[0418] Compound 127 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0419] .sup.1H NMR (CHLOROFORM-d) .delta. 7.44-7.58 (m, 2H),
7.31-7.40 (m, 1H), 7.14-7.27 (m, 2H), 7.07 (d, J=3.5 Hz, 1H), 6.74
(s, 1H), 6.53 (dd, J=3.5, 1.8 Hz, 1H), 4.92 (br. s., 1H), 4.52 (d,
J=13.6 Hz, 1H), 4.34 (d, J=10.5 Hz, 1H), 4.24 (dt, J=13.1, 2.1 Hz,
1H), 3.62 (br. s., 1H), 3.45 (dd, J=13.3, 3.8 Hz, 1H), 3.28 (td,
J=12.4, 3.4 Hz, 1H), 3.01 (dt, J=13.6, 6.9 Hz, 1H), 1.44-1.54 (m,
3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 433.0 (M+H).sup.+.
4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopr-
opylnicotinonitrile (Compound 128)
[0420] Compound 128 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0421] .sup.1H NMR (CHLOROFORM-d) .delta. 7.73-7.81 (m, 1H),
7.44-7.56 (m, 2H), 7.35 (dt, J=8.0, 1.1 Hz, 1H), 7.12-7.27 (m, 2H),
6.75 (s, 1H), 6.61 (dd, J=1.8, 0.8 Hz, 1H), 4.77 (br. s., 1H), 4.31
(d, J=12.0 Hz, 2H), 4.23 (d, J=13.1 Hz, 1H), 3.57 (br. s., 1H),
3.36 (d, J=10.0 Hz, 1H), 3.19 (td, J=12.4, 3.5 Hz, 1H), 3.01 (dt,
J=13.5, 6.9 Hz, 1H), 1.46 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz,
6H). LC-MS: m/z 433.1 (M+H).sup.+.
2-(4-(1H-indole-3-carbonyl)-3-methylpiperazin-1-yl)-4-(3-fluorophenyl)-6-i-
sopropylnicotinonitrile (Compound 129)
[0422] Compound 129 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0423] .sup.1H NMR (CHLOROFORM-d) .delta. 8.85 (s, 1H), 7.75 (d,
J=7.8 Hz, 1H), 7.40-7.54 (m, 3H), 7.35 (d, J=7.8 Hz, 1H), 7.15-7.28
(m, 4H), 6.74 (s, 1H), 4.84 (br. s., 1H), 4.28 (t, J=15.3 Hz, 3H),
3.59 (d, J=11.8 Hz, 1H), 3.41 (d, J=11.0 Hz, 1H), 3.21 (t, J=10.8
Hz, 1H), 3.00 (dt, J=13.8, 6.9 Hz, 1H), 1.45 (d, J=6.5 Hz, 3H),
1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 482.2 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylni-
cotinonitrile (Compound 130)
[0424] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.55-7.58
(m, 2H), 7.50-7.53 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H),
6.60-6.62 (m, 1H), 4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H),
4.22 (d, J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6
Hz, 1H), 3.17 (td, J=12.5, 3.5 Hz, 1H), 3.01 (spt, J=6.9 Hz, 1H),
1.47 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1
(M+H).sup.+.
(R)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-4-phenylnico-
tinonitrile (Compound 131)
[0425] .sup.1H NMR (CHLOROFORM-d) .delta. 7.52-7.57 (m, 2H),
7.47-7.52 (m, 3H), 7.29-7.41 (m, 4H), 7.24-7.28 (m, 1H), 6.75 (s,
1H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.3 Hz, 0.5H), 4.28 (d,
J=13.1 Hz, 1H), 4.06-4.20 (m, 2H), 3.81 (br. s., 2H), 3.70-3.79 (m,
0.5H), 3.54 (t, J=11.3 Hz, 0.5H), 3.18-3.33 (m, 1H), 3.03-3.17 (m,
1H), 2.99 (dt, J=13.8, 6.9 Hz, 1H), 1.33 (br. s., 3H), 1.29 (d,
J=7.0 Hz, 6H). LC-MS: m/z 439.1 (M+H).sup.+.
(S)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-phenylni-
cotinonitrile (Compound 132)
[0426] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.54-7.59
(m, 2H), 7.49-7.54 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H),
6.59-6.63 (m, 1H), 4.76 (br. s., 1H), 4.28 (s, 1H), 4.31 (s, 1H),
4.22 (d, J=13.3 Hz, 1H), 3.57 (br. s., 1H), 3.34 (dd, J=13.2, 3.6
Hz, 1H), 3.17 (td, J=12.5, 3.4 Hz, 1H), 3.01 (spt, J=6.9 Hz, 1H),
1.47 (d, J=6.8 Hz, 3H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 415.1
(M+H).sup.+.
(S)-6-isopropyl-2-(3-methyl-4-(2-phenylacetyl)piperazin-1-yl)-4-phenylnico-
tinonitrile (Compound 133)
[0427] .sup.1H NMR (CHLOROFORM-d) .delta. 7.53-7.56 (m, 2H),
7.47-7.53 (m, 3H), 7.33-7.39 (m, 2H), 7.29-7.33 (m, 2H), 7.24-7.28
(m, 1H), 6.75 (s, 1H), 4.98 (br. s., 0.5H), 4.62 (d, J=13.3 Hz,
0.5H), 4.28 (d, J=12.8 Hz, 1H), 4.08-4.20 (m, 2H), 3.81 (br. s.,
2H), 3.70-3.79 (m, 0.5H), 3.54 (t, J=11.3 Hz, 0.5H), 3.17-3.32 (m,
1H), 3.10 (t, J=12.7 Hz, 1H), 2.98 (dt, J=13.7, 6.8 Hz, 1H),
1.31-1.35 (m, 3H), 1.29 (d, J=7.0 Hz, 6H). LC-MS: m/z 439.1
(M+H).sup.+.
4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-i-
sopropylnicotinonitrile (Compound 134)
[0428] Compound 134 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0429] .sup.1H NMR (DMSO-d.sub.6) .delta. 7.77 (s, 1H), 7.45-7.53
(m, 2H), 7.35 (d, J=8.3 Hz, 1H), 7.17-7.25 (m, 2H), 6.76 (s, 1H),
6.65 (d, J=1.0 Hz, 1H), 4.71 (br. s., 1H), 4.31 (d, J=12.8 Hz, 2H),
3.50-3.69 (m, 1H), 3.27 (dd, J=13.2, 4.4 Hz, 2H), 3.01 (quin, J=7.0
Hz, 1H), 1.56 (d, J=7.0 Hz, 6H), 1.32 (s, 3H), 1.30 (s, 3H). LC-MS:
m/z 447.1 (M+H).sup.+.
2-(3,5-dimethyl-4-(2-phenylacetyl)piperazin-1-yl)-4-(3-fluorophenyl)-6-iso-
propylnicotinonitrile (Compound 135)
[0430] Compound 135 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0431] .sup.1H NMR (CHLOROFORM-d) .delta. 7.43-7.55 (m, 1H),
7.12-7.40 (m, 8H), 6.74 (s, 1H), 4.90 (br. s., 1H), 4.26 (br. s.,
3H), 3.82 (s, 2H), 3.14 (br. s., 2H), 3.00 (dt, J=13.8, 6.9 Hz,
1H), 1.44 (d, J=6.8 Hz, 6H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z
471.1 (M+H).sup.+.
4-(3-fluorophenyl)-2-(4-(furan-2-carbonyl)-3,5-dimethylpiperazin-1-yl)-6-i-
sopropylnicotinonitrile (Compound 136)
[0432] Compound 136 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0433] .sup.1H NMR (CHLOROFORM-d) .delta. 7.45-7.55 (m, 2H),
7.32-7.38 (m, 1H), 7.15-7.28 (m, 2H), 7.08 (d, J=3.5 Hz, 1H), 6.74
(s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.90 (br. s., 2H), 4.34 (d,
J=13.1 Hz, 2H), 3.33 (dd, J=13.1, 4.5 Hz, 2H), 2.93-3.08 (m, 1H),
1.59 (d, J=7.0 Hz, 6H), 1.31 (d, J=6.8 Hz, 6H). LC-MS: m/z 447.0
(M+H).sup.+.
6-cyclohexyl-2-(4-(furan-2-carbonyl)piperazin-1-yl)-4-phenylnicotinonitril-
e (Compound 137)
[0434] Compound 137 was synthesized using benzaldehyde and
1-cyclohexylethanone as starting materials.
[0435] .sup.1H NMR (CHLOROFORM-d) .delta. 7.46-7.61 (m, 6H), 7.08
(dd, J=3.4, 0.9 Hz, 1H), 6.78 (s, 1H), 6.53 (dd, J=3.4, 1.9 Hz,
1H), 4.03 (br. s., 4H), 3.76-3.86 (m, 4H), 2.66 (tt, J=11.6, 3.3
Hz, 1H), 1.92-2.00 (m, 2H), 1.83-1.91 (m, 2H), 1.74-1.82 (m, 1H),
1.55 (qd, J=12.3, 2.8 Hz, 2H), 1.41 (qt, J=12.6, 3.1 Hz, 2H),
1.25-1.35 (m, 1H). LC-MS: m/z 441.0 (M+H).sup.+.
6-cyclohexyl-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-phenylnicot-
inonitrile (Compound 138)
[0436] Compound 138 was synthesized using benzaldehyde and
1-cyclohexylethanone as starting materials.
[0437] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.43-7.61
(m, 6H), 6.77 (s, 1H), 6.61 (s, 1H), 4.76 (br. s., 1H), 4.29 (d,
J=12.3 Hz, 2H), 4.20 (d, J=13.1 Hz, 1H), 3.56 (br. s., 1H), 3.33
(dd, J=13.2, 3.1 Hz, 1H), 3.16 (td, J=12.5, 3.1 Hz, 1H), 2.56-2.72
(m, 1H), 1.95 (d, J=12.5 Hz, 2H), 1.87 (d, J=12.8 Hz, 2H), 1.78 (d,
J=12.8 Hz, 1H), 1.49-1.60 (m, 2H), 1.46 (d, J=6.5 Hz, 3H),
1.35-1.44 (m, 2H), 1.25-1.34 (m, 1H). LC-MS: m/z 455.1
(M+H).sup.+.
6-cyclohexyl-2-((3S,5R)-4-(furan-3-carbonyl)-3,5-dimethylpiperazin-1-yl)-4-
-phenylnicotinonitrile (Compound 142)
[0438] Compound 142 was synthesized using benzaldehyde and
1-cyclohexylethanone as starting materials.
[0439] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (s, 1H), 7.54-7.58
(m, 2H), 7.49-7.53 (m, 3H), 7.48 (t, J=1.6 Hz, 1H), 6.79 (s, 1H),
6.65 (d, J=2.0 Hz, 1H), 4.73 (br. s., 2H), 4.27 (d, J=13.1 Hz, 2H),
3.25 (dd, J=13.1, 4.5 Hz, 2H), 2.66 (tt, J=11.6, 3.4 Hz, 1H), 1.95
(d, J=12.5 Hz, 2H), 1.84-1.92 (m, 2H), 1.78 (d, J=12.5 Hz, 1H),
1.57 (d, J=7.0 Hz, 6H), 1.49-1.54 (m, 2H), 1.38-1.47 (m, 2H),
1.31-1.37 (m, 1H). LC-MS: m/z 469.1 (M+H).sup.+.
6-isopropyl-4-(2-methoxyphenyl)-2-(4-(2-phenylacetyl)piperazin-1-yl)nicoti-
nonitrile (Compound 146)
[0440] Compound 146 was synthesized using 2-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0441] .sup.1H NMR (CHLOROFORM-d) .delta. 7.42-7.48 (m, 1H),
7.28-7.40 (m, 5H), 7.23 (dd, J=7.5, 1.8 Hz, 1H), 7.01-7.10 (m, 2H),
6.73 (s, 1H), 3.83-3.90 (m, 5H), 3.82 (s, 2H), 3.62-3.70 (m, 4H),
3.49-3.56 (m, 2H), 2.91-3.03 (m, 1H), 1.29 (d, J=6.8 Hz, 6H).
LC-MS: m/z 455.2 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-(2-methoxyph-
enyl)nicotinonitrile (Compound 147)
[0442] Compound 147 was synthesized using 2-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0443] .sup.1H NMR (CHLOROFORM-d) .delta. 7.52 (dd, J=1.8, 0.8 Hz,
1H), 7.41-7.48 (m, 1H), 7.25 (dd, J=7.5, 1.8 Hz, 1H), 7.00-7.16 (m,
3H), 6.73 (s, 1H), 6.52 (dd, J=3.5, 1.8 Hz, 1H), 4.91 (br. s., 1H),
4.51 (d, J=12.3 Hz, 1H), 4.32 (d, J=12.5 Hz, 1H), 4.22 (dt, J=13.2,
2.0 Hz, 1H), 3.88 (s, 3H), 3.62 (br. s., 1H), 3.39 (dd, J=13.2, 3.6
Hz, 1H), 3.22 (td, J=12.4, 3.5 Hz, 1H), 3.00 (dt, J=13.7, 6.8 Hz,
1H), 1.49 (d, J=6.8 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z
455.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-(2-metho-
xyphenyl)nicotinonitrile (Compound 148)
[0444] Compound 148 was synthesized using 2-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0445] .sup.1H NMR (CHLOROFORM-d) .delta. 7.76 (dd, J=1.5, 0.8 Hz,
1H), 7.40-7.51 (m, 2H), 7.22-7.28 (m, 1H), 7.01-7.11 (m, 2H),
6.70-6.76 (m, 1H), 6.61 (dd, J=1.8, 0.8 Hz, 1H), 4.75 (br. s., 1H),
4.16-4.45 (m, 3H), 3.88 (s, 3H), 3.55 (br. s., 1H), 3.31 (dd,
J=12.9, 3.4 Hz, 1H), 3.14 (td, J=12.5, 3.4 Hz, 1H), 3.00 (dt,
J=13.7, 6.8 Hz, 1H), 1.46 (d, J=7.0 Hz, 3H), 1.30 (d, J=6.8 Hz,
6H). LC-MS: m/z 445.2 (M+H).sup.+.
6-isopropyl-4-(2-methoxyphenyl)-2-(3-methyl-4-(2-phenylacetyl)piperazin-1--
yl)nicotinonitrile (Compound 149)
[0446] Compound 149 was synthesized using 3-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0447] .sup.1H NMR (CHLOROFORM-d) .delta. 7.41-7.49 (m, 1H),
7.29-7.40 (m, 4H), 7.20-7.28 (m, 2H), 7.01-7.09 (m, 2H), 6.71 (s,
1H), 4.97 (br. s., 1H), 4.60 (d, J=13.3 Hz, 1H), 4.25 (br. s., 1H),
4.16 (d, J=13.3 Hz, 1H), 3.87 (s, 3H), 3.64-3.81 (m, 2H), 3.53 (t,
J=11.4 Hz, 1H), 3.14-3.29 (m, 1H), 2.85-3.14 (m, 2H), 1.62 (s, 3H),
1.29 (s, 6H). LC-MS: m/z 469.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-(3-metho-
xyphenyl)nicotinonitrile (Compound 151)
[0448] Compound 151 was synthesized using 3-methoxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0449] .sup.1H NMR (CHLOROFORM-d) .delta. 7.76 (dd, J=1.5, 0.8 Hz,
1H), 7.38-7.50 (m, 2H), 7.00-7.17 (m, 3H), 6.76-6.81 (m, 1H), 6.61
(dd, J=1.9, 0.9 Hz, 1H), 4.76 (br. s., 1H), 4.29 (d, J=12.8 Hz,
2H), 4.21 (d, J=13.1 Hz, 1H), 3.84-3.92 (m, 3H), 3.56 (br. s., 1H),
3.33 (dd, J=13.2, 3.6 Hz, 1H), 3.17 (td, J=12.5, 3.4 Hz, 1H), 3.00
(dt, J=13.7, 6.8 Hz, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.0
Hz, 6H). LC-MS: m/z 445.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(3-hydroxyphenyl)-6--
isopropylnicotinonitrile (Compound 152)
[0450] Compound 152 was synthesized using 3-hydroxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0451] .sup.1H NMR (CHLOROFORM-d) .delta. 7.74-7.81 (m, 1H),
7.41-7.51 (m, 1H), 7.34 (t, J=7.9 Hz, 1H), 7.11 (s, 1H), 7.05 (d,
J=7.5 Hz, 1H), 6.97 (dd, J=8.2, 2.4 Hz, 1H), 6.79 (s, 1H),
6.57-6.64 (m, 1H), 4.79 (br. s., 1H), 4.15-4.44 (m, 3H), 3.59 (br.
s., 1H), 3.34 (d, J=10.5 Hz, 1H), 3.17 (td, J=12.5, 3.1 Hz, 1H),
2.93-3.04 (m, 1H), 1.47 (d, J=6.8 Hz, 3H), 1.27-1.31 (m, 6H).
LC-MS: m/z 431.2 (M+H).sup.+.
2-(4-(furan-3-carbonyl)-3-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicoti-
nonitrile (Compound 154)
[0452] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (br. s., 1H),
7.50-7.54 (m, 2H), 7.46-7.50 (m, 3H), 7.37-7.43 (m, 3H), 7.34 (t,
J=7.7 Hz, 2H), 7.22-7.27 (m, 1H), 6.67 (s, 1H), 6.52 (br. s., 1H),
5.75 (br. s., 1H), 4.57 (br. s., 2H), 4.29 (d, J=11.5 Hz, 1H), 4.00
(d, J=11.0 Hz, 1H), 3.60-3.74 (m, 1H), 3.55 (d, J=10.5 Hz, 1H),
2.94 (dt, J=13.6, 6.8 Hz, 1H), 1.25-1.27 (m, 3H), 1.23 (d, J=7.0
Hz, 3H). LC-MS: m/z 477.1 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-3-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicoti-
nonitrile (Compound 155)
[0453] .sup.1H NMR (CHLOROFORM-d) .delta. 7.51-7.55 (m, 2H),
7.46-7.50 (m, 4H), 7.45 (d, J=7.5 Hz, 2H), 7.33 (t, J=7.5 Hz, 2H),
7.20-7.25 (m, 1H), 6.92-7.07 (m, 1H), 6.68 (s, 1H), 6.45 (br. s.,
4H), 5.95 (t, J=4.5 Hz, 1H), 4.63 (s, 1H), 4.66 (s, 1H), 4.33 (d,
J=11.0 Hz, 1H), 4.06 (dd, J=13.6, 4.0 Hz, 1H), 3.69 (br. s., 1H),
3.56-3.65 (m, 1H), 2.97 (dt, J=13.7, 6.8 Hz, 1H), 1.24-1.28 (m,
6H). LC-MS: m/z 477.1 (M+H).sup.+.
(R)-4-(3-fluorophenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-i-
sopropylnicotinonitrile (Compound 156)
[0454] Compound 156 was synthesized using 3-fluorobenzaldehyde and
3-methylbutan-2-one as starting materials.
[0455] .sup.1H NMR (CHLOROFORM-d) .delta. 7.77 (dd, J=1.5, 1.0 Hz,
1H), 7.43-7.53 (m, 2H), 7.35 (dq, J=7.7, 0.9 Hz, 1H), 7.12-7.28 (m,
2H), 6.67-6.80 (m, 1H), 6.61 (dd, J=1.9, 0.9 Hz, 1H), 4.76 (br. s.,
1H), 4.17-4.45 (m, 3H), 3.56 (br. s., 1H), 3.36 (dd, J=13.1, 3.5
Hz, 1H), 3.18 (td, J=12.5, 3.5 Hz, 1H), 2.95-3.07 (m, 1H), 1.46 (d,
J=6.8 Hz, 3H), 1.29-1.32 (m, 6H). LC-MS: m/z 433.1 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6--
isopropylnicotinonitrile (Compound 157)
[0456] Compound 157 was synthesized using 2-hydroxybenzaldehyde and
3-methylbutan-2-one as starting materials.
[0457] .sup.1H NMR (CHLOROFORM-d) .delta. 8.01 (dd, J=8.2, 1.4 Hz,
1H), 7.73-7.77 (m, 1H), 7.50-7.60 (m, 1H), 7.46 (t, J=1.6 Hz, 1H),
7.31-7.37 (m, 2H), 7.21 (s, 1H), 6.60 (dd, J=1.6, 0.6 Hz, 1H), 4.71
(br. s., 1H), 4.25 (br. s., 1H), 4.07 (d, J=13.3 Hz, 1H), 3.98 (d,
J=13.8 Hz, 1H), 3.71 (br. s., 1H), 3.45-3.56 (m, 1H), 3.15-3.26 (m,
1H), 3.06 (dt, J=13.7, 6.8 Hz, 1H), 1.32-1.37 (m, 9H). LC-MS: m/z
432.2 (M+H).sup.+.
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-4-o-tolyln-
icotinonitrile (Compound 158)
[0458] Compound 158 was synthesized using 2-methylbenzaldehyde and
3-methylbutan-2-one as starting materials.
[0459] .sup.1H NMR (CHLOROFORM-d) .delta. 7.72-7.79 (m, 1H), 7.47
(t, J=1.6 Hz, 1H), 7.29-7.40 (m, 3H), 7.19 (d, J=6.8 Hz, 1H), 6.65
(s, 1H), 6.60 (dd, J=1.9, 0.9 Hz, 1H), 4.75 (br. s., 1H), 4.17-4.46
(m, 3H), 3.42-3.67 (m, 1H), 3.34 (dd, J=13.1, 3.5 Hz, 1H), 3.16
(td, J=12.5, 3.5 Hz, 1H), 2.92-3.03 (m, 1H), 2.24 (s, 3H), 1.45 (d,
J=6.3 Hz, 3H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 429.1
(M+H).sup.+.
2-(4-(furan-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicoti-
nonitrile (Compound 160)
[0460] .sup.1H NMR (CHLOROFORM-d) .delta. 7.69 (br. s., 1H), 7.64
(s, 1H), 7.45 (br. s., 2H), 7.36-7.44 (m, 4H), 7.31 (br. s., 2H),
7.16-7.26 (m, 3H), 6.57 (br. s., 1H), 5.37 (br. s., 1H), 4.15 (d,
J=9.8 Hz, 2H), 3.96 (d, J=8.8 Hz, 4H), 2.98-3.12 (m, 1H), 1.13 (d,
J=6.8 Hz, 6H). LC-MS: m/z 477.2 (M+H).sup.+.
(R)-2-(3-cyano-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-isopropyl-
pyridin-4-yl)phenyl acetate (Compound 162)
[0461] Compound 162 was synthesized from
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6-
-isopropylnicotinonitrile (Compound 157) by reaction with acetyl
chloride.
[0462] .sup.1H NMR (METHANOL-d.sub.4) .delta. 7.76 (s, 1H),
7.39-7.58 (m, 3H), 7.31 (t, J=1.9 Hz, 1H), 7.24 (dd, J=7.7, 1.9 Hz,
1H), 6.78 (s, 1H), 6.61 (d, J=1.3 Hz, 1H), 4.76 (br. s., 1H),
4.17-4.44 (m, 3H), 3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.4 Hz,
1H), 3.17 (td, J=12.5, 3.5 Hz, 1H), 2.93-3.06 (m, 1H), 2.27-2.43
(m, 3H), 1.46 (d, J=6.8 Hz, 3H), 1.30 (d, J=7.0 Hz, 6H). LC-MS: m/z
473.1 (M+H).sup.+.
(R)-4-(2-ethoxyphenyl)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-6-i-
sopropylnicotinonitrile (Compound 163)
[0463] Compound 163 was synthesized from
(R)-2-(4-(furan-3-carbonyl)-3-methylpiperazin-1-yl)-4-(2-hydroxyphenyl)-6-
-isopropylnicotinonitrile (Compound 157) by treatment with NaH/DMF
followed by ethyl bromide quench.
[0464] .sup.1H NMR (METHANOL-d.sub.4) .delta. 7.76 (s, 1H),
7.37-7.51 (m, 2H), 6.98-7.16 (m, 3H), 6.79 (s, 1H), 6.57-6.64 (m,
1H), 4.76 (br. s., 1H), 4.17-4.45 (m, 3H), 4.12 (q, J=7.0 Hz, 2H),
3.56 (br. s., 1H), 3.34 (dd, J=12.9, 3.6 Hz, 1H), 3.17 (td, J=12.4,
3.3 Hz, 1H), 3.00 (quin, J=6.9 Hz, 1H), 1.47 (dt, J=6.8, 3.5 Hz,
6H), 1.30 (d, J=6.8 Hz, 6H). LC-MS: m/z 459.1 (M+H).sup.+.
2-(4-(furan-2-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-4-phenylnicoti-
nonitrile (Compound 167)
[0465] .sup.1H NMR (CHLOROFORM-d) .delta. 7.64 (s, 1H), 7.52 (s,
1H), 7.36-7.48 (m, 5H), 7.31 (br. s., 2H), 7.22 (d, J=6.5 Hz, 3H),
7.07 (d, J=3.0 Hz, 1H), 6.52 (br. s., 1H), 5.37-5.59 (br. s., 1H),
4.17 (br. s., 3H), 3.98 (br. s., 2H), 3.92 (br. s., 1H), 3.00-3.12
(m, 1H), 1.13 (d, J=6.5 Hz, 3H), 0.79 (br. s., 3H). LC-MS: m/z
477.1 (M+H).sup.+.
2-(4-(1H-indole-3-carbonyl)-2-phenylpiperazin-1-yl)-6-isopropyl-4-phenylni-
cotinonitrile (Compound 169)
[0466] .sup.1H NMR (CHLOROFORM-d) .delta. 9.00 (br. s., 1H), 7.71
(d, J=6.3 Hz, 1H), 7.64 (s, 1H), 7.42 (d, J=7.3 Hz, 6H), 7.24-7.34
(m, 4H), 7.22 (d, J=6.3 Hz, 4H), 5.53 (br. s., 1H), 4.13-4.35 (m,
2H), 4.01 (br. s., 2H), 3.76-3.96 (m, 2H), 3.00-3.13 (m, 1H), 1.14
(d, J=6.5 Hz, 3H), 0.80 (d, J=6.5 Hz, 3H). LC-MS: m/z 526.1
(M+H).sup.+.
Example 11
Preparation of (R)-methyl
5-(4-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazi-
n-1-yl)nicotinate (Compound 244)
[0467] Compound 244 was prepared according to Scheme 8.
##STR00749## ##STR00750##
Step 1:
(R)-5-bromo-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin--
1-yl)nicotinonitrile (58)
[0468] To a solution of
(R)-5-bromo-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(6; Example 1; 1 g, 3.10 mmol) and triethylamine (375 mg, 3.72
mmol) in 20 mL THF was added 1-(chloromethyl)-4-methoxybenzene (485
mg, 3.10 mmol) dropwise at 0.degree. C. The reaction mixture was
stirred at 0.degree. C. for 4 hrs before warmed up to room
temperature and quenched by adding 20 mL of water. Solvent was
removed under reduced pressure and the residue was extracted with
EtOAc (3.times.20 mL). The combined organic layer was then washed
with brine, dried over anhy. Na.sub.2SO.sub.4 and concentrated in
vacuo. Flash column chromatography separation (20% EtOAc/petroleum
ether) then afforded 1.3 g of 58 as thick brown oil. MS (ES) M+H
expected 443.1, found 443.2
Step 2:
(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methyl-
piperazin-1-yl)nicotinonitrile (59)
[0469] To a solution of
(R)-5-bromo-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methylpiperazin-1-yl)-ni-
cotinonitrile (58; 1 g, 2.18 mmol) and 4-fluorophenylboronic acid
(610 mg, 4.36 mmol) in 5 mL of DMF was added Pd(PPh.sub.3).sub.4
(340 mg 0.218 mmol) and K.sub.2CO.sub.3 (360 mg, 2.62 mmol) under
nitrogen protection. The reaction was subjected to microwave
reaction at 150.degree. C. for 1 hour. After dilution with 20 mL of
water, the mixture was extracted with EtOAc (3.times.20 mL). The
combined organic layer was washed with brine, dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Flash column
chromatography separation (20% EtOAc/petroleum ether) then afforded
600 mg of 59 as thick brown oil. MS (ES) M+H expected 459.3, found
459.2.
Step 3:
(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methyl-
piperazin-1-yl)nicotinic acid (60)
[0470] To a solution of
(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-methyl-pipera-
zin-1-yl)nicotinonitrile (600 mg, 1.31 mmol) in 20 mL of ethanol
was added 20 mL 50% aq. NaOH solution. The reaction mixture was
heated to 120.degree. C. overnight, and then acidified with 2N aq.
HCl to pH<6. Ethanol was removed under reduced pressure and the
residue was washed with water several times and filtered. After
air-drying, 500 mg of crude title compound was obtained as a
yellowish solid. MS (ES) M+H expected 478.2, found 478.2.
Step 4:
(R)-methyl-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3-
-methylpiperazin-1-yl)nicotinate (61)
[0471] To a 25 mL of round-bottom flask was charged with 10 mL of
methanol. After cooling at 0.degree. C., 1 mL of thionyl chloride
was added dropwise and the solution was stirred at room temperature
for 30 min, before adding
(R)-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxy-benzyl)-3-methylpipera-
zin-1-yl)nicotinic acid (500 mg, 1.05 mmol) slowly. The resulting
mixture was then heated to reflux temperature for 2 hrs. After
removing the volatile under reduced pressure, 500 mg of crude title
compound was obtained and used without further purification. MS
(ES) M+H expected 492.3, found 492.2.
Step 5: (R)-methyl
5-(4-fluorophenyl)-6-isopropyl-2-(3-methylpiperazin-1-yl)nicotinate
(62)
[0472]
(R)-methyl-5-(4-fluorophenyl)-6-isopropyl-2-(4-(4-methoxybenzyl)-3--
methylpiperazin-1-yl)nicotinate (61; 500 mg, 1.02 mmol) was
dissolved in 15 mL of 2,2,2-trifluoroacetic acid. The mixture was
heated to reflux overnight. After removal of excess of TFA under
reduced pressure, the residue was re-dissolved in methylene
chloride and washed with satd. NaHCO.sub.3, brine. The organic
layer was then dried over anhy. Na.sub.2SO.sub.4, and concentrated
in vacuo. 300 mg of title compound was obtained as yellowish oil
and used subsequently without further purification. MS (ES) M+H
expected 372.2, found 372.2.
Step 6: (R)-methyl
5-(4-fluorophenyl)-6-isopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazi-
n-1-yl)nicotinate (Compound 244)
[0473] .sup.1H NMR (CHLOROFORM-d) .delta. 7.84 (s, 1H), 7.20-7.25
(m, 2H), 7.06-7.15 (m, 2H), 4.86 (br. s., 0.5H), 4.43 (d, J=12.5
Hz, 0.5H), 4.21 (d, J=6.0 Hz, 0.5H), 3.92 (d, J=13.1 Hz, 0.5H),
3.87 (s, 3H), 3.81 (d, J=16.3 Hz, 1H), 3.74 (t, J=6.7 Hz, 3H), 3.64
(br. s., 1H), 3.37 (s, 3H), 3.18-3.34 (m, 1H), 2.96-3.15 (m, 2H),
2.64-2.80 (m, 1H), 2.60 (br. s., 1H), 1.34-1.40 (m, 1.5H),
1.29-1.32 (m, 1.5H), 1.17 (d, J=6.8 Hz, 3H), 1.12 (d, J=6.5 Hz,
3H). LC-MS: m/z 458.2 (M+H).sup.+.
Example 12
Assays for IDH1 R132H Inhibitors
[0474] Assays were conducted in a volume of 76 .mu.l assay buffer
(150 mM NaCl, 10 mM MgCl.sub.2, 20 mM Tris pH 7.5, 0.03% bovine
serum albumin) as follows in a standard 384-well plate: To 25 ul of
substrate mix (8 uM NADPH, 2 mM aKG), 1 .mu.l of test compound was
added in DMSO. The plate was centrifuged briefly, and then 25 .mu.l
of enzyme mix was added (0.2 .mu.g/ml IDH1 R132H) followed by a
brief centrifugation and shake at 100 RPM. The reaction was
incubated for 50 minutes at room temperature, then 25 .mu.l of
detection mix (30 .mu.M resazurin, 36 .mu.g/ml) was added and the
mixture further incubated for 5 minutes at room temperature. The
conversion of resazurin to resorufin was detected by fluorescent
spectroscopy at Ex544 Em590 c/o 590.
[0475] Certain of the compounds of Formula I set forth in Tables 1
and 5 were tested in this assay and the results set forth below in
Table 3. As used in Table 3, "A" refers to an inhibitory activity
against IDH1 R132H with an IC.sub.50.ltoreq.1.0 .mu.M; "B" refers
to an inhibitory activity against IDH1 R132H with an IC.sub.50
greater than 1 .mu.M and .ltoreq.5 .mu.M; "C" refers to an
inhibitory activity against IDH1 R132H with an IC.sub.50 greater
than 5 .mu.M and .ltoreq.15 .mu.M.
TABLE-US-00005 TABLE 3 IDH1 R132H Inhibition by Compounds of
Formula I. Cmpd No. IC.sub.50 100 C 101 B 102 B 103 C 104 C 105 B
106 C 107 B 108 C 109 C 110 B 111 C 113 C 114 B 115 B 116 C 117 C
118 C 119 C 120 B 121 C 122 C 123 C 124 C 125 C 126 B 127 C 128 B
129 C 130 B 131 B 132 B 133 B 134 B 135 B 136 C 137 C 138 B 139 B
140 B 141 C 142 B 143 B 144 B 145 B 146 C 147 C 148 B 149 B 150 B
151 B 152 B 153 C 154 C 155 C 156 B 157 C 158 B 159 C 160 C 161 B
162 B 163 B 164 B 165 B 166 C 167 B 168 B 169 B 170 B 171 B 172 C
173 B 174 B 175 B 176 B 177 B 178 B 179 B 180 B 181 B 182 A 183 B
184 B 185 B 187 A 188 B 189 B 190 C 191 A 192 B 193 B 195 B 196 B
197 B 198 B 199 B 200 B 201 B 202 B 203 B 204 B 205 B 206 B 207 A
208 B 209 B 210 C 211 B 212 A 213 B 214 B 215 B 216 B 217 B 218 B
219 A 220 B 221 B 222 A 223 A 224 A 225 A 226 A 227 A 228 B 229 A
230 B 231 B 232 B 233 B 234 A 235 A 236 A 237 B 238 B 239 B 240 B
241 A 242 A 243 A 244 B 245 B 246 A 247 B 248 A 249 A 250 A 251 A
252 A 253 A 254 B 255 A 256 A 257 A 258 A 259 A 260 A 261 A 262
A
[0476] Certain of the compounds of Formula I set forth in Table 5
were tested in this assay and the assay in Example 13 and the
results set forth below in Table 4. As used in Table 4, "A1" refers
to an inhibitory activity against IDH1 R132H with an
IC.sub.50.ltoreq.0.5 .mu.M or an IC.sub.50 for inhibition of 2-HG
production .ltoreq.0.5 .mu.M; "B1" refers to an inhibitory activity
against IDH1 R132H with an IC.sub.50 greater than 0.5 .mu.M and
.ltoreq.1 .mu.M or an IC.sub.50 for inhibition of 2-HG production
greater than 0.5 .mu.M and .ltoreq.1 .mu.M; "C1" refers to an
inhibitory activity against IDH1 R132H with an IC.sub.50 greater
than 1 .mu.M and .ltoreq.10 .mu.M or an IC.sub.50 for inhibition of
2-HG production greater than 1 .mu.M and .ltoreq.10 .mu.M; and "D1"
refers to an inhibitory activity against IDH1 R132H with an
IC.sub.50 greater than 10 .mu.M or an IC.sub.50 for inhibition of
2-HG production greater than 10 .mu.M.
TABLE-US-00006 TABLE 4 IDH1R 132H HT1080 Cmpd IC50 IC50 U87R132H
No. (.mu.M) (.mu.M) IC50 (.mu.M) 263 A1 B1 C1 264 B1 C1 C1 265 A1
C1 C1 266 A1 C1 C1 267 B1 C1 C1 268 B1 C1 C1 269 A1 C1 C1 270 B1 C1
C1 271 A1 C1 C1 272 B1 C1 C1 273 B1 274 B1 C1 C1 275 A1 C1 C1 276
A1 C1 C1 277 A1 C1 C1 278 B1 C1 C1 279 B1 C1 C1 280 A1 C1 C1 281 B1
282 B1 283 A1 B1 C1 284 B1 285 A1 B1 C1 286 A1 A1 A1 287 A1 C1 C1
288 A1 A1 A1 289 A1 290 A1 291 B1 292 A1 B1 C1 293 A1 C1 C1 294 A1
B1 B1 295 A1 B1 B1 296 A1 B1 B1 297 A1 B1 C1 298 B1 299 A1 B1 B1
300 B1 301 A1 C1 C1 302 A1 C1 C1 303 A1 C1 C1 304 A1 C1 B1 305 B1
306 B1 307 A1 C1 C1 308 A1 C1 C1 309 A1 B1 B1 310 B1 311 B1 312 A1
B1 C1 313 A1 C1 B1 314 B1 315 A1 A1 B1 316 B1 317 B1 318 A1 319 A1
320 A1 B1 A1 321 A1 B1 A1 322 A1 323 A1 B1 B1 324 B1 325 A1 A1 A1
326 A1 B1 A1 327 B1 328 A1 329 B1 330 A1 A1 A1 331 A1 332 B1 333 A1
334 B1 335 A1 B1 A1 336 B1 337 B1 338 A1 339 B1 340 A1 B1 B1 341 A1
342 A1 A1 A1 343 A1 A1 A1 344 B1 345 A1 C1 B1 346 A1 C1 B1 347 A1
A1 A1 348 A1 349 B1 350 A1 C1 B1 351 A1 C1 B1 352 A1 C1 B1 353 A1
B1 B1 354 B1 355 B1 356 A1 C1 C1 357 B1 358 A1 359 A1 360 A1 C1 C1
361 A1 C1 B1 362 A1 363 A1 C1 B1 364 A1 B1 A1 365 366 367 368 B1
369 B1 370 B1 371 B1 372 A1 373 A1 C1 B1 374 A1 C1 B1 375 B1 376 A1
C1 B1 377 A1 B1 A1 378 A1 379 B1 380 A1 B1 B1 381 A1 A1 A1 382 A1
A1 B1 383 A1 C1 C1 384 A1 B1 B1 385 B1 386 A1 C1 B1 387 A1 A1 A1
388 A1 C1 B1 389 A1 A1 A1 390 A1 A1 A1 391 A1 B1 B1 392 A1 393 A1
C1 B1 394 B1 395 B1 396 A1 397 A1 398 A1 C1 B1 399 B1 400 B1 C1 C1
401 B1 C1 C1 402 A1 403 A1 B1 B1 404 B1 405 A1 406 A1 C1 C1 407 A1
A1 A1 408 A1 B1 A1 409 A1 A1 A1 410 A1 A1 A1 411 A1 B1 B1 412 A1 C1
B1 413 B1 414 B1 415 A1 C1 C1 416 B1 C1 B1 417 A1 A1 A1 418 A1 A1
A1 419 A1 A1 A1 420 A1 C1 C1 421 B1 422 B1 423 B1 424 A1 B1 B1 425
B1 C1 C1 426 B1 C1 C1 427 A1 A1 A1 428 A1 A1 B1 429 A1 C1 C1 430 C1
431 B1 B1 B1 432 B1 C1 C1 433 A1 A1 A1 434 A1 C1 C1 435 B1 436 A1
B1 B1 437 B1 438 A1 C1 B1 439 A1 A1 440 A1 441 B1 442 A1 A1 A1 443
A1 A1 A1 444 A1 A1 A1 445 A1 C1 446 A1 A1 C1 447 B1 C1 C1 448 A1 C1
C1 449 B1 C1 C1 450 B1 451 A1 C1 C1 452 A1 C1 C1 453 A1 B1 A1 454
A1 A1 A1 455 B1 456 A1 A1 A1 457 A1 B1 B1 458 A1 B1 B1 459 A1 A1 A1
460 A1 461 B1 462 B1 C1 C1 463 A1 C1 C1 464 B1 465 B1 466 A1 C1 B1
467 B1 468 A1 C1 C1 469 A1 C1 C1 470 A1 C1 C1 471 A1 472 A1 A1 A1
473 A1 C1 B1 474 A1 / 475 A1 B1 A1 476 A1 B1 A1 477 B1 478 B1 479
B1 480 A1 A1 A1 481 A1 A1 A1 482 A1 483 A1 C1 B1 484 B1 485 A1 A1
A1 486 B1 487 A1 488 A1 A1 B1 489 B1 490 B1 491 A1 B1 492 B1 B1 493
B1 494 A1 495 B1 496 B1 B1 A1 497 A1 498 A1 A1 A1 499 B1 C1 C1 500
A1 A1 A1 501 B1 502 B1 503 A1 504 B1 505 A1
506 B1 507 B1 508 A1 A1 A1 509 B1 510 B1 511 A1 B1 512 A1 513 B1
514 A1 A1 515 B1 C1 516 A1 B1 517 A1 B1 518 A1 A1 A1 519 B1 520 B1
A1 521 A1 522 B1 C1 523 B1 524 A1 525 A1 526 B1 A1 A1 527 A1 A1 A1
528 A1 B1 A1 529 A1 B1 530 A1 A1 A1 531 A1 532 A1 533 B1 C1 534 A1
535 A1 A1 536 A1 A1 537 A1 B1 538 A1 539 A1 C1 540 A1 541 A1 A1 A1
542 A1 A1 A1 543 B1 544 A1 B1 545 B1 546 A1 A1 A1 547 A1 A1 A1 548
B1 549 A1 550 B1 A1 A1 551 A1 A1 A1 552 A1 553 A1 A1 554 A1 555 A1
B1 556 A1 557 A1 B1 558 A1 A1 A1 559 A1 C1 560 A1 C1 561 A1 A1 A1
562 A1 A1 A1 563 A1 A1 564 A1 565 A1 B1 B1 566 A1 B1 567 B1 568 A1
A1 A1 569 A1 A1 570 A1 A1 571 A1 A1 572 A1 A1 573 A1 A1 A1 574 A1
A1 575 A1 A1 576 B1 A1 577 A1 A1 578 A1 A1 579 A1 A1 A1 580 A1 A1
A1 581 A1 A1 A1 582 A1 C1 583 B1 584 B1 585 A1 A1 A1 586 A1 587 A1
A1 A1 588 A1 A1 589 A1 A1 A1 590 A1 A1 A1 591 A1 A1 A1 592 A1 A1 A1
593 B1 594 A1 A1 595 A1 A1 A1 596 A1 A1 597 A1 A1 A1 598 A1 B1 599
A1 A1 A1 600 B1 B1 601 A1 602 A1 A1 603 A1 A1 A1 604 A1 A1 605 A1
A1 A1 606 A1 A1 607 A1 A1 608 A1 A1 A1 609 A1 A1 A1 610 A1 A1 A1
611 A1 A1 A1 612 A1 A1 A1 613 A1 A1 A1 614 A1 615 A1 A1 A1 616 A1
617 A1 A1 A1 618 A1 A1 A1 619 A1 A1 620 A1 A1 621 A1 A1 B1 622 B1
C1 623 B1 624 A1 A1 625 A1 A1 A1 626 A1 A1 A1 627 A1 A1 A1 628 A1
A1 A1 629 A1 A1 A1 630 B1 631 A1 A1 A1 632 A1 633 A1 A1 A1 634 A1
A1 A1 635 A1 A1 A1 636 A1 A1 A1 637 A1 A1 A1 638 A1 A1 A1 639 A1 A1
A1 640 A1 641 A1 642 A1 A1 A1 643 A1 A1 B1 644 A1 A1 A1 645 A1 A1
A1 646 A1 647 A1 A1 A1 648 A1 A1 A1 649 A1 A1 A1 650 A1 A1 651 A1
A1 652 A1 A1 A1 653 A1 A1 654 A1 A1 A1 655 A1 A1 656 B1 657 A1 A1
A1 658 A1 A1 659 A1 660 A1 A1 A1 661 A1 662 A1 A1 663 A1 A1 A1 664
A1 A1 665 A1 666 A1 A1 A1 667 A1 A1 A1 668 A1 B1 669 A1 A1 670 A1
A1 A1 671 A1 672 B1 C1 673 B1 674 A1 A1 A1 675 A1 C1 B1 676 A1 A1
A1 677 A1 A1 678 A1 A1 A1 679 A1 A1 680 A1 A1 681 A1 A1 A1 682 A1
683 A1 684 A1 A1 685 C1 686 A1 A1 A1 687 A1 B1 688 A1 A1 A1 689 A1
A1 A1 690 A1 A1 A1 691 A1 A1 A1 692 A1 A1 A1 693 A1 A1 A1 694 A1 B1
A1 695 A1 A1 A1 696 A1 A1 A1 697 A1 A1 A1 698 A1 A1 A1 699 A1 700
A1 A1 701 A1 702 A1 C1 C1 703 A1 A1 A1 704 A1 705 A1 A1 A1 706 A1
A1 A1 707 A1 A1 A1 708 A1 C1 709 A1 A1 A1 710 A1 A1 A1 711 A1 A1 A1
712 A1 C1 713 A1 A1 A1 714 A1 A1 A1 715 A1 A1 A1 716 A1 A1 A1 717
A1 A1 A1 718 A1 B1 A1 719 A1 A1 A1 720 A1 A1 A1 721 A1 A1 A1 722 A1
A1 A1 723 A1 724 A1 A1 A1 725 A1 A1 A1 726 A1 A1 A1 727 A1 A1 A1
728 A1 A1 A1 729 A1 730 A1 A1 A1 731 A1 732 A1 A1 A1 733 A1 B1 A1
734 A1 735 A1 A1 A1 736 A1 A1 A1 737 A1 B1 B1 738 A1 A1 A1 739 A1
740 A1 A1 A1 741 A1 A1 A1 742 A1 A1 A1 743 A1 A1 A1 744 A1 A1 A1
745 A1 A1 A1 746 A1 A1 A1 747 A1 A1 A1 748 A1 A1 A1 749 A1 A1 A1
750 A1 A1 A1 751 A1 A1 A1 752 A1 A1 A1 753 A1 A1 A1 754 A1 A1 A1
755 A1 A1 A1 756 A1 A1 A1
757 A1 A1 758 A1 A1 759 A1 A1 760 A1 A1 A1 761 A1 A1 A1 762 A1 A1
A1 763 A1 A1 A1 764 A1 A1 A1 765 A1 A1 A1 766 A1 A1 A1 767 A1 A1 A1
768 A1 A1 A1 769 A1 A1 A1 770 A1 A1 A1 771 A1 A1 A1 772 B1 773 A1
A1 774 A1 A1 A1 775 A1 A1 A1 776 A1 A1 A1 777 A1 A1 A1 778 A1 A1 A1
779 C1 780 A1 781 A1 A1 A1 782 A1 A1 A1 783 A1 A1 784 A1 A1 A1 785
A1 A1 A1 786 A1 A1 A1 787 A1 A1 A1 788 A1 A1 A1 789 A1 A1 A1 790 A1
791 A1 792 A1 C1 C1 793 A1 A1 A1 794 A1 A1 A1 795 A1 796 A1 A1 A1
797 A1 A1 A1 798 A1 799 A1 A1 A1 800 A1 A1 A1 801 A1 A1 A1 802 A1
803 A1 A1 A1 804 A1 A1 B1 805 A1 A1 A1 806 A1 A1 A1 807 A1 A1 808
A1 A1 809 A1 A1 810 B1 A1 A1 811 A1 A1 A1 812 A1 A1 A1 813 A1 A1 A1
814 B1 815 A1 A1 816 B1 817 A1 A1 818 A1 A1 819 A1 A1 820 A1 821 A1
822 A1 A1 823 A1 A1 824 A1 825 A1 826 A1 827 A1 828 A1 829 A1 830
A1
[0477] In some embodiments, the invention provides a compound
selected from any one of compound numbers 182, 187, 191, 207, 212,
219, 222, 223, 224, 225, 226, 227, 229, 234, 235, 236, 241, 242,
243, 246, 248, 249, 250, 251, 252, 253, 255, 256, 257, 258, 259,
260, 261, and 262.
[0478] In some embodiments, the invention provides a compound
selected from any one of compound numbers 263, 265, 266, 269, 271,
275, 276, 277, 280, 283, 285, 286, 287, 288, 289, 290, 292, 293,
294, 295, 296, 297, 299, 301, 302, 303, 304, 307, 308, 309, 312,
313, 315, 318, 319, 320, 321, 322, 323, 325, 326, 328, 330, 331,
333, 335, 338, 340, 341, 342, 343, 345, 346, 347, 348, 350, 351,
352, 353, 356, 358, 359, 360, 361, 362, 363, 364, 372, 373, 374,
376, 377, 378, 380, 381, 382, 383, 384, 386, 387, 388, 389, 390,
391, 392, 393, 396, 397, 398, 402, 403, 405, 406, 407, 408, 409,
410, 411, 412, 415, 417, 418, 419, 420, 424, 427, 428, 429, 433,
434, 436, 438, 439, 440, 442, 443, 444, 445, 446, 448, 451, 452,
453, 454, 456, 457, 458, 459, 460, 463, 466, 468, 469, 470, 471,
472, 473, 474, 475, 476, 480, 481, 482, 483, 485, 487, 488, 491,
494, 497, 498, 500, 503, 505, 508, 511, 512, 514, 516, 517, 518,
521, 524, 525, 527, 528, 529, 530, 531, 532, 534, 535, 536, 537,
538, 539, 540, 541, 542, 544, 546, 547, 549, 551, 552, 553, 554,
555, 556, 557, 558, 559, 560, 561, 562, 563, 564, 565, 566, 568,
569, 570, 571, 572, 573, 574, 575, 577, 578, 579, 580, 581, 582,
585, 586, 587, 588, 589, 590, 591, 592, 594, 595, 596, 597, 598,
599, 601, 602, 603, 604, 605, 606, 607, 608, 609, 610, 611, 612,
613, 614, 615, 616, 617, 618, 619, 620, 621, 624, 625, 626, 627,
628, 629, 631, 632, 633, 634, 635, 636, 637, 638, 639, 640, 641,
642, 643, 644, 645, 646, 647, 648, 649, 650, 651, 652, 653, 654,
655, 657, 658, 659, 660, 661, 662, 663, 664, 665, 666, 667, 668,
669, 670, 671, 674, 675, 676, 677, 678, 679, 680, 681, 682, 683,
684, 686, 687, 688, 689, 690, 691, 692, 693, 694, 695, 696, 697,
698, 699, 701, 702, 703, 704, 705, 706, 707, 708, 709, 710, 711,
712, 713, 714, 715, 716, 717, 718, 719, 720, 721, 722, 723, 724,
725, 726, 727, 728, 729, 730, 731, 732, 733, 734, 735, 736, 737,
738, 739, 740, 741, 742, 743, 744, 745, 746, 747, 748, 749, 750,
751, 752, 753, 754, 755, 756, 757, 758, 759, 760, 761, 762, 763,
764, 765, 766, 767, 768, 769, 770, 771, 773, 774, 775, 776, 777,
778, 780, 781, 782, 784, 785, 786, 787, 788, 789, 790, 791, 792,
793, 794, 795, 796, 797, 798, 799, 800, 801, 802, 803, 804, 805,
806, 807, 808, 809, 811, 812, 813, 815, 817, 818, 819, 820, 821,
822, 823, 824, 825, 826, 827, 828, 829, and 830.
Example 13
Cellular Assays for IDH1m (R132H or R132C) Inhibitors
[0479] Cells (e.g., HT1080 or U87MG) and are grown in T125 flasks
in DMEM containing 10% FBS, 1.times. penicillin/streptomycin and
500 ug/mL G418. They are harvested by trypsin and seeded into 96
well white bottom plates at a density of 5000 cell/well in 100
ul/well in DMEM with 10% FBS. No cells are plates in columns 1 and
12. Cells are incubated overnight at 37.degree. C. in 5% CO2. The
next day compounds are made up at 2.times. concentration and 100 ul
are added to each cell well. The final concentration of DMSO is
0.2% and the DMSO control wells are plated in row G. The plates are
then placed in the incubator for 48 hours. At 48 hours, 100 .mu.l
of media is removed from each well and analyzed by LC-MS for 2-HG
concentrations. The cell plate is placed back in the incubator for
another 24 hours. At 72 hours post compound addition, 10 mL/plate
of Promega Cell Titer Glo reagent is thawed and mixed. The cell
plate is removed from the incubator and allowed to equilibrate to
room temperature. Then 100 ul of reagent is added to each well of
media. The cell plate is then placed on an orbital shaker for 10
minutes and then allowed to sit at room temperature for 20 minutes.
The plate is then read for luminescence with an integration time of
500 ms.
[0480] The IC.sub.50 for inhibition of 2-HG production
(concentration of test compound to reduce 2HG production by 50%
compared to control) in these two cell lines for various compounds
of formula I is set forth in Table 4 above.
Example 14
Preparation of 2,3,5,6-Tetrasubstituted Pyridines
General procedure 1
##STR00751##
[0481] Step A: 1-cyclopropyl-3-(dimethylamino)prop-2-en-1-one
(2)
##STR00752##
[0483] To a solution of 1-cyclopropylethanone (100 g, 1.2 mol) in
anhydrous DMF (1300 mL) Was added DMFDMA (300 g, 2.5 mol). The
resulting mixture was stirred at 100.degree. C. overnight. The
solvent was removed in vacuum to give crude 2 (110 g) as yellow
solid. .sup.1H NMR (CHLOROFORM-d) .delta. 7.56 (d, J=12.8 Hz, 1H),
5.20 (d, J=12.5 Hz, 1H), 2.78-3.08 (m, 6H), 1.79 (tt, J=7.9, 4.5
Hz, 1H), 0.94-1.04 (m, 2H), 0.67-0.80 (m, 2H).
Step B: 6-cyclopropyl-2-hydroxynicotinonitrile (3)
##STR00753##
[0485] To a mixture of 1-cyclopropyl-3-dimethylamino-propenone (315
g, 2.3 mol) and cyanoacetamide (270 g, 2.3 mol) in a buffer
solution of 47.4 mL of acetic acid and 1485 mL of water was added
piperidine to adjust to pH 9. The mixture was then heated at reflux
for 2 hours, cooled and acidified by 6N HCl to pH 5 below 25
degree. The yellow precipitate was filtered, washed with water and
dried to give 3 as a white solid (561 g). MS (ES) M+H expected
161.1, found 161.0. .sup.1H NMR (CHLOROFORM-d) 13.60 (br. s., 1H),
7.77 (d, J=7.8 Hz, 1H), 5.91 (d, J=7.8 Hz, 1H), 1.96-2.12 (m, 1H),
1.29-1.36 (m, 2H), 1.04-1.11 (m, 2H).
Step C: 5-bromo-6-cyclopropyl-2-hydroxynicotinonitrile (4)
##STR00754##
[0487] A mixture of 6-cyclopropyl-2-hydroxynicotinonitrile (561 g,
3.6 mol) and NBS (624 g, 5.4 mol) in DCE (4500 mL) was heated at
reflux for 3 hrs. The mixture was cooled to room temperature and
the precipitate was filtered, washed with water and dried to give
crude 4 (473 g) as a white solid. MS (ES) M+H expected 239.0, found
238.9. .sup.1H NMR (CHLOROFORM-d) .delta. 8.49-8.72 (br. s., 1H),
7.93 (s, 1H), 2.23-2.34 (m, 1H), 1.36-1.42 (m, 2H), 1.29-1.36 (m,
2H).
Step D: 5-bromo-3-cyano-6-cyclopropylpyridin-2-yl
trifluoromethanesulfonate (5)
##STR00755##
[0489] To a 1 L flask were added
5-bromo-4-cyclopropyl-2-hydroxybenzonitrile (47.6 g, 0.2 mol),
pyridine (32 g, 0.4 mol) and Cat. DMAP (500 mg) in DCM (300 mL),
and the mixture was cooled to 0.degree. C., and
trifluoromethanesulfonic anhydride (59 g, 0.21 mol) in DCM (100 mL)
was added dropwise. After addition, the mixture was stirred for
another 1 h. TLC (PE:EtOAc=10:1) showed conversion of starting
material to product. After reaction, diluted with DCM (300 mL), and
washed with 1N HCl. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated in vacuo afforded the title
compound (70 g) as a yellow solid. .sup.1H NMR (CHLOROFORM-d)
.delta. 8.14-8.19 (m, 1H), 2.55-2.66 (m, 1H), 1.30 (dt, J=7.8, 3.1
Hz, 2H), 1.21-1.27 (m, 2H).
Step E: Exemplified by
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(6-1) (R'=methyl)
##STR00756##
[0491] A mixture of above triflate 5 (1.68 g, 4.6 mmol),
(R)-2-methylpiperazine (790 mg, 6.9 mmol), and triethylamine (1.9
mL, 13.8 mmol) suspended in 5 mL of MeCN was heated at 70.degree.
C. for 2 h. After the mixture was concentrated under reduced
pressure, the residue was extracted between ethyl acetate and
water. The combined organic layer was then washed with aq.
NaHCO.sub.3, brine, dried over anhy. Na.sub.2SO.sub.4 and
concentrated in vacuo to give 1.26 g of crude title compound. MS
(ES) M+H expected 321.1, found 321.2. .sup.1H NMR (CHLOROFORM-d)
.delta. 7.78 (s, 1H), 4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H),
3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, J=12.9, 10.2 Hz,
1H), 2.42-2.52 (m, 1H), 1.16 (d, J=6.3 Hz, 3H), 1.08 (s, 2H), 1.07
(d, J=3.8 Hz, 2H).
##STR00757##
[0492]
(R)-5-bromo-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)nicotinonitr-
ile (6-2) (R'=isopropyl) was synthesized by the same procedure
described above except using (R)-2-isopropylpiperazine instead of
(R)-2-methylpiperazine. MS (ES) M+H expected 349.1, found 349.2.
.sup.1H NMR (CHLOROFORM-d) 7.79 (s, 1H), 4.14-4.24 (m, 2H),
3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd,
1H), 2.12-2.22 (m, 1H), 1.26 (d, 6H), 1.08 (d, 2H), 1.07 (d,
2H).
##STR00758##
[0493]
(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)nicotinoni-
trile (6-3) (R'=cyclopropyl) was synthesized by the same procedure
described above except using (R)-2-cyclopropylpiperazine (building
block 1) instead of (R)-2-methylpiperazine. MS (ES) M+H expected
347.1, found 349.1. .sup.1H NMR (CHLOROFORM-d) 7.77 (s, 1H),
4.14-4.24 (m, 2H), 3.09-3.14 (m, 1H), 3.02-3.07 (m, 1H), 2.96-3.00
(m, 2H), 2.71 (dd, 1H), 2.12-2.24 (m, 1H), 1.25 (d, 2H), 1.16 (d,
2H), 1.08 (d, 2H), 1.07 (d, 2H).
Step F, method 1: Exemplified by
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile (7-1) (R'=methyl, R1=c)
##STR00759##
[0495] To a 25 mL of round-bottom flask was added
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(6-1) (1.26 g, 3.9 mmol), 3-methoxypropanoic acid (0.74 mL, 7.8
mmol), HATU (2.98 g, 7.8 mmol), DIPEA (2 mL, 11.76 mmol) and 10 mL
of methylene chloride. The resulting reaction mixture was stirred
at room temperature overnight until TLC showed the completion of
the reaction. Reaction mixture was with satd. NaHCO.sub.3 and
brine. The combined organic layer was then dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Column chromatography
purification (30% EtOAc/petroleum ether) afforded 1.28 g of title
compound as a white solid. MS (ES) M+H expected 407.1, found 407.0.
.sup.1H NMR (CHLOROFORM-d) 7.78-7.85 (m, 1H), 4.82-4.92 (m, 0.5H),
4.50 (d, J=13.6 Hz, 0.5H), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H),
3.75-3.82 (m, 0.5H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 0.5H), 3.36
(s, 3H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H),
2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H),
1.25 (d, J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).
Step F, Method 2: Exemplified by
(R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopr-
opylnicotinonitrile (7-2) (R'=methyl,
##STR00760##
##STR00761##
[0497] To a 25 mL of round-bottom flask was added
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(6-1) (1 g, 3.2 mmol), cyclopropanecarbonyl chloride (0.4 mL, 3.3
mmol), DIPEA (0.4 mL, 3.4 mmol) and 10 mL of methylene chloride.
The resulting reaction mixture was stirred at room temperature
overnight until TLC showed the completion of the reaction. Reaction
mixture was with Satd. NaHCO.sub.3 and brine. The combined organic
layer was then dried over anhy. Na.sub.2SO.sub.4 and concentrated
in vacuo. Column chromatography purification (10% EtOAc/petroleum
ether) afforded 1.1 g of title compound as a white solid. MS (ES)
M+H expected 389.1, found 389.0. .sup.1H NMR (CHLOROFORM-d) 7.85
(s, 1H), 4.18-4.21 (m, 2H), 4.07-4.16 (m, 1H), 3.70-3.75 (m, 2H),
3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61
(m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d,
J=2.5 Hz, 1.5H), 1.25-1.36 (m, 4H), 1.09 (d, 2H), 1.08 (d, 2H).
Step F, method 3: Exemplified by
(R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile (7-3) (R'=methyl,
##STR00762##
##STR00763##
[0499] To a 25 mL of round-bottom flask was added
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(6-1) (2 g, 6.2 mmol), sodium 2-carboxyethanolate (0.70 g, 6.4
mmol), DIPEA (2 mL, 11.5 mmol) and 10 mL of DMF. The resulting
reaction mixture was stirred at room temperature for 5 h until TLC
showed the completion of the reaction. Reaction mixture was washed
with water and brine. The combined organic layer was then dried
over anhy. Na.sub.2SO.sub.4 and concentrated in vacuo. Column
chromatography purification (50% EtOAc/petroleum ether) afforded
1.2 g of title compound as a white solid. MS (ES) M+H expected
393.1, found 393.1. .sup.1H NMR (CHLOROFORM-d) .delta. 7.85 (m,
1H), 4.88-4.97 (m, 0.5H), 4.75 (d, J=13.6 Hz, 0.5H), 4.29-4.48 (m,
2H), 4.11-4.20 (m, 1H), 3.70-3.75 (m, 2H), 3.45-3.55 (m, 2H),
3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78 (m, 1H), 2.51-2.61
(m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz, 1.5H), 1.25 (d,
J=2.5 Hz, 1.5H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).
##STR00764##
[0500]
(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)pi-
perazin-1-yl)nicotinonitrile (7-4) was synthesized by method 1 in
step F except using 6-3 as the starting material instead of 6-1. MS
(ES) M+H expected 433.1, found 433.3.
##STR00765##
[0501]
(R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl-
)-6-cyclopropylnicotinonitrile (7-5) was synthesized by method 2 in
step F except using 6-3 as the starting material instead of 6-1. MS
(ES) M+H expected 415.1, found 415.1.
##STR00766##
[0502]
(R)-5-bromo-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)pi-
perazin-1-yl)nicotinonitrile (7-6) was synthesized by method 3 in
step F except using 6-3 as the starting material instead of 6-1. MS
(ES) M+H expected 419.1, found 419.1. .sup.1H NMR (CHLOROFORM-d)
.delta. 7.85 (m, 1H), 4.87-4.97 (m, 0.5H), 4.77 (d, J=13.6 Hz,
0.5H), 4.29-4.48 (m, 2H), 4.11-4.20 (m, 1H), 3.70-3.75 (m, 2H),
3.45-3.55 (m, 2H), 3.15-3.27 (m, 1H), 2.92-3.14 (m, 1H), 2.67-2.78
(m, 1H), 2.51-2.61 (m, 1H), 2.40-2.51 (m, 1H), 1.34 (d, J=6.8 Hz,
2H), 1.25 (d, 2H), 1.09 (d, J=3.5 Hz, 2H), 1.08 (s, 2H).
##STR00767##
[0503]
(R)-5-bromo-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)pipe-
razin-1-yl)nicotinonitrile (7-7) was synthesized by method 1 in
step F except using 6-2 as the starting material instead of 6-1. MS
(ES) M+H expected 434.1, found 435.1.
##STR00768##
[0504]
(R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpipe-
razin-1-yl)nicotinonitrile (7-8) was synthesized by method 1 in
step F except using 6-2 as the starting material instead of 6-1. MS
(ES) M+H expected 421.1, found 421.6.
Step G, method 1: Exemplified by
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,-
4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (8-1)
(R'=methyl, R1=c)
##STR00769##
[0506] To a solution of
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile (7-1) (747 mg, 1.8 mmol) in DMF (8 mL) was added
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2 dioxaborolane) (563
mg, 2.2 mmol) and KOAc (538 mg, 5.5 mmol). The resulting mixture
was stirred at room temperature for 5 min before addition of
PdCl.sub.2(dppf).CH.sub.2Cl.sub.2 (45 mg, 0.03 mmol). After
flushing with nitrogen, the reaction mixture was heated at
85.degree. C. for 18 hours. After cooling, the reaction mixture was
diluted with water, and extracted with methylene chloride. The
organic layer was then washed with brine, dried over anhy.
Na.sub.2SO.sub.4, and concentrated in vacuo. Column chromatography
(25% EtOAc/petroleum ether) afforded 334 mg of title compound as a
white solid. MS (ES) M+H expected 455.3, found 455.2.
Step G, method 2: Exemplified by
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,-
4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile
(R'=methyl,
##STR00770##
##STR00771##
[0508] 1.4 g of
(R)-5-bromo-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile (7-3) (3.3 mmol), 2.12 g of
4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (8.34
mmol), 0.7 g of KOAc (7.4 mmol), 154 mg of Xphos (0.32 mmol) and
308 mg of Pd.sub.2(dba).sub.3 (0.33 mmol) in 20 mL of dioxane in a
round bottom flask was stirred under N.sub.2 at 75.degree. C.
overnight. Then the mixture was cooled to room temperature.
Concentrated, purified by column chromatography (petroleum ether:
ethyl acetate from 3:1 to 1:1) to give 670 mg of title compound. MS
(ES) M+H expected 441.2, found 441.2.
General procedure 1, Step H: Exemplified by
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(th-
iophen-2-yl)nicotinonitrile (Compound 273)
[0509] A mixture of 7-1 (26 mg, 0.06 mmol), thiophen-2-ylboronic
acid (14 mg, 0.089 mmol), Pd(PPh.sub.3).sub.4 (3 mg, 0.003 mmol),
and K.sub.2CO.sub.3 (16 mg, 0.119 mmol) suspended in 1 mL of DMF
was subjected to microwave reaction at 150.degree. C. for 45 min.
After the reaction was complete, the reaction mixture was
concentrated in vacuo, and the residue was purified by column
Chromatography to afford 19 mg of title compound as yellowish oil.
.sup.1H NMR (CHLOROFORM-d) .delta. 7.70 (s, 1H), 7.38 (dd, J=3.9,
2.4 Hz, 1H), 7.07-7.14 (m, 2H), 4.90 (br. s., 0.5H), 4.52 (d,
J=13.1 Hz, 0.5H), 4.15-4.41 (m, 2.5H), 3.67-3.89 (m, 2.5H),
3.47-3.63 (m, 0.5H), 3.34-3.43 (m, 3H), 3.20-3.33 (m, 1H),
2.99-3.17 (m, 1.5H), 2.63-2.81 (m, 1H), 2.50-2.62 (m, 1H),
2.26-2.36 (m, 1H), 1.37 (d, J=6.3 Hz, 1.5H), 1.27 (d, J=6.8 Hz,
1.5H), 1.10-1.18 (m, 2H), 0.94-1.05 (m, 2H). LC-MS: m/z 411.1
(M+H).sup.+.
Step I: Exemplified
by(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(-
2-vinylquinazolin-5-yl)nicotinonitrile (Compound 603)
[0510] To a solution of 8-1 (95 mg, 0.197 mmol),
5-chloro-2-vinylquinazoline (25 mg, 0.131 mmol), Xphos (7 mg, 0.013
mmol), Pd.sub.2(dba).sub.3 (6 mg, 0.007 mmol) and
K.sub.3PO.sub.4.H.sub.2O (105 mg, 0.393 mmol) was stirred at
100.degree. C. for 16 hours, the mixture was partitioned between
EtOAc and water, the organic was washed with water, brine and
concentrated to give the crude which was purified by column
chromatography to give 25 mg of the product. .sup.1H NMR
(CHLOROFORM-d) .delta. 9.16 (d, J=3.0 Hz, 1H), 8.05 (d, J=8.5 Hz,
1H), 7.95 (dd, J=8.5, 7.3 Hz, 1H), 7.66 (s, 1H), 7.45-7.58 (m, 1H),
7.06 (dd, J=17.2, 10.4 Hz, 1H), 6.80 (dd, J=17.3, 1.5 Hz, 1H),
5.80-5.96 (m, 1H), 4.87-5.02 (m, 0.5H), 4.56 (d, J=12.0 Hz, 0.5H),
4.35-4.44 (m, 2.5H), 3.84 (d, J=12.8 Hz, 0.5H), 3.69-3.79 (m, 2H),
3.52-3.65 (m, 0.5H), 3.30-3.43 (m, 4H), 3.05-3.24 (m, 1.5H),
2.65-2.81 (m, 1H), 2.48-2.64 (m, 1H), 1.50-1.59 (m, 1H), 1.30-1.44
(m, 3H), 1.13-1.22 (m, 2H), 0.84-0.89 (m, 2H). LC-MS: m/z 483.2
(M+H).sup.+
General Procedure 2
##STR00772##
[0511] Step J: Exemplified by (R)-tert-butyl
4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiper-azine-1--
carboxylate (9-1, R'=cyclopropyl)
##STR00773##
[0513] To a solution of 6-3 (1 g, 2.24 mmol) in DCM (8 mL) was
added (Boc).sub.2O (0.5 g, 2.26 mmol) and Et.sub.3N (0.1 mL). The
resultant solution was stirred at room temperature for 2 h. The
reaction mixture was diluted with water. The organic layer was then
washed with brine, dried over anhy. Na.sub.2SO.sub.4, and
concentrated in vacuo to give the title compound as a white solid
(1.5 g), which can be used directly for the next step. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.85 (s, 1H), 4.14-4.24 (m, 2H), 3.29-3.34
(m, 1H), 3.12-3.18 (m, 1H), 2.96-3.00 (m, 2H), 2.71 (dd, 1H),
2.12-2.24 (m, 1H), 1.5 (s, 9H), 1.25 (d, 2H), 1.16 (d, 2H), 1.08
(d, 2H), 1.07 (d, 2H).
Step K: Exemplified by (R)-tert-butyl
4-(5-cyano-2-cyclopropyl-[3,3'-bipyridin]-6-yl)-2-cyclopropyl
piperazine-1-carboxylate (R'=cyclopropyl, R4=3-pyridinyl)
##STR00774##
[0515] To a solution of (R)-tert-butyl
4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-c-
arboxylate (150 mg, 0.33 mmol) in 2 mL of dioxane and 0.5 mL water
was added pyridin-3-ylboronic acid (45.6 mg, 0.37 mmol),
Pd(dppf)Cl2 (24 mg, 0.033 mmol), CsF (100 mg, 0.66 mmol). The
resulting mixture was stirred at 100.degree. C. under N2 atmosphere
and microwaved for 1 h. After TLC showed the complete conversion of
starting material to product, the reaction mixture was concentrated
and purified by column chromatography (20% EtOAc/petroleum ether)
to afford 100 mg title compound. MS (ES) M+H expected 446.2, found
446.3.
Step L: Exemplified by
(R)-2-cyclopropyl-6-(3-cyclopropylpiperazin-1-yl)-[3,3'-bipyridine]-5-car-
bonitrile (R'=cyclopropyl, R4=3-pyridinyl)
##STR00775##
[0517] To a solution of (R)-tert-butyl
4-(5-cyano-2-cyclopropyl-[3,3'-bipyridin]-6-yl)-2-cyclopropyl
piperazine-1-carboxylate (100 mg, 0.22 mmol) in 3 mL of DCM was
added TFA (1 mL). The resulting mixture was stirred at room
temperature for 2 h. After TLC showed the complete conversion of
starting material to product, the reaction mixture was concentrated
and basified with Na.sub.2CO.sub.3 solution to pH=8. Then the
solution was extracted with DCM (10 mL.times.3). The organic layer
was dried and concentrated and purified by Prep-HPLC (5% DCM/MeOH)
to get 70 mg title compound. MS (ES) M+H expected 346.2, found
346.2.
General Procedure 2, Step M: Exemplified by
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin--
1-yl)-[3,3'-bipyridine]-5-carbonitrile (Compound 524)
[0518] To a solution of
(R)-2-cyclopropyl-6-(3-cyclopropylpiperazin-1-yl)-[3,3'-bipyridine]-5-car-
bonitrile (70 mg, 0.2 mmol) in 10 mL DCM was added
3,3,3-trifluoropropanoic acid (31 mg, 0.24 mmol), and triethylamine
(1 mL), HOBT (54 mg, 0.4 mmol), EDCI (76.8 mg, 0.4 mmol). The
resulting reaction mixture was stirred at r.t. overnight. After TLC
showed the complete conversion of starting material to product, the
reaction mixture was concentrated and purified by Prep-HPLC (50%
EtOAc/petroleum ether) to get 25 mg title compound. .sup.1H NMR
(CHLOROFORM-d) .delta. 8.56-8.77 (m, 2H), 7.77 (d, J=7.8 Hz, 1H),
7.65 (s, 1H), 7.44 (dd, J=7.7, 4.9 Hz, 1H), 4.56 (d, J=13.1 Hz,
1H), 4.44 (d, J=13.1 Hz, 1H), 4.12 (br. s., 1H), 3.63-3.86 (m, 2H),
3.32 (d, J=9.3 Hz, 2H), 3.20 (d, J=13.1 Hz, 1H), 3.11 (d, J=11.8
Hz, 1H), 1.99 (td, J=8.0, 3.8 Hz, 1H), 1.11-1.23 (m, 3H), 1.01 (dd,
J=7.5, 3.5 Hz, 2H), 0.77-0.95 (m, 2H), 0.66 (br. s., 1H), 0.50 (d,
J=5.0 Hz, 2H) LC-MS: m/z 4 456.4 (M+H).sup.+.
General Procedure 3
##STR00776##
[0519] Method 1: Exemplified by
(R)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-meth-
ylpiperazin-1-yl)pyridin-3-yl)phenyl)acetamide (Compound 403)
(R''=H,
##STR00777##
[0521] To a solution of
(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methyl
piperazin-1-yl)nicotinonitrile (50 mg, 0.119 mmol) and
2-chloroacetyl chloride (15 mg, 0.131 mmol) in 2 ml of DCM was
added dropwise TEA (24 mg, 0.238 mmol) at 0.degree. C., then the
mixture was allowed to warm to room temperature and stirred for 2
hours. The mixture was partitioned between EtOAc and water. The
organic layer was dried over Na.sub.2SO.sub.4 and concentrated to
give the crude which was purified by prep-TLC to give 20 mg of the
product. .sup.1H NMR (CHLOROFORM-d) .delta. 8.34 (s, 1H), 7.66-7.75
(m, 1H), 7.62 (s, 1H), 7.50-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.22
(d, J=7.8 Hz, 1H), 4.92 (s, 0.5H), 4.50-4.54 (m, 0.5H), 4.29-4.33
(m, 1H), 4.26 (m, 1H), 4.21-4.25 (m, 0.5H), 3.71-3.84 (m, 2.5H),
3.52-3.57 (m, 0.5H), 3.39 (s, 3H), 3.21-3.32 (m, 1H), 3.13 (d,
J=11.3 Hz, 1H), 3.05 (d, J=12.3 Hz, 0.5H), 2.66-2.81 (m, 1H),
2.54-2.65 (m, 1H), 2.07-2.12 (m, 1H), 1.40 (d, J=6.3 Hz, 1H),
1.28-1.31 (m, 2H), 1.14-1.19 (m, 2H), 0.94-1.00 (m, 2H). LC-MS: m/z
496.2 (M+H).sup.+.
Method 2: Exemplified by
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)pyridin-3-yl)phenyl)propionamide (Compound 424)
[0522] To a 25 mL of round-bottom flask was added
(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methyl
piperazin-1-yl)nicotinonitrile (50 mg, 0.119 mmol), propionic acid
(0.1 mL), HATU (20 mg), DIPEA (0.05 mL) and 10 mL of methylene
chloride. The resulting reaction mixture was stirred at room
temperature overnight until TLC showed the completion of the
reaction. Reaction mixture was with satd. NaHCO.sub.3 and brine.
The combined organic layer was then dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Column chromatography
purification (30% EtOAc/petroleum ether) afforded 45 mg of title
compound as a white solid. .sup.1H NMR (CHLOROFORM-d) 7.75 (s, 1H),
7.68 (s, 1H), 7.59 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.37 (t, J=7.8
Hz, 1H), 7.11 (d, J=7.5 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J=13.3
Hz, 0.5H), 4.14-4.35 (m, 2.5H), 3.67-3.85 (m, 2.5H), 3.49-3.62 (m,
0.5H), 3.37 (s, 3H), 3.17-3.32 (m, 1H), 2.93-3.17 (m, 1.5H),
2.63-2.81 (m, 1H), 2.52-2.63 (m, 1H), 2.37-2.49 (m, 2H), 2.05-2.13
(m, 1H), 1.38 (d, J=6.5 Hz, 1H), 1.22-1.31 (m, 5H), 1.14 (dt,
J=7.4, 3.6 Hz, 2H), 0.88-1.01 (m, 2H). LC-MS: m/z 476.3
(M+H).sup.+.
General Procedure 4
##STR00778## ##STR00779##
[0523] Step O: 5-bromo-3-cyano-6-cyclopropylpyridin-2-yl
4-methylbenzenesulfonate (10)
[0524] To a solution of 4 (2.37 g, 10 mmol) in THF (20 mL) was
added TsCl (1.9 g, 11 mmol) and Et.sub.3N (1 mL). The reaction was
stirred at room temperature for 2 h. The resultant solution was
partitioned between DCM and water. The organic layer was dried over
Na.sub.2SO.sub.4 and concentrated to give the crude which was
purified by column chromatography to give 2.6 g of 10. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.86 (s, 1H), 7.35-7.46 (m, 2H), 7.11-7.25
(m, 2H), 1.99-2.17 (m, 1H), 1.21-1.38 (m, 2H), 1.00-1.20 (m, 2H).
LC-MS: m/z 393.0 (M+H).sup.+.
Step P: Exemplified by
6-cyclopropyl-5-(4-fluorophenyl)-2-hydroxynicotinonitrile (1H)
##STR00780##
[0526] A mixture of 10 (2.6 g, 11 mmol), 4-fluorophenylboronic acid
(1.4 g, 10 mmol), Pd(PPh.sub.3).sub.4 (30 mg), and K.sub.2CO.sub.3
(16 mg, 0.119 mmol) suspended in 10 mL of DMF was subjected to
microwave reaction at 150.degree. C. for 45 min. After the
reaction, the reaction mixture was concentrated in vacuo, and the
residue was purified by column chromatography to afford 1.9 g of
title compound as a yellow solid. LC-MS: m/z 255.0 (M+H).sup.+
Step Q
##STR00781##
[0528] 3-cyano-6-cyclopropyl-5-(4-fluorophenyl)pyridin-2-yl
trifluoromethanesulfonate. .sup.1H NMR (CHLOROFORM-d) .delta.: 7.87
(s, 1H), 7.32-7.57 (m, 2H), 7.13-7.24 (m, 2H), 1.99-2.17 (m, 1H),
1.21-1.38 (m, 2H), 1.00-1.20 (m, 2H). LC-MS: m/z 387.1
(M+H).sup.+.
Step R
[0529] The same procedure as General procedure 1, step E except
using 12-1 as the starting material instead of 5 and the suitable
building blocks described in the "building block" section.
Step S
[0530] The same procedure as General procedure 1, step G except
using the suitable building blocks described in the "building
block" section.
General Procedure 5
##STR00782##
[0531] Step T: Exemplified by (R)-tert-butyl
4-(2'-chloro-5-cyano-2-cyclopropyl-3,4'-bipyridin-6-yl)-2-cyclopropylpipe-
razine-1-carboxylate
##STR00783##
[0533] To a 25 mL flask was added with 9-1 (1000 mg 2.235 mmol),
2-chloropyridin-4-ylboronic acid (457 mg, 2.906 mmol),
Pd(PPh.sub.3).sub.4 (120 mg, 0.1 mmol), K.sub.2CO.sub.3 (926 mg,
6.705 mmol), and 4 mL DMF. The resultant mixture was stirred at
150.degree. C. for 5 h. After washing with satd. NaHCO.sub.3,
brine, the combined organic layer was dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo. Column chromatography
purification (20% EtOAc/petroleum ether) afforded 640 mg of title
compound. .sup.1H NMR (CHLOROFORM-d) .delta. 8.48 (d, J=5.0 Hz,
1H), 7.62 (s, 1H), 7.39-7.47 (m, 1H), 7.32 (dd, J=5.1, 1.3 Hz, 1H),
4.59 (d, J=12.9 Hz, 1H), 4.45 (d, J=13.2 Hz, 1H), 4.09 (d, J=13.5
Hz, 1H), 3.50 (d, J=9.1 Hz, 1H), 3.34-3.43 (m, 1H), 3.27 (dd,
J=13.2, 3.8 Hz, 1H), 3.11 (td, J=12.5, 3.7 Hz, 1H), 1.94-2.06 (m,
1H), 1.77 (br. s., 2H), 1.50 (s, 9H), 1.34 (br. s., 1H), 1.04 (dd,
J=7.9, 3.2 Hz, 2H), 0.56-0.63 (m, 2H), 0.50 (dd, J=8.5, 3.5 Hz,
1H), 0.32-0.42 (m, 1H).
Step U: Exemplified by
(R)-tert-butyl-4-(5-cyano-2-cyclopropyl-2'-vinyl-3,4'-bipyridin-6-yl)-2-c-
yclopropyl piperazine-1-carboxylate
##STR00784##
[0535] To a flask was added with (R)-tert-butyl
4-(2'-chloro-5-cyano-2-cyclopropyl-3,4'-bipyridin-6-yl)-2-cyclopropylpipe-
razine-1-carboxylate (640 mg 1.33 mmol), tributyl(vinyl)stannane
(550 mg, 1.73 mmol), Pd(PPh.sub.3).sub.4 (120 mg, 0.1 mmol),
K.sub.2CO.sub.3 (460 mg, 3.33 mmol), and 4 mL DMF. The resultant
mixture was stirred at 150.degree. C. for 5 h. After washing with
satd. NaHCO.sub.3, brine, the combined organic layer was dried over
anhy. Na.sub.2SO.sub.4 and concentrated in vacuo. Column
chromatography purification (20% EtOAc/petroleum ether) afforded
the compound. LC-MS: m/z 472.2 (M+H).sup.+.
Step V:
(R)-2-cyclopropyl-6-(3-cyclopropylpiperazin-1-yl)-2'-vinyl-3,4'-bi-
pyridine-5-carbonitrile
##STR00785##
[0537] To a flask was added (R)-tert-butyl
4-(5-cyano-2-cyclopropyl-2'-vinyl-3,4'-bipyridin-6-yl)-2-cyclopropylpiper-
azine-1-carboxylate and 12 mL EtOH/HCl (1M). The resulting reaction
mixture was stirred at 0.degree. C. for 30 minutes until TLC showed
the completion of the reaction, which was concentrated in vacuo to
afford a product as light yellowish solid. .sup.1H NMR
(CHLOROFORM-d) .delta.: 8.65 (d, J=5.0 Hz, 1H), 7.62 (s, 1H), 7.38
(s, 1H), 7.23 (dd, J=5.0, 1.8 Hz, 1H), 6.89 (dd, J=17.3, 10.9 Hz,
1H), 6.29 (dd, J=17.6, 1.2 Hz, 1H), 5.57 (dd, J=10.9, 1.2 Hz, 1H),
4.50 (d, J=12.9 Hz, 1H), 4.36 (d, J=13.2 Hz, 1H), 3.28 (br. s.,
1H), 3.22 (d, J=12.3 Hz, 1H), 3.10 (br. s., 1H), 2.95 (br. s., 1H),
1.96-2.06 (m, 1H), 1.21 (t, J=4.1 Hz, 1H), 0.95-1.07 (m, 3H), 0.92
(br. s., 1H), 0.62 (d, J=7.9 Hz, 2H), 0.40 (d, J=4.7 Hz, 2H).
Step W
[0538] The same procedure as General procedure 1, step G except
using the suitable building blocks described in the "building
block" section.
General Procedure 6
##STR00786## ##STR00787##
[0539] Step A': 1-cyclopropylbutane-1,3-dione
##STR00788##
[0541] A mixture of CH3ONa (75.65 g, 1.25 mol) and
1-cyclopropylethanone (105.0 g, 1.25 mol) in THF (1000 mL) was
stirred at 35.degree. C. for 1 h and followed by addition of ethyl
acetate (110.0 g, 1.25 mol) dropwise. After stirring at 50.degree.
C. for 4 hrs, the solvent was removed under reduced pressure and
the residue was dissolved in H2O (500 mL) and adjusted to pH 3.5
with citric acid. The mixture was extracted by ethyl acetate (500
mL.times.3). The combined organic layers were concentrated in
vacuum to give 1-cyclopropylbutane-1,3-dione (110.0 g, yield 69%)
as a yellow oil. .sup.1H NMR (CHLOROFORM-d) .delta. 0.83-0.95 (m,
2H), 1.06-1.10 (m, 2H), 1.54-1.63 (m, 1H), 2.00 (s, 3H).
Step B': 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile
##STR00789##
[0543] A mixture of 1-cyclopropylbutane-1,3-dione (126.0 g, 1.0
mol) and 2-cyanoacetamide (88.0 g, 1.0 mol) and piperidine (60 mL)
in EtOH (1500 mL) was stirred at reflux for 4 hrs. The reaction
mixture was filtered, washed with PE (200 mL) and dried in vacuum
to give 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (90.0 g,
52%) as a white solid. .sup.1H NMR (DMSO-d6) .delta. 12.36 (br. s.,
1H), 5.93 (s, 1H), 2.26 (s, 3H), 1.81-1.91 (m, 1H), 1.06-1.14 (m,
2H), 0.91-0.95 (m, 2H).
Step C':
5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile
##STR00790##
[0545] A mixture of 6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile
(90.0 g, 0.52 mol) and NBS (100.0 g, 0.57 mol) in DCE (1500 mL) was
stirred at reflux temperature for 4 hrs. The reaction mixture was
filtered and the residue was washed with DCE (200 mL) and dried in
vacuum to give
5-bromo-6-cyclopropyl-2-hydroxy-4-methylnicotinonitrile (100.0 g,
76%) as a white solid. MS (ES) M+H expected 253.0, found 253.0.
.sup.1H NMR (CHLOROFORM-d) .delta. 2.68 (s, 3H), 1.79-1.88 (m, 1H),
1.03-1.09 (m, 2H), 0.93-1.01 (m, 2H).
Step D': 5-bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yl
trifluoromethane-sulfonate
##STR00791##
[0547] To a solution of
5-bromo-2-hydroxy-6-isopropylnicotinonitrile (40 g, 0.15 mol) in
200 mL of methylene chloride was added DMAP (1.78 g, 14.6 mmol),
and triethylamine (25 mL, 175 mmol). The mixture was cooled to
0.degree. C. in an ice-water bath, and trifluoromethanesulfonic
anhydride (37 mL, 0.21 mol) was added dropwise by syringe. The
resulting reaction mixture was stirred at 0.degree. C. for 30 min
then allowed to warm to room temperature and stirred overnight.
After TLC showed the complete conversion of starting material to
product, the reaction mixture was concentrated and purified by
column chromatography (20% EtOAc/petroleum ether) to afford 55 g of
title compound. .sup.1H NMR (CHLOROFORM-d). 2.70 (s, 3H), 2.16-2.20
(m, 1H), 1.23-1.25 (m, 2H), 1.19-1.22 (m, 2H)
Step E': Exemplified by
(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitr-
ile (R'''=methyl)
##STR00792##
[0549] A mixture of
5-bromo-3-cyano-6-cyclopropyl-4-methylpyridin-2-yl
trifluoromethanesulfonate (50.0 g, 0.13 mol) and
(R)-2-methylpiperazine (15.6 g, 0.16 mol) and Et3N (26.0 g, 0.26
mol) in THF (500 mL) was stirred at 80.degree. C. overnight. The
resulting mixture concentrated in vacuum to give
(R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methylpiperazin-1-yl)nicotinonitr-
ile (34.8 g, 80%) as a white solid. .sup.1H NMR (CHLOROFORM-d)
.delta. 4.08-4.16 (m, 0.5H), 4.05-4.08 (m, 1H), 4.01-4.04 (m,
0.5H), 2.99-3.08 (m, 1H), 2.97 (d, J=8.8 Hz, 2H), 2.88-2.95 (m,
1H), 2.58-2.65 (m, 1H), 2.55-2.57 (m, 3H), 1.77 (br. s., 1H), 1.12
(s, 1.5H), 1.10 (s, 1.5H), 1.05-1.09 (m, 2H), 1.00-1.05 (m,
2H).
Step F': preparation of
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)-4-methylnicotinonitrile (R'''=methyl,
##STR00793##
##STR00794##
[0551] A mixture of (R)-5-bromo-6-cyclopropyl-4-methyl-2-(3-methyl
piperazin-1-yl)nicotinonitrile (34.8 g, 0.1 mol) and
3-methoxypropanoic acid (16.0 g, 0.15 mol) in pyridine (500 mL) was
stirred at 0.degree. C. for 30 min, and followed by addition of
POCl.sub.3 (28.7 g, 0.19 mol) dropwise. The resulting mixture was
stirred at 20.degree. C. for 2 hrs. The reaction mixture was
concentrated and purified by chromatography to give
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazi-
n-1-yl)-4-methylnicotinonitrile (25.0 g, 59%) as yellow oil.
[0552] .sup.1H NMR (CHLOROFORM-d) .delta. 4.90 (br. s., 0.5H), 4.52
(d, J=13.6 Hz, 0.5H), 4.22 (br. s., 0.5H), 3.95-4.13 (m, 2H), 3.78
(br. s., 0.5H), 3.74 (t, J=5.9 Hz, 2H), 3.50-3.61 (m, 0.5H), 3.38
(s, 3H), 3.07-3.24 (m, 1.5H), 2.90-3.06 (m, 1H), 2.65-2.79 (m, 1H),
2.60 (s, 3H), 2.52-2.63 (m, 1H), 2.17-2.21 (m, 1H), 1.37 (d, J=6.5
Hz, 1.5H), 1.27 (d, J=6.3 Hz, 1.5H), 1.09 (s, 2H), 1.05-1.08 (m,
2H).
[0553] Step G' was similar to Step H in general procedure 1.
General Procedure 7
##STR00795## ##STR00796##
[0554] Step H': 6-cyclopropyl-2-hydroxy-5-nitronicotinonitrile
##STR00797##
[0556] To a solution of 6-cyclopropyl-2-hydroxynicotinonitrile (20
g, 0.125 mmol) in Ac.sub.2O (110 mL) was added dropwise HNO.sub.3
(15 mL) at 0.degree. C..about.40.degree. C. for 30 mins. After the
addition, the reaction mixture was stirred at r.t. for 3 hrs. The
mixture was cooled to 0.degree. C. and the solid was collected by
filtration. The solid was washed with brine dried under vacuum to
give the title compound (15.5 g, 60.4%) as a pale yellow solid.
.sup.1H NMR (CHLOROFORM-d) .delta.10.71 (s, 1H), 8.68 (s, 1H), 3.13
(tt, J=8.6, 5.6 Hz, 1H), 1.57-1.52 (m, 2H), 1.44-1.37 (m, 2H).
LC-MS: m/z 205.9 (M+H).sup.+
Step I': 3-cyano-6-cyclopropyl-5-nitropyridin-2-yl
trifluoromethanesulfonate
##STR00798##
[0558] To a solution of
6-cyclopropyl-2-hydroxy-5-nitronicotinonitrile (7.6 g, 37.7 mmol)
in DCM (150 mL) was added DMAP (30.0 mg) and TEA (7.5 g, 74.1 mmol)
at r.t. Then Tf.sub.2O (15.7 g, 55.6 mmol) was added dropwise to
the above solution at -40.degree. C. for 30 min. The reaction
mixture was stirred at -40.degree. C. for 2 hs. The mixture was
quenched with water at -40.degree. C. The mixture was then
extracted with EtOAc (50 mL.times.2). The combined organic layer
was washed with brine, dried over Na.sub.2SO.sub.4. The organic
phase was filtered and the filtrate was concentrated in vacuum to
give the title compound (12.5 g, crude) as a pale yellow solid.
LC-MS: m/z 337.5 (M+H).sup.+
Step J':
(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-nitronicotinoni-
trile
##STR00799##
[0560] To a solution of 3-cyano-6-cyclopropyl-5-nitropyridin-2-yl
trifluoromethanesulfonate (10.9 g, 32.3 mmol) and
(R)-2-isopropylpiperazine (3.45 g, 27.0 mmol) in CH.sub.3CN (100
mL) was added TEA (6.5 g, 64.7 mmol) at r.t. The reaction mixture
was heated and stirred at 85.degree. C. for 3 hrs. The mixture was
concentrated in vacuo and the residue was extracted with EtOAc (50
mL.times.2). The combined organic layer was washed with brine,
dried over Na.sub.2SO.sub.4. The organic phase was filtered and the
filtrate was concentrated in vacuum to give the title compound (8.5
g, crude) as a brown solid. LC-MS: m/z 316.6 (M+H).sup.+
Step K': (R)-tert-butyl
4-(3-cyano-6-cyclopropyl-5-nitropyridin-2-yl)-2-isopropylpiperazine-1-car-
boxylate
##STR00800##
[0562] To a solution of
(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-nitronicotinonitrile
(8.52 g, 26.2 mmol) and Boc anhydride (8.5 g, 39.3 mmol) in DCM (50
mL) was added TEA (3.9 g, 39.3 mmol) at r.t. The reaction mixture
was stirred at 30.degree. C. for 3 hrs. The solvent was removed in
vacuum and the residue was purified via silica gel column
chromatography (DCM:MeOH) to afford the title compound (10.4 g,
95%) as a yellow liquid. .sup.1H NMR (CHLOROFORM-d) .delta. 8.51
(s, 1H), 4.74 (d, J=13.7 Hz, 1H), 4.55 (d, J=13.1 Hz, 1H), 3.88 (s,
1H), 3.37-3.23 (m, 2H), 3.11 (ddd, J=10.5, 7.7, 5.7 Hz, 2H), 1.86
(tdd, J=13.3, 8.5, 4.9 Hz, 1H), 1.49 (s, 9H), 1.27 (d, J=2.3 Hz,
2H), 1.26-1.17 (m, 4H), 1.01 (d, J=6.6 Hz, 3H), 0.89 (d, J=6.8 Hz,
3H).
Step L': (R)-tert-butyl
4-(5-amino-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-car-
boxylate
##STR00801##
[0564] To a solution of (R)-tert-butyl
4-(3-cyano-6-cyclopropyl-5-nitropyridin-2-yl)-2-isopropylpiperazine-1-car-
boxylate (19 g, 45.8 mmol) in EtOH (200 mL) and H.sub.2O (100 mL)
was added Zinc (30 g, 458 mmol) and NH.sub.4Cl (24.5 g, 458 mmol)
at r.t. The reaction mixture was stirred at 40.degree. C.
overnight. The mixture was filtered through a pad of silica and the
filtrate was extracted with EtOAc (100 mL.times.2). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4.
The organic phase was filtered and the filtrate was concentrated in
vacuum to give the title compound (13.1 g, 74.3%) as a yellow
solid. .sup.1H NMR (CHLOROFORM-d) .delta.: 7.10 (d, J=2.9 Hz, 1H),
4.02 (t, J=19.0 Hz, 3H), 3.81 (t, J=16.8 Hz, 3H), 3.13 (td, J=12.8,
2.4 Hz, 1H), 2.99-2.86 (m, 2H), 2.25 (tt, J=12.9, 6.5 Hz, 1H),
1.97-1.83 (m, 1H), 1.49 (d, J=2.2 Hz, 9H), 1.13-1.06 (m, 2H),
1.06-1.01 (m, 2H), 0.98 (t, J=9.2 Hz, 3H), 0.87 (t, J=6.6 Hz, 3H).
LC-MS: m/z 386.6 (M+H).sup.+
Step M': (R)-tert-butyl
4-(5-((4-chloropyridin-2-yl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-i-
sopropylpiperazine-1-carboxylate
##STR00802##
[0566] To a solution of (R)-tert-butyl
4-(5-amino-3-cyano-6-cyclopropylpyridin-2-yl)-2-isopropylpiperazine-1-car-
boxylate (600 mg, 81.6 mmol) and 2-bromo-4-chloropyridine (390.3
mg, 2.03 mmol) in 1,4-dioxane (15 mL) was added Pd.sub.2(dba).sub.3
(142.7 mg, 0.156 mmol) and Xantphos (135.3 mg, 0.234 mmol) and
Cs.sub.2CO.sub.3 (1.02 g, 3.12 mmol) at r.t. under N.sub.2. The
resulting mixture was heated and stirred at 115.degree. C. under
N.sub.2 in microwave for 1 h. The solvent was removed in vacuum and
the residue was purified via reverse phase silica gel column
chromatography (MeOH:H.sub.2O) to afford the title compound (137
mg, 18%) as a pale yellow solid. .sup.1H NMR (CHLOROFORM-d)
.delta.: 8.07 (d, J=5.4 Hz, 1H), 7.72 (d, J=3.3 Hz, 1H), 6.75 (dd,
J=5.5, 1.7 Hz, 1H), 6.39 (d, J=1.6 Hz, 1H), 6.25 (s, 1H), 4.45 (d,
J=13.2 Hz, 1H), 4.26 (d, J=9.2 Hz, 1H), 4.21-3.61 (m, 2.5H), 3.11
(dt, J=13.5, 6.8 Hz, 2.5H), 2.22-1.98 (m, 2H), 1.52-1.47 (m, 9H),
1.28 (s, 1H), 1.14 (dt, J=8.1, 4.5 Hz, 1H), 1.08 (dd, J=9.7, 4.7
Hz, 1H), 1.01 (dd, J=10.9, 5.2 Hz, 4H), 0.90 (d, J=6.8 Hz, 3H).
LC-MS: m/z 497.6 (M+H).sup.+
Step N': (R)-tert-butyl
4-(3-cyano-6-cyclopropyl-5-((4-vinylpyridin-2-yl)amino)pyridin-2-yl)-2-is-
opropylpiperazine-1-carboxylate
##STR00803##
[0568] To a solution of (R)-tert-butyl
4-(5-((4-chloropyridin-2-yl)amino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-i-
sopropylpiperazine-1-carboxylate (600 mg, 1.21 mmol) in isopropanol
(15 mL) and H.sub.2O (3 mL) was added Vinyltrifluoroboric acid
potassium salt (324.2 mg, 2.42 mmol), Pd(dppf)Cl.sub.2 (98.7 mg,
0.121 mmol) and DIPEA (312.2 mg, 2.42 mmol) at r.t. under N.sub.2.
The reaction mixture was heated and stirred at 125.degree. C. under
N.sub.2 in microwave for 1.5 h. The solvent was removed in vacuum
and the residue was purified via silica gel column chromatography
(DCM:MeOH) to afford the title compound (513 mg, 87%) as a yellow
solid. LC-MS: m/z 489.6 (M+H).sup.+
Step O':
(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-((4-vinylpyridi-
n-2-yl)amino)nicotinonitrile
##STR00804##
[0570] To a solution of (R)-tert-butyl
4-(3-cyano-6-cyclopropyl-5-((4-vinylpyridin-2-yl)amino)pyridin-2-yl)-2-is-
opropylpiperazine-1-carboxylate (513 mg, 1.05 mmol) in anhydrous
DCM (10 mL) was added TFA (5 mL) at r.t. The reaction mixture was
stirred at r.t. for 2 hs. The solvent was removed in vacuum and the
residue was adjusted to pH>7.0. The residue mixture was
extracted with EtOAc (15 mL.times.2). The combined organic layer
was washed with brine, dried over Na.sub.2SO.sub.4. The organic
phase was filtered and the filtrate was concentrated in vacuum to
give out the title compound (crude, 406 mg) as a yellow liquid.
.sup.1H NMR (CHLOROFORM-d) .delta.: 7.99 (d, J=6.6 Hz, 1H), 7.72
(s, 1H), 7.04 (dd, J=6.6, 1.3 Hz, 1H), 6.64 (dd, J=17.4, 10.8 Hz,
1H), 6.47 (s, 1H), 6.12 (d, J=17.5 Hz, 1H), 5.81 (d, J=10.8 Hz,
1H), 5.24 (s, 1H), 4.59 (d, J=13.9 Hz, 1H), 4.45 (d, J=14.3 Hz,
1H), 3.63-3.48 (m, 2H), 3.30 (dd, J=14.1, 11.1 Hz, 2H), 3.18 (s,
1H), 2.15-2.01 (m, 2H), 1.28 (d, J=4.8 Hz, 1H), 1.16 (dd, J=10.2,
6.9 Hz, 8H), 1.12-1.09 (m, 1H). LC-MS: m/z 389.5 (M+H).sup.+
Step P':
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin--
1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile (Compound
757)
[0571] To a solution of
(R)-6-cyclopropyl-2-(3-isopropylpiperazin-1-yl)-5-((4-vinylpyridin-2-yl)a-
mino)nicotinonitrile (300 mg, 0.77 mmol) in DMF (15 mL) was added
sodium 3-hydroxypropanoate (208.8 mg, 1.55 mmol), HATU (442.5 mg,
1.2 mmol) and DIPEA (200 mg, 1.55 mmol) at r.t. The reaction
mixture was stirred at r.t. for 3 hs. The solvent was removed in
vacuum and the residue was purified via silica gel column
chromatography (DCM: MeOH) to afford the title compound (138 mg,
38.8%) as a pale yellow solid. .sup.1H NMR (CHLOROFORM-d) .delta.:
8.12 (d, J=5.4 Hz, 1H), 7.85 (d, J=5.5 Hz, 1H), 6.84 (d, J=5.4 Hz,
1H), 6.59 (dd, J=17.6, 10.8 Hz, 1H), 6.46 (s, 1H), 6.42 (s, 1H),
5.91 (d, J=17.5 Hz, 1H), 5.48 (d, J=10.9 Hz, 1H), 4.69 (d, J=10.4
Hz, 0.5H), 4.44 (d, J=12.6 Hz, 1.5H), 4.31-4.23 (m, 1H), 3.93 (s,
2H), 3.75 (d, J=13.5 Hz, 0.5H), 3.51-3.38 (m, 2H), 3.14-2.97 (m,
2H), 2.61 (dt, J=5.7, 4.8 Hz, 2H), 2.36-2.25 (m, 0.5H), 2.19 (ddd,
J=12.9, 8.1, 4.9 Hz, 1H), 1.29 (t, J=16.6 Hz, 1H), 1.18-0.97 (m,
7H), 0.95-0.88 (m, 1.5H), 0.86 (d, J=6.8 Hz, 1.5H). LC-MS: m/z
461.6 (M+H).sup.+
General Procedure 8
##STR00805## ##STR00806##
[0572] Step Q': ((R)-tert-butyl
4-(3-cyano-6-cyclopropyl-5-hydroxypyridin-2-yl)-2-cyclopropylpiperazine-1-
-carboxylate
##STR00807##
[0574] To a mixture of (R)-tert-butyl
4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-c-
arboxylate (0.35 g, 1.0 mmol), potassium hydroxide (0.22 g, 4 mmol)
in a 50 mL flask was added Pd.sub.2(dba).sub.3 (0.092 g, 0.1 mmol),
t-Bu-Xphos (0.082 g, 0.2 mol). Then 10 mL 1,4-dioxane and 1.0 mL
water was added, the mixture was stirred at 80.degree. C. for 16
hours, cooled and acidified with 2N HCl to pH 6 (temperature held
below 25.degree. C.). Then the mixture was extracted with ethyl
acetate (15 mL.times.2), the organic phase was combined and
concentrated to give brown oil, which was further purified by
silica gel chromatography (PE:EA=3:1), to give 0.16 g of (1) as a
white solid (41% yield). LC-MS: m/z 386.0 (M+H).sup.+
Step R': (R)-tert-butyl
4-(5-(2-chloropyridin-4-yloxy)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclo-
propylpiperazine-1-carboxylate
##STR00808##
[0576] A mixture of (R)-tert-butyl
4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropyl
piperazine-1-carboxylate (0.16 g, 0.41 mol),
2-chloro-4-iodopyridine (0.15 g, 0.62 mol), 9 mg Cu(I)Br (0.06
mmol) and 12 mg 2,2,6,6-tetramethylheptane-3,5-dione (0.06 mmol),
0.28 g Cs.sub.2CO.sub.3 was heated under microwave in 4 mL DMSO for
30 min. The mixture was cooled to room temperature and washed with
water and purified by silica gel chromatography (DCM: MeOH=20:1) to
give 0.10 g of (2) as a yellow solid (52% yield). LC-MS: m/z 486.0
(M+H).sup.+
Step S':
(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpip-
erazin-1-yl)nicotinonitrile
##STR00809##
[0578] A mixture of (R)-tert-butyl
4-(5-(2-chloropyridin-4-yloxy)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclo-
propylpiperazine-1-carboxylate (0.10 g, 0.21 mmol) and TFA (0.35
mL) was stirred in DCM (10 mL) for 2 hrs. The solvent was removed
and the residue was basified with NaHCO.sub.3 solution and
extracted with DCM (10 mL), the organic phase was separated and
concentrated to give a yellow solid (3) (0.075 g, 0.19 mmol, crude
yield 90%). LC-MS: m/z 397.1 (M+H).sup.+
Step T':
(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4--
(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (Compound
694)
[0579] A mixture of
(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-
-yl)nicotinonitrile (0.35 g, 0.88 mmol), sodium 3-hydroxypropanoate
(0.10 g, 0.88 mmol), HATU (0.50 g, 1.32 mmol) and 0.23 g DIEA (1.76
mmol) was stirred in 8 mL DMF for 4 hrs. Then the mixture was
quenched by adding 6 mL water and extracted with EA (15
mL.times.2), the organic phase was combined and concentrated to
give a yellow oil, which was further purified by silica gel
chromatography (DCM:MeOH=20:1) to give 0.10 g of product as a
yellow solid (52% yield). .sup.1H NMR (CHLOROFORM-d) .delta.: 8.30
(d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H), 6.81 (dt, J=5.6, 2.0 Hz,
2H), 4.70 (s, 1H), 4.41 (d, J=13.0 Hz, 1H), 4.29 (d, J=13.0 Hz,
1H), 4.12 (dd, J=18.6, 7.4 Hz, 1H), 3.93 (s, 2H), 3.84-3.67 (m,
1H), 3.18 (d, J=12.8 Hz, 1H), 3.13-2.99 (m, 1H), 2.61 (s, 2H),
2.32-2.22 (m, 0.5H), 2.02 (t, J=4.6 Hz, 1H), 1.35 (s, 1H), 1.29 (d,
J=9.4 Hz, 3H), 1.14 (dd, J=7.4, 3.0 Hz, 2H), 1.04 (dt, J=7.9, 3.1
Hz, 2H), 0.66-0.67 (m, 2H), 0.46-0.51 (m, 2H). LC-MS: m/z 468.1
(M+H).sup.+
Step U':
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazi-
n-1-yl)-5-(2-vinylpyridin-4-yloxy)nicotinonitrile (Compound
692)
[0580] A mixture of
(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydro-
xy propanoyl)piperazin-1-yl)nicotinonitrile (4) 0.35 g, (0.75
mmol), potassium trifluoro(vinyl)borate (0.15 g, 1.1 mmol),
PdCl.sub.2dppf (80 mg, 0.075 mmol) and DIEA (0.24 mL, 1.5 mmol) was
heated in isopropanol at reflux at 85.degree. C. under nitrogen for
5 hrs. Then mixture was then concentrated under reduced pressure to
give a yellow solid which was further purified by silica
chromatography (PE/EA/MeOH=150/120/8) to give 0.19 g of product as
a white solid (55% yield). .sup.1H NMR (CHLOROFORM-d) .delta.: 8.47
(d, J=5.6 Hz, 1H), 7.48-7.49 (m, 0.5H), 6.86 (d, J=2.3 Hz, 1H),
6.77 (dd, J=17.4, 10.8 Hz, 1H), 6.66 (dd, J=5.6, 2.4 Hz, 1H), 6.22
(dd, J=17.4, 0.9 Hz, 1H), 5.53 (dd, J=10.8, 0.8 Hz, 1H), 4.68 (d,
J=11.7 Hz, 1H), 4.38 (d, J=12.9 Hz, 1H), 4.30-4.22 (m, 1H),
4.15-4.04 (m, 1H), 3.92 (s, 2H), 3.75 (d, J=20.7 Hz, 1H), 3.47 (d,
J=21.7 Hz, 1H), 3.25-3.12 (m, 1H), 3.09-2.95 (m, 1H), 2.60 (s, 2H),
2.32-2.22 (m, 0.5H), 2.11-2.05 (m, 1H), 1.37 (d, J=20.5 Hz, 1H),
1.27 (d, J=2.0 Hz, 1H), 1.16-1.10 (m, 2H), 1.01 (ddd, J=10.1, 6.7,
3.3 Hz, 2H), 0.65 (t, J=33.7 Hz, 2H), 0.45-0.48 (m, 2H). LC-MS: m/z
460.1 (M+H).sup.+
General Procedure 9
##STR00810##
[0582] Core 7-1 (120 mg, 0.295 mmol) and amine (0.295 mmol) were
dissolved in toluene (2 mL). K3PO4 (125.0 mg, 0.590 mmol), Xantphos
(cat.) and Pd2(dba)3(cat.) were added to above mixture under N2.
The mixture was shaken at 120.degree. C. for 16 hrs. The crude
product was purified by prep-HPLC.
Example 15
Building Blocks Syntheses
Building Block 1: (R)-2-cyclopropylpiperazine
##STR00811##
[0583] Step 1
[0584] To a solution of
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2--
vinylquinazolin-5-yl)nicotinonitrile (100 g, 0.87 mol) in water
(1250 ml), NaHCO.sub.3 (175 g, 2.08 mol) was add at room
temperature, then a solution of (Boc).sub.2O in THF (1250 mL) was
added and the reaction mixture was heated to reflux overnight. Then
the resulting mixture was concentrated to remove THF under reduced
pressure. EtOAc (1250 mL) was added to the residue and the
resulting mixture was cooled to 5.degree. C. and then adjusted to
pH 3 with saturated aqueous NaHSO.sub.4. The layers were separated
and the aqueous was extracted with EtOAc (1000 mL.times.3). The
combined EtOAc layers were washed with water and brine, dried over
Na.sub.2SO.sub.4 and concentrated under reduced pressure to give
(R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (165 g,
yield 88%). .sup.1H NMR (MeOD 400 MHz) 3.16-3.14 (d, J=8.8, 1H),
1.11 (s, 9H), 0.73-0.78 (m, 1H), 0.28-0.2 (m, 3H), 0.18-0.15 (m,
1H) 100 ee %.
Step 2
[0585] Isobutyl chloroformate (81.6 g, 0.6 mol.) was added over 1
hr to a stirred mixture of
(R)-2-(tert-butoxycarbonylamino)-2-cyclopropylacetic acid (129 g,
0.6 mol.) and Et.sub.3N (67 g, 0.66 mol.) in DCM (1000 mL) at
0.degree. C.-5.degree. C. and the reaction mixture was stirred 1 hr
at 0.degree. C.-5.degree. C. In a separate flask, a mixture of
glycine methyl ester hydrochloride (82.8 g, 0.66 mol.), Et.sub.3N
(73 g, 0.72 mol.) and DCM (1000 mL) was stirred for 1 hr and the
mixture was then added to the flask over 2 hrs. After the addition
was complete, the mixture was stirred overnight at room temperature
for 40 hrs and then washed with water and brine, dried with
Na.sub.2SO.sub.4, concentrated under reduced pressure and the
residue was purified by column chromatography to give (R)-methyl
2-(2-(tert-butoxycarbonylamino)-2-cyclopropyl acetamido)acetate
(100 g, yield 58%) as white solid. 100 ee %. .sup.1H NMR (DMSO 400
MHz) .delta. 8.2-8.16 (t, J=5.6, 1H), 6.66-6.86 (d, J=8.8, 9H),
3.71-3.92 (m, 2H), 3.62 (s, 3H), 3.46-3.51 (t, J=8.4, 1H), 1.36 (s,
9H), 0.97-1.01 (m, 1H), 0.38-0.44 (m, 3H), 0.25-0.28 (m, 1H).
Step 3
[0586] To a solution of (R)-methyl
2-(2-(tert-butoxycarbonylamino)-2-cyclopropylacetamido) acetate
(290 g, 1.014 mol) in DCM (1740 mL), TFA (870 mL) was added
dropwise at 0.degree. C. The reaction solution was stirred
overnight at room temperature. The resulting solution was
concentrated under reduced pressure to give (R)-methyl
2-(2-amino-2-cyclopropylacetamido) acetate (511 g crude).
Step 4
[0587] To a solution (R)-methyl
2-(2-amino-2-cyclopropylacetamido)acetate (255.5 g crude, 0.507
mol) in MeOH (1250 ml), Et.sub.3N (750 ml, 10.78 mol) was added was
added dropwise at 0.degree. C. Then the reaction solution was
stirred two days at room temperature. The resulting mixture was
filtered and the precipitate was washed with MTBE and dried by high
vacuum to give (R)-3-cyclopropylpiperazine-2,5-dione (60 g, yield
76.9%). .sup.1H NMR (DMSO 400 MHz) .delta. 7.98 (s, 1H), 7.74 (s,
1H), 3.68-6.64 (d, J=17.6, 1H), 3.30-3.36 (m, 1H), 2.9-2.93 (dd,
J=3.2, 1H), 0.87-0.92 (m, 1H), 0.21-0.27 (m, 3H), 0.18-0.21 (m,
1H).
Step 5
[0588] To a suspension mixture of
(R)-3-cyclopropylpiperazine-2,5-dione (30 g, 0.195 mmol) in THF
(1000 mL), AlLiH.sub.4 (45 g, 1.184 mol) was added in portions over
1.5 hrs at 0.degree. C. Then the reaction mixture was heated to
70.degree. C. overnight. After cooling, water (45 mL) was added
dropwise at 0.degree. C. and then a solution of KOH (45 mL, 1%) was
added dropwise at 0.degree. C. The resulting mixture was filtered
and the residue was washed with EtOAc and MeOH (3:1) and the
filtrate was concentrated under reduced pressure to give crude
product. Then the crude product was washed with DCM and the
filtrate was concentrated under reduced pressure to give
(R)-2-cyclopropylpiperazine (18.5 g, yield 75.5%). 99.5 ee %.
.sup.1H NMR (MeOD 400 MHz) .delta. 2.9-2.96 (m, 1H), 2.8-2.88 (m,
1H), 2.7-2.8 (m, 1H), 2.55-2.68 (m, 2H), 2.4-2.5 (q, J=10.4, 1H),
1.65-1.73 (m, 1H), 0.55-0.67 (m, 1H), 0.35-0.45 (m, 2H), 0.05-0.25
(m, 2H).
Building Block 2: 2-(2,2,2-trifluoroethyl)piperazine
##STR00812##
[0589] Step 1
[0590] To a solution of 2-amino-4,4,4-trifluorobutanoic acid (450
mg, 3 mmol) in 5 mL H.sub.2O and 5 mL THF was added NaHCO.sub.3
(504 mg, 6 mmol), followed by a solution of di-tert-butyl
dicarbonate (650 mg, 3 mmol) in THF (3 mL). The resulting mixture
was stirred at 80.degree. C. overnight. After removal of THF,
poured into water and extracted with methylene chloride. The
combined organic layer was dried over anhy. Na.sub.2SO.sub.4 and
concentrated in vacuo. 723 mg of
2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid was
obtained as a crude product and used in subsequent reaction without
further purification. MS (ES) M+H expected 258, found 258. .sup.1H
NMR (CHLOROFORM-d) 5.25 (d, J=7.8 Hz, 1H), 4.40-4.67 (m, 1H),
2.60-2.90 (m, 2H), 1.46 (s, 9H).
Step 2
[0591] To a 25 mL of round-bottom flask was added
2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanoic acid (723 mg,
2.8 mmol), Et.sub.3N (560 mg, 5.6 mmol), isobutyl carbonochloridate
(380 g, 2.8 mmol) in 5 mL methylene chloride. The resulting
reaction mixture was stirred at 0.degree. C. for 0.5 hours. And
methyl 2-aminoacetate (352 mg, 2.8 mmol) was added. The resulting
mixture was stirred at room temperature overnight. After washing
with Satd. NaHCO.sub.3, brine, the combined organic layer was dried
over anhy. Na.sub.2SO.sub.4 and concentrated in vacuo. 900 mg of
methyl
2-(2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanamido)acetate
was obtained as a crude product and used in subsequent reaction
without further purification. MS (ES) M+H expected 329.1, found
329.0. .sup.1H NMR (CHLOROFORM-d) .delta. 7.11 (br. s., 1H), 5.28
(br. s., 1H), 4.44-4.67 (m, 1H), 3.84-4.07 (m, 2H), 3.69-3.83 (s,
3H), 2.72-2.95 (m, 1H), 2.42-2.64 (m, 1H), 1.38-1.50 (m, 9H).
Step 3
[0592] A mixture of methyl
2-(2-(tert-butoxycarbonylamino)-4,4,4-trifluorobutanamido)acetate
(900 mg, 2.7 mmol) in 5 mL 1,2-dichlorobenzene was heated to
180.degree. C. overnight. The mixture was cooled down and was added
MTBE (5 mL). A brown yellowish precipitate was formed. The filter
cake was washed with MTBE and air-dried to give 200 mg of
3-(2,2,2-trifluoroethyl)piperazine-2,5-dione. .sup.1H NMR (DMSO-d6)
.delta. 8.28 (d, J=9.3 Hz, 2H), 4.00-4.26 (m, 1H), 3.68-3.87 (m,
2H), 2.66-2.88 (m, 2H).
Step 4
[0593] To a flask was added
3-(2,2,2-trifluoroethyl)piperazine-2,5-dione (200 mg, 1 mmol) in TH
F(5 mL), and LAH (2.5 mL, 6 mmol) was added dropwise under N.sub.2
at 0.degree. C. And the mixture was heated to 65.degree. C.
overnight. After reaction, the mixture was cooled down. And 0.23 mL
H.sub.2O was added followed by 0.2.times.3 mL 10% NaOH and 0.46 mL
H.sub.2O, and the mixture was filtered. The cake washed with EtOAc.
The organic phase was concentrated to give
2-(2,2,2-trifluoroethyl)piperazine 140 mg, which was used without
further purification. 1H NMR (CHLOROFORM-d) .delta. 2.75-3.02 (m,
7H), 2.52 (dd, J=11.7, 9.9 Hz, 1H), 2.10-2.17 (m, 2H).
Building Block 3: 2-(difluoromethyl)piperazine
##STR00813##
[0595] To a solution of 1,4-dibenzyl-2-(difluoromethyl)piperazine
(synthesized according to Synthetic Communications, 2011, vol. 41,
#14, 2031-2035)(80 mg, 0.253 mmol) in 40 mL of EtOH was added
Pd(OH).sub.2/C (15 mg). The resulting mixture was hydrogenated
under 50 Psi at r.t. for two days. The reaction mixture was
filtered, and the filtrate was concentrated to afford
2-(difluoromethyl)piperazine, which was used directly without
further purification. LC-MS: m/z 137.1 (M+H).sup.+
Building Block 4: 6-fluoro-1,4-diazepane
##STR00814##
[0596] Step 1
[0597] To a solution of 1,4-ditosyl-1,4-diazepan-6-ol (synthesized
according to Synthesis, 2003, 2, 223-226) (200 mg, 0.47 mmol) in 5
mL of DCM was added DAST (190 mg, 1.18 mmol). The resulting mixture
was stirred at r.t. overnight. The reaction mixture was quenched
with aq NaHCO.sub.3. The aqueous layer was extracted with DCM and
the combined organic phases were dried and concentrated. The
residue was purified by prep-TLC to afford
6-fluoro-1,4-ditosyl-1,4-diazepane (120 mg). .sup.1H NMR
(CHLOROFORM-d) .delta. 7.66-7.71 (m, 4H), 7.34 (d, J=8.0 Hz, 4H),
5.02-4.92 (m, 1H), 3.60 (dd, J=18.1, 5.3 Hz, 4H), 3.34-3.53 (m,
4H), 2.46 (s, 6H).
Step 2
[0598] A suspension of 6-fluoro-1,4-ditosyl-1,4-diazepane (82 mg,
0.19 mmol) in HOAc--HBr (3 mL, 30 wt %) was heated to 100.degree.
C. for 3 mins in a pressure tube using microwave irradiation. The
solvent was removed in vacuum and the residue triturated with
Et.sub.2O, washed with Et.sub.2O to give 6-fluoro-1,4-diazepane,
which was used directly without further purification. LC-MS: m/z
119.1 (M+H).sup.+
Building Block 5: 6-fluoro-2-methyl-1,4-diazepane
##STR00815##
[0599] Step 1
[0600] 6-fluoro-2-methyl-1,4-ditosyl-1,4-diazepane (120 mg) was
obtained from 2-methyl-1,4-ditosyl-1,4-diazepan-6-ol (synthesized
according to Synthesis, 2003, 2, 223-226) (200 mg, 0.47 mmol) (200
mg) by the method similar to 6-fluoro-1,4-ditosyl-1,4-diazepane.
.sup.1H NMR (CHLOROFORM-d) .delta. 7.62-7.75 (m, 4H), 7.30-7.37 (m,
4H), 5.00-4.84 (m, 1H), 4.09-4.37 (m, 2H), 3.73-3.95 (m, 1H),
3.37-3.62 (m, 2H), 3.12-3.32 (m, 1H), 3.05 (ddd, J=13.6, 7.2, 4.0
Hz, 1H), 2.43-2.46 (m, 6H), 1.05-1.14 (m, 3H).
Step 2
[0601] 6-fluoro-2-methyl-1,4-diazepane was obtained from
6-fluoro-2-methyl-1,4-ditosyl-1,4-diazepane by the method similar
to 6-fluoro-1,4-ditosyl-1,4-diazepane. LC-MS: m/z 133.1
(M+H).sup.+
Building Block 6: 2-(oxetan-2-yl)acetic acid
##STR00816##
[0602] Step 1
[0603] A mixture of 3-buten-1-ol (18.03 g, 0.25 mol), TEA (2.4 mL,
0.02 mol) and sodium hydroxide (15 g, 0.38 mol) in hexane (200 mL)
was stirred at 50.degree. C. for 0.5 h. Benzyl bromide (32.7 mL,
0.27 mol) in hexane (50 mL) was added dropwise over a period of 0.5
h. Afterwards, the resulting mixture was heated to reflux overnight
(oil temperature: 85.degree. C.). The precipitate was removed via
filtration and washed with ethyl acetate twice. The combined
organic phase was washed with brine and dried over sodium sulfate.
Such obtained product was pure enough for the next reaction step.
Yield: 38.21 g, 94.2%, colorless oil. .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.46-7.29 (m, 6H), 5.89 (ddt, J=17.0, 10.1, 6.7
Hz, 1H), 5.21-5.03 (m, 2H), 4.56 (s, 2H), 3.57 (t, J=6.8 Hz, 2H),
2.43 (qd, J=6.7, 1.1 Hz, 2H).
Step 2
[0604] To solution of ((but-3-en-1-yloxy)methyl)benzene (38.21 g,
0.24 mol) in dichloromethane (400 mL) was added mCPBA (77.15 g,
0.38 mol) at -20.degree. C. as solid in portions. Afterwards, the
resulting suspension was allowed to warm to rt and stirred
overnight. The precipitate was filtered off and washed with
dichloromethane. Afterwards, the combined organic phase was washed
with saturated NaHCO3 and Na2SO3 and brine. The white precipitate
was occurred while removing solvents under reduced pressure. More
n-hexane was added and the most appeared white solid was filtered
off. This procedure was repeated third times. The crude product was
subjected to column chromatography on silica gel using a mixture of
ethyl acetate with petroleum ether as eluent (EtOAc:PE=1/50 to 1/5)
to afford the title compound. Yield: 35.26 g, 84.0%, pale yellow
oil. .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.29 (m, 5H),
4.56 (s, 2H), 3.73-3.59 (m, 2H), 3.15-3.06 (m, 1H), 2.85-2.77 (m,
1H), 2.55 (dd, J=5.0, 2.7 Hz, 1H), 1.95 (dddd, J=13.4, 7.2, 6.2,
4.7 Hz, 1H), 1.81 (dq, J=14.3, 5.9 Hz, 1H). LC-MS: m/z 220.0
(M+CH.sub.3CN).sup.+.
Step 3
[0605] To a round bottom flask charged with HOAc (60.1 mg, 1.0 mol
%) in toluene (20 mL) was added Jacobsen salen Co(II) catalyst
(0.30 g, 0.5 mol %) at rt and the resulting solution was stirred at
rt for 0.5 h while the flask is open to air in order to absorb
oxygen. The volatiles were removed under reduced pressure to give
rise to a dark solid. Racemic epoxide (17.82 g, 100 mmol) was added
neat, followed by the addition of distilled water (1.0 mL, 56 mmol)
dropwise at 0.degree. C. The resulting reaction mixture was allowed
to warm to it slowly and stirred at it overnight. The reaction
mixture was diluted with n-hexane and then passed through a pad of
celite. Epoxide was obtained by using petroleum ether and diol was
obtained by using a mixture of methanol with dichloromethane
(1/30). The obtained epoxide (red oil) was distilled and the
desired product was obtained at 145-165.degree. C. (oil
temperature); similarly, the diol was obtained at 185-205.degree.
C. (oil temperature). Yield of epoxide: 7.83 g, 43.9%, pale yellow
oil; Yield of diol: 8.46 g, 43.1%, bright yellow oil. For chiral
epoxide: .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.41-7.29 (m,
5H), 4.56 (s, 2H), 3.73-3.59 (m, 2H), 3.15-3.06 (m, 1H), 2.85-2.77
(m, 1H), 2.55 (dd, J=5.0, 2.7 Hz, 1H), 1.95 (dddd, J=13.4, 7.2,
6.2, 4.7 Hz, 1H), 1.81 (dq, J=14.3, 5.9 Hz, 1H). LC-MS: m/z 220.0
(M+CH.sub.3CN).sup.+. For chiral diol: .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. 7.41-7.29 (m, 5H), 4.53 (s, 2H), 3.94 (s, 1H),
3.86-3.41 (m, 5H), 3.18 (s, 1H), 1.91-1.66 (m, 2H). LC-MS: m/z
219.0 (M+Na).sup.+. ee>99%.
Step 4
[0606] A mixture of potassium tert-butoxide (1.68 g, 15 mmol) and
trimethyloxosulphonium iodide (3.30 g, 15 mmol) in tert-butoxide
(35 mL) was stirred at 50.degree. C. for 1 h. A solution of chiral
epoxide (0.89 g, 5 mmol) in tert-butoxide (15 mL) was added
dropwise while keeping the temperature around 50.degree. C.
Afterwards, the resulting reaction mixture was stirred at
50.degree. C. overnight. The precipitate was removed via filtration
and washed with ethyl acetate. The combined organic phase was dried
under reduced pressure and diluted with ethyl acetate. The diluted
solution was washed with brine and dried over sodium sulfate. The
crude product was subjected to column chromatography on silica gel
using EtOAc:PE=1/10 as eluent to afford the title compound. Yield:
0.55 g, 57.7%; colorless oil. .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. 7.41-7.29 (m, 5H), 5.09-4.94 (m, 1H), 4.70 (dd, J=14.0, 7.8
Hz, 1H), 4.62-4.38 (m, 3H), 3.67-3.51 (m, 2H), 2.72 (dq, J=13.9,
7.8 Hz, 1H), 2.43 (dt, J=10.7, 7.6 Hz, 1H), 2.16 (td, J=13.3, 5.8
Hz, 1H), 2.02 (td, J=13.6, 6.0 Hz, 1H). LC-MS: m/z 234.1
(M+CH3CN).sup.+. ee>99%.
Step 5
[0607] A mixture of (R)-2-(2-(benzyloxy)ethyl)oxetane (4.35 g,
22.63 mmol) and palladium hydroxide on carbon (20%, with 50% of
water, 0.80 g, 2.5 mol %) in methanol (50 mL) and dichloromethane
(15 mL) was stirred at rt overnight with an input of hydrogen gas.
The precipitate was removed via filtration through a pad of celite
and washed with dichloromethane. The combined organic phase was
dried using water pump at 30.degree. C. and was confirmed pure
enough for the next reaction. Yield: 2.28 g, 98.7%; colorless oil.
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 5.09 (qd, J=7.5, 4.6 Hz,
1H), 4.70 (td, J=8.0, 6.0 Hz, 1H), 4.57 (dt, J=9.1, 5.9 Hz, 1H),
3.82 (ddd, J=11.8, 7.3, 4.6 Hz, 1H), 3.74 (ddd, J=11.1, 6.5, 4.9
Hz, 1H), 3.11-2.77 (m, 1H), 2.77-2.62 (m, 1H), 2.45 (ddt, J=11.0,
9.1, 7.4 Hz, 1H), 2.13-1.98 (m, 1H), 1.91 (ddt, J=14.3, 7.3, 4.7
Hz, 1H). ee>99%.
Step 6
[0608] To a mixture of oxetane (3.10 g, 30.48 mmol), sodium
periodate (19.56 g, 91.44 mmol), water (30 mL), acetonitrile (60
mL) and carbon tetrachloride (30 mL) was added ruthenium
trichloride plus three water (79.7 mg, 1 mol %) at 0-5.degree. C.
Afterwards, the resulting mixture was allowed to warm to rt and
stirred at this temperature for 2 h. The precipitate was removed
via filtration through a pad of celite and washed with diethyl
ether (around 100 mL.times.5). The combined organic phase was
washed with brine (50 mL.times.3) and then dried using water pump
at 35.degree. C. and was confirmed pure enough for the next
reaction. Yield: 2.26 g, 63.8%; light yellow oil. .sup.1H NMR (400
MHz, methanol-d4) .delta. 5.26-5.15 (m, 1H), 4.69 (ddd, J=8.3, 7.8,
5.9 Hz, 1H), 4.58 (dt, J=9.2, 5.9 Hz, 1H), 2.88-2.70 (m, 3H), 2.51
(ddt, J=11.2, 9.1, 7.3 Hz, 1H). ee>99%.
Building Block 7: 5-bromoisoquinoline 2-oxide
##STR00817##
[0610] To a solution of 5-bromoisoquinoline (1.5 g, 7.2 mmol) in
dichloromethane (20 mL) was added mCPBA (1.5 g, 8.6 mmol) at room
temperature all at once. The reaction mixture was stirred at room
temperature for 2 h. Then the mixture was washed with water (20 mL)
and brine (20 mL), dried over Na.sub.2SO.sub.4. The solvent was
removed and the residue was purified by column chromatography over
silica gel (EtOAc) to give 0.97 g of title compound as a pale
yellow solid. .sup.1H NMR (CHLOROFORM-d) .delta. 8.71-8.80 (m, 1H),
8.22 (dd, J=7.3, 1.5 Hz, 1H), 8.06 (d, J=7.3 Hz, 1H), 7.81-7.91 (m,
1H), 7.70 (d, J=8.2 Hz, 1H), 7.43-7.54 (m, 1H). LC-MS: m/z 222.9
(M+H).sup.+
Building Block 8: 5-bromo-1-chloroisoquinoline
##STR00818##
[0612] To a solution of 5-bromoisoquinoline 2-oxide (0.4 g, 2.4
mmol) in CHCl.sub.3 (10 mL) was added POCl.sub.3 (0.7 mL, 3 eq).
Then the mixture was refluxed for 2 h. After cooling to room
temperature, the reaction mixture was poured into ice-water,
neutralized with saturated NaHCO3 (aq), extracted with EtOAc. The
solvent was removed and 0.45 g crude product was obtained which was
used in next step with further purification. .sup.1H NMR
(CHLOROFORM-d) .delta. 8.33-8.44 (m, 2H), 8.02-8.08 (m, 1H), 8.00
(d, J=5.6 Hz, 1H), 7.52-7.61 (m, 1H). LC-MS: m/z 242.9
(M+H).sup.+.
Building Block 9: 5-bromo-1-methoxyisoquinoline
##STR00819##
[0614] To a solution of 5-bromo-1-chloroisoquinoline (1.2 g, 5.0
mmol) in methanol (10 mL) was added NaOMe (324 mg, 6.0 mmol). The
mixture was refluxed for 2 h. The solvent was removed and the
residue was purified by column chromatography over silica gel
(10-20% EtOAc/petroleum ether) to obtain 600 mg of title compound
as a white solid. .sup.1H NMR (DMSO-d.sub.6) .delta. 8.26 (d, J=8.3
Hz, 1H), 8.12 (d, J=6.0 Hz, 1H), 7.95 (dd, J=7.5, 1.0 Hz, 1H), 7.58
(d, J=6.0 Hz, 1H), 7.41 (t, J=7.9 Hz, 1H), 4.17 (s, 3H). LC-MS: m/z
237.0 (M+H).sup.+
Building Block 10: 5-bromo-1-methoxyisoquinoline
##STR00820##
[0616] To a suspension of 5-bromo-1-chloroisoquinoline (300 mg, 1.2
mmol) in water (10 mL) was added NaOH (240 mg, 6 mmol). The mixture
was refluxed for 2 h. After cooling to room temperature, the pH of
the mixture was adjusted to 7 with 2N HCl. The precipitate was
filtered and dried to get 205 mg crude product as a white solid
which was used directly in next step. LC-MS: m/z 222.9
(M+H).sup.+
Building Block 11: 5-bromo-1-methoxyisoquinoline
##STR00821##
[0618] A mixture of 5-bromoisoquinoline 2-oxide (224 mg, 1.0 mmol),
diethyl phosphorocyanidate (489 mg, 3.0 mmol) and Et3N (101 mg, 1.0
mmol) in CH3CN (5 mL) was heated at 150.degree. C. for 1.5 h in a
microwave oven. After cooling to room temperature, the precipitate
was filtered and dried to obtain 110 mg product as a yellow solid.
.sup.1H NMR (CHLOROFORM-d) .delta. 8.79 (d, J=5.8 Hz, 1H), 8.38 (d,
J=8.5 Hz, 1H), 8.29 (d, J=5.8 Hz, 1H), 8.14 (d, J=7.5 Hz, 1H), 7.70
(t, J=7.9 Hz, 1H). LC-MS: m/z 231.9 (M+H).sup.+
Building Block 12: 5-bromo-3-chloroisoquinoline
##STR00822##
[0619] Step 1
[0620] To a solution of 1,3-dichloroisoquinoline (4 g, 20.2 mmol)
in CH3CN (100 mL) was added H2SO4 (4 mL), followed by NBS (4.4 g,
24.2 mmol). The mixture was stirred at room temperature for 90 h.
Then the precipitate was collected by filtration, washed with
water, dried to afford 3.4 g of 5-bromo-1,3-dichloroisoquinoline as
a pale yellow solid. .sup.1H NMR (CHLOROFORM-d) .delta. 8.33 (d,
J=8.5 Hz, 1H), 8.03-8.10 (m, 2H), 7.56 (dd, J=8.4, 7.7 Hz, 1H).
LC-MS: m/z 276.9 (M+H).sup.+
Step 2
[0621] To a suspension of 5-bromo-1,3-dichloroisoquinoline (3 g,
10.8 mmol) in AcOH (30 mL) and conc. HCl (6 mL) was added Sn powder
(3.86 g, 32.4 mmol). The mixture was stirred at 60.degree. C. for
20 min. After cooling to room temperature, the mixture was
neutralized with NaOH (aq), filtered through celite. The filtrate
was extracted with EtOAc (2.times.30 mL). The solvent was removed
and the residue was purified by column chromatography over silica
gel (5-10% EtOAc/petroleum ether) to afford 0.8 g of
5-bromo-3-chloroisoquinoline as a white solid. .sup.1H NMR
(CHLOROFORM-d) .delta. 9.04 (s, 1H), 8.04 (s, 1H), 7.90-8.02 (m,
2H), 7.47 (t, J=7.9 Hz, 1H).
Building Block 13: 4-chloro-2-vinyl-1,7-naphthyridine
##STR00823##
[0622] Step 1
[0623] To a stirred solution of ethyl-2-aminonicotinate (1 g, 6.02
mmol) and ethyl acetate (13 g, 147.7 mmol) in 15 mL of anhydrous
THF was added sodium tert-butoxide (1.45 g, 15.1 mmol) portionwise
over 1 min. The resulting mixture was stirred at room temperature
for 40 mins and at 100.degree. C. for 4 hours. After this time the
reaction was cooled to r.t. and evaporated in vacuo. The resulting
solid was dissolved in water (20 mL) and neutralized to pH 7 with
1.0M aqueous HCl. The resulting solid was filtered and dried under
vacuum overnight to give ethyl
3-(3-acetamidoisonicotinamido)isonicotinate as a tan solid (0.58 g,
59%). LC-MS: m/z 329.1 (M+H).sup.+ 1H NMR (CHLOROFORM-d) .delta.:
11.96 (s, 1H), 10.74 (br. s., 1H), 10.12 (s, 1H), 9.99 (s, 1H),
8.56 (d, J=5.3 Hz, 1H), 8.59 (d, J=5.0 Hz, 1H), 7.89-7.96 (m, 1H),
7.66 (d, J=5.3 Hz, 1H), 4.51 (q, J=7.0 Hz, 2H), 2.24-2.33 (m, 3H),
2.19 (s, 2H), 1.43-1.54 (t, 3H).
Step 2
[0624] A stirred solution of ethyl
3-(3-acetamidoisonicotinamido)isonicotinate (400 mg, 2.47 mmol) in
phosphorus oxychloride (2.5 mL) was heated to 120.degree. C. for 3
hours. After this time the reaction was cooled to r.t. and
evaporated in vacuo. The resulting residue was carefully basified
to pH>10 with an aqueous solution of Na.sub.2CO.sub.3 and the
resulting solid was filtered, washed with water and dried under
vacuum to give 2,4-dichloro-1,7-naphthyridine (200 mg, 83%).
.sup.1H NMR (CHLOROFORM-d) .delta.: 9.48 (s, 1H), 8.79 (d, J=5.9
Hz, 1H), 8.01 (d, J=5.9 Hz, 1H), 7.74 (s, 1H). LC-MS: m/z 200
(M+H).sup.+
Step 3
[0625] To 5 mg PdCl.sub.2(dppf). CH.sub.2Cl.sub.2 in a reaction
tube under nitrogen were added 3 mL isopropanol, 1 mL water, 93.6
mg (0.8 mmol) DIPEA, 52 mg (0.39 mmol) potassium vinyl
trifluoroborate and 78 mg (0.39 mmol)
4-chloro-2-vinyl-1,7-naphthyridine. The reaction solution was
heated to 100.degree. C. for half hour under microwave irradiation.
The reaction mixture was extracted into ethyl acetate, washed
several times with water and purified by prepTLC (petrol: ethyl
acetate=1:1) to give 4-chloro-2-vinyl-1,7-naphthyridine 50 mg
(66.8%). .sup.1H NMR (CHLOROFORM-d) .delta.: 9.51 (d, J=0.6 Hz,
1H), 8.70 (d, J=5.6 Hz, 1H), 7.98-8.04 (m, 1H), 7.89 (s, 1H), 7.02
(dd, J=17.6, 10.9 Hz, 1H), 6.41 (d, J=17.6 Hz, 1H), 5.83 (d, J=11.2
Hz, 1H). LC-MS: m/z 191.6 (M+H).sup.+
Building Block 14: 5-chloro-2-vinylquinoxaline
##STR00824##
[0626] Step 1
[0627] To a solution of 5-chloroquinoxaline (1.4 g, 8.54 mmol) in
50 mL of dichloromethane was added mCPBA (1.62 g, 9.39 mmol). The
resulting mixture was stirred at room temperature overnight. After
removal of dichloromethane, the crude product obtained was purified
by doing column chromatography (100% DCM) to afford 1.5 g of
5-chloroquinoxaline 1-oxide as a white solid.
Step 2
[0628] To a solution of 5-chloroquinoxaline 1-oxide (450 mg, 2.5
mmol) in 5 mL of chloroform was added POCl.sub.3 (1.9 g, 12.5 mmol)
slowly. The resulting mixture was heated to 80.degree. C. and held
stirring at 80.degree. C. overnight. After removal of chloroform
and excess POCl.sub.3, the crude product obtained was purified by
doing column chromatography (5% PE/EA) to afford 240 mg of
2,5-dichloroquinoxaline as a white solid. MS (ES) M+H expected 198,
found 199. .sup.1H NMR (CHLOROFORM-d) .delta.: 8.89 (s, 1H), 7.98
(d, 1H), 7.92 (d, 1H), 7.76 (t, 1H).
Step 3
[0629] To a flask was added 2,5-dichloroquinoxaline (315 mg, 1.59
mmol), potassium trifluoro(vinyl)borate (234 mg, 1.75 mmol),
PdCl.sub.2DPPF (130 mg, 0.16 mmol), K.sub.2CO.sub.3 (442 mg, 3.18
mmol), propan-2-ol (4 mL), and H.sub.2O (1 mL), the mixture was
degassed with N.sub.2, then heated to 90.degree. C. with stirring
for about 3 hrs. TLC (5% PE/EA) showed the consumption of the
starting material and new spot appeared. The mixture was then
filtered through celite, the cake was washed with ethyl acetate.
The filtrate was concentrated in vacuo, the residue was purified by
column chromatography (1-5% PE/EA) to afford 256 mg of
5-chloro-2-vinylquinoxaline as a white solid. .sup.1H NMR
(CHLOROFORM-d) .delta.: 9.10 (s, 1H), 8.02 (d, 1H), 7.85 (d, 1H),
7.71 (t, 1H), 7.09 (q, 1H), 6.57 (d, 1H), 5.89 (d, 1H). MS (ES) M+H
expected 190, found 191.
Building Block 15:
2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(-
morpholin-2-yl)nicotinonitrile
##STR00825##
[0630] Step 1
[0631] A mixture of 7-2 (500 mg, 1.28 mmol), Potassium
vinyltrifluoroborate (258 mg, 1.93 mmol), TEA (650 mg, 6.4 mmol)
and Pd(dppf)Cl.sub.2(52 mg, 0.064 mmol) in i-PrOH and water was
heated at 100.degree. C. under microwave irradiation for 0.5 hr.
The reaction mixture was concentrated and the residue was purified
by column chromatography (50% PE/EA) to afford 420 mg of title
compound. .sup.1H NMR (CHLOROFORM-d) .delta. 7.80 (s, 1H), 6.99
(dd, J=17.3, 10.8 Hz, 1H), 5.58 (dd, J=17.3, 0.8 Hz, 1H), 5.36 (dd,
J=11.0, 0.8 Hz, 1H), 4.86 (br. s., 0.5H), 4.53 (br. s., 0.5H), 4.44
(br. s., 0.5H), 4.09-4.29 (m, 2.5H), 3.65 (br. s., 0.5H), 3.41 (br.
s., 0.5H), 3.12-3.24 (m, 2H), 2.14-2.26 (m, 1H), 1.76 (br. s., 1H),
1.25-1.42 (m, 3H), 1.10-1.17 (m, 2H), 0.96-1.10 (m, 4H), 0.82 (dd,
J=7.8, 1.8 Hz, 2H).
Step 2
[0632] A mixture of
(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-v-
inylnicotinonitrile (200 mg, 0.59 mmol),
N-(2-hydroxyethyl)-4-nitrobenzenesulfonamide (174 mg, 0.71 mmol,
synthesized in accordance with Organic Letters, 2011, 13, #4, p.
728-731), and NIS (159 mg, 0.71 mmol) suspended in 10 mL of MeCN
was stirred at r.t. for 2 hrs. After the mixture was concentrated
in vacuo, the residue was purified by column chromatography (50%
PE/EA) to afford 100 mg of
N-(2-(1-(5-cyano-6-((R)-4-(cyclopropanecarbonyl)-3-methylpipera-
zin-1-yl)-2-cyclopropyl
pyridin-3-yl)-2-iodoethoxy)ethyl)-4-nitrobenzenesulfonamide as a
light yellowish solid. .sup.1H NMR (CHLOROFORM-d) .delta. 8.36-8.45
(m, J=8.8 Hz, 2H), 8.08-8.17 (m, J=8.8 Hz, 2H), 7.60 (s, 1H), 5.57
(br. s., 1H), 4.83 (br. s., 0.5H), 4.60-4.71 (m, 1H), 4.53 (br. s.,
0.5H), 4.40 (br. s., 0.5H), 4.19-4.34 (m, 2.5H), 3.54-3.72 (m, 1H),
3.15-3.48 (m, 8H), 1.88-1.98 (m, 1H), 1.75 (br. s., 1H), 1.34-1.40
(m, 3H), 1.00-1.18 (m, 6H), 0.81 (d, J=7.8 Hz, 2H).
Step 3
[0633] A mixture of
N-(2-(1-(5-cyano-6-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)--
2-cyclopropylpyridin-3-yl)-2-iodoethoxy)ethyl)-4-nitrobenzenesulfonamide
(100 mg, 0.14 mmol), K.sub.2CO.sub.3 (97 mg, 0.71 mmol) in 10 mL of
MeCN was stirred at r.t. overnight. After the mixture was filtered,
the filtrate was concentrated and the residue was purified by
column chromatography (50% PE/EA) to afford 66 mg of
2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(-
4-((4-nitrophenyl)sulfonyl)morpholin-2-yl)nicotinonitrile as a
light yellowish solid. .sup.1H NMR (CHLOROFORM-d) .delta. 8.39-8.49
(m, J=8.5 Hz, 2H), 7.90-8.02 (m, J=8.3 Hz, 2H), 7.70 (s, 1H), 4.91
(dd, J=10.2, 2.1 Hz, 1H), 4.84 (br. s., 0.5H), 4.52 (br. s., 0.5H),
4.42 (br. s., 0.5H), 4.16 (dd, J=11.8, 2.5 Hz, 4H), 3.86-4.00 (m,
2H), 3.76 (d, J=11.5 Hz, 1H), 3.61 (br. s., 0.5H), 3.14-3.38 (m,
3H), 2.52-2.69 (m, 1H), 1.97-2.09 (m, 1H), 1.74 (br. s., 1H),
1.28-1.48 (m, 3H), 1.19-1.25 (m, 2H), 1.11-1.19 (m, 2H), 1.04-1.11
(m, 2H), 0.81 (d, J=7.5 Hz, 2H).
Step 4
[0634] A mixture of
2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(-
4-((4-nitrophenyl)sulfonyl)morpholin-2-yl)nicotinonitrile (50 mg,
0.075 mmol), butane-1-thiol (3 d) and LiOH.H.sub.2O(20 mg) in 10 mL
of MeCN was stirred at r.t. overnight. After the mixture was
filtered, the filtrate was concentrated and the residue was
purified by column chromatography (10% DCM/MeOH) to afford 21 mg of
2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(-
morpholin-2-yl)nicotinonitrile. .sup.1H NMR (CHLOROFORM-d) .delta.
7.81 (br. s., 1H), 4.96 (br. s., 1H), 4.34-4.63 (m, 1H), 4.14 (br.
s., 3H), 3.97 (br. s., 1H), 3.46 (br. s., 3H), 3.32 (br. s., 2H),
3.09 (br. s., 3H), 2.75 (br. s., 1H), 2.09 (br. s., 1H), 1.74 (br.
s., 1H), 1.26 (br. s., 5H), 1.03 (br. s., 4H), 0.80 (br. s.,
2H).
Building Block 16: 5-chloro-2-vinylquinazoline
##STR00826##
[0635] Step 1
[0636] To a solution of 1-chloro-2-methyl-3-nitrobenzene (10.0 g,
58.3 mmol) in 150 mL of anhydrous DMF was added
1,1-dimethoxy-N,N-dimethylmethanamine (21.0 g, 175 mmol). The
resulting mixture was stirred at 140.degree. C. for 16 hours. After
cooling to 0.degree. C., the mixture was added slowly a solution of
NaIO.sub.4 (37.4 g, 175 mmol) in H.sub.2O and DMF. The mixture was
stirred for another 6 hours. The mixture was filtered and
partitioned between EtOAc and water. The organic layer was washed
with water and dried over Na.sub.2SO.sub.4 and concentrated to give
the crude which was purified by column to afford 6.5 g of
2-chloro-6-nitrobenzaldehyde. .sup.1H NMR (CHLOROFORM-d) .delta.
10.39 (s, 1H), 7.95-8.04 (m, 1H), 7.74-7.80 (m, 1H), 7.64 (t, J=8.0
Hz, 1H). LC-MS: m/z 186.0 (M+H).sup.+
Step 2
[0637] To a solution of 2-chloro-6-nitrobenzaldehyde (1 g, 0.0054
mmol) in ethanol was added Fe (1.8 g, 0.032 mmol), AcOH (10 ml) and
2N aqueous HCl (5 mL). The resulting mixture was stirred at
25.degree. C. for 2 hours. The mixture was filtered and the
filtrate was partitioned between DCM and water, the organic layer
was washed with water and brine, concentrated to give
2-amino-6-chlorobenzaldehyde under 25.degree. C. which was without
purification for next step. LC-MS: m/z 156.01 (M+H).
Step 3
[0638] The mixture of compound 2-amino-6-chlorobenzaldehyde (2.8 g,
0.018 mol), guanidine (3.43 g, 0.36 mol) and Na.sub.2CO.sub.3 (3.82
g, 0.36 mol) in naphthalene was stirred at 180.degree. C. for 2
hours. After cooling to room temperature, the mixture was filtered
and the solid was washed with water and DCM to give the yellow
solid 5-chloroquinazolin-2-amine which was used without
purification for next step. .sup.1H NMR (DMSO-d6) .delta.9.28 (s,
1H), 7.65 (dd, J=8.5, 7.8 Hz, 1H), 7.39 (d, J=8.5 Hz, 1H), 7.31 (d,
J=7.5 Hz, 1H), 7.16 (s, 2H). LC-MS: m/z 180.0 (M+H).
Step 4
[0639] The mixture of 5-chloroquinazolin-2-amine (2.2 g, 12.2
mmol), isoamyl nitrite (4.30 g, 36.7 mmol), CuI (1.17 g, 6.12 mmol)
and CH.sub.2I.sub.2 (16.4 g, 61.2 mmol) in THF was stirred at
60.degree. C. for 72 hours. After cooling to room temperature, the
mixture was filtered and the filtrate was partitioned between EtOAc
and water, the organic layer was washed with water and brine, dried
over Na.sub.2SO.sub.4. Then the organic layer was concentrate to
give the crude which was purified by column to give
5-chloro-2-iodoquinazoline as yellow solid. .sup.1H NMR
(CHLOROFORM-d) 9.46 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.86 (dd,
J=8.5, 7.5 Hz, 1H), 7.72 (dd, J=7.4, 1.1 Hz, 1H).
[0640] LC-MS: m/z 291.1 (M+H).
Step 5
[0641] The mixture of 5-chloro-2-iodoquinazoline (1.3 g, 4.48
mmol), potassium vinyltrifluoroborate (600 mg, 4.48 mmol),
Pd(dppf)Cl.sub.2 (165 mg, 0.224 mmol) and CsF (2.04 g, 13.4 mmol)
in dioxane/H.sub.2O was stirred at 80.degree. C. for 16 hours.
After cooling to room temperature, the mixture was partitioned
between EtOAc and water. The organic layer was washed with water,
brine and dried over Na.sub.2SO.sub.4, concentrated to give the
crude which was purified by column to give 500 mg of
5-chloro-2-vinylquinazoline as yellow solid. .sup.1H NMR
(CHLOROFORM-d) .delta. 9.75 (s, 1H), 7.93 (d, J=8.5 Hz, 1H), 7.80
(t, J=8.0 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.06 (dd, J=17.2, 10.4
Hz, 1H), 6.85 (dd, J=17.3, 1.8 Hz, 1H), 5.90 (dd, J=10.5, 1.5 Hz,
1H). LC-MS: m/z 191.0 (M+H).
Building Block 17: 4-chloro-2-vinyl-1,8-naphthyridine
##STR00827##
[0642] Step 1
[0643] A mixture of 25 g of 2-aminonicotinic acid (0.18 mol), 25 g
of K.sub.2CO.sub.3 (0.18 mol) in 250 mL of DMF was stirred at
140.degree. C. for 30 minutes, then cooled to 10.degree. C. in
ice/H.sub.2O, 11 mL of MeI (0.18 mol) was added at 10.degree. C.
dropwise, the mixture was stirred at room temperature overnight.
The mixture was filtered, the filtrate was concentrated, residue
was dissolved in EtOAc, and filtered again through a pad of silica
gel, the filtrate was concentrated to give 15 g of methyl
2-aminonicotinate. .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.:
7.67 (d, J=7.0 Hz, 1H), 7.69 (d, J=7.8 Hz, 1H), 7.60-7.44 (m, 1H),
3.54 (br. s., 3H).
Step 2
[0644] To methyl 2-aminonicotinate (7.48 g, 49 mmol) in EtOAc/THF
(150 mL/150 mL) was added 13.8 g of KtOBu (123 mmol) in portions
slowly at room temperature, and the mixture was stirred at room
temperature for 50 minutes before it was refluxed for 4 hours.
After cooling to room temperature, the mixture was concentrated,
the residue was dissolved in 200 mL of H.sub.2O, pH was adjusted to
pH=7 with 1N HCl with vigorous stirring, the resulting suspension
was filtered, the solid obtained was dried in vacuum to give 7 g of
1,8-naphthyridine-2,4-diol.
Step 3
[0645] A mixture of 8.0 g of 1,8-naphthyridine-2,4-diol (49 mmol)
in 80 mL of POCl.sub.3 was refluxed for 1.5 hour, excessive
POCl.sub.3 was removed under reduced pressure, the residue was
poured into satd NaHCO.sub.3 slowly with vigorous stirring, the
mixture was extracted with EtOAc, and the organic layers were dried
over Na.sub.2SO.sub.4, concentrated to give 2 g of
2,4-dichloro-1,8-naphthyridine, which was used in the subsequent
reaction without further purification. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.: 9.21-9.12 (m, 1H), 8.59 (dd, J=1.8, 8.3 Hz,
1H), 7.67-7.58 (m, 2H).
Step 4
[0646] 100 mg of 2,4-dichloro-1,8-naphthyridine (0.5 mmol), 68 mg
of potassium vinyltrifluoroborate (0.5 mmol), 130 mg of DIPEA (1
mmol) in iPrOH/H.sub.2O (3 mL/1 mL) was added
Pd(dppf).sub.2Cl.sub.2, then the mixture was stirred at 105.degree.
C. in a sealed tube for 1 hour. When TLC (Petroleum ether: Ethyl
acetate=3:1) indicated the completion of the reaction, the mixture
was cooled to room temperature, filtered through a pad of celite,
the filtrate was concentrated to give 120 mg of crude
4-chloro-2-vinyl-1,8-naphthyridine, and was used in the subsequent
reaction without further purification. .sup.1H NMR (400 MHz,
CHLOROFORM-d) .delta.: 9.17 (dd, J=1.8, 4.3 Hz, 1H), 8.58 (dd,
J=1.9, 8.4 Hz, 1H), 7.62-7.49 (m, 2H), 7.13-6.94 (m, 1H), 6.52 (d,
J=17.6 Hz, 1H), 5.81 (d, J=10.8 Hz, 1H).
Building Block 18: 5-chloro-3-vinylpyridazine
##STR00828##
[0648] The mixture of 5-chloropyridazin-3-ol (500 mg, 3.36 mmol),
potassium vinyltrifluoroborate (450 mg, 3.36 mmol),
Pd(dppf)Cl.sub.2 (124 mg, 0.168 mmol) and CsF (1.5 g, 10.07 mmol)
in dioxane/H.sub.2O (8 mL/2 mL) was stirred at 100.degree. C. for
16 hours. The mixture was diluted with EtOAc (50 mL) and filtered.
The filtrate was partitioned between EtOAc (50 mL) and water (30
mL), the organic layer was washed with water (30 mL), brine and
dried over Na.sub.2SO.sub.4 and concentrated to give the crude
which was purified by prep-TLC to give 200 mg of the product.
.sup.1H NMR (CHLOROFORM-d) .delta. 9.06 (d, J=2.3 Hz, 1H), 7.60 (d,
J=2.3 Hz, 1H), 7.02 (dd, J=17.8, 11.0 Hz, 1H), 6.32 (d, J=17.6 Hz,
1H), 5.77 (d, J=10.9 Hz, 1H). LC-MS: m/z 141.0 (M+H).sup.+
Building Block 19 and 20: tert-butyl
6-chloropyridazin-4-ylcarbamate and tert-butyl
5-chloropyridazin-3-ylcarbamate
##STR00829##
[0650] The mixture of 3,5-dichloropyridazine (400 mg, 2.68 mmol),
BocNH2 (314 mg, 2.68 mmol), Pd(dppf)Cl2 (99 mg, 0.134 mmol),
Xantphos (155 mg, 0.268 mmol) and Cs.sub.2CO.sub.3 (2.61 g, 8.05
mmol) in toluene was stirred at 80.degree. C. for 16 hours. The
mixture was diluted with EtOAc (50 mL) and filtered. The filtrate
was partitioned between EtOAc (50 mL) and water (30 mL), the
organic layer was washed with water (30 mL), brine and dried over
Na.sub.2SO.sub.4 and concentrated to give the crude which was
purified by prep-TLC to give 150 mg of the product 19 and 120 mg of
20.
tert-butyl 6-chloropyridazin-4-ylcarbamate
[0651] .sup.1H NMR (CHLOROFORM-d) .delta. 8.86 (d, J=2.0 Hz, 1H),
8.37 (d, J=2.3 Hz, 1H), 8.12 (br. s., 1H), 1.56 (s, 9H). LC-MS: m/z
230.1 (M+H).sup.+
tert-butyl 5-chloropyridazin-3-ylcarbamate
[0652] .sup.1H NMR (CHLOROFORM-d) .delta. 8.94 (s, 1H), 8.04 (s,
1H), 7.37 (br. s., 1H), 1.48-1.63 (s, 9H). LC-MS: m/z 230.1
(M+H).sup.+
Building Block 21: 4-chloro-6-vinyl-1H-pyrrolo[2,3-b]pyridine
##STR00830##
[0654] To a solution of 4,6-dichloro-1H-pyrrolo[2,3-b]pyridine (20
mg, 0.1 mmol), potassium vinyl trifluoroborate (13 mg, 0.1 mmol), 5
mg PdCl.sub.2(dppf). CH.sub.2Cl.sub.2 and CsF (45 mg, 0.3 mmol) in
dioxane/H.sub.2O (5:1) 3 mL was stirred at 100.degree. C. for 1
hours. Then the mixture was partitioned between EtOAc and water,
the organic was washed with water, brine and concentrated to give
the crude which was purified by column to give 14 mg of the
product. .sup.1H NMR (CHLOROFORM-d) .delta.: 11.19 (br. s., 1H),
7.39 (br. s., 1H), 7.28 (s, 2H), 6.91 (dd, J=17.3, 10.9 Hz, 1H),
6.62 (br. s., 1H), 6.21 (d, J=17.3 Hz, 1H), 5.55 (d, J=10.9 Hz,
1H). LC-MS: m/z 179.6 (M+H).sup.+
Building Block 22: 2-vinyl-1,7-naphthyridin-5-yl
trifluoromethanesulfonate
##STR00831##
[0655] Step 1
[0656] To a suspension of
5-(4-methoxybenzyloxy)-1,7-naphthyridin-2-ol (180 mg, 0.64 mmol) in
DMF (5 mL) was added POCl.sub.3 (293 mg, 1.92 mmol). The mixture
was heated at 45.degree. C. for 6 h. After cooling to room
temperature, the reaction mixture was poured into ice-water,
neutralized with NaHCO3, extracted with EtOAc (3.times.20 mL). The
organic layer washed with water (20 mL) and brine (20 mL). The
solvent was removed and 150 mg crude product was obtained which was
used in next step without further purification. LC-MS: m/z 300
(M+H).sup.+
Step 2
[0657] To a solution of
2-chloro-5-(4-methoxybenzyloxy)-1,7-naphthyridine (150 mg, 0.5
mmol) in EtOH (10 mL) was added 1N HCl (2.5 mL). Then the mixture
was heated at 90.degree. C. for 2 h. After cooling to room
temperature, 190 mg of K.sub.2CO.sub.3 was added and followed 10 mL
of methanol. The mixture was stirred vigorously for 1 h at which
time silica gel was added. The solvent was removed and the residue
was purified by column chromatography (5% methanol/dichloromethane)
to give 70 mg of title compound (83%). LC-MS: m/z 180
(M+H).sup.+
Step 3
[0658] A mixture of 2-chloro-1,7-naphthyridin-5-ol (70 mg, 0.39
mmol), Potassium vinyltrifluorobrate (104 mg, 0.78 mmol),
Pd(dppf)Cl2 (32 mg, 0.039 mmol) and CsF (119 mg, 0.78 mmol) in
dioxane:H.sub.2O=5:1 (5 ml+1 ml) was purged with N2 for three
times. Then the mixture was heated at 100.degree. C. for 2 h. The
solvent was removed and the residue was purified by column
chromatography (5% methanol/dichloromethane) to give 30 mg of title
compound (45%).
[0659] LC-MS: m/z 173 (M+H).sup.+
Step 4
[0660] To a solution of 2-vinyl-1,7-naphthyridin-5-ol (30 mg, 0.17
mmol) and Et3N (35 mg, 0.34 mmol) in dichloromethane (3 mL) was
added Tf2O (59 mg, 0.21 mmol) at 0.degree. C. Then the temperature
was raised to room temperature and stirred for 2 h. The solvent was
removed and the residue was purified by prep. TLC (EtOAc/petroleum
ether=3/7) to give 10 mg of title compound (20%). LC-MS: m/z 305
(M+H).sup.+
Building Block 23:
4-chloro-1-methyl-6-vinyl-1H-pyrazolo[3,4-b]pyridine
##STR00832##
[0662] A mixture of
4,6-dichloro-1-methyl-1H-pyrazolo[3,4-b]pyridine (0.8 g, 4.0 mmol),
Potassium vinyltrifluorobrate (540 mg, 4.0 mmol), Pd(dppf)Cl2 (98
mg, 0.12 mmol) and CsF (1.22 g, 8 mmol) in dioxane:H2O=5:1 (10 mL+2
mL) was purged with N2 three times. Then the mixture was heated at
100.degree. C. for 2 h. The solvent was removed and the residue was
purified by column chromatography (30% EtOAc/petroleum ether) to
give 500 mg of title compound (65%). .sup.1H NMR (CHLOROFORM-d)
.delta. 8.03 (s, 1H), 7.24 (s, 1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H),
6.36 (d, J=17.3 Hz, 1H), 5.64 (d, J=10.9 Hz, 1H), 4.16 (s, 3H).
LC-MS: m/z 193 (M+H).sup.+
Building Block 24: 7-bromo-2-vinylquinoline
##STR00833##
[0663] Step 1
[0664] 7-bromoquinoline 1-oxide: to a solution of 7-bromoquinoline
(1.04 g, 5 mmol) in 20 mL of DCM was added m-Chloroperbenzoic acid
(1.01 g, 5 mmol) at room temperature. The reaction mixture was then
stirred at room temperature overnight. After LC-MS showed the
completion of reaction, the mixture was poured into water and
extracted with methylene chloride. The combined organic layer was
dried over anhy. Na.sub.2SO.sub.4 and concentrated in vacuo. Column
chromatography (hexane/ethyl acetate=3/1) afforded 1.0 g of title
compound as a white solid. LC-MS: m/z 225.1 (M+H).sup.+
Step 2
[0665] 7-bromo-2-chloroquinoline: to a solution of 7-bromoquinoline
1-oxide (1.0 g, 4.5 mmol) in 20 mL of chloroform was added
Phosphorus oxychloride (3.42 g, 22 mmol) at room temperature. The
reaction mixture was then heated at reflux for 3 hours. After LC-MS
showed the completion of reaction, the mixture was poured into
water and extracted with methylene chloride. The combined organic
layer was dried over anhy. Na.sub.2SO.sub.4 and concentrated in
vacuo. Column chromatography (hexane/ethyl acetate=3/1) afforded
0.75 g of title compound as a white solid. LC-MS: m/z 244.1
(M+H).sup.+
Step 3
[0666] 7-bromo-2-vinylquinoline: to a solution of
7-bromo-2-chloroquinoline (0.75 g, 3 mmol) in 1,4-dioxane (10 mL)
was added Potassium vinyltrifluoroborate (0.42 g, 3 mmol),
dichlorobis (triphenylphosphine) palladium (II) (143 mg) and Cesium
fluoride (1.40 g, 9 mmol), and the mixture was stirred at
100.degree. C. for 10 hours under nitrogen. The mixture was diluted
with ethyl acetate and water. The organic layer was separated,
washed with brine, dried over magnesium sulfate and evaporated. The
residue was purified by column chromatography on silica gel
(hexane/ethyl acetate=4/1) afforded 0.42 g of title compound as a
white solid. LC-MS: m/z 234.9 (M+H).sup.+
Building Block 25: (R)-2-(tetrahydrofuran-2-yl)acetic acid
##STR00834##
[0667] Step 1
[0668] (R)-2-(2-(benzyloxy)ethyl)tetrahydrofuran: to a well stirred
suspension of 1.28 g (52 mmol) of NaH in dry diglyme (15 mL) was
added 6.86 g (31.2 mmol) of trimethylsulfoxonium iodide at room
temperature. The mixture was gently heated to 120.degree. C., and
compound 1 (Step 4 product in building block 6 scheme) (1 g, 5.2
mmol) in diglyme (3 mL) was added in one portion. The reaction
mixture was stirred at 120.degree. for 4 hours, cooled, carefully
quenched with water, and extracted three times with n-hexane. The
combined extracts were washed with water and brine and dried over
Na2SO4. Removal of solvent and purification by chromatography on
silica gel gave the compound 2 (0.5 g, 46%). .sup.1H NMR
(CHLOROFORM-d) .delta. 7.34-7.42 (m, 4H), 7.26-7.34 (m, 1H),
4.43-4.63 (m, 2H), 3.91-4.05 (m, 1H), 3.83-3.91 (m, 1H), 3.74 (td,
J=7.9, 6.5 Hz, 1H), 3.62 (t, J=6.6 Hz, 2H), 1.96-2.05 (m, 1H),
1.73-1.95 (m, 4H), 1.52 (dd, J=11.9, 8.7 Hz, 1H).
Step 2
[0669] (R)-2-(tetrahydrofuran-2-yl)ethanol: to a solution of
compound 2 (0.3 g, 1.45 mmol) in MeOH (15 mL) was added 10%
Pd(OH).sub.2/C (20 mg). The reaction mixture was purged with
hydrogen and stirred under an atmosphere of hydrogen for 2 d. The
black suspension was passed through a plug of celite eluting with
MeOH, then the solution was concentrated to yield the desired
product as colorless oil (0.15 g, 89%). .sup.1H NMR (CHLOROFORM-d,
400 MHz): .delta. 4.00-4.08 (m, 1H), 3.86-4.00 (m, 1H), 3.66-3.86
(m, 3H), 2.87 (br. s., 1H), 1.98-2.10 (m, 1H), 1.84-1.98 (m, 2H),
1.70-1.84 (m, 2H), 1.46-1.63 ppm (m, 1H).
Step 3
[0670] (R)-2-(tetrahydrofuran-2-yl)acetic acid: to a mixture of
compound 3 (0.15 g, 1.3 mmol), sodium periodate (0.72 G, 2.6 mmol),
water (10 mL), acetonitrile (20 mL) and carbon tetrachloride (20
mL) was added ruthenium trichloride (29 mg, 10 mol %) at
0-5.degree. C. Afterwards, the resulting mixture was allowed to
warm to rt and stirred at this temperature for 2 h. The precipitate
was removed via filtration through a pad of celite and washed with
diethylether (around 100 mL.times.5). The combined organic phase
was washed with brine (50 mL.times.3) and then dried under reduced
pressure to get the compound 4 (60 mg, contain about 8% of the
byproduct). .sup.1H NMR (CHLOROFORM-d, 400 MHz): .delta. 4.19-4.33
(m, 1H), 3.89-4.06 (m, 1H), 3.83 (td, J=7.8, 6.5 Hz, 1H), 2.62 (dd,
J=6.5, 1.5 Hz, 2H), 2.07-2.23 (m, 1H), 1.89-2.06 (m, 2H), 1.54-1.72
(m, 1H).
Example 16
The Following Compounds were Made Following Methods Analogous to
Those for Compound 273
(R)-5-(2-cyanophenyl)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)p-
iperazin-1-yl)nicotinonitrile (Compound 274; General procedure 1,
Step H)
[0671] .sup.1H NMR (CHLOROFORM-d) .delta. 7.76-7.82 (m, 1H), 7.69
(td, J=7.7, 1.4 Hz, 1H), 7.58-7.63 (m, 1H), 7.52 (td, J=7.7, 1.1
Hz, 1H), 7.46 (d, J=7.8 Hz, 1H), 4.56-4.79 (m, 1.5H), 4.44 (t,
J=10.3 Hz, 1.5H), 3.86 (d, J=13.8 Hz, 0.5H), 3.70-3.79 (m, 2H),
3.51-3.65 (m, 0.5H), 3.34-3.49 (m, 3.5H), 3.03-3.24 (m, 2H),
2.87-3.00 (m, 0.5H), 2.53-2.82 (m, 2H), 2.05-2.29 (m, 1H),
1.63-1.77 (m, 1H), 1.26 (br. s., 1H), 0.93-1.23 (m, 7H), 0.87-0.92
(m, 1.5H), 0.84 (d, J=6.8 Hz, 1.5H). LC-MS: m/z 458.2
(M+H).sup.+
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
2-methoxyphenyl)nicotinonitrile (Compound 275; General procedure 1,
Step H)
[0672] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58 (d, J=2.5 Hz, 1H),
7.39 (td, J=7.9, 1.8 Hz, 1H), 7.18-7.25 (m, 1H), 7.04 (td, J=7.4,
1.0 Hz, 1H), 6.99 (d, J=8.0 Hz, 1H), 4.69 (d, J=12.8 Hz, 0.5H),
4.49-4.60 (m, 1H), 4.44 (d, J=10.5 Hz, 0.5H), 4.25-4.38 (m, 1H),
3.79-3.89 (m, 4H), 3.68-3.78 (m, 2H), 3.51-3.63 (m, 0.5H),
3.34-3.42 (m, 3H), 2.90-3.16 (m, 2.5H), 2.53-2.82 (m, 2H),
2.09-2.36 (m, 1H), 1.75-1.88 (m, 1H), 1.02-1.18 (m, 5H), 0.79-0.96
(m, 5H). LC-MS: m/z 463.2 (M+H).sup.+
COMPOUND AGI-0007758/NB162-086 (General Procedure 1, Step H)
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
2-(trifluoromethoxy)phenyl)nicotinonitrile (Compound 276; General
procedure 1, Step H)
[0673] .sup.1H NMR (CHLOROFORM-d) .delta. 7.54 (d, J=2.0 Hz, 1H),
7.43-7.48 (m, 1H), 7.33-7.41 (m, 3H), 4.69 (d, J=13.3 Hz, 0.5H),
4.60 (t, J=13.3 Hz, 1H), 4.41 (dd, J=16.8, 13.3 Hz, 1.5H), 3.85 (d,
J=13.3 Hz, 0.5H), 3.70-3.79 (m, 2H), 3.52-3.62 (m, 0.5H), 3.35-3.49
(m, 3.5H), 3.03-3.23 (m, 2H), 2.89-3.02 (m, 0.5H), 2.53-2.82 (m,
2H), 1.67-1.78 (m, 1H), 1.04-1.12 (m, 5H), 0.77-0.98 (m, 6H).
LC-MS: m/z 517.2 (M+H).sup.+
(R)-1-(4-(6-cyclopropyl-5-(4-fluorophenyl)-3-(3-methyl-1,2,4-oxadiazol-5-y-
l)pyridin-2-yl)-2-methylpiperazin-1-yl)-3-methoxypropan-1-one
(Compound 831)
##STR00835##
[0675] To a solution of N'-hydroxyacetimidamide (221 mg, 2 mmol)
hydrochloride in 10 mL anhydrous THF was added NaH (48 mg, 2 mmol).
The reaction mixture was heated reflux for 0.5 h and (R)-methyl
6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)nicotinate (455 mg, 1 mmol) was added to this solution.
The reaction was continued reflux for 2 h. The reaction was cooled
down to RT and filtered. The filtrate was concentrated to dryness
and 120 mg product was obtained by prep-TLC. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.99 (s, 1H), 7.33-7.49 (m, 2H), 7.05-7.23
(m, 2H), 4.85 (br. s., 0.5H), 4.42 (d, J=13.1 Hz, 0.5H), 4.17 (br.
s., 0.5H), 3.77-3.93 (m, 2H), 3.47-3.77 (m, 6H), 3.37 (s, 4H),
3.06-3.26 (m, 2H), 2.81-3.06 (m, 1H), 2.51-2.80 (m, 3H), 2.31-2.49
(m, 3H), 1.87-2.11 (m, 1H), 1.28-1.43 (m, 1.5H), 1.15-1.28 (m,
3.5H), 1.12 (br. s., 1H), 0.80-1.06 (m, 2H).
(R)-5-(3-cyanophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 283; General procedure 1, Step
H)
[0676] .sup.1H NMR (CHLOROFORM-d) .delta. 7.66-7.71 (m, 2H),
7.62-7.65 (m, 1H), 7.55-7.60 (m, 2H), 4.90 (br. s., 0.5H), 4.53 (d,
J=12.8 Hz, 0.5H), 4.18-4.40 (m, 2.5H), 3.67-3.88 (m, 2.5H),
3.46-3.62 (m, 0.5H), 3.38 (s, 3H), 3.24-3.35 (m, 1H), 2.99-3.20 (m,
1.5H), 2.64-2.81 (m, 1H), 2.49-2.63 (m, 1H), 1.85-1.97 (m, 1H),
1.38 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=6.5 Hz, 1.5H), 1.14-1.21 (m,
2H), 0.94-1.04 (m, 2H). LC-MS: m/z 430.2 (M+H).sup.+
(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 285; General procedure 1, Step
H)
[0677] .sup.1H NMR (CHLOROFORM-d) .delta. 7.57-7.60 (m, 1H), 7.22
(t, J=7.8 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.68-6.74 (m, 2H), 4.89
(br. s., 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.09-4.31 (m, 2.5H),
3.67-3.81 (m, 2.5H), 3.47-3.60 (m, 0.5H), 3.37 (s, 3H), 3.18-3.29
(m, 1H), 2.95-3.16 (m, 1.5H), 2.63-2.78 (m, 1H), 2.52-2.61 (m, 1H),
2.09-2.17 (m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz,
1.5H), 1.06-1.16 (m, 2H), 0.88-0.99 (m, 2H). LC-MS: m/z 420.1
(M+H).sup.+
(R)-6-cyclopropyl-5-(isoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)nicotinonitrile (Compound 286; General procedure 1,
Step H)
[0678] .sup.1H NMR (CHLOROFORM-d) .delta. 9.34 (s, 1H), 8.53 (d,
J=6.0 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.68-7.75 (m, 1H), 7.61-7.68
(m, 2H), 7.43 (t, J=5.6 Hz, 1H), 4.94 (br. s., 0.5H), 4.57 (d,
J=13.1 Hz, 0.5H), 4.18-4.47 (m, 2.5H), 3.69-3.86 (m, 2.5H),
3.54-3.67 (m, 0.5H), 3.37-3.44 (m, 3H), 3.34 (dd, J=13.1, 6.3 Hz,
1H), 3.04-3.25 (m, 1.5H), 2.67-2.78 (m, 1H), 2.54-2.67 (m, 1H),
1.48-1.58 (m, 1H), 1.39-1.47 (m, 1.5H), 1.29-1.39 (m, 1.5H),
1.09-1.21 (m, 2H), 0.75-0.89 (m, 2H). LC-MS: m/z 456.1
(M+H).sup.+
(R)-6-cyclopropyl-5-(1H-indol-4-yl)-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 287; General procedure 1, Step
I)
[0679] .sup.1H NMR (CHLOROFORM-d) .delta. 8.40 (br. s., 1H), 7.74
(s, 1H), 7.44 (d, J=8.3 Hz, 1H), 7.24-7.29 (m, 1H), 7.02-7.10 (m,
1H), 6.37-6.45 (m, 1H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.6 Hz,
0.5H), 4.17-4.39 (m, 2.5H), 3.71-3.86 (m, 2.5H), 3.51-3.65 (m,
0.5H), 3.35-3.44 (m, 3H), 3.20-3.32 (m, 1H), 2.98-3.17 (m, 1.5H),
2.66-2.81 (m, 1H), 2.54-2.64 (m, 1H), 1.94-2.04 (m, 1H), 1.40-1.46
(m, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.08-1.17 (m, 2H), 0.80-0.91
(m, 2H). LC-MS: m/z 444.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(qui-
nolin-5-yl)nicotinonitrile (Compound 288; General procedure 1, Step
H)
[0680] .sup.1H NMR (CHLOROFORM-d) .delta. 8.97 (dd, J=4.1, 1.6 Hz,
1H), 8.23 (d, J=8.5 Hz, 1H), 7.94-8.05 (m, 1H), 7.82 (dd, J=8.5,
7.0 Hz, 1H), 7.61-7.66 (m, 1H), 7.48-7.55 (m, 1H), 7.40-7.48 (m,
1H), 4.83-5.06 (m, 0.5H), 4.56 (d, J=13.1 Hz, 0.5H), 4.15-4.43 (m,
2.5H), 3.69-3.91 (m, 2.5H), 0.57 (d, J=10.5 Hz, 0.5H), 3.36-3.45
(m, 3H), 3.33 (dd, J=13.1, 3.5 Hz, 1H), 3.01-3.26 (m, 1.5H),
2.65-2.82 (m, 1H), 2.52-2.64 (m, 1H), 1.48-1.56 (m, 1H), 1.39-1.47
(m, 1.5H), 1.29-1.38 (m, 1.5H), 1.07-1.18 (m, 2H), 0.74-0.91 (m,
2H). LC-MS: m/z 456.1 (M+H).sup.+
(R)-6-cyclopropyl-5-(1H-indol-6-yl)-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 289; General procedure 1, Step
I)
[0681] .sup.1H NMR (CHLOROFORM-d) .delta. 8.41 (br. s., 1H), 7.69
(d, J=8.0 Hz, 1H), 7.66 (s, 1H), 7.39 (s, 1H), 7.27-7.30 (m, 1H),
7.13 (dd, J=8.0, 1.5 Hz, 1H), 6.60 (t, J=2.1 Hz, 1H), 4.91 (br. s.,
0.5H), 4.53 (d, J=13.6 Hz, 0.5H), 4.13-4.32 (m, 2.5H), 3.68-3.84
(m, 2.5H), 3.49-3.65 (m, 0.5H), 3.38 (s, 3H), 3.17-3.31 (m, 1H),
2.93-3.16 (m, 1.5H), 2.64-2.82 (m, 1H), 2.53-2.63 (m, 1H),
2.13-2.23 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.30 (d, J=6.8 Hz,
1.5H), 1.09-1.17 (m, 2H), 0.84-0.98 (m, 2H).
[0682] LC-MS: m/z 444.2 (M+H).sup.+
(R)-6-cyclopropyl-5-(4-fluoronaphthalen-1-yl)-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile (Compound 290; General
procedure 1, Step H)
[0683] .sup.1H NMR (CHLOROFORM-d) .delta. 8.19 (d, J=8.0 Hz, 1H),
7.50-7.65 (m, 4H), 7.30-7.37 (m, 1H), 7.22 (dd, J=10.2, 7.9 Hz,
1H), 4.93 (br. s., 0.5H), 4.56 (d, J=13.3 Hz, 0.5H), 4.15-4.42 (m,
2.5H), 3.69-3.90 (m, 2.5H), 3.50-3.68 (m, 0.5H), 3.36-3.43 (m, 3H),
3.24-3.34 (m, 1H), 3.00-3.23 (m, 1.5H), 2.65-2.85 (m, 1H),
2.55-2.64 (m, 1H), 1.54-1.61 (m, 1H), 1.40-1.48 (m, 1.5H), 1.33
(dd, J=6.3, 3.5 Hz, 1.5H), 1.07-1.18 (m, 2H), 0.72-0.85 (m, 2H).
LC-MS: m/z 473.1 (M+H).sup.+
(R)-methyl
2-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)pyridin-3-yl)phenyl)acetate (Compound 291; General
procedure 1, Step H)
[0684] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.36-7.45
(m, 1H), 7.25-7.34 (m, 3H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.1
Hz, 0.5H), 4.26 (t, J=12.5 Hz, 2.5H), 3.64-3.85 (m, 7H), 3.50-3.61
(m, 0.5H), 3.38 (s, 3H), 3.19-3.30 (m, 1H), 2.93-3.18 (m, 2H),
2.63-2.81 (m, 1H), 2.49-2.63 (m, 1H), 2.02-2.12 (m, 1H), 1.39 (d,
J=6.3 Hz, 1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.10-1.20 (m, 2H),
0.89-1.00 (m, 2H). LC-MS: m/z 477.1 (M+H).sup.+
(R)-6-cyclopropyl-5-(1H-indazol-5-yl)-2-(4-(3-methoxypropanoyl)-3-methylpi-
perazin-1-yl)nicotinonitrile (Compound 295; General procedure 2,
Step M)
[0685] .sup.1H NMR (CHLOROFORM-d) .delta. 8.14 (br. s., 1H), 7.75
(s, 1H), 7.65 (s, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.42 (dd, J=8.7, 1.4
Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.12-4.39
(m, 2.5H), 3.69-3.89 (m, 2.5H), 3.50-3.64 (m, 0.5H), 3.38 (s, 3H),
3.20-3.33 (m, 1H), 2.97-3.20 (m, 1.5H), 2.66-2.82 (m, 1H),
2.52-2.64 (m, 1H), 1.99-2.14 (m, 1H), 1.36-1.46 (m, 1.5H), 1.30 (d,
J=6.8 Hz, 1.5H), 1.13-1.21 (m, 2H), 0.90-0.99 (m, 2H). LC-MS: m/z
445.4 (M+H).sup.+
(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)pyridin-3-yl)benzamide (Compound 296; General procedure 1, Step
H)
[0686] .sup.1H NMR (CHLOROFORM-d) .delta. 7.84-7.96 (m, J=8.5 Hz,
2H), 7.57-7.66 (m, 1H), 7.45-7.56 (m, 2H), 6.27 (br. s., 1H), 5.99
(br. s., 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.3 Hz, 0.5H),
4.14-4.38 (m, 2.5H), 3.70-3.87 (m, 2.5H), 3.47-3.62 (m, 0.5H),
3.33-3.43 (m, 3H), 3.27 (t, J=10.3 Hz, 1H), 2.99-3.21 (m, 1.5H),
2.64-2.83 (m, 1H), 2.50-2.64 (m, 1H), 1.95-2.09 (m, 1H), 1.38 (d,
J=6.3 Hz, 1.5H), 1.25-1.31 (m, 1.5H), 1.13-1.21 (m, 2H), 0.92-1.02
(m, 2H). LC-MS: m/z 448.5 (M+H).sup.+
(R)-6-cyclopropyl-5-(3-(2-hydroxyethyl)phenyl)-2-(4-(3-methoxypropanoyl)-3-
-methylpiperazin-1-yl)nicotinonitrile (Compound 297; General
procedure 1, Step H)
[0687] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.35-7.42
(m, 1H), 7.23-7.27 (m, 3H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.1
Hz, 0.5H), 4.14-4.31 (m, 2.5H), 3.91 (t, J=6.7 Hz, 2H), 3.68-3.83
(m, 2.5H), 3.49-3.61 (m, 0.5H), 3.37 (s, 3H), 3.19-3.29 (m, 1H),
2.97-3.18 (m, 1.5H), 2.91-2.97 (m, 2H), 2.64-2.81 (m, 1H),
2.52-2.62 (m, 1H), 2.02-2.14 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H),
1.27-1.32 (m, 1.5H), 1.08-1.19 (m, 2H), 0.89-1.02 (m, 2H). LC-MS:
m/z 449.6 (M+H).sup.+
(R)-3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)pyridin-3-yl)benzamide (Compound 305; General procedure 1, Step
H)
[0688] .sup.1H NMR (METHANOL-d.sub.4) .delta. 7.96 (t, J=1.5 Hz,
1H), 7.91 (dt, J=7.7, 1.6 Hz, 1H), 7.81 (s, 1H), 7.62-7.67 (m, 1H),
7.56-7.62 (m, 1H), 4.82 (br. s., 0.5H), 4.38-4.48 (m, 1H),
4.16-4.29 (m, 2H), 3.97 (d, J=13.6 Hz, 0.5H), 3.68-3.76 (m, 2H),
3.54-3.67 (m, 0.5H), 3.36 (s, 4H), 3.05-3.26 (m, 1.5H), 2.72-2.89
(m, 1H), 2.57-2.70 (m, 1H), 1.99-2.10 (m, 1H), 1.40 (d, J=6.5 Hz,
1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 1.20 (dq, J=4.4, 3.1 Hz, 2H),
0.93-1.04 (m, 2H). LC-MS: m/z 448.3 (M+H).sup.+
(R)-6-cyclopropyl-5-(3-(hydroxymethyl)phenyl)-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile (Compound 306; General
procedure 1, Step H)
[0689] .sup.1H NMR (METHANOL-d.sub.4) .delta. 7.71 (br. s., 1H),
7.37-7.48 (m, 3H), 7.32 (d, J=7.5 Hz, 1H), 4.80 (br. s., 1H), 4.68
(s, 3H), 4.36-4.51 (m, 1H), 4.13-4.30 (m, 2H), 3.95 (d, J=13.6 Hz,
0.5H), 3.67-3.78 (m, 2H), 3.50-3.65 (m, 0.5H), 3.27-3.35 (m, 2.5H),
2.99-3.20 (m, 1.5H), 2.70-2.84 (m, 1H), 2.61-2.67 (m, 1H),
2.06-2.13 (m, 1H), 1.40 (d, J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz,
1.5H), 1.12-1.24 (m, 2H), 0.96 (dd, J=7.3, 3.5 Hz, 2H). LC-MS: m/z
435.3 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-o-
xoindolin-6-yl)nicotinonitrile (Compound 313; General procedure 1,
Step H)
[0690] .sup.1H NMR (CHLOROFORM-d) .delta. 8.40 (s, 1H), 7.53-7.64
(m, 1H), 7.29 (d, J=7.8 Hz, 1H), 6.98-7.07 (m, 1H), 6.87-6.93 (m,
1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.4 Hz, 0.5H), 4.13-4.37 (m,
2.5H), 3.68-3.88 (m, 2.5H), 3.49-3.65 (m, 2.5H), 3.34-3.43 (m, 3H),
3.20-3.31 (m, 1H), 2.95-3.18 (m, 1.5H), 2.51-2.81 (m, 2H),
2.02-2.15 (m, 1H), 1.38-1.40 (m, 1.5H), 1.26-1.31 (m, 1.5H),
1.07-1.20 (m, 2H), 0.90-1.04 (m, 2H). LC-MS: m/z 460.2
(M+H).sup.+
(R)-6'-amino-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)-3,3'-bipyridine-5-carbonitrile (Compound 314; General procedure
1, Step H)
[0691] .sup.1H NMR (CHLOROFORM-d) .delta. 8.10 (d, J=2.0 Hz, 1H),
7.54 (s, 1H), 7.44-7.50 (m, 1H), 6.55-6.64 (m, 1H), 4.89 (br. s.,
0.5H), 4.72 (br. s., 2H), 4.52 (d, J=13.3 Hz, 0.5H), 4.15-4.31 (m,
2.5H), 3.69-3.85 (m, 2.5H), 3.49-3.63 (m, 0.5H), 3.34-3.43 (m, 3H),
3.19-3.31 (m, 1H), 2.96-3.17 (m, 1.5H), 2.51-2.81 (m, 2H),
1.99-2.08 (m, 1H), 1.23-1.41 (m, 3H), 1.11-1.18 (m, 2H), 0.90-0.99
(m, 2H). LC-MS: m/z 421.4 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(qui-
nolin-4-yl)nicotinonitrile (Compound 315; General procedure 1, Step
H)
[0692] .sup.1H NMR (CHLOROFORM-d) .delta. 8.99 (d, J=4.5 Hz, 1H),
8.23 (d, J=8.5 Hz, 1H), 7.78 (t, J=7.5 Hz, 1H), 7.61-7.71 (m, 2H),
7.53-7.61 (m, 1H), 7.36 (d, J=4.0 Hz, 1H), 4.93 (br. s., 0.5H),
4.56 (d, J=12.5 Hz, 0.5H), 4.25-4.45 (m, 2.5H), 3.68-3.91 (m,
2.5H), 3.57 (d, J=9.3 Hz, 0.5H), 3.29-3.45 (m, 4H), 3.01-3.27 (m,
1.5H), 2.65-2.84 (m, 1H), 2.51-2.65 (m, 1H), 1.54 (td, J=8.2, 4.1
Hz, 1H), 1.42 (d, J=5.5 Hz, 1.5H), 1.32 (t, J=5.0 Hz, 1.5H),
1.05-1.21 (m, 2H), 0.74-0.92 (m, 2H). LC-MS: m/z 456.0
(M+H).sup.+
(R)-6-cyclopropyl-5-(2,6-dimethoxyphenyl)-2-(4-(3-methoxypropanoyl)-3-meth-
ylpiperazin-1-yl)nicotinonitrile (Compound 316; General procedure
1, Step H)
[0693] .sup.1H NMR (CHLOROFORM-d) .delta. 7.51-7.57 (m, 1H),
7.30-7.38 (m, 1H), 6.65 (d, J=8.3 Hz, 2H), 4.90 (br. s., 0.5H),
4.52 (d, J=13.6 Hz, 0.5H), 4.11-4.34 (m, 2.5H), 3.67-3.84 (m,
8.5H), 3.47-3.62 (m, 0.5H), 3.32-3.43 (m, 3H), 2.95-3.24 (m, 2.5H),
2.63-2.84 (m, 1H), 2.51-2.63 (m, 1H), 1.65-1.72 (m, 1H), 1.41 (d,
J=6.5 Hz, 1.5H), 1.31 (d, J=6.8 Hz, 1.5H), 1.00-1.12 (m, 2H),
0.75-0.86 (m, 2H). LC-MS: m/z 465.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(-
2,2,2-trifluoroacetyl)-1H-indol-5-yl)nicotinonitrile (Compound 317;
General procedure 1, Step H)
[0694] .sup.1H NMR (CHLOROFORM-d) .delta. 8.44 (s, 1H), 8.10-8.18
(m, 1H), 7.67 (s, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.37 (d, J=8.3 Hz,
1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.17-4.39 (m,
2.5H), 3.69-3.88 (m, 2.5H), 3.52-3.69 (m, 0.5H), 3.35-3.45 (m, 3H),
3.22-3.35 (m, 1H), 0.98-3.20 (m, 1.5H), 2.54-2.82 (m, 2H),
2.04-2.13 (m, 1H), 1.38-1.47 (m, 1.5H), 1.31 (d, J=6.5 Hz, 1.5H),
1.14-1.19 (m, 2H), 0.90-0.97 (m, 2H). LC-MS: m/z 540.2
(M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(qui-
nolin-8-yl)nicotinonitrile (Compound 342; General procedure 1, Step
H)
[0695] .sup.1H NMR (CHLOROFORM-d) .delta. 8.94 (dd, J=4.1, 1.6 Hz,
1H), 8.23 (dd, J=8.3, 1.8 Hz, 1H), 7.90 (dd, J=8.2, 1.4 Hz, 1H),
7.73 (s, 1H), 7.66-7.71 (m, 1H), 7.59-7.66 (m, 1H), 7.45 (dd,
J=8.3, 4.3 Hz, 1H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H),
4.13-4.38 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.50-3.64 (m, 0.5H), 3.38
(s, 3H), 3.24 (t, J=12.8 Hz, 1H), 2.96-3.17 (m, 1.5H), 2.52-2.82
(m, 2H), 1.59-1.68 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.33 (d,
J=6.5 Hz, 1.5H), 1.07 (br. s., 2H), 0.78 (br. s., 2H)
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)acetamide (Compound 284; General
procedure 3, step N, method 1)
[0696] .sup.1H NMR (CHLOROFORM-d) .delta. 7.64 (s, 1H), 7.58 (s,
2H), 7.46 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12 (d, J=7.8
Hz, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.11-4.36
(m, 2.5H), 3.67-3.86 (m, 2.5H), 3.54 (t, J=10.9 Hz, 0.5H),
3.33-3.43 (m, 3H), 3.18-3.31 (m, 1H), 2.94-3.17 (m, 1.5H),
2.63-2.79 (m, 1H), 2.51-2.63 (m, 1H), 2.17-2.28 (m, 3H), 2.06-2.14
(m, 1H), 1.38 (d, J=6.5 Hz, 1.5H), 1.27 (d, J=7.0 Hz, 1.5H),
1.08-1.17 (m, 2H), 0.91-1.00 (m, 2H). LC-MS: m/z 462.2
(M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)acrylamide (Compound 343; General
procedure 3, Step N, method 1)
[0697] .sup.1H NMR (CHLOROFORM-d) .delta. 7.70-7.79 (m, 2H),
7.54-7.63 (m, 2H), 7.41 (t, J=7.9 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H),
6.48 (dd, J=16.8, 1.0 Hz, 1H), 6.31 (dd, J=16.8, 10.0 Hz, 1H), 5.81
(dd, J=10.2, 1.1 Hz, 1H), 4.91 (br. s., 1H), 4.54 (d, J=13.1 Hz,
0.5H), 4.12-4.36 (m, 2.5H), 3.69-3.88 (m, 2.5H), 3.49-3.65 (m,
0.5H), 3.38 (s, 3H), 3.20-3.33 (m, 1H), 2.96-3.17 (m, 1.5H),
2.54-2.81 (m, 2H), 2.07-2.16 (m, 1H), 1.39 (d, J=6.5 Hz, 1.5H),
1.25-1.35 (m, 1.5H), 1.15 (quin, J=3.6 Hz, 2H), 0.89-1.02 (m, 2H).
LC-MS: m/z 474.6 (M+H).sup.+
(R,E)-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)pyridin-3-yl)phenyl)but-2-enamide (Compound 415; General
procedure 3, Step N, method 2)
[0698] .sup.1H NMR (CHLOROFORM-d) .delta. 7.64-7.76 (m, 2H),
7.60-7.63 (m, 1H), 7.49-7.53 (m, 1H), 7.37-7.44 (m, 1H), 7.30-7.35
(m, 1H), 7.14 (d, J=7.8 Hz, 1H), 6.95-7.10 (m, 1H), 5.99 (dd,
J=15.1, 1.8 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=12.8 Hz, 0.5H),
4.20-4.32 (m, 2.5H), 3.76 (t, J=6.3 Hz, 2H), 3.50-3.62 (m, 0.5H),
3.39 (s, 3H), 3.18-3.34 (m, 1.5H), 2.97-3.16 (m, 1.5H), 2.65-2.80
(m, 1H), 2.53-2.65 (m, 1H), 2.09-2.16 (m, 1H), 1.95 (dd, J=6.8, 1.5
Hz, 3H), 1.40 (d, J=6.3 Hz, 1H), 1.29-1.31 (m, 2H), 1.12-1.19 (m,
2H), 0.92-1.01 (m, 2H)
[0699] LC-MS: m/z 487.3 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)-2-oxopropanamide (Compound 416;
General procedure 3, step N, method 2)
[0700] .sup.1H NMR (CHLOROFORM-d) .delta. 7.38-7.66 (m, 4H), 7.32
(dd, J=3.9, 1.9 Hz, 1H), 7.12-7.25 (m, 1H), 4.89 (s, 0.5H), 4.52
(d, J=10.8 Hz, 0.5H), 4.22-4.34 (m, 2H), 4.10-4.22 (m, 0.5H),
3.66-3.85 (m, 2.5H), 3.55 (d, J=3.5 Hz, 0.5H), 3.39 (d, J=1.5 Hz,
3H), 3.20-3.31 (m, 1H), 3.10-3.14 (m, 1.5H), 2.97-3.09 (m, 1H),
2.66-2.80 (m, 1H), 2.53-2.64 (m, 1H), 1.97-2.07 (m, 1H), 1.55-1.58
(m, 3H), 1.35-1.42 (m, 2H), 1.10-1.17 (m, 1H), 1.05-1.10 (m, 1H),
0.73-0.96 (m, 4H). LC-MS: m/z 490.2 (M+H).sup.+
(R)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)pyridin-3-yl)phenyl)acetamide (Compound 403;
General procedure 3, Step N, method 1)
[0701] .sup.1H NMR (CHLOROFORM-d) .delta. 8.34 (s, 1H), 7.66-7.75
(m, 1H), 7.62 (s, 1H), 7.50-7.55 (m, 1H), 7.42-7.48 (m, 1H), 7.22
(d, J=7.8 Hz, 1H), 4.92 (s, 0.5H), 4.50-4.54 (m, 0.5H), 4.29-4.33
(m, 1H), 4.26 (m, 1H), 4.21-4.25 (m, 0.5H), 3.71-3.84 (m, 2.5H),
3.52-3.57 (m, 0.5H), 3.39 (s, 3H), 3.21-3.32 (m, 1H), 3.13 (d,
J=11.3 Hz, 1H), 3.05 (d, J=12.3 Hz, 0.5H), 2.66-2.81 (m, 1H),
2.54-2.65 (m, 1H), 2.07-2.12 (m, 1H), 1.40 (d, J=6.3 Hz, 1H),
1.28-1.31 (m, 2H), 1.14-1.19 (m, 2H), 0.94-1.00 (m, 2H). LC-MS: m/z
495.2 (M+H).sup.+
(R)-1-chloro-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)pyridin-3-yl)phenyl)methanesulfonamide (Compound
404; General procedure 3, Step N, method 1)
[0702] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 7.44-7.52
(m, 1H), 7.36-7.41 (m, 1H), 7.29-7.36 (m, 2H), 7.11 (br. s., 1H),
4.92 (s, 1H), 4.45-4.63 (m, 2.5H), 4.18-4.40 (m, 2.5H), 3.66-3.89
(m, 2.5H), 3.50-3.57 (m, 0.5H), 3.39 (s, 3H), 3.29 (t, J=10.2 Hz,
1H), 2.99-3.20 (m, 1.5H), 2.65-2.83 (m, 1H), 2.52-2.64 (m, 1H),
1.99-2.06 (m, 1H), 1.40 (d, J=6.3 Hz, 1H), 1.30 (s, 2H), 1.15-1.22
(m, 2H), 0.96-1.03 (m, 2H). LC-MS: m/z 531.2 (M+H).sup.+
(R)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-m-
ethylpiperazin-1-yl)pyridin-3-yl)phenyl)propanamide (Compound 462;
General procedure 3, Step N, method 2)
[0703] .sup.1H NMR (CHLOROFORM-d) .delta. 8.54 (s, 1H), 7.67-7.73
(m, 1H), 7.60 (s, 1H), 7.49-7.57 (m, 1H), 7.38-7.45 (m, 1H),
7.14-7.22 (m, 1H), 4.90 (br. s., 0.5H), 4.44-4.64 (m, 1.5H),
4.16-4.37 (m, 2.5H), 3.68-3.86 (m, 2.5H), 3.50-3.63 (m, 0.5H), 3.37
(s, 3H), 3.19-3.32 (m, 1H), 2.96-3.17 (m, 1.5H), 2.53-2.78 (m, 2H),
2.05-2.12 (m, 1H), 1.83 (d, J=7.0 Hz, 3H), 1.39 (d, J=6.5 Hz,
1.5H), 1.28 (dd, J=6.9, 2.6 Hz, 1.5H), 1.10-1.19 (m, 2H), 0.90-1.02
(m, 2H). LC-MS: m/z 510.2 (M+H).sup.+
(R)--N-(4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)acetamide (Compound 412; General
procedure 1, Step H)
[0704] .sup.1H NMR (CHLOROFORM-d) .delta. 7.55-7.67 (m, 3H),
7.31-7.44 (m, 3H), 4.91 (s, 0.5H), 4.54 (d, J=13.6 Hz, 0.5H),
4.14-4.33 (m, 2.5H), 3.65-3.93 (m, 2.5H), 3.46-3.65 (m, 0.5H), 3.39
(s, 3H), 3.20-3.30 (m, 1H), 2.98-3.19 (m, 1.5H), 2.51-2.81 (m, 1H),
2.16-2.31 (m, 3H), 1.98-2.13 (m, 1H), 1.24-1.44 (m, 4H), 1.08-1.18
(m, 2H), 0.84-0.99 (m, 2H). LC-MS: m/z 462.6 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)propionamide (Compound 424; General
procedure 3, Step N, method 2)
[0705] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (s, 1H), 7.68 (s,
1H), 7.59 (s, 1H), 7.49 (d, J=8.0 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H),
7.11 (d, J=7.5 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J=13.3 Hz, 0.5H),
4.14-4.35 (m, 2.5H), 3.67-3.85 (m, 2.5H), 3.49-3.62 (m, 0.5H), 3.37
(s, 3H), 3.17-3.32 (m, 1H), 2.93-3.17 (m, 1.5H), 2.63-2.81 (m, 1H),
2.52-2.63 (m, 1H), 2.37-2.49 (m, 2H), 2.05-2.13 (m, 1H), 1.38 (d,
J=6.5 Hz, 1H), 1.22-1.31 (m, 5H), 1.14 (dt, J=7.4, 3.6 Hz, 2H),
0.88-1.01 (m, 2H). LC-MS: m/z 476.3 (M+H).sup.+
(R)-1-cyano-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methyl-
piperazin-1-yl)pyridin-3-yl)phenyl)cyclopropanecarboxamide
(Compound 425; General procedure 3, Step N, method 2)
[0706] .sup.1H NMR (CHLOROFORM-d) .delta. 8.11 (s, 1H), 7.65 (s,
1H), 7.61 (s, 1H), 7.42-7.50 (m, 2H), 7.19-7.25 (m, 1H), 4.92 (s,
0.5H), 4.55 (d, J=12.3 Hz, 0.5H), 4.17-4.39 (m, 2.5H), 3.71-3.76
(m, 2.5H), 3.55-3.58 (m, 0.5H), 3.36-3.46 (m, 3H), 3.21-3.33 (m,
1H), 3.14 (d, J=13.3 Hz, 1.5H), 3.05 (d, J=12.0 Hz, 1H), 2.63-3.75
(s, 1H), 2.61-3.63 (m, 1H), 2.02-2.12 (m, 1H), 1.81-1.91 (m, 2H),
1.66 (q, J=4.5 Hz, 2H), 1.40 (d, J=5.5 Hz, 1H), 1.25-1.33 (m, 2H),
1.12-1.20 (m, 2H), 0.92-1.01 (m, 2H). LC-MS: m/z 513.2
(M+H).sup.+
Compound 427 (General Procedure 3, Step N, method 1)
[0707] .sup.1H NMR (CHLOROFORM-d) .delta. 7.62 (s, 1H), 7.47-7.56
(m, 1H), 7.35-7.44 (m, 1H), 7.18-7.25 (m, 2H), 6.42 (dd, J=16.8,
2.0 Hz, 1H), 6.16 (dd, J=16.6, 10.3 Hz, 1H), 5.57 (dd, J=10.2, 1.6
Hz, 1H), 4.92 (d, J=12.8 Hz, 0.5H), 4.55 (d, J=12.8 Hz, 0.5H),
4.13-4.41 (m, 3H), 3.69-3.90 (m, 3H), 3.58 (d, J=9.3 Hz, 1H), 3.39
(s, 3H), 3.42 (s, 3H), 3.29 (t, J=9.5 Hz, 1H), 3.01-3.21 (m, 2H),
2.65-2.80 (m, 1H), 2.47-2.65 (m, 1H), 1.88-2.07 (m, 1H), 1.65 (br.
s., 3H), 1.35-1.44 (m, 2H), 1.25-1.35 (m, 2H), 1.09-1.25 (m, 2H),
0.92-1.09 (m, 2H). LC-MS: m/z 488.2 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)propiolamide (Compound 428; General
procedure 3, Step N, Method 2)
[0708] .sup.1H NMR (CHLOROFORM-d) .delta. 7.63-7.69 (m, 2H), 7.61
(s, 1H), 7.41-7.50 (m, 2H), 7.20 (d, J=7.3 Hz, 1H), 4.92 (s, 0.5H),
4.54 (d, J=11.8 Hz, 0.5H), 4.12-4.40 (m, 2.5H), 3.72-3.79 (m,
2.5H), 3.51-3.57 (m, 0.5H), 3.40 (s, 3H), 3.23-3.32 (m, 1H), 3.14
(d, J=13.1 Hz, 1H), 3.05 (d, J=11.0 Hz, 1H), 2.99 (s, 1H),
2.65-2.81 (m, 1H), 2.54-2.65 (m, 1H), 2.05-2.13 (m, 1H), 1.40 (d,
J=6.5 Hz, 1H), 1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H), 0.88-0.93 (m,
2H).
[0709] LC-MS: m/z 472.2 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)ethenesulfonamide (Compound 429;
General procedure 3, Step N, method 1)
[0710] To a solution of
(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)nicotinonitrile (20 mg, 0.048 mmol) and
2-chloroethanesulfonyl chloride (8.6 mg, 0.052 mmol) in 5 ml of DCM
was added dropwised TEA (15 mg, 0.143 mmol) at 0.degree. C., then
the resulting mixture was allowed to warm to room temperature and
stirred for 2 hours. The mixture was partitioned between EtOAc and
water. The organic layer was dried over Na.sub.2SO.sub.4 and
concentrated to give the crude which was purified by prep-TLC to
give 15 mg of the product. .sup.1H NMR (CHLOROFORM-d) .delta.
7.55-7.61 (m, 1H), 7.37-7.46 (m, 1H), 7.15-7.26 (m, 3H), 6.70 (d,
J=12.8 Hz, 1H), 6.62 (dd, J=16.4, 9.9 Hz, 1H), 6.34 (d, J=16.3 Hz,
1H), 6.02 (d, J=9.8 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=13.3 Hz,
0.5H), 4.19-4.37 (m, 2.5H), 3.73-3.79 (m, 3H), 3.52-3.61 (m, 0.5H),
3.39 (s, 3H), 3.28 (t, J=10.4 Hz, 1H), 3.02-3.14 (m, 1H), 2.65-2.80
(m, 1H), 2.55-2.64 (m, 1H), 1.98-2.07 (m, 1H), 1.27 (s, 3H),
1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H).
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)-2-fluoroacrylamide (Compound 431;
General procedure 3, Step N, method 2)
[0711] .sup.1H NMR (CHLOROFORM-d) .delta. 8.19 (d, J=4.5 Hz, 1H),
7.75 (s, 1H), 7.61 (s, 1H), 7.57 (dd, J=8.0, 1.3 Hz, 1H), 7.43 (t,
J=7.9 Hz, 1H), 7.16-7.23 (m, 1H), 5.84 (dd, J=18.0 Hz, J=3.3 Hz,
0.5H), 5.21-5.35 (m, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz,
0.5H), 4.10-4.38 (m, 2.5H), 3.66-3.86 (m, 2.5H), 3.50-3.64 (m,
0.5H), 3.38 (s, 3H), 3.19-3.33 (m, 1H), 2.95-3.18 (m, 1.5H),
2.56-2.78 (m, 2H), 2.04-2.16 (m, 1H), 1.39 (d, J=6.3 Hz, 1.5H),
1.28 (d, J=6.8 Hz, 1.5H), 1.11-1.22 (m, 2H), 0.91-1.03 (m, 2H).
LC-MS: m/z 492.7 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)-2,2-difluoroacetamide (Compound 432;
General procedure 3, Step N, method 2)
[0712] .sup.1H NMR (CHLOROFORM-d) .delta. 8.79 (br. s., 1H), 7.77
(s, 1H), 7.55-7.65 (m, 2H), 7.44 (t, J=7.9 Hz, 1H), 7.22 (d, J=7.8
Hz, 1H), 6.05 (t, J=56.0 Hz, 1H), 4.89 (br. s., 0.5H), 4.51 (d,
J=13.3 Hz, 0.5H), 4.08-4.37 (m, 2.5H), 3.66-3.88 (m, 2.5H),
3.49-3.63 (m, 0.5H), 3.36 (s, 3H), 2.96-3.25 (m, 2.5H), 2.81 (s,
6H), 2.50-2.79 (m, 2H), 2.03-2.13 (m, 1H), 1.32-1.45 (m, 1.5H),
1.27 (d, J=6.8 Hz, 1.5H), 1.10-1.17 (m, 2H), 0.91-1.02 (m, 2H)
[0713] LC-MS: m/z 498.8 (M+H).sup.+
(R)-5-(4-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)nicotinonitrile (Compound 383; General procedure 1, Step
H)
[0714] .sup.1H NMR (CHLOROFORM-d) .delta. 7.53-7.62 (m, 1H),
7.11-7.21 (m, 2H), 6.70-6.83 (m, 2H), 4.89 (br. s., 0.5H), 4.52 (d,
J=13.6 Hz, 0.5H), 4.04-4.28 (m, 2.5H), 3.64-3.88 (m, 4.5H),
3.47-3.64 (m, 0.5H), 3.30-3.43 (m, 3H), 3.14-3.27 (m, 1H),
2.92-3.14 (m, 1.5H), 2.50-2.79 (m, 2H), 2.08-2.15 (m, 1H),
1.34-1.43 (m, 1.5H), 1.28-1.30 (m, 1.5H), 1.06-1.15 (m, 2H),
0.84-0.95 (m, 2H). LC-MS: m/z 420.1 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-o-
xoindolin-5-yl)nicotinonitrile (Compound 384; General procedure 1,
Step H)
[0715] .sup.1H NMR (CHLOROFORM-d) .delta. 8.22 (s, 1H), 7.50-7.64
(m, 1H), 7.21-7.26 (m, 2H), 6.85-7.03 (m, 1H), 4.90 (br. s., 0.5H),
4.53 (d, J=13.6 Hz, 0.5H), 4.10-4.37 (m, 2.5H), 3.68-3.86 (m,
2.5H), 3.48-3.64 (m, 2.5H), 3.35-3.44 (m, 3H), 3.19-3.31 (m, 1H),
2.94-3.17 (m, 1.5H), 2.52-2.82 (m, 2H), 1.99-2.09 (m, 1H), 1.39 (d,
J=6.5 Hz, 1.5H), 1.28 (d, J=6.8 Hz, 1.5H), 1.09-1.20 (m, 2H),
0.91-0.99 (m, 2H). LC-MS: m/z 460.5 (M+H).sup.+
(R)-6-cyclopropyl-5-(1H-indazol-6-yl)-2-(4-(3-methoxypropanoyl)-3-methylpi-
perazin-1-yl)nicotinonitrile (Compound 385; General procedure 1,
Step H)
[0716] .sup.1H NMR (CHLOROFORM-d) .delta. 8.14 (br. s., 1H), 7.82
(d, J=8.3 Hz, 1H), 7.66 (s, 1H), 7.50 (s, 1H), 7.16-7.24 (m, 1H),
4.91 (br. s., 0.5H), 4.54 (d, J=12.5 Hz, 0.5H), 4.16-4.39 (m,
2.5H), 3.69-3.85 (m, 2.5H), 3.50-3.65 (m, 0.5H), 3.38 (s, 3H),
3.20-3.32 (m, 1H), 2.98-3.14 (m, 1.5H), 2.52-2.82 (m, 2H),
2.04-2.13 (m, 1H), 1.28-1.43 (m, 3H), 0.91-0.98 (m, 2H), 0.81-0.89
(m, 2H).
[0717] LC-MS: m/z 445.5 (M+H).sup.+
(R)-6-cyclopropyl-5-(isoquinolin-5-yl)-2-(3-methyl-4-(3,3,3-trifluoropropa-
noyl)piperazin-1-yl)nicotinonitrile (Compound 386; General
procedure 2, Step M)
[0718] .sup.1H NMR (CHLOROFORM-d) .delta. 9.30-9.40 (m, 1H),
8.49-8.58 (m, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.67-7.75 (m, 1H),
7.62-7.67 (m, 2H), 7.36-7.45 (m, 1H), 4.95 (br. s., 0.5H),
4.58-4.61 (m, 0.5H), 4.27-4.49 (m, 2H), 4.14 (br. s., 0.5H),
3.59-3.73 (m, 1H), 3.11-3.39 (m, 4.5H), 1.45-1.55 (m, 2.5H), 1.37
(dd, J=6.4, 4.4 Hz, 1.5H), 1.07-1.19 (m, 2H), 0.77-0.87 (m, 2H).
LC-MS: m/z 480.1 (M+H).sup.+
[0719]
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)pipe-
razin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile (Compound 387;
General procedure 2, Step M)
[0720] .sup.1H NMR (CHLOROFORM-d) .delta. 9.40 (br. s., 1H), 8.56
(d, J=4.5 Hz, 1H), 8.10 (d, J=8.0 Hz, 1H), 7.72-7.78 (m, 1H),
7.64-7.71 (m, 2H), 7.46 (dd, J=12.5, 5.8 Hz, 1H), 4.58 (dt, J=13.1,
2.1 Hz, 1H), 4.47 (d, J=12.0 Hz, 1H), 4.09-4.26 (m, 0.5H),
3.80-3.86 (m, 1.5H), 3.08-3.44 (m, 5H), 1.49-1.57 (m, 1H), 1.33
(br. s., 1H), 1.08-1.22 (m, 2H), 0.82-0.91 (m, 2H), 0.41-0.72 (m,
4H).
[0721] LC-MS: m/z 506.7 (M+H).sup.+
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2'-vin-
yl-3,4'-bipyridine-5-carbonitrile (Compound 390)
##STR00836##
[0723] A mixture of 7-1 (410 mg, 1.01 mmol),
2-chloropyridin-4-ylboronic acid (237 mg, 0.95 mmol),
K.sub.2CO.sub.3 (414 mg, 3.03 mmol) and Pd(PPh.sub.3).sub.4 (40 mg,
0.035 mmol) in DMF (2 mL) was stirred at 150.degree. C. in the
microwave reactor for 1 h. The resultant mixture was partitioned
between EtOAc and water, the organic phase was washed with water,
brine and concentrated and purified by prepTLC (PE:EA=1:1) to give
375 mg of
(R)-2'-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)-3,4'-bipyridine-5-carbonitrile. .sup.1H NMR (CHLOROFORM-d)
.delta. 8.34-8.61 (m, 1H), 7.60 (s, 1H), 7.39 (d, J=1.0 Hz, 1H),
4.90 (br. s., 0.5H), 4.52 (d, J=11.8 Hz, 0.5H), 4.21-4.41 (m,
2.5H), 3.68-3.91 (m, 2.5H), 3.54 (d, J=4.0 Hz, 1H), 3.25-3.45 (m,
4H), 2.95-3.25 (m, 1H), 2.63-2.92 (m, 1H), 2.42-2.63 (m, 1H),
1.87-2.07 (m, 1H), 1.36 (d, J=6.5 Hz, 1.5H), 1.11-1.31 (m, 3.5H),
0.81-1.11 (m, 2H). LC-MS: m/z 440.1 (M+H).sup.+
[0724] A mixture of
(R)-2'-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)-3,4'-bipyridine-5-carbonitrile (40 mg, 0.09 mmol), vinyl
tributyl stananne (30 mg, 0.09 mmol), KOAc (10 mg) and
Pd(PPh.sub.3).sub.4 (5 mg) in DMF (2 mL) was stirred at 120.degree.
C. in the microwave reactor for 20 min. The resulting mixture was
concentrated and purified by prepTLC (PE: EA=1:1) to give 25 mg of
the title product. .sup.1H NMR (CHLOROFORM-d) .delta. 8.64 (d,
J=5.0 Hz, 1H), 7.63 (s, 1H), 7.31-7.45 (m, 1H), 7.22 (dd, J=5.0,
1.8 Hz, 1H), 6.87 (dd, J=17.6, 10.8 Hz, 1H), 6.27 (dd, J=17.6, 1.0
Hz, 1H), 5.41-5.71 (m, 1H), 4.90 (m, 0.5H), 5.51 (m, 6.5H),
4.16-4.44 (m, 3H), 3.74 (t, J=6.1 Hz, 3H), 3.38 (s, 4H), 3.31 (d,
J=4.0 Hz, 1H), 3.14 (br. s., 2H), 2.59 (t, J=6.0 Hz, 2H), 1.86-2.06
(m, 1H), 1.38 (d, J=6.3 Hz, 1.5H), 1.24-1.33 (m, 1.5H), 1.10-1.24
(m, 2H), 0.83-1.10 (m, 2H). LC-MS: m/z 432.6 (M+H).sup.+
(R)-2'-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1--
yl)-3,4'-bipyridine-5-carbonitrile (Compound 401)
[0725] .sup.1H NMR (CHLOROFORM-d) .delta. 8.34-8.61 (m, 1H), 7.60
(s, 1H), 7.39 (d, J=1.0 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d,
J=11.8 Hz, 0.5H), 4.21-4.41 (m, 2.5H), 3.68-3.91 (m, 2.5H), 3.54
(d, J=4.0 Hz, 1H), 3.25-3.45 (m, 4H), 2.95-3.25 (m, 1H), 2.63-2.92
(m, 1H), 2.42-2.63 (m, 1H), 1.87-2.07 (m, 1H), 1.36 (d, J=6.5 Hz,
1.5H), 1.11-1.31 (m, 3.5H), 0.81-1.11 (m, 2H). LC-MS: m/z 440.1
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(isoquinolin-5-yl)nicotinonitrile (Compound 391; General
procedure 1, Step H)
[0726] .sup.1H NMR (CHLOROFORM-d) .delta. 9.41 (s, 1H), 8.54 (d,
J=5.3 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.68-7.81 (m, 2H), 7.61-7.67
(m, 1H), 7.45-7.56 (m, 1H), 4.58 (d, J=11.5 Hz, 1H), 4.46 (d,
J=13.1 Hz, 1H), 3.49-4.23 (m, 2.5H), 3.16-3.33 (m, 2.5H), 1.58-1.69
(m, 1H), 1.42-1.54 (m, 1H), 1.17 (t, J=4.9 Hz, 2H), 1.00-1.10 (m,
3H), 0.76-0.87 (m, 4H), 0.69 (br. s., 1H), 0.41-0.62 (m, 3H);
LC-MS: m/z 464.2 (M+H)
(R)-1-(4-(6-cyclopropyl-5-(4-fluorophenyl)-3-(1,3,4-oxadiazol-2-yl)pyridin-
-2-yl)-2-methylpiperazin-1-yl)-3-methoxypropan-1-one (Compound
392)
##STR00837## ##STR00838##
[0727] Step 1
[0728]
(R)-5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinonitrile
(2 g, 6.3 mmol) was dissolved in MeOH (5 mL) and NaOH (20% wt aq,
10 mL) and the reaction solution was heated to reflux overnight.
The resultant solution was concentrated and then dissolved in MeOH
(10 mL), treated with SOCl.sub.2 (0.1 ml) and then heated to reflux
for 2 h. The resulting solution was concentrated, washed with brine
and exacted with EA (50 mL). The organic phase was dried,
concentrated and purified with flash column (EA:PE=1:3) to give
(R)-methyl
5-bromo-6-cyclopropyl-2-(3-methylpiperazin-1-yl)nicotinate as a
white solid (804 mg, 50% yield).
Step 2
[0729] Following the same procedure as General procedure 1, step F,
method 1.
Step 3
[0730] Following the same procedure as General procedure 1, step
H.
Step 4
[0731]
(R)-methyl6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl-
)-3-methylpiperazin-1-yl)nicotinate (500 mg, 1.1 mmol) and 2 mL
hydrazine hydrate was dissolved in 10 mL ethanol. The reaction
mixture was heated reflux overnight and cooled down to rt. The
mixture was filtered and the residue was washed with cold ethanol.
200 mg title compound was obtained without further
purification.
Step 5
[0732]
(R)-6-cyclopropyl-5-(4-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-me-
thylpiperazin-1-yl)nicotine-hydrazide (200 mg, 0.44 mmol) was
dissolved in trimethoxymethane (25 mL). The reaction mixture was
heated to reflux overnight. The rest of trimethoxymethane was
removed under reduced pressure and purified by prep-TLC to give 50
mg of title compound. .sup.1H NMR (CHLOROFORM-d) .delta. 9.33 (s,
1H), 8.51 (d, J=6.0 Hz, 1H), 8.10 (s, 1H), 8.02 (d, J=7.8 Hz, 1H),
7.62-7.89 (m, 2H), 7.27 (s, 1H), 4.63-4.78 (m, 2H), 4.47-4.63 (m,
1H), 3.55-3.84 (m, 3H), 3.39 (s, 4H), 3.19 (dd, J=13.3, 3.5 Hz,
1H), 2.91-3.12 (m, 2H), 2.66-2.88 (m, 3H), 2.44-2.66 (m, 2H),
1.28-1.43 (m, 1.5H), 1.15-1.28 (m, 3.5H), 1.12 (br. s., 1H),
0.80-1.06 (m, 2H); LC-MS: m/z 466.2 (M+H).
2-(4-(cyclopropanecarbonyl)-3-(trifluoromethyl)piperazin-1-yl)-6-cycloprop-
yl-5-(isoquinolin-5-yl)nicotinonitrile (Compound 397; General
procedure 4, Step R and S)
[0733] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (s, 1H), 8.54 (t,
J=6.4 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.60-7.76 (m, 3H), 7.35-7.49
(m, 1H), 5.39 (br. s., 0.5H), 4.28-4.86 (m, 3.5H), 3.70-3.97 (m,
1H), 3.44 (d, J=14.3 Hz, 1H), 3.23-3.39 (m, 1H), 1.68-1.91 (m, 1H),
1.53 (td, J=7.8, 3.5 Hz, 1H), 1.08-1.23 (m, 3H), 0.77-1.07 (m, 5H).
LC-MS: m/z 492.2 (M+H).sup.+
6-cyclopropyl-5-(isoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-(trifluorom-
ethyl)piperazin-1-yl)nicotinonitrile (Compound 398; General
procedure 4, Step R and S)
[0734] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (br. s., 1H), 8.55
(t, J=6.0 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.60-7.80 (m, 3H), 7.42
(dd, J=19.3, 5.5 Hz, 1H), 5.29-5.48 (m, 0.5H), 4.71-4.92 (m, 1.5H),
4.44-4.62 (m, 1H), 4.02 (d, J=13.3 Hz, 0.5H), 3.63-3.86 (m, 2.5H),
3.33-3.51 (m, 3.5H), 3.19-3.32 (m, 2H), 2.75-2.94 (m, 1H),
2.52-2.75 (m, 1H), 2.06 (br. s., 1H), 1.52 (tq, J=8.0, 4.1 Hz, 1H),
1.10-1.22 (m, 2H), 0.76-0.93 (m, 2H). LC-MS: m/z 510.4
(M+H).sup.+
6-cyclopropyl-5-(isoquinolin-5-yl)-2-(3-(trifluoromethyl)-4-(3,3,3-trifluo-
ropropanoyl)piperazin-1-yl)nicotinonitrile (Compound 399; General
procedure 4, Step R and S)
[0735] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (s, 1H), 8.54 (t,
J=6.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.55-7.80 (m, 3H), 7.32-7.45
(m, 1H), 5.26-5.49 (m, 0.5H), 4.45-5.03 (m, 2.5H), 3.72-3.95 (m,
2H), 3.22-3.52 (m, 5H), 1.54 (tq, J=8.0, 4.2 Hz, 1H), 1.10-1.22 (m,
2H), 0.78-0.94 (m, 3H). LC-MS: m/z 534.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(iso-
quinolin-5-yl)nicotinonitrile (Compound 402; General procedure 1,
Step H)
[0736] .sup.1H NMR (CHLOROFORM-d) .delta. 9.36 (br. s., 1H), 8.55
(d, J=5.8 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.52-7.77 (m, 3H), 7.44
(t, J=6.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.25-4.48 (m, 2.5H), 4.21
(br. s., 0.5H), 3.95 (br. s., 2H), 3.66-3.86 (m, 1.5H), 3.56-3.66
(m, 1H), 3.28-3.47 (m, 1H), 2.99-3.28 (m, 2H), 2.49-2.77 (m, 1H),
1.40-1.57 (m, 3H), 1.11-1.40 (m, 2H), 0.75-1.04 (m, 2H); LC-MS: m/z
442.2 (M+H).
(R)-6-cyclopropyl-5-(3-(dimethylamino)phenyl)-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile (Compound 413; General
procedure 1, Step H)
[0737] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61-7.69 (m, 1H),
7.29-7.34 (m, 1H), 6.65-6.83 (m, 3H), 4.91 (br. s., 0.5H), 4.54 (d,
J=13.3 Hz, 0.5H), 4.14-4.34 (m, 2.5H), 3.70-3.87 (m, 2.5H), 3.56
(t, J=11.2 Hz, 0.5H), 3.34-3.46 (m, 3H), 3.00-3.28 (m, 8.5H),
2.54-2.83 (m, 2H), 2.14-2.23 (m, 1H), 1.29-1.43 (m, 3H), 1.07-1.20
(m, 2H), 0.84-1.01 (m, 2H). LC-MS: m/z 448.4 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(-
methylamino)phenyl)nicotinonitrile (Compound 414; General procedure
1, Step H)
[0738] .sup.1H NMR (CHLOROFORM-d) .delta. 7.63 (s, 1H), 7.23-7.27
(m, 1H), 6.72 (d, J=7.8 Hz, 1H), 6.62-6.68 (m, 1H), 6.56-6.62 (m,
1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.15-4.33 (m,
2.5H), 3.70-3.88 (m, 2.5H), 3.52-3.62 (m, 0.5H), 3.39 (s, 3H),
3.00-3.28 (m, 2.5H), 2.89 (s, 3H), 2.65-2.83 (m, 1H), 2.51-2.65 (m,
1H), 2.14-2.21 (m, 1H), 1.30-1.47 (m, 3H), 1.10-1.19 (m, 2H),
0.89-0.98 (m, 2H). LC-MS: m/z 434.5 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(isoquinolin-5-yl)nicotinonitrile (Compound 409; General procedure
1, Step H)
[0739] .sup.1H NMR (CHLOROFORM-d) .delta. 9.36 (br. s., 1H), 8.54
(d, J=4.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.60-7.84 (m, 3H), 7.44
(dd, J=12.3, 6.0 Hz, 1H), 4.71-4.73 (m, 0.5H), 4.56 (d, J=11.8 Hz,
1H), 4.38-4.50 (m, 1H), 4.07-4.19 (m, 0.5H), 3.91 (d, J=11.0 Hz,
0.5H), 3.69-3.83 (m, 3H), 3.51 (s, 3H), 3.20-3.29 (m, 1.5H), 3.13
(br. s., 1H), 2.61-2.70 (m, 2H), 1.52 (ddd, J=12.0, 7.9, 4.6 Hz,
1H), 1.40 (br. s., 1H), 1.12-1.20 (m, 2H), 0.80-0.90 (m, 2H),
0.48-0.77 (m, 4H). LC-MS: m/z 482.6 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(isoquinolin-5-yl)nicotinonitrile (Compound 419; General procedure
1, Step H)
[0740] .sup.1H NMR (CHLOROFORM-d) .delta. 9.40 (br. s., 1H),
8.48-8.69 (m, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.63-7.86 (m, 3H),
7.44-7.55 (m, 1H), 4.70-4.73 (m, 0.5H), 4.57 (dd, J=13.1, 2.0 Hz,
1H), 4.41-4.52 (m, 1H), 4.13 (d, J=7.8 Hz, 0.5H), 3.94 (br. s.,
2H), 3.69-3.82 (m, 1H), 3.13-3.26 (m, 3H), 2.50-2.71 (m, 2H),
1.48-1.57 (m, 1H), 1.39-1.48 (m, 1H), 1.12-1.21 (m, 2H), 0.86-0.91
(m, 2H), 0.42-0.69 (m, 4H). LC-MS: m/z 468.5 (M+H).sup.+
(R)-5-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)pyridin-3-yl)isoquinoline 2-oxide (Compound 420)
[0741] .sup.1H NMR (CHLOROFORM-d) .delta. 8.88 (br. s., 1H), 8.15
(d, J=6.5 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.73 (t, J=7.7 Hz, 1H),
7.63 (s, 1H), 7.52-7.58 (m, 1H), 7.44-7.52 (m, 1H), 4.94 (br. s.,
0.5H), 4.55-4.59 (m, 0.5H), 4.21-4.44 (m, 2.5H), 3.57-3.86 (m, 3H),
3.34-3.40 (m, 4H), 3.19-3.22 (m, 1.5H), 2.58-2.86 (m, 2H),
1.47-1.55 (m, 1H), 1.30-1.38 (m, 3H), 1.09-1.21 (m, 2H), 0.78-0.95
(m, 2H). LC-MS: m/z 472.4 (M+H).sup.+
6-cyclopropyl-5-(isoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)piperazin-1-yl-
)nicotinonitrile (Compound 421; General procedure 1, Step H)
[0742] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (br. s., 1H), 8.53
(d, J=5.0 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.68-7.75 (m, 1H),
7.60-7.67 (m, 2H), 7.42 (d, J=5.8 Hz, 1H), 3.39-3.85 (m, 10H), 3.38
(s, 3H), 2.63-2.75 (m, 2H), 1.46-1.55 (m, 1H), 1.08-1.18 (m, 2H),
0.75-0.85 (m, 2H). LC-MS: m/z 442.5 (M+H).sup.+
2-(4-(cyclopropanecarbonyl)-3-(difluoromethyl)piperazin-1-yl)-6-cyclopropy-
l-5-(isoquinolin-5-yl)nicotinonitrile (Compound 422; General
procedure 4, Step R and S)
[0743] .sup.1H NMR (CHLOROFORM-d) .delta. 9.37 (br. s., 1H), 8.56
(br. s., 1H), 8.09 (d, J=8.0 Hz, 1H), 7.60-7.79 (m, 3H), 7.43 (d,
J=10.3 Hz, 1H), 6.09 (br. s., 1H), 4.97-5.45 (m, 4H), 3.12-3.89 (m,
3H), 1.98-2.08 (m, 1H), 1.80-1.87 (m, 1H), 1.00-1.21 (m, 4H),
0.83-0.92 (m, 4H). LC-MS: m/z 474.5 (M+H).sup.+
2-(4-(cyclopropanecarbonyl)-3-(2,2,2-trifluoroethyl)piperazin-1-yl)-6-cycl-
opropyl-5-(isoquinolin-5-yl)nicotinonitrile (Compound 423; General
procedure 4, Step R and S)
[0744] .sup.1H NMR (CHLOROFORM-d) .delta. 9.36 (s, 1H), 8.55 (dd,
J=5.8, 3.5 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.59-7.81 (m, 3H),
7.33-7.50 (m, 1H), 5.24 (br. s., 0.5H), 4.34 (d, J=13.1 Hz, 1H),
4.26-4.50 (m, 2.5H), 3.69 (br. s., 0.5H), 3.20-3.45 (m, 2H), 3.13
(br. s., 0.51H), 2.58-2.75 (m, 2H), 1.77 (br. s., 1H), 1.47-1.61
(m, 1H), 1.09-1.24 (m, 4H), 0.77-0.93 (m, 4H). LC-MS: m/z 506.5
(M+H).sup.+
(R)-2-cyclopropyl-2'-ethyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)-3,4-bipyridine-5-carbonitrile (Compound 426)
[0745] Compound 390 (18 mg) in EtOH was treated with Pd/C and
hydrogenated at room temperature and normal pressure to give the
title compound as a white solid. 1H NMR (CHLOROFORM-d) .delta. 8.63
(d, J=4.8 Hz, 1H), 7.63 (s, 1H), 7.23 (d, J=4.5 Hz, 2H), 4.92 (br.
s., 1H), 4.55 (d, J=12.8 Hz, 1H), 4.14-4.43 (m, 3H), 3.64-3.89 (m,
3H), 3.57 (br. s., 1H), 3.40 (s, 3H), 3.32 (d, J=11.8 Hz, 1H), 3.14
(d, J=14.3 Hz, 1H), 2.94 (q, J=7.4 Hz, 2H), 2.65-2.83 (m, 1H),
2.39-2.65 (m, 1H), 2.03 (td, J=8.0, 3.9 Hz, 2H), 1.25-1.42 (m, 8H),
1.11-1.25 (m, 3H), 1.01 (dd, J=7.8, 3.0 Hz, 2H). LC-MS: m/z 434.2
(M+H).sup.+
Compound 430 (General Procedure 1, Step I)
[0746] .sup.1H NMR (CHLOROFORM-d) .delta. 8.41 (dd, J=7.9, 1.4 Hz,
1H), 8.14 (s, 1H), 7.72-7.84 (m, 1H), 7.57-7.71 (m, 2H), 4.93 (d,
J=13.3 Hz, 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.14-4.43 (m, 3H),
3.69-3.90 (m, 3H), 3.53-3.68 (m, 1H), 3.34-3.46 (m, 3H), 3.27 (t,
J=11.2 Hz, 1H), 2.97-3.22 (m, 2H), 2.54-2.84 (m, 2H), 1.55-1.80 (m,
2H), 1.43 (d, J=6.5 Hz, 2H), 1.18-1.38 (m, 3H), 1.09 (br. s., 1H),
0.70-0.99 (m, 2H).
[0747] LC-MS: m/z 473.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-m-
ethylisoquinolin-5-yl)nicotinonitrile (Compound 433)
[0748] .sup.1H NMR (CHLOROFORM-d) .delta. 9.23 (s, 1H), 7.93-8.03
(m, 1H), 7.50-7.66 (m, 3H), 7.21 (d, J=6.0 Hz, 1H), 4.92 (br. s.,
0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.19-4.42 (m, 2.5H), 3.83 (d,
J=12.3 Hz, 0.5H), 3.65-3.78 (m, 2H), 3.56 (d, J=16.8 Hz, 0.5H),
3.37 (s, 3H), 3.31 (d, J=13.1 Hz, 1H), 2.98-3.25 (m, 1.5H),
2.68-2.84 (m, 1H), 2.53-2.68 (m, 5H), 1.47-1.57 (m, 1H), 1.43 (d,
J=6.3 Hz, 1.5H), 1.29-1.36 (m, 1.5H), 1.13 (dd, J=6.5, 4.0 Hz, 2H),
0.76-0.84 (m, 2H). LC-MS: m/z 470.2 (M+H).sup.+
(R)-6-cyclopropyl-5-(1-methoxyisoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)--
3-methylpiperazin-1-yl)nicotinonitrile (Compound 434)
[0749] .sup.1H NMR (CHLOROFORM-d) .delta. 8.32 (dd, J=7.5, 1.3 Hz,
1H), 7.98 (d, J=6.0 Hz, 1H), 7.52-7.65 (m, 3H), 6.94 (t, J=5.9 Hz,
1H), 4.85 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.20-4.40 (m,
2.5H), 4.15 (s, 3H), 3.66-3.89 (m, 3H), 3.38 (s, 3H), 3.31 (d,
J=8.3 Hz, 1H), 3.17 (d, J=13.3 Hz, 1.5H), 2.65-2.84 (m, 1H),
2.51-2.65 (m, 1H), 1.48-1.60 (m, 1H), 1.42 (m, 1.5H), 1.29-1.36 (m,
1.5H), 1.03-1.19 (m, 2H), 0.81 (dd, J=8.0, 3.0 Hz, 2H). LC-MS: m/z
486.2 (M+H).sup.+
(1R,2R)-ethyl
2-((R)-4-(3-cyano-6-cyclopropyl-5-(isoquinolin-5-yl)pyridin-2-yl)-2-methy-
l piperazine-1-carbonyl)cyclopropanecarboxylate (Compound 435)
[0750] .sup.1H NMR (CHLOROFORM-d) .delta. 9.34 (s, 1H), 8.53 (d,
J=5.8 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.62-7.80 (m, 3H), 7.42 (t,
J=5.9 Hz, 1H), 4.87 (br. s., 0.5H), 4.38-4.65 (m, 1.5H), 4.33 (d,
J=12.0 Hz, 2H), 4.19 (q, J=7.0 Hz, 2H), 3.62-3.85 (m, 0.5H), 3.46
(d, J=13.1 Hz, 0.5H), 3.10-3.40 (m, 2H), 2.36 (br. s., 1H),
2.17-2.31 (m, 1H), 2.09 (br. s., 1H), 1.38-1.45 (m, 2H), 1.22-1.37
(m, 6H), 1.03-1.22 (m, 2H), 0.69-0.94 (m, 2H). LC-MS: m/z 461.2
(M+H).sup.+
(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2--
cyclopropylpyridin-3-yl)isoquinoline 2-oxide (Compound 439)
[0751] .sup.1H NMR (CHLOROFORM-d) .delta. 8.87 (br. s., 1H),
8.06-8.26 (m, 1H), 7.70-7.83 (m, 2H), 7.61-7.69 (m, 1H), 7.54 (br.
s., 2H), 4.59 (d, J=7.0 Hz, 1H), 4.47 (d, J=12.5 Hz, 1H), 3.51-4.30
(m, 3H), 3.32 (br. s., 1H), 3.17 (br. s., 1H), 1.96-2.10 (m, 1H),
1.75 (br. s., 1H), 1.43-1.54 (m, 1H), 1.14-1.23 (m, 2H), 1.00-1.12
(m, 2H), 0.81-0.94 (m, 4H), 0.38-0.73 (m, 4H). LC-MS: m/z 480.2
(M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)-N-(vinylsulfonyl)ethenesulfonamide
(Compound 440; General procedure 3, Step N, method 1)
[0752] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60-7.64 (m, 1H),
7.50-7.56 (m, 2H), 7.29-7.37 (m, 3H), 7.01-7.16 (m, 2H), 6.26-6.40
(m, 2H), 6.11-6.25 (m, 2H), 4.92 (s, 0.5H), 4.54 (d, J=13.3 Hz,
0.5H), 4.19-4.37 (m, 2.5H), 3.73-3.79 (m, 3H), 3.52-3.61 (m, 0.5H),
3.39 (s, 3H), 3.28 (t, J=10.4 Hz, 1H), 3.02-3.14 (m, 1H), 2.65-2.80
(m, 1H), 2.55-2.64 (m, 1H), 1.98-2.07 (m, 1H), 1.27 (s, 3H),
1.14-1.19 (m, 2H), 0.95-1.01 (m, 2H). LC-MS: m/z 600.2
(M+H).sup.+
(R,E)-N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)pyridin-3-yl)phenyl)-4-(dimethylamino)but-2-enamide
(Compound 441; General procedure 3, Step N, method 2)
[0753] .sup.1H NMR (CHLOROFORM-d) .delta. 9.22 (s, 1H), 7.68 (s,
1H), 7.53-7.60 (m, 1H), 7.41-7.53 (m, 1H), 7.31 (s, 1H), 7.08 (d,
J=7.3 Hz, 1H), 6.86 (s, 1H), 6.61 (d, J=15.3 Hz, 1H), 4.83 (s,
0.5H), 4.46 (d, J=11.0 Hz, 0.5H), 4.22 (d, J=9.8 Hz, 2.5H), 3.90
(s, 1.5H), 3.67-3.81 (m, 2.5H), 3.52 (s, 0.5H), 3.28-3.41 (m, 3H),
3.24 (s, 1H), 3.04-3.15 (m, 1H), 2.94-3.04 (m, 1H), 2.88 (s, 2H),
2.82 (s, 6H), 2.57 (d, J=15.8 Hz, 1H), 1.97-2.08 (m, 1H), 1.33-1.40
(m, 2H), 1.18-1.30 (m, 2H), 1.02-1.15 (m, 2H), 0.89 (s, 2H). LC-MS:
m/z 531.3 (M+H).sup.+
(R)-6-cyclopropyl-5-(2-hydroxyquinolin-5-yl)-2-(4-(3-methoxypropanoyl)-3-m-
ethylpiperazin-1-yl)nicotinonitrile (Compound 442)
[0754] 1H NMR (CHLOROFORM-d) .delta. 7.88 (d, J=9.5 Hz, 1H),
7.63-7.70 (m, 1H), 7.43-7.63 (m, 3H), 6.80 (d, J=9.5 Hz, 1H), 4.92
(br. s., 0.5H), 4.57 (d, J=13.1 Hz, 0.5H), 4.15-4.45 (m, 3H),
3.66-3.87 (m, 2H), 3.40 (s, 2H), 3.29 (t, J=9.7 Hz, 1H), 3.11-3.22
(m, 1H), 2.66-2.88 (m, 1H), 2.48-2.66 (m, 1H), 1.96-2.10 (m, 1H),
1.36-1.56 (m, 1.5H), 1.08-1.36 (m, 3.5H), 0.97 (dd, J=7.8, 3.0 Hz,
2H). LC-MS: m/z 472.3 (M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-2'-v-
inyl-3,4'-bipyridine-5-carbonitrile (Compound 443; General
procedure 5, Step W):
[0755] 1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=4.3 Hz, 1H),
7.59-7.67 (m, 1H), 7.35-7.45 (m, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.89
(dd, J=17.3, 10.8 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.58 (d, J=10.8
Hz, 1H), 4.87 (br. s., 1H), 4.56 (br. s., 1H), 4.30 (d, J=13.3 Hz,
1H), 4.13 (br. s., 1H), 3.58-3.88 (m, 1H), 3.33 (d, J=10.0 Hz, 1H),
3.20 (br. s., 2H), 1.91-2.09 (m, 1H), 1.38-1.51 (m, 1.5H),
1.11-1.38 (m, 2.5H), 0.87-1.08 (m, 6H), 0.79-0.87 (m, 2H). LC-MS:
m/z 414.4 (M+H).sup.+
(R)-2-cyclopropyl-6-(3-methyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-yl)--
2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 444; General
procedure 5, Step W)
[0756] 1H NMR (CHLOROFORM-d) .delta. 7.59-7.69 (m, 1H), 7.34-7.43
(m, 1H), 7.15-7.27 (m, 1H), 6.89 (dd, J=17.6, 10.8 Hz, 1H),
6.23-6.37 (m, 1H), 5.58 (d, J=11.5 Hz, 1H), 4.94 (br. s., 1H),
4.20-4.48 (m, 2H), 3.51-3.79 (m, 1H), 3.37 (d, J=5.5 Hz, 1H),
3.05-3.34 (m, 4H), 1.87-2.07 (m, 1H), 1.42-1.51 (m, 2H), 1.13-1.42
(m, 3H), 0.95-1.08 (m, 2H). LC-MS: m/z 456.8 (M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-
-2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 485; General
procedure 5, Step W)
[0757] .sup.1H NMR (CHLOROFORM-d) .delta. 8.77 (br. s., 1H), 7.96
(br. s., 1H), 7.80-7.92 (m, 2H), 7.12-7.27 (m, 1H), 6.82 (d, J=17.6
Hz, 1H), 6.06 (d, J=10.8 Hz, 1H), 4.67 (d, J=12.3 Hz, 1H), 4.54 (d,
J=11.5 Hz, 2H), 4.24 (br. s., 1H), 3.67 (br. s., 1H), 3.33 (br. s.,
1H), 3.18 (br. s., 1H), 1.93 (br. s., 1H), 1.67 (br. s., 1H), 1.25
(br. s., 2H), 1.04-1.23 (m, 3H), 0.89-1.04 (m, 3H), 0.47 (d, J=4.8
Hz, 2H), 0.39 (br. s., 2H). LC-MS: m/z 440.2 (M+H).sup.+
Compound 527 (General Procedure 5, Step W)
[0758] .sup.1H NMR (CHLOROFORM-d) .delta. 8.65 (d, J=4.7 Hz, 1H),
7.65 (s, 1H), 7.38 (s, 1H), 7.23 (d, J=4.1 Hz, 1H), 6.87 (dd,
J=17.5, 10.7 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz,
1H), 4.55 (d, J=13.2 Hz, 1H), 4.43 (d, J=12.6 Hz, 1H), 4.03-4.16
(m, 1H), 3.91 (br. s., 2H), 3.65-3.82 (m, 1H), 3.40-3.53 (m, 1H),
3.02-3.32 (m, 3H), 2.49-2.69 (m, 2H), 1.98-2.10 (m, 1H), 1.13-1.38
(m, 3H), 1.01 (dd, J=7.5, 3.4 Hz, 2H), 0.63 (br. s., 1H), 0.55 (br.
s., 1H), 0.32-0.51 (m, 2H). LC-MS: m/z 444.3 (M+H).sup.+
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 498; General
procedure 5, Step W)
[0759] .sup.1H NMR (CHLOROFORM-d) .delta. 8.54-8.72 (m, 1H),
7.57-7.74 (m, 1H), 7.38 (d, J=1.0 Hz, 1H), 7.23 (dd, J=5.1, 1.6 Hz,
1H), 6.88 (dd, J=17.3, 10.8 Hz, 1H), 6.28 (dd, J=17.4, 1.1 Hz, 1H),
5.48-5.63 (m, 1H), 4.56 (dd, J=13.2, 1.9 Hz, 1H), 4.45 (d, J=13.1
Hz, 1H), 4.11 (br. s., 1H), 3.65-3.88 (m, 2H), 3.32 (q, J=9.6 Hz,
2H), 3.20 (d, J=12.0 Hz, 1H), 2.98-3.15 (m, 1H), 2.04 (tt, J=8.0,
4.7 Hz, 1H), 1.30-1.39 (m, 1H), 1.14-1.25 (m, 2H), 0.96-1.07 (m,
2H), 0.65 (br. s., 1H), 0.56 (br. s., 1H), 0.41-0.54 (m, 2H).
LC-MS: m/z 482.5 (M+H).sup.+
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2'-vin-
yl-3,4'-bipyridine-5-carbonitrile (Compound 500; General procedure
5, Step W)
[0760] 1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=5.0 Hz, 1H),
7.60-7.71 (m, 1H), 7.41 (s, 1H), 7.26 (dd, J=5.0, 1.3 Hz, 1H), 6.90
(dd, J=17.4, 10.9 Hz, 1H), 6.31 (d, J=17.1 Hz, 1H), 5.60 (d, J=11.0
Hz, 1H), 4.72-4.99 (m, 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.22-4.49
(m, 2H), 3.74 (d, J=13.6 Hz, 1H), 3.56 (br. s., 1H), 3.40 (br. s.,
1H), 3.32 (td, J=8.6, 3.9 Hz, 1H), 2.95-3.25 (m, 2H), 2.68 (br. s.,
1H), 2.44-2.65 (m, 2H), 2.00-2.19 (m, 1H), 1.16-1.45 (m, 3H),
0.95-1.12 (m, 3H), 0.90 (t, J=6.8 Hz, 1H). LC-MS: m/z 418.6
(M+H).sup.+
(R)-2-cyclopropyl-6-(4-(4,4-dimethoxybutanoyl)-3-methylpiperazin-1-yl)-2'--
vinyl-[3,4'-bipyridine]-5-carbonitrile (Compound 606; General
procedure 5, Step W)
[0761] .sup.1H NMR (CHLOROFORM-d) .delta. 8.64 (d, J=5.0 Hz, 1H),
7.63 (s, 1H), 7.38 (s, 1H), 7.23 (dd, J=5.0, 1.5 Hz, 1H), 6.81-6.93
(m, 1H), 6.28 (d, J=11.0 Hz, 1H), 5.56 (d, J=11.0 Hz, 1H), 4.88 (s,
0.5H), 4.24-4.53 (m, 1.5H), 4.24-4.36 (m, 2.5H), 3.78 (d, 0.5H),
3.54 (t, 0.5H), 3.27-3.37 (m, 4H), 3.02-3.18 (m, 1.5H), 2.35-2.56
(m, 2H), 1.92-2.06 (m, 4H), 1.38 (d, 1.5H), 1.28 (d, 1.5H),
1.18-1.21 (m, 2H), 0.99-1.02 (m, 2H). LC-MS: m/z 476.2
(M+H).sup.+
(R)-2-cyclopropyl-6-(3-methyl-4-(4-oxobutanoyl)piperazin-1-yl)-2'-vinyl-[3-
,4'-bipyridine]-5-carbonitrile (Compound 607), which was obtained
as the by-product of Compound 606
[0762] .sup.1H NMR (CHLOROFORM-d) .delta. 9.90 (s, 1H), 8.65 (d,
J=5.0 Hz, 1H), 7.64 (s, 1H), 7.38 (s, 1H), 7.24 (d, J=5.0 Hz, 1H),
6.88 (q, 1H), 6.28 (d, 1H), 5.56 (d, 1H), 4.85 (br. s., 0.5H), 4.48
(d, J=12.8 Hz, 0.5H), 4.25-4.37 (m, 2.5H), 3.80 (br. s., 0.5H),
3.60 (br. s., 0.5H), 3.03-3.38 (m, 3H), 2.62-2.89 (m, 4.5H), 2.03
(m, 1H), 1.42 (d, 1.5H), 1.28 (d, 1.5H), 1.18-1.21 (m, 2H),
0.99-1.10 (m, 2H). LC-MS: m/z 430.2 (M+H).sup.+
(S)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-2-
'-vinyl-[3,4'-bipyridine]-5-carbonitrile (Compound 587; General
procedure 5, Step W)
[0763] .sup.1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=5.0 Hz, 1H),
7.62-7.73 (m, 1H), 7.39 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88
(dd, J=17.6, 10.8 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8
Hz, 1H), 4.56 (d, J=13.1 Hz, 1H), 4.43 (d, J=11.3 Hz, 1.5H), 4.09
(d, J=8.8 Hz, 0.5H), 3.93 (d, J=5.0 Hz, 2H), 3.75-3.82 (m, 1.5H),
3.43 (br. s., 1H), 3.16-3.32 (m, 1.5H), 3.02-3.16 (m, 1H),
2.43-2.71 (m, 2H), 2.00-2.09 (m, 1H), 1.67 (s, 1H), 1.16-1.25 (m,
2H), 0.95-1.08 (m, 2H), 0.40-0.80 (m, 4H). LC-MS: m/z 444.2
(M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(qui-
noxalin-6-yl)nicotinonitrile (Compound 445; General procedure 1,
Step H)
[0764] .sup.1H NMR (CHLOROFORM-d) .delta. 8.90 (d, J=3.0 Hz, 2H),
8.05-8.34 (m, 2H), 7.85 (d, J=8.5 Hz, 1H), 7.74 (s, 1H), 4.92 (br.
s., 0.5H), 4.26-4.56 (m, 3H), 3.57-3.84 (m, 3H), 3.31-3.38 (m, 4H),
3.13-3.16 (m, 1.5H), 2.27-2.78 (m, 2H), 2.04-2.16 (m, 1H), 1.41 (d,
J=5.8 Hz, 1.5H), 1.30 (d, J=6.0 Hz, 1.5H), 1.22 (br. s., 2H),
0.94-1.06 (m, 2H). LC-MS: m/z 457.2 (M+H).sup.+
Compound 446 (General Procedure 3, Step N, method 1)
[0765] 1H NMR (CHLOROFORM-d) .delta. 7.58-7.67 (m, 1H), 7.38-7.50
(m, 2H), 7.32 (dd, J=7.7, 1.6 Hz, 2H), 6.49 (dd, J=16.6, 10.0 Hz,
1H), 6.25 (d, J=16.6 Hz, 1H), 6.06 (d, J=10.0 Hz, 1H), 4.91 (br.
s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.13-4.41 (m, 3H), 3.71-3.87
(m, 2H), 3.49-3.63 (m, 1H), 3.39 (s, 3H), 3.21-3.34 (m, 4H),
2.95-3.21 (m, 2H), 2.51-2.81 (m, 2H), 1.91-2.17 (m, 1H), 1.73 (br.
s., 2H), 1.23-1.50 (m, 5H), 0.94-1.23 (m, 4H). LC-MS: m/z 524.2
(M+H).sup.+
(S)-2-chloro-N-(3-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-m-
ethylpiperazin-1-yl)pyridin-3-yl)phenyl)propanamide (Compound 447;
General procedure 3, Step N, method 2)
[0766] .sup.1H NMR (CHLOROFORM-d) .delta. 8.57 (s, 1H), 7.70 (s,
1H), 7.57-7.64 (m, 1H), 7.47-7.56 (m, 1H), 7.42 (t, J=7.8 Hz, 1H),
7.18 (d, J=7.5 Hz, 1H), 4.90 (br. s., 0.5H), 4.47-4.65 (m, 1.5H),
4.18-4.30 (m, 2.5H), 3.73-3.81 (m, 2.5H), 3.48-3.64 (m, 0.5H), 3.37
(s, 3H), 3.21-3.31 (m, 1H), 2.95-3.18 (m, 1.5H), 2.53-2.79 (m, 2H),
2.04-2.12 (m, 1H), 1.83 (d, J=7.0 Hz, 3H), 1.38 (d, J=6.3 Hz,
1.5H), 1.28 (d, J=6.5 Hz, 1.5H), 1.11-1.18 (m, 2H), 0.89-1.03 (m,
2H). LC-MS: m/z 510.1 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)ethanesulfonamide (Compound 448;
General procedure 3, Step N, method 1)
[0767] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.38-7.49
(m, 2H), 7.30-7.34 (m, 1H), 7.26 (dd, J=8.0, 1.3 Hz, 1H), 7.18 (d,
J=7.8 Hz, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.3 Hz, 0.5H),
4.13-4.40 (m, 2.5H), 3.67-3.93 (m, 2.5H), 3.51-3.66 (m, 0.5H), 3.38
(s, 3H), 3.02-3.32 (m, 4.5H), 2.55-2.84 (m, 2H), 2.00-2.11 (m, 1H),
1.38-1.44 (m, 4H), 1.24-1.31 (m, 2H), 1.12-1.21 (m, 2H), 0.90-1.03
(m, 2H). LC-MS: m/z 512.1 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)methacrylamide (Compound 449; General
procedure 3, Step N, method 1)
[0768] .sup.1H NMR (CHLOROFORM-d) .delta. 7.83 (s, 1H), 7.72 (s,
1H), 7.60 (s, 1H), 7.51-7.57 (m, 1H), 7.40 (t, J=7.9 Hz, 1H), 7.15
(d, J=7.8 Hz, 1H), 5.83 (s, 1H), 5.43-5.54 (m, 1H), 4.89 (br. s.,
0.5H), 4.52 (d, J=13.3 Hz, 0.5H), 4.13-4.36 (m, 2.5H), 3.68-3.87
(m, 2.5H), 3.55 (t, J=11.3 Hz, 0.5H), 3.35-3.46 (m, 3H), 3.20-3.31
(m, 1H), 2.96-3.17 (m, 1.5H), 2.81 (s, 2H), 2.51-2.77 (m, 2H),
2.03-2.19 (m, 4H), 1.38 (d, J=6.3 Hz, 1.5H), 1.28 (d, J=6.5 Hz,
1.5H), 1.10-1.18 (m, 2H), 0.88-1.02 (m, 2H). LC-MS: m/z 488.1
(M+H).sup.+
(R)--N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl-
)-2-cyclopropylpyridin-3-yl)phenyl)propiolamide (Compound 451;
General procedure 3, Step N, method 1)
[0769] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.35-7.47
(m, 1H), 7.28 (s, 1H), 7.23-7.27 (m, 1H), 7.15-7.22 (m, 2H), 6.63
(dd, J=16.6, 9.8 Hz, 1H), 6.26-6.39 (m, 1H), 6.01 (d, J=9.8 Hz,
1H), 4.52 (d, J=12.5 Hz, 1H), 4.40 (d, J=12.3 Hz, 1H), 4.07-4.24
(m, 1H), 3.65-3.90 (m, 1H), 3.22-3.52 (m, 1.5H), 3.10 (s, 1.5H),
2.03-2.10 (m, 1H), 1.29-1.36 (m, 1H), 1.14-1.21 (m, 2H), 0.93-1.12
(m, 4H), 0.85-0.92 (m, 1H), 0.76-0.85 (m, 2H), 0.60-0.71 (m, 1H),
0.38-0.60 (m, 3H). LC-MS: m/z 518.2 (M+H).sup.+
(R)--N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl-
)-2-cyclopropylpyridin-3-yl)phenyl)-N-(vinylsulfonyl)ethenesulfonamide
(Compound 452; General procedure 3, Step N, method 1)
[0770] .sup.1H NMR (CHLOROFORM-d) .delta. 7.63 (s, 1H), 7.49-7.58
(m, 2H), 7.33-7.36 (m, 1H), 7.31 (dt, J=6.7, 2.3 Hz, 1H), 7.07 (d,
J=9.8 Hz, 1H), 7.10-7.13 (m, 1H), 6.28-6.38 (m, 2H), 6.14-6.22 (m,
2H), 4.41-4.62 (m, 2.5H), 3.98-4.18 (m, 1H), 3.75-3.90 (m, 1H),
3.09-3.33 (2.5, 1H), 2.00-2.07 (m, 1H), 1.15-1.25 (m, 3H),
0.97-1.11 (m, 4H), 0.86-0.92 (m, 1H), 0.82 (dd, J=7.8, 2.3 Hz, 2H),
0.39-0.67 (m, 4H). LC-MS: m/z 608.2 (M+H).sup.+
(R)--N-(3-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)pyridin-3-yl)phenyl)-2-fluoro-N-methylacrylamide (Compound
453; General procedure 3, Step N, method 2)
[0771] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.43-7.54
(m, 1H), 7.34 (d, J=7.8 Hz, 1H), 7.17-7.26 (m, 2H), 5.44 (d, J=3.3
Hz, 1H), 5.18-5.38 (m, 1H), 4.82-5.11 (m, 2H), 4.54 (d, J=12.3 Hz,
1H), 4.10-4.40 (m, 3H), 3.75 (br. s., 2H), 3.57 (d, J=7.8 Hz, 1H),
3.35-3.48 (m, 6H), 3.28 (br. s., 1H), 3.14 (d, J=10.5 Hz, 1H),
2.94-3.10 (m, 1H), 2.73 (br. s., 1H), 2.60 (br. s., 1H), 2.19 (s,
1H), 1.90-2.10 (m, 1H), 1.78 (br. s., 1H), 1.23-1.51 (m, 8H),
1.06-1.23 (m, 2H), 0.78-1.06 (m, 3H). LC-MS: m/z 506.2
(M+H).sup.+
(R)--N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl-
)-2-cyclopropylpyridin-3-yl)phenyl)acrylamide (Compound 454;
General procedure 3, Step N, method 1)
[0772] .sup.1H NMR (CHLOROFORM-d) .delta. 7.73-7.80 (m, 2H), 7.63
(s, 1H), 7.51-7.59 (m, 1H), 7.42 (t, J=7.8 Hz, 1H), 7.17 (d, J=7.5
Hz, 1H), 6.40-6.54 (m, 1H), 6.31 (dd, J=16.8, 10.3 Hz, 1H), 5.81
(d, J=10.3 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 4.39 (d, J=12.3 Hz,
1H), 3.92-4.27 (m, 1H), 3.51-3.94 (m, 1H), 3.25 (m, 1H), 2.85-3.42
(m, 3H), 2.08-2.15 (m, 1H), 1.29-1.36 (m, 1H), 1.13-1.20 (m, 2H),
0.94-1.11 (m, 4H), 0.86-0.93 (m, 1H), 0.75-0.85 (m, 2H), 6.68 (d,
J=12.5 Hz, 1H), 0.40-0.54 (m, 3H). LC-MS: m/z 482.2 (M+H).sup.+
Compound 455 (General Procedure 3, Step N, Method 2)
[0773] .sup.1H NMR (CHLOROFORM-d) 7.61 (s, 1H), 7.47 (d, J=7.5 Hz,
1H), 7.31-7.36 (m, 1H), 5.87 (s, 1H), 4.83-5.04 (m, 1H), 4.19-4.42
(m, 3H), 3.76 (br. s., 2H), 3.56 (br. s., 1H), 3.36-3.49 (m, 6H),
3.30 (br. s., 1H), 2.91-3.20 (m, 4H), 2.74 (br. s., 1H), 2.68 (br.
s., 1H), 2.61 (br. s., 1H), 1.93-2.02 (m, 1H), 1.15-1.45 (m, 16H),
0.99 (dd, J=7.8, 2.8 Hz, 2H), 0.76-0.94 (m, 2H). LC-MS: m/z 512.2
(M+H).sup.+
Compound 456 (General Procedure 3, Step N, Method 2)
[0774] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 7.52 (t,
J=7.7 Hz, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.29-7.37 (m, 2H), 4.10-4.39
(m, 3H), 3.70-3.90 (m, 2H), 3.66 (s, 1H), 3.49 (s, 1H), 3.38 (s,
5H), 3.30 (d, J=14.8 Hz, 1H), 3.14 (br. s., 2H), 2.71-2.91 (m, 2H),
2.48-2.71 (m, 2H), 2.05 (dt, J=7.8, 4.0 Hz, 2H), 1.13-1.42 (m, 8H),
0.91-1.08 (m, 2H). LC-MS: m/z 486.2 (M+H).sup.+
(R)-6-cyclopropyl-5-(1-hydroxyisoquinolin-5-yl)-2-(4-(3-methoxypropanoyl)--
3-methylpiperazin-1-yl)nicotinonitrile (Compound 457; General
procedure 1, Step I)
[0775] .sup.1H NMR (CHLOROFORM-d) .delta. 10.93 (s, 1H), 8.51 (dd,
J=6.8, 2.3 Hz, 1H), 7.51-7.67 (m, 3H), 6.32 (s, 1H), 4.92 (br. s.,
0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.18-4.41 (m, 2.5H), 3.53-3.92
(m, 3.5H), 3.40 (s, 1H), 3.16-3.38 (m, 2.5H), 2.51-2.83 (m, 2H),
1.61 (br. s., 1H), 1.39-1.49 (m, 1.5H), 1.31-1.39 (m, 1.5H), 1.14
(dd, J=8.3, 4.8 Hz, 2H), 0.79-0.93 (m, 2H). LC-MS: m/z 472.2
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(3-methylisoquinolin-5-yl)nicotinonitrile (Compound 458; General
procedure 1, Step I)
[0776] .sup.1H NMR (CHLOROFORM-d) .delta. 9.25 (s, 1H), 8.00 (dd,
J=7.2, 1.6 Hz, 1H), 7.54-7.67 (m, 3H), 7.16-7.27 (m, 1H), 4.57 (d,
J=12.5 Hz, 1H), 4.46 (d, J=12.5 Hz, 1H), 3.62-4.63 (m, 2H),
3.10-3.40 (m, 2.5H), 2.67 (d, J=4.5 Hz, 3H), 2.25-2.49 (m, 0.5H),
1.74 (br. s., 1H), 1.54 (dtd, J=12.7, 3.9, 1.9 Hz, 2H), 1.13-1.23
(m, 2H), 0.95-1.13 (m, 2H), 0.77-0.91 (m, 4H), 0.70 (br. s., 1H),
0.39-0.60 (m, 3H). LC-MS: m/z 478.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-(-
2-oxo-2,5-dihydro-1H-pyrrol-1-yl)phenyl)nicotinonitrile (Compound
459)
##STR00839##
[0778] A mixture of
(R)-5-(3-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)nicotinonitrile (300 mg), pentane-2,4-dione (100 mg)
and TFA (1 drop) in cyclohexane was refluxed for 3 h. After
evaporation, the residue was dissolved in CH.sub.3CN and some
Na.sub.2SO4 was added followed by select-F-TEDA-BF.sub.4 (800 mg).
The mixture was refluxed for overnight. After evaporation, the
residue was purified by pre-TLC to give the title compound (75 mg).
.sup.1H NMR (CHLOROFORM-d) .delta. 7.86 (s, 1H), 7.58-7.75 (m, 2H),
7.47 (t, J=8.0 Hz, 1H), 7.10-7.26 (m, 2H), 6.33 (dt, J=6.0, 1.8 Hz,
1H), 4.91 (br. s., 0.5H), 4.42-4.63 (m, 2.5H), 4.13-4.40 (m, 2.5H),
3.65-3.95 (m, 2.5H), 3.39 (s, 3H), 3.21-3.32 (m, 1H), 2.99-3.20 (m,
2H), 2.52-2.81 (m, 2H), 2.00-2.29 (m, 1H), 1.35-1.53 (m, 1.5H),
1.23-1.35 (m, 1.5H), 1.07-1.23 (m, 2H), 0.92-1.07 (m, 2H). LC-MS:
m/z 486.2 (M+H).sup.+
(R)-6-Cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-m-
ethyl-1-oxoisoindolin-4-yl)nicotinonitrile (Compound 460; General
procedure 1, Step I)
[0779] .sup.1H NMR (CHLOROFORM-d) .delta. 7.93-7.88 (m, 1H),
7.61-7.55 (m, 2H), 7.45 (dd, J=7.5, 0.9 Hz, 1H), 4.97 (ddd, J=13.1,
10.1, 1.5 Hz, 1H), 4.42-4.15 (m, 5H), 3.90-3.49 (m, 3H), 3.39 (d,
J=5.2 Hz, 3H), 3.32 (dd, J=13.1, 3.6 Hz, 1H), 3.26-3.09 (m, 4H),
2.85-2.53 (m, 2H), 2.12-1.88 (m, 1H), 1.17 (dd, J=7.5, 3.1 Hz, 3H),
0.96 (dd, J=7.9, 3.2 Hz, 2H), 0.90 (t, J=6.8 Hz, 3H).
[0780] LC-MS: m/z 474.6 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(2-
-methyl-1-oxoisoindolin-4-yl)nicotinonitrile (Compound 461; General
procedure 1, Step I)
[0781] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.93 (d, J=7.5 Hz,
1H), 7.64-7.57 (m, 2H), 7.53-7.47 (m, 1H), 7.44 (s, 1H), 4.93-4.21
(m, 6H), 4.21-2.84 (m, 6H), 1.82-1.65 (m, 2H), 1.55-1.29 (m, 4H),
1.17 (dd, J=7.0, 3.8 Hz, 2H), 1.10-0.97 (m, 2H), 0.95 (dd, J=7.8,
3.2 Hz, 2H), 0.84-0.75 (m, 2H).
[0782] LC-MS: m/z 458.6.3 (M+H).sup.+
(R)-2-(4-(Cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-oxoisoindolin-4-yl)nicotinonitrile (Compound 464; General
procedure 1, Step I)
[0783] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 7.95 (dd, J=7.6,
0.8 Hz, 1H), 7.64-7.59 (m, 2H), 7.51 (dd, J=5.4, 2.1 Hz, 1H), 6.76
(s, 1H), 5.07-4.24 (m, 6H), 3.22 (d, J=59.5 Hz, 2H), 2.05 (dt,
J=15.3, 7.7 Hz, 1H), 1.31 (s, 2H), 1.19 (dd, J=4.4, 3.2 Hz, 2H),
0.96 (dd, J=7.9, 3.2 Hz, 2H), 0.90 (t, J=6.8 Hz, 3H), 0.82 (dd,
J=7.9, 2.4 Hz, 2H), 0.49 (ddd, J=18.9, 9.9, 4.8 Hz, 3H). LC-MS: m/z
468.6 (M+H).sup.+
[0784]
(R)-2-(4-(Cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cycloprop-
yl-5-(2-methyl-1-oxoisoindolin-4-yl)nicotinonitrile (Compound 465;
General procedure 1, Step I)
[0785] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=7.90 (d, J=7.6 Hz,
1H), 7.61-7.54 (m, 2H), 7.45 (d, J=7.5 Hz, 1H), 5.04-3.99 (m, 6H),
3.78-3.06 (m, 6H), 2.13-1.83 (m, 1H), 1.31 (d, J=5.5 Hz, 4H),
1.20-1.14 (m, 2H), 1.09-0.99 (m, 2H), 0.95 (dd, J=7.9, 3.2 Hz, 2H),
0.83 (dd, J=7.9, 1.3 Hz, 2H). LC-MS: m/z 466.6 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2,3-dioxoindolin-7-yl)nicotinonitrile (Compound 513; General
procedure 1, Step I)
[0786] A mixture of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile
(103.9 mg, 0.25 mol), 7-bromoisatin (67.8 mg, 0.30 mmol),
Pd(PPh.sub.3).sub.4 (29 mg, 0.03 mmol), and K.sub.2CO.sub.3 (86.3
mg, 0.63 mmol) suspended in 5 mL of 1,4-dioxane was subjected to
microwave reaction at 120.degree. C. for 1 h. After the reaction,
the reaction mixture was concentrated in vacuo, residue was
purified by column chromatography to afford the title compound.
Yield: 14.1 mg (11.7%). .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
7.75-7.65 (m, 2H), 7.64 (s, 1H), 7.53 (dd, J=7.8, 1.2 Hz, 1H), 7.25
(d, J=7.7 Hz, 1H), 4.62 (d, J=13.4 Hz, 1H), 4.49 (d, J=12.2 Hz,
1H), 4.24 (m, 1H), 3.77 (m, 1H), 3.26 (m, 2H), 1.88-1.77 (m, 1H),
1.73 (s, 2H), 1.30-1.16 (m, 3H), 1.16-0.96 (m, 4H), 0.83 (dd,
J=7.9, 2.5 Hz, 2H), 0.52 (dd, J=17.5, 12.8 Hz, 3H). LC-MS: m/z
482.3 (M+H).sup.+
(R)-5-(benzo[d]oxazol-6-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiper-
azin-1-yl)-6-cyclopropylnicotinonitrile (Compound 466; General
procedure 1, Step I)
[0787] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.18 (s, 1H), 7.88 (d,
J=8.3 Hz, 1H), 7.68 (s, 1H), 7.65 (d, J=1.0 Hz, 1H), 7.43 (dd,
J=8.2, 1.6 Hz, 1H), 4.55 (d, J=12.5 Hz, 1H), 4.43 (d, J=12.5 Hz,
1H), 4.18-4.34 (m, 1H), 3.91-4.18 (m, 1H), 3.73 (br. s., 1H), 3.28
(br. s., 1H), 3.12 (br. s., 1H), 2.00-2.12 (m, 1H), 1.73 (br. s.,
1H), 1.44 (br. s., 1H), 1.18-1.24 (m, 2H), 0.94-1.12 (m, 4H),
0.77-0.87 (m, 2H), 0.68 (br. s., 1H), 0.40-0.61 (m, 3H). LC-MS: m/z
454.5 (M+H).sup.+
(R)-5-(benzo[d]oxazol-6-yl)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin--
1-yl)-6-cyclopropylnicotinonitrile (Compound 467; General procedure
1, Step I)
[0788] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.15-8.21 (m, 1H),
7.84-7.90 (m, 1H), 7.67 (s, 1H), 7.61-7.66 (m, 1H), 7.39-7.47 (m,
1H), 4.59 (br. s., 1H), 4.21-4.46 (m, 3H), 3.43-3.61 (m, 1H), 3.39
(br. s., 1H), 3.18 (br. s., 1H), 2.00-2.10 (m, 1H), 1.78 (br. s.,
1H), 1.25-1.32 (m, 3H), 1.16-1.24 (m, 2H), 1.00-1.11 (m, 2H),
0.93-1.00 (m, 2H), 0.83 (dd, J=7.8, 1.8 Hz, 2H). LC-MS: m/z 428.5
(M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(3-methylisoquinolin-5-yl)nicotinonitrile (Compound 471;
General procedure 2, Step M)
[0789] .sup.1H NMR (CHLOROFORM-d) .delta. 9.26 (s, 1H), 7.96-8.06
(m, 1H), 7.55-7.69 (m, 3H), 7.21 (d, J=15.1 Hz, 1H), 4.57 (dt,
J=13.1, 2.3 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 4.15 (br. s., 0.5H),
3.69-3.95 (m, 1.5H), 3.21-3.45 (m, 3H), 3.04-3.21 (m, 2H), 2.67 (d,
J=4.5 Hz, 3H), 1.40-1.61 (m, 2H), 1.24-1.31 (m, 1H), 1.07-1.21 (m,
2H), 0.77-0.91 (m, 2H), 0.70 (br. s., 1H), 0.43-0.56 (m, 2H).
LC-MS: m/z 520.2 (M+H).sup.+
(R)--N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl-
)-2-cyclopropylpyridin-3-yl)phenyl)ethenesulfonamide (Compound 472;
General procedure 3, Step N, method 2)
[0790] To a solution of
(R)-5-(3-aminophenyl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin--
1-yl)-6-cyclopropylnicotinonitrile (30 mg, 0.07 mmol) in DCM was
added propiolic acid (5 mg, 0.07 mmol) and DCC (18 mg, 0.084 mmol).
The mixture was stirred at 25.degree. C. for 16 hours. TLC and
LC-MS showed product and the mixture was purified by prep-TLC to
give 15 mg of the compound. .sup.1H NMR (CHLOROFORM-d) .delta. 8.19
(s, 1H), 7.66-7.77 (m, 1H), 7.62 (s, 1H), 7.47-7.56 (m, 1H),
7.36-7.47 (m, 1H), 7.19 (d, J=7.8 Hz, 1H), 4.51 (d, J=12.0 Hz,
1.5H), 4.29-4.45 (m, 1.5H), 4.08-4.29 (m, 1H), 3.42-3.87 (m, 1H),
3.13-3.42 (m, 1H), 2.99-3.13 (m, 1H), 2.98 (s, 1H), 2.05-2.14 (m,
1H), 1.68-1.77 (m, 1H), 1.11-1.21 (m, 3H), 1.04-1.11 (m, 1H),
0.93-1.04 (m, 3H), 0.76-0.86 (m, 2H), 0.66 (s, 1H), 0.38-0.60 (m,
3H). LC-MS: m/z 480.2 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-hydroxyquinolin-5-yl)nicotinonitrile (Compound 476; General
procedure, Step I)
[0791] .sup.1H NMR (CHLOROFORM-d) .delta. 7.89 (d, J=9.5 Hz, 1H),
7.67 (s, 1H), 7.52-7.64 (m, 3H), 6.81 (d, J=9.5 Hz, 1H), 4.53 (d,
J=12.5 Hz, 2H), 4.41 (d, J=12.3 Hz, 2H), 3.28 (br. s., 2H), 3.11
(br. s., 1H), 1.96-2.07 (m, 2H), 1.14-1.32 (m, 2H), 0.93-1.11 (m,
4H), 0.76-0.92 (m, 2H), 0.67 (br. s., 1H), 0.31-0.60 (m, 3H).
LC-MS: m/z 490.2 (M+H)
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-vinylquinolin-5-yl)nicotinonitrile (Compound 475)
##STR00840##
[0792] Step 1
[0793] To a solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(2-hydroxyquinolin-5-yl)nicotinonitrile (50 mg, 0.104 mmol),
Et3N (12 mg, 0.12 mmol) in DCM (2 mL) was added dropwise Tf2O (30.3
mg, 0.107 mmol) at 0.degree. C. and stirred at r.t. for 3 h. Water
was added and the organic layer was combined, dried, concentrated
to give 50 mg product after prep-TLC.
Step 2
[0794] To a solution of
(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-
-cyclopropylpyridin-3-yl)quinolin-2-yl trifluoromethanesulfonate
(50 mg, 0.082 mmol), tributyl(vinyl)stannane (27 mg, 0.086 mmol),
LiCl (5.2 mg, 0.123 mmol) in THF (2 mL) was added
Pd(PPh.sub.3).sub.4(4.7 mg, 0.0041 mmol) under N2 and the reaction
mixture was heated to 85.degree. C. for 2 h. The mixture was cooled
and the solvent was removed. Product (9 mg) was obtained by
prep-TLC. .sup.1H NMR (CHLOROFORM-d) .delta. 8.16 (t, J=9.3 Hz,
2H), 7.72-7.86 (m, 3H), 7.68 (d, J=8.5 Hz, 1H), 7.04-7.14 (m, 2H),
6.34 (d, J=17.6 Hz, 1H), 5.73 (d, J=11.0 Hz, 1H), 4.53 (d, J=12.5
Hz, 2H), 4.41 (d, J=12.3 Hz, 2H), 3.28 (br. s., 2H), 3.11 (br. s.,
1H), 1.67 (br. s., 2H), 0.95-1.16 (m, 6H), 0.77-0.95 (m, 6H).
LC-MS: m/z 490.2 (M+H).
2-(4-(cyclopropanecarbonyl)-6-fluoro-1,4-diazepan-1-yl)-6-cyclopropyl-5-(i-
soquinolin-5-yl)nicotinonitrile (Compound 477; General procedure 4,
Step R and S)
[0795] .sup.1H NMR (CHLOROFORM-d) .delta. 9.36 (s, 1H), 8.48-8.65
(m, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.69-7.77 (m, 1H), 7.62-7.69 (m,
2H), 7.42 (d, J=6.0 Hz, 1H), 4.99 (br. s., 0.5H), 4.84 (br. s.,
0.5H), 4.72 (br. s., 1.5H), 4.60 (br. s., 1H), 4.49 (d, J=13.8 Hz,
1H), 4.17-4.39 (m, 2H), 3.76 (br. s., 0.5H), 3.32-3.57 (m, 2H),
3.22 (br. s., 1H), 1.70 (br. s., 1H), 1.54 (br. s., 1H), 1.14-1.20
(m, 2H), 1.04-1.12 (m, 2H), 0.83-0.90 (m, 4H). LC-MS: m/z 456.1
(M+H)
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1H-pyrazol-4-yl)nicotinonitrile (Compound 479; General
procedure 1, Step H)
[0796] .sup.1H NMR (CHLOROFORM-d) .delta. 7.70-7.81 (m, 2H), 7.65
(S, 1H), 4.49 (d, J=13.1 Hz, 1H), 4.37 (d, J=12.3 Hz, 1H), 4.13 (d,
J=14.8 Hz, 1H), 3.79 (s, 1H), 3.25 (s, 1.5H), 3.08 (s, 1.5H),
2.19-2.28 (m, 1H), 1.64-1.80 (m, 1H), 1.15-1.22 (m, 2H), 0.95-1.11
(m, 4H), 0.86-0.93 (m, 1H), 0.81 (dd, J=7.8, 2.3 Hz, 2H), 0.66 (s,
1H), 0.38-0.59 (m, 3H). LC-MS: m/z 442.2 (M+H).sup.+
6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2R)-2-(methoxymethyl)cyclopropan-
ecarbonyl)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile
(Compound 480)
[0797] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (s, 1H), 8.54 (dd,
J=6.0, 1.5 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.65-7.74 (m, 3H), 7.43
(dd, J=6.0 Hz, 1H), 4.58 (br. s., 0.5H), 4.46 (d, J=11.8 Hz, 1H),
4.26 (br. s., 0.5H), 4.09 (br. s., 0.5H), 3.83 (br. s., 0.5H), 3.68
(br. s., 0.5H), 3.52 (dd, J=10.3, 5.3 Hz, 1H), 3.29-3.41 (m, 4H),
3.23 (br. s., 2H), 1.67-1.75 (m, 2H), 1.39-1.59 (m, 2H), 1.26-1.36
(m, 3H), 1.16-1.19 (m, 2H), 0.82-0.85 (m, 3H), 0.55 (br. s., 2H),
0.48 (br. s., 2H). LC-MS: m/z 508.1 (M+H).sup.+
Compound 481
[0798] .sup.1H NMR (CHLOROFORM-d) .delta. 9.38 (br. s., 1H), 8.55
(d, J=5.3 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.66-7.75 (m, 3H),
7.44-7.47 (m, 1H), 4.45-4.59 (m, 2.5H), 4.09-4.19 (m, 1H), 3.86 (s,
0.5H), 3.57-3.68 (m, 3.5H), 3.05-3.45 (m, 2.5H), 1.93 (br. s., 1H),
1.51-1.54 (m, 1H), 1.18-1.25 (m, 6H), 0.83-0.91 (m, 4H), 0.49-0.68
(m, 4H). LC-MS: m/z 508.3 (M+H).sup.+
(R)-5-(benzo[d]oxazol-7-yl)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin--
1-yl)-6-cyclopropylnicotinonitrile (Compound 482; General procedure
1, Step H)
[0799] .sup.1H NMR (CHLOROFORM-d) .delta. 8.16 (s, 1H), 7.85 (dd,
J=7.8, 1.0 Hz, 1H), 7.49 (t, J=7.7 Hz, 1H), 7.42 (dd, J=7.5, 1.0
Hz, 1H), 4.58 (br. s., 1H), 4.32 (d, J=13.1 Hz, 2H), 3.49-3.62 (m,
1H), 3.46 (br. s., 1H), 3.21 (br. s., 2H), 1.85-1.93 (m, 1H), 1.78
(br. s., 1H), 1.31-1.45 (m, 3H), 1.18-1.25 (m, 2H), 1.00-1.11 (m,
2H), 0.89-0.99 (m, 2H), 0.84 (d, J=6.8 Hz, 2H). LC-MS: m/z 428.5
(M+H).sup.+
(R)-5-(benzo[d]oxazol-7-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiper-
azin-1-yl)-6-cyclopropylnicotinonitrile (Compound 483; General
procedure 1, Step H)
[0800] .sup.1H NMR (CHLOROFORM-d) .delta. 8.16 (s, 1H), 7.82-7.87
(m, 1H), 7.79 (s, 1H), 7.49 (t, J=7.8 Hz, 1H), 7.42 (dd, J=7.5, 1.0
Hz, 1H), 4.59 (d, J=12.8 Hz, 1H), 4.47 (d, J=12.0 Hz, 1H),
3.95-4.20 (m, 2H), 3.79 (br. s., 1H), 3.30 (br. s., 1H), 3.15 (br.
s., 1H), 1.85-1.97 (m, 1H), 1.61 (br. s., 2H), 1.19-1.25 (m, 2H),
1.06 (d, J=16.8 Hz, 2H), 0.91-0.98 (m, 2H), 0.82 (d, J=6.5 Hz, 2H),
0.68 (br. s., 1H), 0.40-0.61 (m, 3H). LC-MS: m/z 454.5
(M+H).sup.+2-(4-(cyclopropanecarbonyl)-6-fluoro-3-methyl-1,4-di-
azepan-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)nicotinonitrile
(Compound 484; General procedure 4, Step R and S): .sup.1H NMR
(CHLOROFORM-d) .delta. 9.40 (br. s., 1H), 8.56 (br. s., 1H), 8.12
(d, J=8.0 Hz, 1H), 7.69-7.81 (m, 2H), 7.68 (d, J=1.0 Hz, 1H),
7.47-7.54 (m, 1H), 4.54-4.98 (m, 6H), 3.25-3.44 (m, 1H), 3.17 (br.
s., 1H), 1.77-1.89 (m, 1H), 1.49-1.54 (m, 1H), 1.25-1.30 (m, 3H),
1.19-1.23 (m, 2H), 1.10 (br. s., 2H), 0.84-0.91 (m, 4H). LC-MS: m/z
470.2 (M+H)
(R)-5-(1-(cyanomethyl)-1H-pyrazol-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cycl-
opropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile (Compound
486)
[0801] To a solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(1H-pyrazol-4-yl)nicotinonitrile (60 mg, 0.149 mmol) in DMF was
added K.sub.2CO.sub.3 (42 mg, 0.298 mmol) and 2-bromoacetonitrile
(27 mg, 0.224 mmol). The resulting mixture was stirred for 16
hours. Then the mixture was partitioned between EtOAc and water,
the organic layer was washed with water, brine and dried over
Na.sub.2SO.sub.4, concentrated to give the crude which was purified
by prep-TLC to give 25 mg of the product. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.72 (s, 1H), 7.69 (s, 1H), 7.61 (s, 1H),
5.17 (s, 2H), 4.32-4.52 (m, 2.5H), 3.65-3.89 (m, 1H), 4.01-4.22 (m,
1H), 3.55-4.92 (m, 1H), 2.89-3.33 (m, 2.5H), 2.10-2.23 (m, 1H),
1.72 (s, 1H), 1.31-1.47 (m, 1H), 1.14-1.22 (m, 2H), 0.92-1.09 (m,
4H), 0.75-0.86 (m, 2H), 0.39-0.63 (m, 4H). LC-MS: m/z 442.2
(M+H).sup.+
2-((R)-4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-(3-hydroxycyclopentyl)-1H-pyrazol-4-yl)nicotinonitrile
(Compound 493)
##STR00841##
[0802] Step 1
[0803] To a solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(1H-pyrazol-4-yl)nicotinonitrile (100 mg, 0.248 mmol) in
CH.sub.2Cl.sub.2 was added cyclopent-2-enone (51 mg, 0.621 mmol)
and ScCl.sub.3 (338 mg, 2.24 mmol). The mixture was stirred for 16
hours at room temperature. The mixture was partitioned between
EtOAc and water. The organic layer was washed with water, brine and
dried over Na.sub.2SO.sub.4, concentrated to give the crude which
was purified by prep-TLC to give 50 mg of the product. LC-MS: m/z
485.3 (M+H).sup.+
Step 2
[0804] a solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(1H-pyrazol-4-yl)nicotinonitrile (40 mg, 0.0825 mmol) in MeOH
was added NaBH.sub.4, the mixture was stirred for 2 hours at room
temperature. The mixture was partitioned between EtOAc and water.
The organic layer was washed with water, brine and dried over
Na.sub.2SO.sub.4, concentrated to give the crude which was purified
by prep-TLC to give 15 mg of the product. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.56-7.70 (m, 3H), 4.85 (br. s., 1H),
4.25-4.70 (m, 4H), 4.00-4.25 (m, 1H), 3.50-3.90 (m, 1H), 2.95-3.41
(m, 3H), 2.12-2.41 (m, 6H), 1.90-2.03 (m, 1H), 1.37-1.54 (m, 1H),
1.23-1.37 (m, 1H), 1.17-1.28 (m, 2H), 0.94-1.09 (m, 4H), 0.76-0.85
(m, 2H), 0.39-0.64 (m, 4H). LC-MS: m/z 487.3 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-(methylsulfonyl)-1H-pyrazol-4-yl)nicotinonitrile (Compound
502)
[0805] To a solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(1H-pyrazol-4-yl)nicotinonitrile (30 mg, 0.074 mmol) in DCM was
added TEA (15 mg, 0.149 mmol) and methanesulfonyl chloride (9.4 mg,
0.082 mmol) and the mixture was stirred at r.t. for 2 h. The
mixture was partitioned between EtOAc and water. The organic layer
was washed with H.sub.2O, brine and dried over Na.sub.2SO.sub.4,
concentrated to give the crude which was purified by prep-TLC to
give 15 mg of the product. .sup.1H NMR (CHLOROFORM-d) .delta. 8.16
(s, 1H), 7.97 (s, 1H), 7.65 (s, 1H), 4.40-4.60 (m, 2.5H), 4.09-4.25
(m, 1H), 3.53-3.90 (m, 1H), 3.45 (s, 3H), 3.05-3.41 (m, 2.5H),
2.06-2.19 (m, 1H), 1.12-1.26 (m, 3H), 0.95-1.12 (m, 4H), 0.89 (t,
J=6.8 Hz, 1H), 0.75-0.85 (m, 2H), 0.36-0.64 (m, 4H). LC-MS: m/z
481.2 (M+H).sup.+
(R)-2-(4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-
-2-cyclopropylpyridin-3-yl)-1H-pyrazol-1-yl)acetamide (Compound
501)
[0806] To a solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(1H-pyrazol-4-yl)nicotinonitrile (30 mg, 0.0745 mmol) in DMF
was added K.sub.2CO.sub.3 (21 mg, 0.149 mmol) and 2-bromoacetamide
(12 mg, 0.082 mmol). The mixture was stirred for 16 hours at room
temperature, then the mixture was partitioned between EtOAc and
water. The organic layer was partitioned between EtOAc and water,
the organic layer was washed with water, brine and dried over
Na.sub.2SO.sub.4 concentrated to give 25 mg of the product. .sup.1H
NMR (CHLOROFORM-d) .delta. 7.75 (s, 1H), 7.57-7.69 (m, 2H), 6.43
(br. s., 1H), 6.04 (br. s., 1H), 4.88 (s, 2H), 4.30-4.60 (m, 2.5H),
3.84-4.23 (m, 1H), 3.50-3.80 (m, 1H), 3.00-3.45 (m, 2.5H),
2.13-2.25 (m, 1H), 1.92 (s, 1H), 1.71 (s, 1H), 1.12-1.21 (m, 2H),
0.94-1.10 (m, 4H), 0.72-0.84 (m, 2H), 0.35-0.63 (m, 4H). LC-MS: m/z
460.2 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-((methylthio)methyl)-1H-pyrazol-4-yl)nicotinonitrile
(Compound 510)
[0807] To a solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(1H-pyrazol-4-yl)nicotinonitrile (50 mg, 0.124 mmol) in DMF was
added NaH (10 mg, 0.248 mmol) and (chloromethyl)(methyl)sulfane (24
mg, 0.248 mmol). The mixture was stirred for 2 hours at room
temperature. The mixture was partitioned between EtOAc and water,
the organic layer was washed with water, brine and dried over
Na.sub.2SO.sub.4, concentrated to give the crude which was purified
by prep-TLC to give 15 mg of the product. .sup.1H NMR
(CHLOROFORM-d) .delta. 7.73 (s, 1H), 7.59-7.68 (m, 2H), 5.20 (s,
2H), 4.28-4.48 (m, 2.5H), 4.26-4.30 (m, 1H), 3.50-3.80 (m, 1H),
2.99-3.40 (m, 2.5H), 2.22-2.28 (m, 1H), 2.21 (s, 3H), 1.73 (s, 1H),
1.30-1.48 (m, 1H), 1.14-1.23 (m, 2H), 0.94-1.10 (m, 4H), 0.75-0.85
(m, 2H), 0.39-0.64 (m, 4H). LC-MS: m/z 463.2 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-(2-hydroxyethyl)-1H-pyrazol-4-yl)nicotinonitrile (Compound
490):
[0808] .sup.1H NMR (CHLOROFORM-d) .delta. 7.66 (s, 1H), 7.58-7.64
(m, 2H), 4.47 (d, J=12.3 Hz, 1H), 4.25-4.41 (m, 3H), 3.97-4.18 (m,
3H), 3.77 (s, 1H), 3.23 (s, 2H), 3.07 (s, 1H), 2.16-2.30 (m, 1H),
1.23-1.35 (m, 2H), 1.12-1.21 (m, 2H), 0.95-1.09 (m, 4H), 0.74-0.87
(m, 2H), 0.38-0.64 (m, 4H). LC-MS: m/z 446.2M+H).sup.+
(R)-5-(benzo[d]thiazol-6-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpipe-
razin-1-yl)-6-cyclopropylnicotinonitrile (Compound 487; General
procedure 1, Step I)
[0809] 1H NMR (CHLOROFORM-d) .delta. 9.07 (s, 1H), 8.22 (d, J=8.3
Hz, 1H), 8.00 (d, J=1.5 Hz, 1H), 7.68-7.73 (m, 1H), 7.58 (dd,
J=8.4, 1.6 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.43 (d, J=12.3 Hz,
1H), 3.50 (d, J=9.0 Hz, 2H), 3.29 (br. s., 2H), 3.13 (br. s., 1H),
2.04-2.12 (m, 1H), 1.29-1.40 (m, 2H), 1.18-1.25 (m, 2H), 0.94-1.12
(m, 4H), 0.77-0.86 (m, 2H), 0.68 (br. s., 1H), 0.40-0.61 (m, 3H);
LC-MS: m/z 470.2 (M+H).
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(furan-3-carbonyl)piperazin-1-yl)-5-(-
isoquinolin-5-yl)nicotinonitrile (Compound 488; General procedure
4, Step R and S)
[0810] 1H NMR (CHLOROFORM-d) .delta. 9.36 (s, 1H), 8.55 (dd, J=5.8,
2.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.64-7.79 (m, 4H), 7.41-7.50
(m, 2H), 6.59 (s, 1H), 4.61 (dd, J=13.1, 2.0 Hz, 1H), 4.43 (br. s.,
2H), 3.98 (br. s., 1H), 3.73 (br. s., 1H), 3.22-3.36 (m, 1H),
3.07-3.22 (m, 1H), 1.50-1.57 (m, 2H), 1.12-1.21 (m, 2H), 0.81-0.89
(m, 2H), 0.65-0.78 (m, 1H), 0.53-0.62 (m, 1H), 0.47 (br. s., 2H).
LC-MS: m/z 490.6 (M+H).sup.+
(R)-methyl
4-(3-cyano-6-cyclopropyl-5-(isoquinolin-5-yl)pyridin-2-yl)-2-cy-
clopropylpiperazine-1-carboxylate (Compound 489; General procedure
4, Step R and S)
[0811] 1H NMR (CHLOROFORM-d) .delta. 9.37 (br. s., 1H), 8.55 (br.
s., 1H), 8.08 (d, J=8.0 Hz, 1H), 7.70-7.77 (m, 1H), 7.60-7.70 (m,
2H), 7.46 (dd, J=12.0, 5.8 Hz, 1H), 4.50-4.60 (m, 1H), 4.37-4.47
(m, 1H), 4.17 (d, J=12.5 Hz, 1H), 3.76 (s, 3H), 3.45-3.59 (m, 2H),
3.29 (ddd, J=12.9, 6.4, 3.8 Hz, 1H), 3.13 (tdd, J=12.5, 7.2, 3.5
Hz, 1H), 1.47-1.57 (m, 1H), 1.34-1.47 (m, 1H), 1.18 (dd, J=7.3, 4.0
Hz, 2H), 0.85-0.93 (m, 2H), 0.60-0.72 (m, 1H), 0.48-0.60 (m, 2H),
0.36-0.48 (m, 1H). LC-MS: m/z 454.5 (M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-
-[3,3'-bipyridine]-5,5'-dicarbonitrile (Compound 494; General
procedure 1, Step H)
[0812] .sup.1H NMR (CHLOROFORM-d) .delta. 8.92 (br. s., 2H),
7.99-8.07 (m, 1H), 7.63 (s, 1H), 4.63 (d, J=12.8 Hz, 1H), 4.50 (d,
J=12.3 Hz, 1H), 3.33 (br. s., 1H), 3.17 (m, 2H), 1.80-1.90 (m, 2H),
1.73 (m., 1H), 1.19-1.31 (m, 4H), 0.94-1.12 (m, 4H), 0.76-0.88 (m,
2H), 0.36-0.60 (m, 4H). LC-MS: m/z 439.5 (M+H).sup.+
(R)-5-(cinnolin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-
-yl)-6-cyclopropylnicotinonitrile (Compound 495; General procedure
1, Step H)
[0813] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.28 (d, J=2.0 Hz, 1H),
8.66 (d, J=8.5 Hz, 1H), 7.88-7.97 (m, 1H), 7.72-7.85 (m, 2H),
7.66-7.72 (m, 2H), 4.60-4.74 (m, 1.5H), 4.43-4.60 (m, 1.5H),
3.60-3.89 (m, 1H), 3.35 (br. s., 1H), 3.22 (br. s., 1H), 1.49-1.58
(m, 1H), 1.16-1.36 (m, 4H), 0.99-1.16 (m, 2H), 0.78-0.99 (m, 4H),
0.63-0.78 (m, 1H), 0.42-0.63 (m, 3H). LC-MS: m/z 465.6
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-vinylpyrimidin-4-yl)nicotinonitrile (Compound 496)
[0814] The procedure was similar to the synthesis of Compound 390.
.sup.1H NMR (CHLOROFORM-d) .delta. 8.67-8.84 (m, 1H), 8.07 (s, 1H),
7.43 (d, J=5.0 Hz, 1H), 6.87-7.03 (m, 1H), 6.74 (dd, J=17.4, 1.6
Hz, 1H), 5.76-5.88 (m, 1H), 4.68 (d, J=13.1 Hz, 1H), 4.55 (d,
J=13.3 Hz, 1H), 4.07 (br. s., 1H), 3.88 (s, 1H), 3.66 (br. s., 1H),
3.33 (br. s., 1H), 3.17 (br. s., 1H), 2.34-2.47 (m, 1H), 1.96-2.08
(m, 2H), 1.30-1.42 (m, 2H), 1.00-1.11 (m, 3H), 0.85-0.93 (m, 1H),
0.82 (dd, J=8.0, 2.5 Hz, 2H), 0.65 (br. s., 1H), 0.39-0.59 (m, 3H).
LC-MS: m/z 441.2 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-methylisoquinolin-5-yl)nicotinonitrile (Compound 497; General
procedure 1, Step I)
[0815] .sup.1H NMR (CHLOROFORM-d) .delta. 8.40 (dd, J=6.0, 2.0 Hz,
1H), 8.24 (d, J=8.3 Hz, 1H), 7.68-7.76 (m, 1H), 7.31 (d, J=6.5 Hz,
2H), 4.58 (d, J=10.5 Hz, 1H), 4.46 (d, J=12.5 Hz, 1H), 4.23 (br.
s., 1H), 3.82 (br. s., 1H), 3.67 (br. s., 1H), 3.32 (br. s., 1H),
3.17 (br. s., 1H), 2.93-3.12 (m, 3H), 1.74 (br. s., 1H), 1.47-1.57
(m, 2H), 1.14-1.22 (m, 2H), 1.00-1.12 (m, 2H), 0.83 (dd, J=6.7, 4.6
Hz, 4H), 0.70 (br. s., 1H), 0.41-0.63 (m, 3H). LC-MS: m/z 478.3
(M+H).sup.+
(R)-6'-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2'-cycloprop-
yl-6-vinyl-2,3'-bipyridine-5'-carbonitrile (Compound 499; General
procedure 1, Step H)
[0816] The procedure was similar to the synthesis of Compound 390.
.sup.1H NMR (CHLOROFORM-d) .delta. 7.95 (s, 1H), 7.75 (t, J=7.8 Hz,
1H), 7.39-7.45 (m, 1H), 7.32-7.37 (m, 1H), 6.82-6.96 (m, 1H), 6.31
(dd, J=17.6, 1.3 Hz, 1H), 5.49-5.59 (m, 1H), 4.58 (d, J=12.8 Hz,
1H), 4.45 (d, J=12.5 Hz, 1H), 4.19 (br. s., 0.5H), 4.06 (br. s.,
0.5H), 3.78 (br. s., 0.5H), 3.60 (br. s., 0.5H), 3.28 (br. s., 2H),
3.11 (br. s., 1H), 2.29-2.39 (m, 1H), 1.67-1.79 (m, 1H), 1.32-1.45
(m, 1H), 1.18-1.25 (m, 2H), 0.96-1.12 (m, 4H), 0.74-0.87 (m, 2H),
0.65 (br. s., 1H), 0.35-0.58 (m, 3H). LC-MS: m/z 440.6
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(imidazo[1,2-a]pyrazin-3-yl)nicotinonitrile (Compound 503;
General procedure 1, Step I)
[0817] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=9.20 (s, 1H), 7.89
(dd, J=25.5, 17.4 Hz, 3H), 7.73 (s, 1H), 4.66 (d, J=12.8 Hz, 1H),
4.53 (d, J=12.8 Hz, 1H), 3.49 (s, 4H), 3.36-3.10 (m, 2H), 2.15-1.83
(m, 3H), 1.53 (m, 1H), 1.08-0.95 (m, 4H), 0.84 (m, 3H), 0.61-0.40
(m, 3H). LC-MS: m/z 454.1 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2,3-dioxoindolin-5-yl)nicotinonitrile (Compound 504; General
procedure 1, Step I)
[0818] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.=8.38 (s, 1H), 7.68
(d, J=1.8 Hz, 1H), 7.64-7.57 (m, 2H), 7.04 (d, J=8.4 Hz, 1H),
5.48-5.23 (m, 1H), 4.98 (m, 1H), 3.38-3.05 (m, 2H), 2.14-1.88 (m,
4H), 1.01 (dd, J=7.9, 3.4 Hz, 3H), 0.90 (dd, J=9.0, 4.7 Hz, 5H),
0.86-0.77 (m, 3H), 0.57-0.40 (m, 3H). LC-MS: m/z 482.2
(M+H).sup.+
5-(4-acryloylmorpholin-2-yl)-2-((R)-4-(cyclopropanecarbonyl)-3-methylpiper-
azin-1-yl)-6-cyclopropylnicotinonitrile (Compound 600)
[0819] A mixture of
2-((R)-4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(-
morpholin-2-yl)nicotinonitrile (13 mg, 0.03 mmol), acryloyl
chloride (1 drop) and TEA (1 drop) in 10 mL of DCM was stirred at
r.t. for 10 mins. After the mixture was quenched and worked up, the
filtrate was concentrated and the residue was purified by column
chromatography (50% PE/EA) to afford 11 mg of title compound.
.sup.1H NMR (CHLOROFORM-d) .delta. 7.86 (s, 1H), 6.48-6.69 (m, 1H),
6.31-6.48 (m, 1H), 5.80 (d, J=9.3 Hz, 1H), 4.91 (d, J=13.1 Hz, 1H),
4.71 (d, J=8.8 Hz, 1H), 4.44-4.63 (m, 1.5H), 4.05-4.34 (m, 4H),
3.92 (d, J=12.5 Hz, 0.5H), 3.74 (d, J=9.8 Hz, 1.5H), 3.35-3.52 (m,
1.5H), 3.04-3.29 (m, 3H), 2.62 (t, J=11.3 Hz, 0.5H), 2.10 (br. s.,
1H), 1.75 (br. s., 1H), 1.40 (br. s., 1.5H), 1.27 (br. s., 1.5H),
1.13 (br. s., 2H), 1.03 (br. s., 4H), 0.81 (d, J=7.0 Hz, 2H).
LC-MS: m/z 450.2 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(6-vinylpyridazin-4-yl)nicotinonitrile (Compound 613)
##STR00842##
[0820] Step 1
[0821] A mixture of 8-4 (50 mg, 0.11 mmol), 5-chloropyridazin-3-ol
(21 mg, 0.16 mmol), CsF (33 mg, 0.22 mmol) and Pd(dppf)Cl.sub.2(5
mg) in dioxane and water was heated at 100.degree. C. for 1 hr. The
reaction mixture was concentrated and the residue was purified by
pre-TLC to afford 35 mg of title compound. .sup.1H NMR
(CHLOROFORM-d) .delta. 12.68 (br. s., 1H), 7.97 (s, 1H), 7.65 (s,
1H), 7.02 (br. s., 1H), 4.51-4.64 (m, 2.5H), 4.21 (br. s., 1H),
3.56-3.84 (m, 1H), 3.17-3.32 (m, 2.5H), 1.99 (br. s., 1H), 1.71
(br. s., 1H), 1.24 (br. s., 3H), 1.01-1.08 (m, 4H), 0.72-0.92 (m,
2H), 0.32-0.64 (m, 4H). LC-MS: m/z 431.1 (M+H).sup.+
Step 2
[0822] A solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(6-hydroxypyridazin-4-yl)nicotinonitrile, Tf.sub.2O and TEA in
DCM was stirred for 1 hr. The reaction mixture was washed with
water, dried and concentrated. The residue was purified by pre-TLC
to afford 150 mg of title compound. .sup.1H NMR (CHLOROFORM-d, 400
MHz) .delta. 9.42 (br. s., 1H), 7.72 (s, 1H), 7.52 (s, 1H),
4.58-4.75 (m, 2.5H), 4.32 (br. s., 0.5H), 4.00 (br. s., 0.5H), 3.73
(br. s., 1H), 3.25-3.39 (m, 2.5H), 1.89-1.94 (m, 1H), 1.72 (br. s.,
1H), 1.31 (br. s., 3H), 1.00-1.18 (m, 4H), 0.84 (d, J=6.3 Hz, 2H),
0.45-0.66 (m, 4H).
Step 3
[0823] A mixture of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(6-vinylpyridazin-4-yl)nicotinonitrile (50 mg, 0.09 mmol),
potassium vinyltrifluoroborate (24 mg, 0.18 mmol), TEA(27 mg, 0.27
mmol) and Pd(dppf)Cl.sub.2(5 mg) in i-PrOH and water was heated at
100.degree. C. for 1 hr. The reaction mixture was concentrated and
the residue was purified by pre-TLC to afford 11 mg of title
compound. .sup.1H NMR (CHLOROFORM-d) 9.20 (br. s., 1H), 7.68 (br.
s., 1H), 7.61 (br. s., 1H), 7.04-7.22 (m, 1H), 6.36 (d, J=17.6 Hz,
1H), 5.78 (d, J=10.8 Hz, 1H), 4.53-4.58 (m, 2.5H), 4.17 (br. s.,
1H), 3.72 (br. s., 1H), 3.19-3.34 (m, 1H), 1.94 (br. s., 1H), 1.80
(br. s., 1H), 1.26 (br. s., 3H), 1.07 (br. s., 4H), 0.82 (br. s.,
2H), 0.46-0.65 (m, 4H). LC-MS: m/z 441.2 (M+H).sup.+
(R)-5-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)pyridin-3-yl)pyridazin-3-yl trifluoromethanesulfonate (Compound
614):
[0824] .sup.1H NMR (CHLOROFORM-d) .delta. 9.41 (s, 1H), 7.71 (s,
1H), 7.50 (d, J=1.3 Hz, 1H), 4.93 (br. s., 0.5H), 4.56 (d, J=7.8
Hz, 0.5H), 4.47 (d, J=7.3 Hz, 1.5H), 4.25-4.40 (m, 1H), 3.86 (d,
J=12.5 Hz, 0.5H), 3.76 (br. s., 2H), 3.57 (br. s., 0.5H), 3.36-3.48
(m, 4H), 3.30 (br. s., 0.5H), 3.11-3.24 (m, 1H), 2.71 (br. s., 1H),
2.61 (br. s., 1H), 1.89-1.93 (m, 1H), 1.37 (d, J=5.5 Hz, 1.5H),
1.22-1.32 (m, 3.5H), 1.08-1.22 (m, 2H). LC-MS: m/z 555.1
(M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-v-
inylpyridazin-4-yl)nicotinonitrile (Compound 615)
[0825] The procedure is similar to Compound 613. .sup.1H NMR
(CHLOROFORM-d) .delta. 9.20 (br. s., 1H), 7.67 (s, 1H), 7.58-7.65
(m, 1H), 7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.37 (d, J=17.8 Hz, 1H),
5.79 (d, J=11.0 Hz, 1H), 4.92 (br. s., 0.5H), 4.48-4.62 (m, 0.5H),
4.35-4.48 (m, 1.5H), 4.31 (d, J=14.1 Hz, 1H), 3.83 (d, J=13.3 Hz,
0.5H), 3.67-3.80 (m, 2H), 3.51-3.63 (m, 0.5H), 3.30-3.45 (m, 4H),
3.13-3.28 (m, 1.5H), 2.65-2.82 (m, 1H), 2.51-2.65 (m, 1H),
1.92-1.96 (m, 1H), 1.38 (d, J=5.5 Hz, 1.5H), 1.24-1.27 (m, 3.5H),
1.07 (d, J=4.8 Hz, 2H). LC-MS: m/z 433.1 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(6-hydroxypyridazin-4-yl)nicotinonitrile (Compound 616)
[0826] .sup.1H NMR (CHLOROFORM-d) .delta. 12.68 (br. s., 1H), 7.97
(s, 1H), 7.65 (s, 1H), 7.02 (br. s., 1H), 4.51-4.64 (m, 2.5H), 4.21
(br. s., 1H), 3.56-3.84 (m, 1H), 3.17-3.32 (m, 2.5H), 1.99 (br. s.,
1H), 1.71 (br. s., 1H), 1.24 (br. s., 3H), 1.01-1.08 (m, 4H),
0.72-0.92 (m, 2H), 0.32-0.64 (m, 4H). LC-MS: m/z 431.1
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-methyl-6-oxo-1,6-dihydropyridazin-4-yl)nicotinonitrile
(Compound 640)
[0827] .sup.1H NMR (CHLOROFORM-d) .delta. 7.85 (br. s., 1H), 7.60
(br. s., 1H), 6.95 (br. s., 1H), 4.50-4.63 (m, 2.5H), 4.21 (br. s.,
1H), 3.84 (br. s., 3H), 3.69 (br. s., 1H), 3.17-3.30 (m, 2.5H),
1.99 (br. s., 1H), 1.76 (br. s., 1H), 1.22 (br. s., 3H), 1.07 (br.
s., 4H), 0.81 (br. s., 2H), 0.51 (br. s., 4H). LC-MS: m/z 445.2
(M+H).sup.+
(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2--
cyclopropylpyridin-3-yl)pyridazine-3-carbonitrile (Compound
641)
[0828] .sup.1H NMR (CHLOROFORM-d) .delta. 9.51 (d, J=2.3 Hz, 1H),
7.93 (d, J=2.3 Hz, 1H), 7.70 (s, 1H), 4.59-4.72 (m, 2.5H),
4.09-4.26 (m, 1H), 3.75 (br. s., 1H), 3.23-3.39 (m, 2.5H),
1.82-1.95 (m, 1H), 1.65 (br. s., 1H), 1.26-1.34 (m, 3H), 0.96-1.20
(m, 4H), 0.76-0.91 (m, 2H), 0.38-0.75 (m, 4H). LC-MS: m/z 440.2
(M+H).sup.+
(R)-2-(4-acetyl-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(isoquinolin-5-yl)-
nicotinonitrile (Compound 516; General procedure 4, Step R and
S)
[0829] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (s, 1H), 8.54 (d,
J=5.8 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.64-7.74 (m, 3H), 7.43 (t,
J=5.9 Hz, 1H), 4.91 (br. s., 0.5H), 4.57-4.53 (d, 0.5H), 4.18-4.39
(m, 2.5H), 3.6-3.77 (m, 1H), 3.34 (br. s., 1H), 3.05-3.25 (m,
1.5H), 1.91 (br. s., 3H), 1.33-1.54 (m, 4H), 1.14-1.17 (m, 2H),
0.82-0.85 (m, 2H). LC-MS: m/z 412.2 (M+H).sup.+
6-cyclopropyl-2((R)-4((1S,2R)-2-ethoxycyclopropanecarbonyl)-3-methylpipera-
zin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile (Compound 517;
General procedure 4, Step R and S)
[0830] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (s, 1H), 8.54 (d,
J=5.8 Hz, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.59-7.76 (m, 3H), 7.44 (t,
J=6.8 Hz, 1H), 4.87-5.02 (m, 0.5H), 4.61-4.64 (m, 0.5H), 4.12-4.43
(m, 2.5), 3.05-3.70 (m, 5.5H), 2.0 (s, 1H), 1.76-1.86 (m, 1H),
1.40-1.62 (m, 3H), 1.27-1.35 (m, 2H), 1.16-1.21 (m, 4H), 0.92-0.99
(m, 1H), 0.81-0.84 (m, 2H). LC-MS: m/z 482.2 (M+H).sup.+
6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl-
)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile (Compound 518;
General procedure 4, Step R and S)
[0831] 1H NMR (CHLOROFORM-d) .delta. 9.37 (s, 1H), 8.54 (dd, J=6.0,
2.0 Hz, 1H), 8.08 (d, J=8.0 Hz, 1H), 7.73 (t, 1H), 7.64-7.69 (m,
2H), 7.46 (q, 1H), 4.73 (m, 0.5H), 4.43-4.62 (m, 2.5H), 4.13-4.26
(m, 2H), 3.68-3.87 (m, 1.5H), 3.50-3.60 (m, 3.5H), 3.19-3.30 (s,
2H), 1.97-2.19 (m, 2H), 1.50-1.54 (m, 1H), 1.16-1.23 (m, 6H),
0.82-0.91 (m, 5H), 0.64-0.68 (m, 2H), 0.43-0.51 (m, 2H). LC-MS: m/z
508.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(4-oxobutanoyl)piperazin-1-yl)-5-(iso-
quinolin-5-yl)nicotinonitrile (Compound 519; General procedure 4,
Step R and S)
[0832] .sup.1H NMR (CHLOROFORM-d) .delta. 9.91 (s, 1H), 9.38 (s,
1H), 8.55 (br. s., 1H), 8.09 (d, J=8.0 Hz, 1H), 7.74 (t, 1H),
7.66-7.70 (m, 2H), 7.47 (q, 1H), 4.55-4.58 (d, 1H), 4.44-4.47 (d,
1H), 4.09 (br. s., 1H), 3.90 (br. s., 1H), 3.07-3.40 (m, 2.5H),
2.69-2.91 (m, 3.5H), 2.05 (m, 2H), 14.53 (m, 1H), 0.83-0.92 (m,
6H), 0.44-0.71 (br. s., 4H). LC-MS: m/z 480.2 (M+H).sup.+
6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2R)-2-ethoxycyclopropanecarbonyl-
)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile (Compound 526;
General procedure 4, Step R and S)
[0833] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (br. s., 1H), 8.53
(br. s., 1H), 8.07 (d, J=8.0 Hz, 1H), 7.68-7.74 (t, 1H), 7.64-7.67
(m, 2H), 7.45 (dd, J=5.8 Hz, 1H), 4.58 (d, J=12.8 Hz, 1H), 4.49 (d,
J=11.3 Hz, 1H), 4.13-4.27 (m, 1.5H), 3.80 (br. s., 0.5H), 3.52-3.59
(m, 3H), 3.22 (br. s., 2H), 1.82 (d, J=7.5 Hz, 1H), 1.47-1.57 (m,
2H), 1.17-1.20 (m, 6H), 0.82-0.99 (m, 5H), 0.45-0.65 (m, 4H).
LC-MS: m/z 508.3 (M+H).sup.+
6-cyclopropyl-2-((R)-4-((1R,2R)-2-(hydroxymethyl)cyclopropanecarbonyl)-3-m-
ethylpiperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile (Compound
505; General procedure 4, Step R and S)
[0834] .sup.1H NMR (CHLOROFORM-d) .delta. 9.39 (br. s., 1H), 8.56
(br. s., 1H), 8.08 (d, J=8.0 Hz, 1H), 7.71-7.76 (m, 1H), 7.66-7.70
(m, 1H), 7.64 (s, 1H), 7.47 (br. s., 1H), 4.18-4.89 (m, 4H),
3.25-3.80 (m, 5H), 2.01-2.08 (m, 1H), 1.46-1.57 (m, 2H), 1.24-1.39
(m, 4H), 1.10-1.20 (m, 2H), 0.79-0.91 (m, 3H). LC-MS: m/z 468.2
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(quinoxalin-5-yl)nicotinonitrile (Compound 531; General
procedure 1, Step I)
[0835] .sup.1H NMR (CHLOROFORM-d) .delta. 8.88 (d, J=1.8 Hz, 1H),
8.91 (d, J=1.5 Hz, 1H), 8.21 (dd, J=8.4, 1.4 Hz, 1H), 7.88 (t,
J=8.4, 7.2 Hz, 1H), 7.79 (dd, J=7.2, 1.4 Hz, 1H), 7.73 (s, 1H),
4.53 (d, 1H), 4.56 (d, 1H), 4.53-4.27 (m, 2.5H), 3.05-3.45 (m,
2.5H), 1.74 (br. s., 1H), 1.56-1.65 (m, 1H), 0.97-1.26 (m, 6H),
0.42-0.87 (m, 8H). LC-MS: m/z 465.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(quinoxalin-5-yl)nicotinonitrile (Compound 532; General
procedure 1, Step I)
[0836] .sup.1H NMR (CHLOROFORM-d) .delta. 8.89-8.92 (m, 2H), 8.22
(dd, J=8.4, 1.4 Hz, 1H), 7.89 (t, J=8.3, 7.3 Hz, 1H), 7.79-7.81
(dd, J=8.3, 7.3 Hz, 1H), 7.75 (s, 1H), 4.53 (d, J=13.1 Hz, 1H),
4.44 (d, J=12.0 Hz, 1H), 4.14 (br. s., 0.5H), 3.75-3.89 (m, 1.5H),
3.07-3.37 (m, 5H), 1.62 (m, 1H), 1.19 (br. s., 2H), 0.48-0.84 (m,
6H). LC-MS: m/z 507.3 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inylquinoxalin-5-yl)nicotinonitrile (Compound 579; General
procedure 1, Step I)
[0837] .sup.1H NMR (CHLOROFORM-d) .delta. 9.00 (s, 1H), 8.13 (dd,
J=8.5, 1.3 Hz, 1H), 7.84 (dd, J=8.3, 7.3 Hz, 1H), 7.67-7.74 (m,
1H), 7.01-7.12 (m, 1H), 6.50 (d, J=11.3 Hz, 1H), 5.84 (d, J=11.3
Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (br. s., 0.5H), 4.19-4.40 (m,
2.5H), 3.68-3.78 (m, 2.5H), 3.58 (br. s., 0.5H), 3.39 (s, 3H),
3.02-3.31 (m, 2.5H), 2.58-2.75 (m, 2H), 1.86 (br. s., 1H), 1.62 (m,
1H), 1.43 (d, J=6.3 Hz, 1.5H), 1.33 (d, J=6.3 Hz, 1.5H), 1.16 (br.
s., 2H), 0.81 (br. s., 2H). LC-MS: m/z 485.2 (M+H).sup.+
(R,E)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-
-(2-(2-vinylquinoxalin-5-yl)vinyl)quinoxalin-5-yl)nicotinonitrile
(Compound 604)
[0838] It was obtained as the by-product of Compound 579. .sup.1H
NMR (CHLOROFORM-d) .delta. 9.23 (s, 1H), 9.09 (s, 1H), 8.17-8.20
(m, 2H), 8.08 (d, J=8.5 Hz, 1H), 7.70-7.87 (m, 5H), 7.04-7.11 (q,
1H), 6.53 (d, J=11.3 Hz, 1H), 5.85 (d, J=11.3 Hz, 1H), 4.94 (br.
s., 0.5H), 4.56 (d, J=12.8 Hz, 0.5H), 4.26-4.37 (m, 2.5H),
3.75-3.84 (m, 2.5H), 3.59 (t, 0.5H), 3.40 (s, 3H), 3.06-3.32 (m,
2.5H), 2.59-2.81 (m, 2H), 1.61-1.73 (m, 1H), 1.45 (d, J=6.3 Hz,
1.5H), 1.32 (d, J=6.3 Hz, 1.5H), 1.25-1.29 (m, 2H), 0.83-0.86 (m,
2H). LC-MS: m/z 637.3 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
2-vinylquinoxalin-5-yl)nicotinonitrile (Compound 605; General
procedure 1, Step I)
[0839] .sup.1H NMR (CHLOROFORM-d) .delta. 9.00 (s, 1H), 8.13 (d,
J=8.5 Hz, 1H), 7.83 (t, J=7.8 Hz, 1H), 7.62-7.77 (m, 2H), 6.97-7.13
(q, 1H), 6.50 (d, J=11.0 Hz, 1H), 5.84 (d, J=11.0 Hz, 1H),
4.58-4.73 (m, 1.5H), 4.39-4.48 (m, 1.5H), 3.87 (d, J=13.3 Hz,
0.5H), 3.74 (m, 2H), 3.42-3.60 (m, 1H), 3.39 (d, J=3.3 Hz, 3H),
2.93-3.17 (m, 2.5H), 2.53-2.83 (m, 2H), 2.16-2.33 (m, 1H), 1.62
(br. s., 1H), 1.07-1.10 (m, 4H), 0.82-0.93 (m, 6H). LC-MS: m/z
511.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inylquinoxalin-5-yl)nicotinonitrile (Compound 618; General
procedure 1, Step I)
[0840] .sup.1H NMR (CHLOROFORM-d) .delta. 9.00 (s, 1H), 8.13 (dd,
J=8.5, 1.3 Hz, 1H), 7.84 (dd, J=8.3, 7.3 Hz, 1H), 7.67-7.74 (m,
2H), 7.02-7.07 (m, 1H), 6.50 (d, J=11.3 Hz, 1H), 5.82 (d, J=11.3
Hz, 1H), 4.92 (br. s., 0.5H), 4.57 (br. s., 0.5H), 4.19-4.33 (m,
3H), 3.93 (s, 2.5H), 3.58 (br. s., 0.5H), 3.01-3.48 (m, 4H),
2.48-2.75 (m, 3H), 1.63 (m, 1H), 1.43 (d, J=6.3 Hz, 1.5H), 1.35 (d,
J=6.3 Hz, 1.5H), 1.16 (br. s., 2H), 0.82 (br. s., 2H). LC-MS: m/z
469.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinoxalin-5-yl)nicotinonitrile (Compound 644; General
procedure 1, Step I)
[0841] .sup.1H NMR (CHLOROFORM-d) .delta. 9.00 (s, 1H), 8.13 (dd,
J=8.5, 1.3 Hz, 1H), 7.70-7.72 (m, 2H), 7.01-7.12 (q, 1H), 6.50 (d,
J=11.3 Hz, 1H), 5.84 (d, J=11.3 Hz, 1H), 4.71 (br. s., 0.5H), 4.52
(d, 1H), 4.41 (d, 1H), 4.12 (br. s., 0.5H), 3.89 (br. s., 0.5H),
3.74 (m, 2H), 3.39 (s, 3H), 3.01-3.31 (m, 3H), 2.59-2.83 (m, 2H),
1.58-1.68 (m, 1H), 0.97-1.32 (m, 4H), 0.46-0.89 (m, 7H). LC-MS: m/z
509.1 (M+H).sup.+
(R)-2'-bromo-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cy-
clopropyl-3,4'-bipyridine-5-carbonitrile (Compound 508; General
procedure 1, Step H)
[0842] .sup.1H NMR CHLOROFORM-d) .delta. 8.46 (d, J=5.0 Hz, 1H),
7.63 (s, 1H), 7.57-7.61 (m, 1H), 7.34 (dd, J=5.0, 1.5 Hz, 1H), 4.61
(d, J=12.8 Hz, 1H), 4.49 (d, J=13.6 Hz, 1H), 4.18-4.38 (m, 1H),
3.76 (br. s., 2H), 3.31 (br. s., 1H), 3.15 (br. s., 1H), 1.93-2.08
(m, 1H), 1.72 (br. s., 1H), 1.33 (br. s., 1H), 1.17-1.26 (m, 2H),
0.95-1.12 (m, 4H), 0.76-0.91 (m, 2H), 0.66 (br. s., 1H), 0.35-0.60
(m, 3H). LC-MS: m/z 493.4 (M+H).sup.+
(R)-2'-chloro-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-c-
yclopropyl-3'-fluoro-3,4'-bipyridine-5-carbonitrile (Compound 509;
General procedure 1, Step H)
[0843] .sup.1H NMR (CHLOROFORM-d) .delta. 8.29 (d, J=5.0 Hz, 1H),
7.59-7.75 (s, 1H), 7.11-7.41 (d, J=5.0 Hz, 1H), 4.63 (d, J=13.1 Hz,
1H), 4.50 (d, J=12.5 Hz, 1H), 4.06 (br. s., 1H), 3.75 (br. s., 1H),
3.65 (br. s., 1H), 3.31 (br. s., 1H), 3.16 (br. s., 1H), 1.70-1.81
(m, 1H), 1.30-1.42 (m, 1H), 1.13-1.25 (m, 2H), 0.94-1.13 (m, 4H),
0.75-0.87 (m, 2H), 0.66 (br. s., 1H), 0.35-0.60 (m, 3H). LC-MS: m/z
466.9 (M+H).sup.+
(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2--
cyclopropylpyridin-3-yl)isoquinoline-1-carbonitrile (Compound
511)
[0844] .sup.1H NMR (CHLOROFORM-d) .delta. 8.66 (dd, J=5.8, 1.8 Hz,
1H), 8.45 (d, J=8.3 Hz, 1H), 7.87-7.97 (m, 1H), 7.80 (ddd, J=7.2,
2.1, 1.0 Hz, 1H), 7.70 (ddd, J=11.1, 5.8, 0.9 Hz, 1H), 7.64 (d,
J=0.8 Hz, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.49 (d, J=12.8 Hz, 1H),
3.42-4.43 (m, 2H), 3.10-3.40 (m, 3H), 1.75 (br. s., 1H), 1.38-1.47
(m, 2H), 0.95-1.12 (m, 2H), 0.75-0.93 (m, 6H), 0.70 (br. s., 1H),
0.38-0.61 (m, 3H). LC-MS: m/z 489.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(1-hydroxyisoquinolin-5-yl)nicotinonitrile (Compound 547;
General procedure 2, Step M)
[0845] .sup.1H NMR (CHLOROFORM-d) .delta. 10.95 (s, 1H), 8.53 (dd,
J=6.4, 3.1 Hz, 1H), 7.57-7.72 (m, 3H), 7.17 (br. s., 1H), 6.31 (dd,
J=12.9, 7.4 Hz, 1H), 4.38-4.61 (m, 2H), 4.15 (br. s., 0.5H),
3.69-3.95 (m, 1.5H), 3.03-3.41 (m, 5H), 1.53-1.77 (m, 3H), 1.16
(dd, J=8.3, 4.5 Hz, 2H), 0.81-0.98 (m, 2H), 0.47-0.64 (m, 3H).
LC-MS: m/z 522.2 (M+H).sup.+
(R)-5-(3-chloroisoquinolin-5-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropyl-
piperazin-1-yl)-6-cyclopropylnicotinonitrile (Compound 555; General
procedure 1, Step H)
[0846] .sup.1H NMR (CHLOROFORM-d) .delta. 9.17 (s, 1H), 8.06 (d,
J=7.5 Hz, 1H), 7.66-7.73 (m, 2H), 7.64 (d, J=1.0 Hz, 1H), 7.49 (d,
J=14.8 Hz, 1H), 4.61 (d, J=12.0 Hz, 1H), 4.49 (d, J=12.8 Hz, 1H),
3.42-4.43 (m, 2H), 3.10-3.40 (m, 3H), 1.69 (br. s., 1H), 1.39-1.57
(m, 2H), 1.15-1.23 (m, 2H), 1.08 (br. s., 2H), 0.79-0.93 (m, 4H),
0.70 (br. s., 1H), 0.38-0.63 (m, 3H). LC-MS: m/z 498.2
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-hydroxyisoquinolin-5-yl)nicotinonitrile (Compound 566;
General procedure 1, Step H)
[0847] .sup.1H NMR (CHLOROFORM-d) .delta. 11.20 (br. s., 1H), 8.52
(dd, J=7.0, 2.3 Hz, 1H), 7.51-7.76 (m, 3H), 7.12-7.24 (m, 1H), 6.33
(dd, J=12.7, 7.4 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H), 4.44 (d, J=12.3
Hz, 1H), 3.52-4.35 (m, 2H), 3.05-3.45 (m, 3H), 1.63 (td, J=7.8, 4.0
Hz, 1H), 1.27-1.45 (m, 2H), 0.96-1.23 (m, 4H), 0.77-0.96 (m, 4H),
0.70 (br. s., 1H), 0.36-0.62 (m, 3H). LC-MS: m/z 480.2
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(3-vinylisoquinolin-5-yl)nicotinonitrile (Compound 565; General
procedure 1, Step H)
[0848] .sup.1H NMR (CHLOROFORM-d) .delta. 9.29 (s, 1H), 8.03 (d,
J=7.5 Hz, 1H), 7.55-7.77 (m, 3H), 7.31 (d, J=12.5 Hz, 1H), 6.88
(ddd, J=17.3, 10.6, 6.8 Hz, 1H), 6.38 (ddd, J=17.2, 5.6, 1.3 Hz,
1H), 5.44-5.59 (m, 1H), 4.59 (d, J=11.8 Hz, 1H), 4.47 (d, J=12.5
Hz, 1H), 3.55-4.35 (m, 2H), 3.05-3.45 (m, 3H), 1.68-1.80 (m, 1H),
1.42-1.61 (m, 2H), 1.22-1.34 (m, 2H), 1.00-1.14 (m, 2H), 0.76-0.92
(m, 4H), 0.71 (br. s., 1H), 0.39-0.63 (m, 3H). LC-MS: m/z 490.2
(M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-m-
ethylisoquinolin-5-yl)nicotinonitrile (Compound 588; General
procedure 1, Step H)
[0849] .sup.1H NMR (CHLOROFORM-d) .delta. 9.23 (s, 1H), 7.99 (d,
J=7.3 Hz, 1H), 7.53-7.67 (m, 3H), 7.21 (d, J=6.5 Hz, 1H), 4.91 (br.
s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.15-4.43 (m, 2.5H),
3.86-4.02 (m, 2H), 3.68-3.83 (m, 0.5H), 3.51-3.68 (m, 0.5H),
3.26-3.42 (m, 1H), 2.97-3.24 (m, 1.5H), 2.49-2.78 (m, 5H),
1.49-1.58 (m, 1H), 1.41-1.49 (m, 1.5H), 1.30-1.40 (m, 1.5H),
1.06-1.20 (m, 2H), 0.72-0.91 (m, 2H). LC-MS: m/z 456.2
(M+H).sup.+
(R)-5-(5-chloro-2-vinylpyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclo-
propylpiperazin-1-yl)-6-cyclopropylnicotinonitrile (Compound 533;
General procedure 1, Step H)
[0850] 1H NMR (CHLOROFORM-d) .delta. 8.69-8.87 (m, 1H), 7.70-7.91
(m, 1H), 6.91 (dd, J=17.3, 10.5 Hz, 1H), 6.59-6.78 (m, 1H),
5.71-5.98 (m, 1H), 4.66 (d, J=12.8 Hz, 1H), 4.53 (d, J=12.5 Hz,
1H), 3.09-4.42 (m, 5H), 1.76-1.85 (m, 1H), 1.39-1.46 (m, 1H),
1.21-1.25 (m, 2H), 0.99-1.10 (m, 4H), 0.90 (t, J=6.9 Hz, 1H),
0.78-0.85 (m, 2H), 0.66 (br. s., 1H), 0.41-0.60 (m, 3H). LC-MS: m/z
475.2 (M+H).sup.+
Compound 541
##STR00843##
[0851] Step 1:
(R)-5-(6-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylp-
iperazin-1-yl)-6-cyclopropylnicotinonitrile
##STR00844##
[0853] To a solution of 4,6-dichloropyrimidine (50 mg, 0.32 mmol)
in a mixture of dimethoxyethane (3 mL) and a 2M aqueous sodium
carbonate solution (0.6 mL) were added 8-4 (100 mg, 0.22 mmol) and
tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.1 eq) under
nitrogen atmosphere, and the mixture was heated for 2 hours at
100.degree. C. After cooling to ambient temperature, the separated
organic layer was evaporated under reduced pressure. The residue
was taken up into ethyl acetate, washed in turn with a 10% aqueous
potassium carbonate solution and brine, and dried over sodium
sulfate. After evaporation, the residue was purified on silica gel
eluding with 5%-20% ethyl acetate in petroleum ether to give
4-chloro-6-phenylpyrimidine (75 mg), 69% yield. .sup.1H NMR
(CHLOROFORM-d) .delta. 8.67-8.84 (m, 1H), 8.07 (s, 1H), 7.43 (d,
J=5.0 Hz, 1H), 4.68 (d, J=13.1 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H),
4.07 (br. s., 1H), 3.88 (s, 1H), 3.68 (br. s., 1H), 3.33 (br. s.,
1H), 3.17 (br. s., 1H), 2.34-2.47 (m, 1H), 1.96-2.08 (m, 2H),
1.30-1.42 (m, 2H), 1.00-1.11 (m, 3H), 0.85-0.93 (m, 1H), 0.82 (dd,
J=8.0, 2.5 Hz, 2H), 0.65 (br. s., 1H), 0.39-0.59 (m, 3H). LC-MS:
m/z 449.2 (M+H).sup.+
Step 2:
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyc-
lopropyl-5-(6-vinylpyrimidin-4-yl)nicotinonitrile (Compound
541)
[0854] A mixture of above
(R)-5-(6-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylp-
iperazin-1-yl)-6-cyclopropylnicotinonitrile (60 mg, 0.06 mmol) (60
mg, 0.13 mmol), vinyl potassium-trifluoroborate (25 mg, 0.2 mmol),
Pd(PPh3)4 (3 mg, 0.1 eq), and CsF (40 mg, 0.26 mmol) were suspended
in 5 mL of dioxane and 1 mL of water, the resulting mixture was
refluxed for 1 h. After the reaction was complete, the reaction
mixture was concentrated in vacuo, and the residue was purified by
column chromatography to afford 35 mg of title compound as yellow
solid. 75% yield. .sup.1H NMR (CHLOROFORM-d) .delta. 9.16-9.30 (m,
1H), 7.93-8.07 (m, 1H), 7.49-7.56 (m, 1H), 6.82 (dd, J=17.3, 10.5
Hz, 1H), 6.57 (dd, J=17.3, 1.0 Hz, 1H), 5.72-5.83 (m, 1H), 4.68 (d,
J=13.1 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.39-3.11 (br. s., 5H),
2.34-2.43 (m, 1H), 1.70 (br. s., 1H), 1.31-1.40 (m, 2H), 0.99-1.11
(m, 4H), 0.89-0.94 (m, 1H), 0.82 (dd, J=7.9, 2.4 Hz, 2H), 0.64 (br.
s., 1H), 0.41-0.58 (m, 3H). LC-MS: m/z 441.2 (M+H).sup.+
(S)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(6-vinylpyrimidin-4-yl)nicotinonitrile (Compound 578)
[0855] .sup.1H NMR (CHLOROFORM-d) .delta.9.24 (d, J=1.3 Hz, 1H),
7.94-8.05 (m, 1H), 7.46-7.58 (m, 1H), 6.82 (dd, J=17.3, 10.8 Hz,
1H), 6.57 (dd, J=17.3, 1.0 Hz, 1H), 5.73-5.84 (m, 1H), 4.68 (d,
J=12.5 Hz, 1H), 4.55 (d, J=12.3 Hz, 1H), 4.08 (br. s., 1H), 3.76
(s, 1H), 3.66 (t, J=6.7 Hz, 1H), 3.40-3.58 (m, 1H), 3.33 (br. s.,
1H), 3.17 (br. s., 1H), 2.34-2.45 (m, 1H), 1.29-1.35 (m, 2H),
1.00-1.11 (m, 4H), 0.89-0.92 (m, 1H), 0.82 (dd, J=7.9, 2.4 Hz, 2H),
0.64 (br. s., 1H), 0.43-0.58 (m, 3H). LC-MS: m/z 441.2
(M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-v-
inylpyrimidin-4-yl)nicotinonitrile (Compound 621)
[0856] .sup.1H NMR (CHLOROFORM-d) .delta. 9.24 (d, J=1.3 Hz, 1H),
7.82-8.04 (m, 1H), 7.47-7.61 (m, 1H), 6.68-6.93 (m, 1H), 6.42-6.62
(m, 1H), 5.64-5.88 (m, 1H), 4.88 (br. s., 1H), 4.29-4.57 (m, 3H),
4.17 (br. s., 1H), 3.93 (br. s., 2H), 3.74 (d, J=13.3 Hz, 1H),
3.47-3.63 (m, 1H), 3.29-3.41 (m, 1H), 3.05-3.25 (m, 2H), 2.51-2.72
(m, 2H), 2.33-2.42 (m, 1H), 1.32-1.44 (m, 2H), 1.22-1.28 (m, 3H),
1.02-1.11 (m, 2H). LC-MS: m/z 419.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(6-vinylpyrimidin-4-yl)nicotinonitrile (Compound 638)
[0857] .sup.1H NMR (CHLOROFORM-d) .delta. 9.24 (s, 1H), 7.95-8.11
(m, 1H), 7.50-7.56 (m, 1H), 6.74-6.87 (m, 1H), 6.48-6.65 (m, 1H),
5.74-5.89 (m, 1H), 4.67 (d, J=12.8 Hz, 1H), 4.53 (d, J=11.0 Hz,
1H), 4.10 (br. s., 0.5H), 3.83-3.93 (m, 0.5H), 3.61-3.81 (m, 3H),
3.39 (s, 3H), 3.21-3.35 (m, 2H), 3.08-3.21 (m, 1H), 2.72 (br. s.,
1H), 2.65 (br. s., 1H), 2.33-2.43 (m, 1H), 1.21-1.36 (m, 3H),
1.03-1.13 (m, 2H), 0.60 (br. s., 2H), 0.45 (br. s., 2H). LC-MS: m/z
459.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
6-vinylpyrimidin-4-yl)nicotinonitrile (Compound 639)
[0858] 1H NMR (CHLOROFORM-d) .delta. 9.09-9.32 (m, 1H), 7.99 (s,
1H), 7.51 (s, 1H), 6.81 (dd, J=17.3, 10.5 Hz, 1H), 6.56 (d, J=17.3
Hz, 1H), 5.78 (d, J=11.3 Hz, 1H), 4.67-4.76 (m, 1H), 4.50 (d,
J=14.6 Hz, 1H), 3.88 (d, J=13.6 Hz, 1H), 3.68-3.79 (m, 2H), 3.60
(d, J=10.5 Hz, 1H), 3.39-3.55 (m, 1H), 3.02-3.24 (m, 2H), 2.85-3.02
(m, 1H), 2.52-2.82 (m, 2H), 2.33-2.43 (m, 1H), 1.92-2.05 (m, 1H),
1.23-1.31 (m, 2H), 1.00-1.10 (m, 5H), 0.83-0.92 (m, 3H). LC-MS: m/z
461.3 (M+H).sup.+
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-v-
inylpyrimidin-4-yl)nicotinonitrile (Compound 597)
[0859] 1H NMR (CHLOROFORM-d) .delta. 9.22 (s, 1H), 7.98 (s, 1H),
7.50 (s, 1H), 6.80 (dd, J=17.3, 10.8 Hz, 1H), 6.44-6.69 (m, 1H),
5.64-5.92 (m, 1H), 4.89 (br. s., 0.5H), 4.52 (d, J=9.5 Hz, 0.5H),
4.28-4.46 (m, 2H), 3.65-3.95 (m, 3H), 3.44-3.65 (m, 1H), 3.27-3.44
(m, 4H), 3.00-3.27 (m, 2H), 2.51-2.81 (m, 2H), 2.25-2.47 (m, 1H),
1.14-1.44 (m, 5H), 0.93-1.14 (m, 2H). LC-MS: m/z 433.2
(M+H).sup.+
(R)-6-cyclopropyl-5-(6-(1-fluorovinyl)pyrimidin-4-yl)-2-(4-(3-methoxypropa-
noyl)-3-methylpiperazin-1-yl)nicotinonitrile (Compound 602)
##STR00845##
[0861] To a solution of
(R)-5-(6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile (80 mg 0.21 mmol), CuI (10 mg,
10%), and Pd(PPh3)2Cl2 (15 mg) in 5 ml of DMF was added
(1-fluorovinyl)(methyl)diphenylsilane (7.6 mg, 0.41 mmol). The
mixture was stirred at room temperature for 2 h under nitrogen
atmosphere. After removal of the solvent under reduced pressure,
the residue was purified by prep-TLC (20% ethyl acetate in
petroleum ether) to afford 20 mg of pure product, 30% yield.
.sup.1H NMR (CHLOROFORM-d) 9.25 (s, 1H), 8.04 (s, 1H), 7.76 (s,
1H), 6.11 (d, J=3.0 Hz, 1H), 5.99 (d, J=3.0 Hz, 1H), 5.27 (dd,
J=15.8, 3.0 Hz, 1H), 4.91 (br. s., 1H), 4.54 (d, J=10.3 Hz, 1H),
4.31-4.49 (m, 1H), 3.71-3.78 (m, 1H), 3.49-3.63 (m, 1H), 3.31-3.44
(m, 4H), 3.16-3.28 (m, 1H), 3.13 (br. s., 1H), 2.51-2.81 (m, 2H),
2.30-2.44 (m, 1H), 1.35 (d, J=6.5 Hz, 2H), 1.25 (dd, J=4.3, 2.8 Hz,
3H), 1.04-1.13 (m, 2H). LC-MS: m/z 451.2 (M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-
-2% (prop-1-en-2-yl)-3,4% bipyridine-5-carbonitrile (Compound
544)
[0862] Synthesized according to the procedure described for
Compound 602 except using trimethyl(prop-1-en-2-yl)silane instead
of (1-fluorovinyl)(methyl)diphenylsilane. .sup.1H NMR
(CHLOROFORM-d) .delta.8.67 (d, J=5.0 Hz, 1H), 7.65 (s, 1H), 7.53
(s, 1H), 7.16-7.27 (m, 1H), 5.92 (s, 1H), 5.38 (s, 1H), 4.57 (d,
J=12.3 Hz, 1H), 4.45 (d, J=12.3 Hz, 1H), 4.07 (br. s., 1H), 3.78
(br. s., 1H), 3.56-3.74 (m, 1H), 3.50 (s, 1H), 3.29 (br. s., 1H),
3.14 (br. s., 1H), 2.26 (s, 3H), 1.98-2.10 (m, 1H), 1.72 (br. s.,
1H), 1.17-1.27 (m, 2H), 0.97-1.09 (m, 4H), 0.86-0.95 (m, 1H),
0.76-0.84 (m, 2H), 0.66 (br. s., 1H), 0.40-0.59 (m, 3H). LC-MS: m/z
453.2 (M+H).sup.+
(R)-5-(2-aminopyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpip-
erazin-1-yl)-6-cyclopropylnicotinonitrile (Compound 507)
##STR00846##
[0864] To a solution NH.sub.3/MeOH (10 mL, 7 M) was added
(R)-5-(2-chloropyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylp-
iperazin-1-yl)-6-cyclopropylnicotinonitrile (40 mg, 0.09 mmol), the
mixture was stirred at 50 C overnight. After removal of the solvent
under reduced pressure, the residue was purified by prep-TLC (30%
ethyl acetate in petroleum ether) to afford 21 mg of pure product,
51% yield. .sup.1H NMR (CHLOROFORM-d) .delta. 8.36 (d, J=5.3 Hz,
1H), 7.97 (s, 1H), 6.90 (d, J=5.0 Hz, 1H), 5.25 (br. s., 2H), 4.64
(d, J=12.5 Hz, 1H), 4.51 (d, J=12.3 Hz, 1H), 3.69 (br. s., 1H),
3.32 (br. s., 1H), 3.26 (br. s., 1H), 3.15 (br. s., 2H), 2.32-2.45
(m, 1H), 2.03-2.08 (m, 1H), 1.02-1.10 (m, 4H), 0.77-0.89 (m, 4H),
0.63 (br. s., 2H), 0.43-0.58 (m, 3H). LC-MS: m/z 430.2
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-(dimethylamino)pyrimidin-4-yl)nicotinonitrile (Compound
506)
[0865] Synthesized according to the procedure described for
Compound 507 except using dimethylamine instead of NH.sub.3.EtOH.
.sup.1H NMR (CHLOROFORM-d) .delta. 8.38 (d, J=5.0 Hz, 1H),
7.90-8.06 (m, 1H), 6.72 (d, J=5.0 Hz, 1H), 4.61 (d, J=12.8 Hz, 1H),
4.49 (d, J=12.5 Hz, 1H), 4.09-4.26 (m, 1H), 3.30-3.58 (m, 2H), 3.26
(s, 6H), 3.16-3.24 (m, 1H), 3.11 (d, J=18.3 Hz, 1H), 2.48-2.56 (m,
1H), 1.19-1.24 (m, 3H), 0.98-1.08 (m, 4H), 0.86-0.92 (m, 1H),
0.76-0.84 (m, 2H), 0.64 (br. s., 1H), 0.40-0.58 (m, 3H). LC-MS: m/z
458.3 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(2-(dimethylamino)pyrimidin-4-yl)nicotinonitrile (Compound
534)
[0866] 1H NMR (CHLOROFORM-d) .delta.8.37 (d, J=5.3 Hz, 1H), 7.97
(s, 1H), 6.89 (d, J=5.0 Hz, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.51 (d,
J=12.8 Hz, 1H), 4.00-4.17 (m, 1H), 3.68-3.87 (m, 1H), 3.17-3.38 (m,
3H), 3.12 (d, J=11.8 Hz, 1H), 2.82 (s, 2H), 2.33-2.45 (m, 1H), 1.35
(br. s., 1H), 1.18-1.25 (m, 2H), 0.98-1.10 (m, 2H), 0.64 (br. s.,
1H), 0.57 (br. s., 1H), 0.38-0.54 (m, 2H). LC-MS: m/z 472.2
(M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-(2-hydroxyethylamino)pyrimidin-4-yl)nicotinonitrile (Compound
512)
[0867] Synthesized according to the procedure described in Compound
507 except using 2-(methylamino)ethanol instead of NH.sub.3.EtOH.
.sup.1H NMR (CHLOROFORM-d) .delta. 8.32 (d, J=5.0 Hz, 1H), 7.94 (s,
1H), 6.83 (d, J=5.3 Hz, 1H), 5.91 (br. s., 1H), 4.63 (d, J=12.8 Hz,
1H), 4.50 (d, J=12.5 Hz, 1H), 3.96-4.33 (m, 1H), 3.82-3.92 (m, 2H),
3.63-3.72 (m, 2H), 3.29 (br. s., 1H), 3.14 (br. s., 1H), 2.68-2.78
(m, 1H), 2.66 (br. s., 1H), 2.34-2.44 (m, 1H), 1.20-1.35 (m, 4H),
1.04 (dd, J=7.7, 3.4 Hz, 4H), 0.77-0.90 (m, 3H), 0.64 (br. s., 1H),
0.49-0.55 (m, 1H), 0.44 (dt, J=9.3, 4.4 Hz, 1H). LC-MS: m/z 474.2
(M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(2-(dimethylamino)pyrimidin-4-yl)nicotinonitrile (Compound
521)
[0868] 1H NMR (CHLOROFORM-d) .delta. 8.42 (d, J=5.3 Hz, 1H), 8.00
(s, 1H), 6.75 (d, J=5.3 Hz, 1H), 4.62 (d, J=13.1 Hz, 1H), 4.50 (d,
J=12.8 Hz, 1H), 3.96-4.20 (m, 1H), 3.68-3.96 (m, 1H), 3.28-3.42 (m,
2H), 3.09-3.15 (m, 1H), 2.42-2.54 (m, 1H), 1.39-1.56 (m, 1H),
1.14-1.25 (m, 2H), 0.98-1.08 (m, 2H), 0.65 (br. s., 1H), 0.56 (br.
s., 1H), 0.43-0.53 (m, 2H). LC-MS: m/z 500.2 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(6-vinylpyrazin-2-yl)nicotinonitrile (Compound 515)
##STR00847##
[0869] Step 1
[0870] To a flask was added with
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile
(70 mg, 0.151 mmol), 2,6-dichloropyrazine (30 mg, 0.197 mmol),
Pd(PPh.sub.3).sub.4 (17 mg, 0.015 mmol), K.sub.2CO.sub.3 (63 mg,
0.453 mmol), and 1.5 mL DMF. The mixture was stirred at 120.degree.
C. for 2 h. After washing with Satd. NaHCO3, brine, the combined
organic layer was dried over anhy. Na.sub.2SO.sub.4 and
concentrated in vacuo. Prep-TLC purification (20% EtOAc/petroleum
ether) afforded 25 mg
of(R)-5-(6-chloropyrazin-2-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylp-
iperazin-1-yl)-6-cyclopropylnicotinonitrile.
Step 2
[0871] To a flask was added with
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(6-vinylpyrazin-2-yl)nicotinonitrile (18 mg 0.04 mmol),
tributyl(vinyl)stannane (17 mg, 0.052 mmol), Pd(PPh.sub.3).sub.4(5
mg, 0.004 mmol), K.sub.2CO.sub.3 (14 mg, 0.052 mmol), and 1.5 mL
DMF. The mixture was stirred at 120.degree. C. for 2 h. After
washing with Satd. NaHCO.sub.3, brine, the combined organic layer
was dried over anhy. Na.sub.2SO.sub.4 and concentrated in vacuo.
Prep-TLC purification (20% EtOAc/petroleum ether) afforded 10 mg of
title compound. .sup.1H NMR (CHLOROFORM-d) .delta. 8.72 (s, 1H),
8.56 (s, 1H), 8.00 (s, 1H), 6.90 (dd, J=17.3, 10.8 Hz, 1H), 6.47
(dd, J=17.6, 1.0 Hz, 1H), 5.70 (dd, J=10.8, 1.0 Hz, 1H), 4.65 (d,
J=13.1 Hz, 1H), 4.52 (d, J=12.8 Hz, 1H), 3.99-4.29 (m, 1H),
3.52-3.91 (m, 1H), 3.32 (br. s., 1H), 3.16 (br. s., 1H), 2.22-2.35
(m, 1H), 1.23-1.38 (m, 5H), 0.97-1.14 (m, 4H), 0.81 (dd, J=7.8, 2.3
Hz, 2H), 0.65 (br. s., 1H), 0.48-0.55 (m, 1H), 0.45 (dt, J=9.6, 4.6
Hz, 1H).
[0872] LC-MS: m/z 441.2 (M+H).sup.+
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-2-
'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 530; General
procedure 5, Step W)
[0873] 1H NMR (CHLOROFORM-d) .delta. 8.61 (d, J=5.0 Hz, 1H),
7.55-7.68 (m, 1H), 7.36 (s, 1H), 7.21 (dd, J=10, 1.5 Hz, 1H), 6.84
(dd, J=17.6, 10.8 Hz, 1H), 6.17-6.35 (m, 1H), 5.53 (dd, J=10.8, 0.8
Hz, 1H), 4.53 (d, J=12.5 Hz, 1H), 4.32-4.47 (m, 1H), 4.01-4.16 (m,
0.5H), 3.86 (d, J=12.5 Hz, 0.5H), 3.70 (t, J=5.5 Hz, 3H), 3.35 (s,
3H), 3.18 (d, J=11.3 Hz, 2H), 2.94-3.14 (m, 1H), 2.56-2.73 (m, 2H),
1.90-2.10 (m, 1H), 1.22-1.34 (m, 1H), 1.14-1.32 (m, 2H), 0.83-1.06
(m, 2H), 0.58 (br. s., 1H), 0.52 (br. s., 1H), 0.28-0.48 (m, 2H).
LC-MS: m/z 458.2 (M+H).sup.+
(R)-6-(4-acetyl-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-2'-vinyl-3,4'-b-
ipyridine-5-carbonitrile (Compound 562; General procedure 5, Step
W)
[0874] 1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=4.5 Hz, 1H), 7.65
(s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.0 Hz, 1H), 6.88 (dd, J=17.3,
10.8 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H),
4.65 (br. s., 0.5H), 4.55 (d, J=12.5 Hz, 1H), 4.43 (d, J=12.0 Hz,
1H), 4.08 (br. s., 0.5H), 3.77 (br. s., 1H), 3.21 (br. s., 2H),
3.11 (br. s., 1H), 2.17 (br. s., 2H), 2.11 (br. s., 1H), 2.03 (br.
s., 1H), 1.28 (d, J=12.0 Hz, 2H), 1.24-1.50 (br. s., 3H), 0.60 (br.
s., 2H), 0.45 (br. s., 2H). LC-MS: m/z 414.3 (M+H).sup.+
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxy-3-methylbutanoyl)piperazin-
-1-yl)-2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 561;
General procedure 5, Step W)
[0875] 1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=5.0 Hz, 1H), 7.66
(s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.0 Hz, 1H), 6.88 (dd, J=17.6,
10.8 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H),
5.16 (br. s., 1H), 4.56 (d, J=13.1 Hz, 1H), 4.43 (d, J=12.5 Hz,
1H), 4.14 (d, J=8.8 Hz, 0.5H), 3.65-3.78 (m, 1H), 3.17-3.91 (m,
1.5H), 3.04-3.14 (m, 1H), 2.43-2.57 (m, 2H), 2.02-2.07 (m, 1H),
1.33 (s, 6H), 1.25-1.30 (m, 2H), 1.21 (br. s., 2H), 1.02 (dd,
J=7.5, 3.3 Hz, 2H), 0.65 (d, J=6.5 Hz, 1H), 0.42-0.53 (m, 2H).
LC-MS: m/z 472.3 (M+H).sup.+
(R)-2-cyclopropyl-6-(4-(2-ethoxyacetyl)-3-methylpiperazin-1-yl)-2'-vinyl-3-
,4'-bipyridine-5-carbonitrile (Compound 573; General procedure 5,
Step W)
[0876] 1H NMR (CHLOROFORM-d) .delta. 8.65 (d, J=5.0 Hz, 1H), 7.64
(s, 1H), 7.36-7.41 (m, 1H), 7.23 (dd, J=5.0, 1.8 Hz, 1H), 6.88 (dd,
J=17.6, 10.8 Hz, 1H), 6.21-6.35 (m, 1H), 5.57 (dd, J=10.9, 0.9 Hz,
1H), 4.84 (br. s., 0.5H), 4.35 (br. s., 2H), 4.27 (br. s., 1H),
4.20 (br. s., 2H), 3.89 (br. s., 0.5H), 3.53-3.65 (m, 2.5H),
3.24-3.35 (m, 1H), 3.17 (br. s., 1.5H), 1.98-2.08 (m, 1H),
1.29-1.41 (m, 3H), 1.23-1.28 (m, 3H), 1.15-1.23 (m, 2H), 0.95-1.07
(m, 2H). LC-MS: m/z 432.2 (M+H).sup.+
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-2'-v-
inyl-3,4'-bipyridine-5-carbonitrile (Compound 590; General
procedure 5, Step W)
[0877] 1H NMR (CHLOROFORM-d) .delta. 8.63 (d, J=5.0 Hz, 1H),
7.53-7.75 (m, 2H), 7.37 (s, 1H), 7.22 (dd, J=4.8, 1.5 Hz, 1H), 6.86
(dd, J=17.6, 10.8 Hz, 1H), 6.19-6.37 (m, 1H), 5.54 (d, J=11.5 Hz,
1H), 4.55 (d, J=13.1 Hz, 1H), 4.42 (d, J=12.8 Hz, 1H), 4.11-4.17
(m, 2H), 3.44 (s, 4H), 3.19-3.25 (m, 1H), 3.04-3.11 (m, 1H), 2.80
(s, 1H), 1.89-2.07 (m, 2H), 1.17-1.27 (m, 4H), 0.95-1.02 (m, 2H),
0.41-0.54 (m, 3H). LC-MS: m/z 444.2 (M+H).sup.+
2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-2'-vinyl-3-
,4'-bipyridine-5-carbonitrile (Compound 572; General procedure 5,
Step W)
[0878] 1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=5.0 Hz, 1H),
7.61-7.69 (m, 1H), 7.36-7.44 (m, 1H), 7.24 (dd, J=5.0, 1.8 Hz, 1H),
6.89 (dd, J=17.3, 10.8 Hz, 1H), 6.29 (dd, J=17.6, 1.0 Hz, 1H), 5.58
(dd, J=10.8, 0.8 Hz, 1H), 4.90 (br. s., 0.5H), 4.54 (d, J=13.3 Hz,
0.5H), 4.26-4.40 (m, 2H), 4.12-4.23 (m, 1H), 3.93 (br. s., 2H),
3.74 (d, J=13.1 Hz, 1H), 3.29-3.34 (m, 1H), 3.06-3.18 (m, 1H),
2.50-2.63 (m, 1H), 2.17-2.25 (m, 1H), 2.02-2.07 (m, 1H), 1.41 (d,
J=6.8 Hz, 1H), 1.29-1.33 (m, 2H), 1.28 (d, J=2.8 Hz, 1H), 1.19-1.22
(m, 1.5H), 1.02 (dd, J=7.9, 3.1 Hz, 1.5H). LC-MS: m/z 418.2
(M+H).sup.+
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(furan-3-carbonyl)piperazin-1-yl)-2'--
vinyl-3,4'-bipyridine-5-carbonitrile (Compound 546; General
procedure 5, Step W)
[0879] 1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=4.5 Hz, 1H), 7.73
(s, 1H), 7.65 (s, 1H), 7.46 (s, 1H), 7.36-7.44 (m, 1H), 7.25 (d,
J=4.3 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz, 1H), 6.56 (s, 1H), 6.26
(d, J=17.6 Hz, 1H), 5.56 (d, J=10.8 Hz, 1H), 4.60 (d, J=13.1 Hz,
1H), 4.44 (d, J=12.8 Hz, 1H), 4.27 (br. s., 1H), 3.93 (br. s., 1H),
3.66 (br. s., 1H), 3.19-3.38 (m, 1H), 3.09 (t, J=11.3 Hz, 1H), 2.03
(dd, J=7.4, 3.1 Hz, 1H), 1.35-1.50 (m, 1H), 1.13-1.35 (m, 2H),
0.90-1.08 (m, 2H), 0.59-0.76 (m, 1H), 0.52 (t, J=8.0 Hz, 1H), 0.42
(br. s., 2H). LC-MS: m/z 466.2 (M+H).sup.+
2-cyclopropyl-6-((R)-3-cyclopropyl-4-((S)-3-hydroxybutanoyl)piperazin-1-yl-
)-2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 595; General
procedure 5, Step W)
[0880] 1H NMR (CHLOROFORM-d) .delta. 8.65 (d, J=4.8 Hz, 1H), 7.65
(s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4,
10.9 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H),
4.49-4.79 (m, 2H), 4.43 (d, J=12.5 Hz, 1H), 4.17-4.33 (m, 2H),
3.96-4.17 (m, 1H), 3.79 (br. s., 1H), 3.71 (d, J=11.8 Hz, 1H),
3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48 (m, 1H), 2.04 (m,
1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br. s., 1H), 0.63
(br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H). LC-MS: m/z
458.2 (M+H).sup.+
(R)-2-cyclopropyl-6-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-2'--
vinyl-3,4'-bipyridine-5-carbonitrile (Compound 631; General
procedure 5, Step W)
[0881] 1H NMR (CHLOROFORM-d) .delta. .sup.1H NMR (CHLOROFORM-d) v
8.61 (d, J=5.0 Hz, 1H), 7.60 (d, J=2.5 Hz, 1H), 7.20 (dd, J=5.0,
1.5 Hz, 1H), 6.84 (dd, J=17.3, 10.8 Hz, 1H), 6.25 (d, J=17.6 Hz,
1H), 5.52 (d, J=11.0 Hz, 1H), 4.50-4.79 (m, 2H), 4.28-4.50 (m, 2H),
3.85 (d, J=13.6 Hz, 1H), 3.63-3.79 (m, 2H), 3.57 (d, J=10.0 Hz,
1H), 3.30-3.49 (m, 3H), 2.99-3.27 (m, 2H), 2.83-2.98 (m, 1H),
2.49-2.79 (m, 1H), 2.17 (dt, J=10.5, 6.7 Hz, 1H), 1.08-1.30 (m,
3H), 0.78-1.08 (m, 7H). LC-MS: m/z 460.1 (M+H).sup.+
(R)-2-cyclopropyl-6-(4-(2-hydroxyacetyl)-3-methylpiperazin-1-yl)-2'-vinyl--
3,4'-bipyridine-5-carbonitrile (Compound 632; General procedure 5,
Step W)
[0882] 1H NMR (CHLOROFORM-d) .delta. 8.64 (d, J=5.0 Hz, 1H), 7.64
(s, 1H), 7.31-7.50 (m, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.87 (dd,
J=17.4, 10.9 Hz, 1H), 6.27 (dd, J=17.4, 0.9 Hz, 1H), 5.42-5.72 (m,
1H), 4.84 (br. s., 1H), 4.20-4.40 (m, 3H), 4.00-4.20 (m, 1H),
3.36-3.65 (m, 2H), 3.20-3.36 (m, 2H), 2.97-3.20 (m, 1H), 2.70-2.96
(m, 4H), 1.86-2.06 (m, 1H), 1.40 (d, J=6.3 Hz, 1H), 1.09-1.36 (m,
4H), 0.79-1.09 (m, 2H). LC-MS: m/z 404.0 (M+H).sup.+
2-cyclopropyl-6-((R)-3-cyclopropyl-4-((R)-3-hydroxybutanoyl)piperazin-1-yl-
)-2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 585; General
procedure 5, Step W)
[0883] 1H NMR (CHLOROFORM-d) .delta. 8.65 (d, J=4.8 Hz, 1H), 7.65
(s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4,
10.9 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H),
4.49-4.79 (m, 2H), 4.43 (d, J=12.5 Hz, 1H), 4.17-4.33 (m, 2H),
3.96-4.17 (m, 1H), 3.79 (br. s., 1H), 3.71 (d, J=11.8 Hz, 1H),
3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48 (m, 1H), 2.04 (m,
1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br. s., 1H), 0.63
(br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H). LC-MS: m/z
458.2 (M+H).sup.+
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(1H-pyrrolo[2,3-b]pyridin-5-yl)nicotinonitrile (Compound
539; General procedure 2, Step M)
[0884] .sup.1H NMR (CHLOROFORM-d) .delta. 10.76 (br. s., 1H), 8.37
(br. s., 1H), 8.00 (s, 1H), 7.65-7.77 (m, 1H), 7.48 (d, J=3.3 Hz,
1H), 6.59 (d, J=3.3 Hz, 1H), 4.71 (br. s., 0.5H), 4.52 (d, J=13.1
Hz, 1H), 4.41 (d, J=12.5 Hz, 1H), 4.14 (d, J=7.3 Hz, 0.5H),
3.66-3.95 (m, 1.5H), 3.15-3.44 (m, 4.5H), 2.40 (br. s., 1H),
2.05-2.15 (m, 1H), 1.39-1.48 (m, 1H), 1.17-1.25 (m, 2H), 0.94-1.04
(m, 2H), 0.44-0.81 (m, 4H). LC-MS: m/z 495.3 (M+H).sup.+
6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl-
)piperazin-1-yl)-5-(4-fluorophenyl)nicotinonitrile (Compound 548;
General procedure 3, Step R and S)
[0885] .sup.1H NMR (CHLOROFORM-d) .delta. 7.58-7.63 (m, 1H),
7.33-7.43 (m, 2H), 7.09-7.21 (m, 2H), 4.39-4.50 (m, 2.5H),
4.05-4.13 (m, 1H), 3.82 (br. s., 0.5H), 3.50-3.72 (m, 4H),
2.97-3.29 (m, 3H), 1.99-2.06 (m, 1H), 1.84-1.96 (m, 1H), 1.14-1.27
(m, 7H), 0.93-1.00 (m, 2H), 0.38-0.72 (m, 4H). LC-MS: m/z 475.3
(M+H).sup.+
(R)-5-(2-chloroquinolin-5-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpip-
erazin-1-yl)-6-cyclopropylnicotinonitrile (Compound 549)
[0886] 1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.09 (d, J=8.5 Hz,
1H), 7.91 (dd, J=11.4, 8.9 Hz, 1H), 7.82 (t, J=7.9 Hz, 1H), 7.64
(s, 1H), 7.46-7.57 (m, 1H), 7.39 (d, J=8.8 Hz, 1H), 4.78 (dq,
J=13.5, 6.8 Hz, 0.5H), 4.57 (d, J=11.8 Hz, 1.5H), 4.45 (d, J=11.0
Hz, 1H), 3.92-4.07 (m, 0.5H), 3.57-3.76 (m, 0.5H), 3.40 (q, J=7.0
Hz, 1H), 3.18-3.35 (m, 2H), 1.65-1.82 (m, 1H), 1.20-1.31 (m, 4H),
1.07-1.20 (m, 2H), 0.64-0.91 (m, 4H), 0.38-0.60 (m, 4H). LC-MS: m/z
498.2 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(4-
-fluorophenyl)nicotinonitrile (Compound 550)
[0887] 1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.33-7.43 (m,
2H), 7.09-7.20 (m, 2H), 4.55 (br. s., 1H), 4.47 (br. s., 1H), 4.25
(d, J=13.1 Hz, 3H), 3.40 (br. s., 1H), 3.31 (br. s., 1H), 3.15 (br.
s., 1H), 1.95-2.10 (m, 1H), 1.77 (br. s., 2H), 1.64 (br. s., 2H),
1.39-1.53 (m, 2H), 1.34 (br. s., 2H), 0.90-1.12 (m, 5H), 0.69-0.90
(m, 2H). LC-MS: m/z 405.2 (M+H).sup.+
6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1R,2S)-2-ethoxycyclopropanecarbonyl-
)piperazin-1-yl)-5-(4-fluorophenyllnicotinonitrile (Compound
564)
[0888] .sup.1H NMR (CHLOROFORM-d) .delta. 7.60 (s, 1H), 7.33-7.41
(m, 2H), 7.15 (t, J=8.7 Hz, 2H), 4.69-4.72 (m, 0.5H), 4.31-4.58 (m,
2H), 4.20 (d, J=13.8 Hz, 1H), 3.16-3.82 (m, 7.5H), 1.98-2.09 (m,
1H), 1.77-1.90 (m, 1H), 1.08-1.32 (m, 7H), 0.86-1.08 (m, 2H),
0.31-0.62 (m, 4H). LC-MS: m/z 475.3 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(i-
soquinolin-5-yl)nicotinonitrile (Compound 556; General procedure 2,
Step M)
[0889] .sup.1H NMR (CHLOROFORM-d) .delta. 9.36 (br. s., 1H), 8.52
(br. s., 1H), 8.07 (d, J=8.0 Hz, 1H), 7.70-7.75 (m, 1H), 7.65-7.69
(m, 1H), 7.63 (s, 1H), 7.47 (t, J=5.6 Hz, 1H), 4.89-5.55 (m, 3H),
4.15-4.58 (m, 4H), 1.56-1.68 (m, 1H), 1.42-1.56 (m, 1H), 1.12-1.21
(m, 2H), 0.97-1.09 (m, 4H), 0.75-0.96 (m, 6H). LC-MS: m/z 438.3
(M+H).sup.+
(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-2-(4-(cyclopropanecarbon-
yl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile (Compound
575; General procedure 1, Step I)
[0890] 1H NMR (CHLOROFORM-d) .delta. 7.49 (s, 1H), 6.47-6.77 (m,
1H), 6.22-6.44 (m, 1H), 5.88 (br. s., 1H), 5.76 (d, J=10.0 Hz, 1H),
3.01-4.86 (m, 11H), 2.40 (br. s., 2H), 1.95-2.16 (m, 1H), 1.76 (br.
s., 1H), 1.29-1.38 (m, 3H), 1.08-1.19 (m, 2H), 0.92-1.08 (m, 4H),
0.71-0.86 (m, 2H). LC-MS: m/z 448.0 (M+H).sup.+
5-(1-acryloylpiperidin-3-yl)-2-((R)-4-(cyclopropanecarbonyl)-3-methylpiper-
azin-1-yl)-6-cyclopropylnicotinonitrile (Compound 576; General
procedure 1, Step I)
[0891] 1H NMR (CHLOROFORM-d) .delta. 7.51-7.57 (m, 1H), 6.53-6.73
(m, 1H), 6.25-6.41 (m, 1H), 5.65-5.80 (m, 1H), 4.02-5.02 (m, 6H),
2.94-4.00 (m, 5H), 2.37-2.49 (m, 1H), 2.28-2.37 (m, 1H), 1.92-2.13
(m, 1H), 1.57-1.80 (m, 6H), 0.96-1.22 (m, 6H), 0.69-0.88 (m, 2H).
LC-MS: m/z 448.2 (M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-3,3'-
-bipyridine-5,6'-dicarbonitrile (Compound 583; General procedure 1,
Step H)
[0892] .sup.1H NMR (CHLOROFORM-d) .delta. 8.80 (d, J=1.8 Hz, 1H),
7.91 (dd, J=8.0, 2.3 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (s, 1H),
4.09-4.85 (m, 4H), 3.22-3.64 (m, 3H), 1.82-1.93 (m, 1H), 1.75 (br.
s., 1H), 1.19-1.27 (m, 2H), 0.96-1.12 (m, 4H), 0.73-0.92 (m, 2H).
LC-MS: m/z 413.2 (M+H).sup.+
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-3,3'-b-
ipyridine-5,6'-dicarbonitrile (Compound 584; General procedure 1,
Step I)
[0893] .sup.1H NMR (CHLOROFORM-d) 8.79 (d, J=1.5 Hz, 1H), 7.90 (dd,
J=8.0, 2.3 Hz, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.62 (s, 1H), 4.89 (br.
s., 0.5H), 4.52 (d, J=9.8 Hz, 0.5H), 4.19-4.44 (m, 2.5H), 3.65-3.78
(m, 2.5H), 3.54 (t, J=11.0 Hz, 0.5H), 3.28-3.43 (m, 4H), 3.03-3.27
(m, 1.5H), 2.50-2.80 (m, 2H), 1.82-1.92 (m, 1H), 1.36 (d, J=6.5 Hz,
1.5H), 1.23-1.28 (m, 1.5H), 1.17-1.23 (m, 2H), 0.94-1.06 (m, 2H);
LC-MS: m/z 431.2 (M+H)
(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-2'-e-
thynyl-3,4'-bipyridine-5-carbonitrile (Compound 593; General
procedure 1, Step H)
[0894] 1H NMR (CHLOROFORM-d) .delta. 8.67 (d, J=5.3 Hz, 1H), 7.62
(s, 1H), 7.46-7.59 (m, 1H), 7.35 (dd, J=5.1, 1.6 Hz, 1H), 4.15-4.90
(m, 4H), 3.13-3.75 (m, 4H), 1.94-2.04 (m, 1H), 1.76 (br. s., 1H),
1.28-1.39 (m, 3H), 1.21 (dt, J=7.0, 3.5 Hz, 2H), 0.95-1.09 (m, 4H),
0.76-0.88 (m, 2H). LC-MS: m/z 413.9 (M+H).sup.+
(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(1-
-propioloyl-1,2,5,6-tetrahydropyridin-3-yl)nicotinonitrile
(Compound 594; General procedure 1, Step H)
[0895] 1H NMR (CHLOROFORM-d) .delta. 7.48 (d, J=5.5 Hz, 1H), 5.90
(d, J=11.3 Hz, 1H), 4.01-4.85 (m, 7), 3.96 (t, J=5.9 Hz, 1H), 3.82
(t, J=5.9 Hz, 1H), 3.03-3.80 (m, 4H), 2.82 (s, 1H), 2.44 (d, J=3.5
Hz, 1H), 2.38 (d, J=3.5 Hz, 1H), 2.06-2.12 (m, 1H), 1.31-1.37 (m,
3H), 0.97-1.17 (m, 6H), 0.81 (d, J=7.8 Hz, 2H). LC-MS: m/z 444.1
(M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-
-3'-fluoro-2'-vinyl-3,4'-bipyridine-5-carbonitrile (Compound 520;
General procedure 1, Step I)
[0896] .sup.1H NMR (CHLOROFORM-d) .delta. 8.46 (d, J=4.8 Hz, 1H),
7.64 (s, 1H), 7.19 (t, J=5.1 Hz, 1H), 7.08 (ddd, J=17.4, 11.0, 1.3
Hz, 1H), 6.51 (dd, J=17.3, 1.8 Hz, 1H), 5.66 (dd, J=10.9, 1.6 Hz,
1H), 4.59 (d, J=12.8 Hz, 1H), 4.47 (d, J=12.5 Hz, 1H), 4.22 (br.
s., 0.5H), 4.05 (br. s., 0.5H), 3.76 (dt, J=8.2, 4.0 Hz, 1H),
3.47-3.70 (m, 1H), 3.29 (br. s., 1H), 3.14 (br. s., 1H), 1.77-1.85
(m, 1H), 1.57-1.70 (m, 1H), 1.32-1.41 (m, 1H), 1.14-1.24 (m, 2H),
0.88-1.11 (m, 4H), 0.73-0.86 (m, 2H), 0.59-0.73 (m, 1H), 0.36-0.59
(m, 3H). LC-MS: m/z 458.5 (M+H).sup.+
6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl-
)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile (Compound 514;
General procedure 2, Step M)
[0897] .sup.1H NMR (CHLOROFORM-d) .delta. 9.35 (s, 1H), 8.54 (dd,
J=5.9, 1.9 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.69-7.75 (m, 1H),
7.64-7.68 (m, 2H), 7.44 (dd, J=12.5, 6.0 Hz, 1H), 4.46-4.59 (m,
2.5H), 4.08-4.18 (m, 1H), 3.86 (br. s., 0.5H), 3.53-3.74 (m, 3H),
3.21-3.32 (m, 2H), 1.87-2.06 (m, 2H), 1.49-1.58 (m, 1H), 1.33 (d,
J=5.8 Hz, 1H), 1.14-1.28 (m, 7H), 0.81-0.90 (m, 2H), 0.65 (br. s.,
1H), 0.36-0.59 (m, 3H). LC-MS: m/z 508.2 (M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cyclopropyl-3,4'-
-bipyridine-2',5-dicarbonitrile (Compound 522; General procedure 1,
Step H)
[0898] .sup.1H NMR (CHLOROFORM-d) .delta. 8.81 (d, J=5.0 Hz, 1H),
7.80 (s, 1H), 7.63 (s, 1H), 7.59 (dd, J=5.1, 1.6 Hz, 1H), 4.86 (br.
s., 1H), 4.48 (br. s., 1H), 4.35 (d, J=13.6 Hz, 2H), 3.63 (br. s.,
0.5H), 3.53 (br. s., 1H), 3.25 (br. s., 1.5H), 1.85-1.99 (m, 1H),
1.76 (br. s., 1H), 1.60 (br. s., 3H), 1.17-1.34 (m, 4H), 1.07 (dd,
J=7.8, 3.0 Hz, 4H). LC-MS: m/z 413.5 (M+H).sup.+
(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-
-2'-methyl-3,4'-bipyridine-5-carbonitrile (Compound 523; General
procedure 1, Step H)
[0899] .sup.1H NMR (CHLOROFORM-d) 8.56 (d, J=5.0 Hz, 1H), 7.62 (s,
1H), 7.21 (s, 1H), 7.17 (d, J=5.3 Hz, 1H), 4.56 (d, J=12.5 Hz, 1H),
4.44 (d, J=12.3 Hz, 1H), 4.04 (br. s., 1H), 3.75 (br. s., 1.5H),
3.28 (br. s., 1.5H), 3.12 (br. s., 1H), 2.58-2.68 (m, 3H),
1.97-2.07 (m, 1H), 1.72 (br. s., 1H), 1.37 (br. s., 1H), 1.14-1.23
(m, 2H), 0.93-1.10 (m, 4H), 0.74-0.85 (m, 2H), 0.65 (br. s., 1H),
0.36-0.58 (m, 3H). LC-MS: m/z 428.5 (M+H).sup.+
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-[3,3'-bipyridine]-5,5'-dicarbonitrile (Compound 525; General
procedure 2, Step M)
[0900] .sup.1H NMR (CHLOROFORM-d) .delta.8.90 (d, 2H), 8.04 (s,
1H), 7.64 (s, 1H), 4.63 (d, J=13.1 Hz, 1H), 4.51 (d, J=12.3 Hz,
1H), 4.13 (br. s., 1H), 3.78 (br. s., 1H), 3.51 (s, 1H), 3.33 (d,
J=9.0 Hz, 2H), 3.24 (d, J=12.5 Hz, 1H), 3.15 (d, J=12.3 Hz, 1H),
2.03 (dt, J=15.3, 7.4 Hz, 1H), 1.01-1.12 (m, 3H), 0.82-0.95 (m,
4H), 0.66 (br. s., 1H), 0.45-0.53 (m, 1H)
[0901] LC-MS: m/z 481.4 (M+H).sup.+
Compound 540 (General Procedure 2, Step M)
(R)-5'-cyano-2'-cyclopropyl-6'-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)-
piperazin-1-yl)-[3,3'-bipyridine]-5-carboxamide
[0902] .sup.1H NMR (METHANOL-d) .delta.9.05 (br. s., 1H), 8.81 (br.
s., 1H), 8.26 (t, J=2.1 Hz, 1H), 7.60-7.77 (m, 1H), 6.81 (br. s.,
1H), 6.25 (br. s., 1H), 4.57 (d, J=13.1 Hz, 1H), 4.46 (d, J=12.3
Hz, 1H), 4.01-4.25 (m, 1H), 3.65-3.88 (m, 2H), 3.12-3.38 (m, 4H),
2.03-2.24 (m, 1H), 1.86-1.96 (m, 1H), 1.15-1.28 (m, 4H), 0.97-1.06
(m, 2H), 0.28-0.58 (m, 4H)
[0903] LC-MS: m/z 499.5 (M+H).sup.+
Compound 554 (General Procedure, Step I)
(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-
-5'-(1H-tetrazol-5-yl)-[3,3'-bipyridine]-5-carbonitrile
[0904] .sup.1H NMR (CHLOROFORM-d) .delta.9.47 (br. s., 1H), 8.86
(s, 1H), 8.62 (s, 1H), 7.73 (s, 1H), 4.59-4.47 (m., 7H), 1.19-1.30
(m, 1H), 1.14-1.05 (m, 3H), 0.84-0.98 (m, 10H), 0.42-0.57 (m,
4H)
[0905] LC-MS: m/z 482.5 (M+H).sup.+
Compound 601 (General Procedure, Step I)
(R)-6-cyclopropyl-5-(5-fluoro-4-vinylpyrimidin-2-yl)-2-(4-(3-methoxypropan-
oyl)-3-methylpiperazin-1-yl)nicotinonitrile
[0906] .sup.1H NMR (CHLOROFORM-d) .delta.8.62 (d, J=1.8 Hz, 1H),
8.35-8.44 (m, 1H), 7.03 (dd, J=17.3, 10.8 Hz, 1H), 6.70-6.82 (m,
1H), 5.81-5.92 (m, 1H), 4.90 (br. s., 0.5H), 4.52 (m, 3.5H),
4.28-4.47 (m, 3H), 3.68-3.86 (m, 3H), 3.54 (br. s., 1H), 3.01-3.21
(m, 3H), 2.63-2.79 (m, 1H), 2.51-2.63 (m, 1H), 1.23-1.26 (m, 4H),
1.18-1.23 (m, 2H), 1.04 (m, 2H)
[0907] LC-MS: m/z 451.5 (M+H).sup.+
Compound 538 (General Procedure 1, Step I)
(R)-5-(2-aminoquinazolin-5-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpi-
perazin-1-yl)-6-cyclopropylnicotinonitrile
[0908] .sup.1H NMR (CHLOROFORM-d) .delta. 8.82 (d, J=9.5 Hz, 1H),
7.70-7.84 (m, 1H), 7.55-7.70 (m, 2H), 7.11-7.23 (m, 1H), 5.52 (br.
s., 2H), 4.39-4.67 (m, 2.5H), 4.16-4.32 (m, 1H), 3.60-3.85 (m, 1H),
3.10-3.41 (m, 2.5H), 1.73 (s, 1H), 1.53-1.65 (m, 1H), 1.27-1.33 (m,
1H), 1.18-1.24 (m, 1H), 1.11-1.18 (m, 1H), 0.98-1.10 (m, 2H),
0.79-0.90 (m, 4H), 0.61-0.74 (m, 1H), 0.40-0.61 (m, 3H)
[0909] LC-MS: m/z 480.2 (M+H).sup.+
Compound 567 (General Procedure 1, Step H)
(R)-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-
-6'-(trifluoromethyl)-[3,3'-bipyridine]-5-carbonitrile
[0910] .sup.1H NMR (CHLOROFORM-d) .delta. 8.83 (d, J=1.8 Hz, 1H),
7.94 (dd, J=8.0, 2.0 Hz, 1H), 7.77-7.87 (m, 1H), 7.65 (s, 1H),
4.40-4.72 (m, 2.5H), 3.97-4.20 (m, 1H), 3.51-3.78 (m, 1H),
3.08-3.62 (m, 2.5H), 1.86-1.98 (m, 1H), 1.72 (s, 1H), 1.34-1.45 (m,
1H), 1.20-1.28 (m, 2H), 0.97-1.10 (m, 4H), 0.76-0.87 (m, 2H),
0.40-0.67 (m, 3H)
[0911] LC-MS: m/z 482.2 (M+H).sup.+
Compound 586 (General Procedure 1, Step H)
(R)-2,6'-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazi-
n-1-yl)-[3,4'-bipyridine]-5-carbonitrile
[0912] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 1H), 7.34 (s,
2H), 4.91 (s, 0.5H), 4.50-4.56 (m, 0.5H), 4.22-4.50 (m, 2.5H),
3.68-3.89 (m, 2.5H), 3.49-3.62 (m, 0.5H), 3.28-3.43 (m, 4H),
3.06-3.27 (m, 1.5H), 2.64-2.83 (m, 1H), 2.55-2.64 (m, 1H),
1.92-2.01 (m, 1H), 1.37 (d, J=6.5 Hz, 2H), 1.21-1.31 (m, 3H),
1.01-1.12 (m, 2H)
[0913] LC-MS: m/z 474.1 (M+H).sup.+
Compounnd 622
(R)-2-cyclopropyl-2'-methoxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)-6'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[0914] The mixture of
(R)-2'-chloro-2-cyclopropyl-6'-methoxy-6-(4-(3-methoxypropanoyl)-3-methyl-
piperazin-1-yl)-[3,4'-bipyridine]-5-carbonitrile (40 mg, 0.085
mmol), Potassium vinyltrifluoroborate (18 mg, 0.128 mmol),
Pd(dppf)Cl.sub.2 (4 mg, 0.0043 mmol), CsF (39 mg, 0.255 mmol) in
dioxane/H.sub.2O was stirred at 100.degree. C. for 16 hours, the
mixture was partitioned between EtOAc and water, the organic was
washed with water, brine and concentrated to give the crude which
was purified by column to give 15 mg of the product.
[0915] .sup.1H NMR (CHLOROFORM-d) 7.60 (s, 1H), 6.86 (d, J=1.0 Hz,
1H), 6.75 (dd, J=17.1, 10.5 Hz, 1H), 6.66 (d, J=1.0 Hz, 1H), 6.36
(dd, J=17.2, 1.6 Hz, 1H), 5.49 (dd, J=10.5, 1.8 Hz, 1H), 4.90 (s,
0.5H), 4.53 (d, J=13.3 Hz, 0.5H), 4.22-4.38 (m, 2.5H), 4.02 (s,
3H), 3.78-3.84 (m, 0.5H), 3.75 (t, J=6.1 Hz, 2H), 3.51-3.58 (m,
0.5H), 3.38 (s, 3H), 3.28 (t, J=9.9 Hz, 1H), 3.00-3.19 (m, 1.5H),
2.65-2.79 (m, 1H), 2.54-2.64 (m, 1H) 2.03-2.10 (m, 1H), 1.38 (d,
J=6.3 Hz, 1H), 1.28 (d, J=6.8 Hz, 2H), 1.13-1.21 (m, 2H), 0.94-1.03
(m, 2H)
[0916] LC-MS: m/z 461.2 (M+H).sup.+
Compound 623
(R)-2'-chloro-2-cyclopropyl-6'-methoxy-6-(4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)-[3,4'-bipyridine]-5-carbonitrile
[0917] To a solution of
(R)-2',6'-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)-[3,4'-bipyridine]-5-carbonitrile (300 mg, 0.623 mmol)
MeOH was added NaOMe (69 mg, 1.26 mmol), the mixture was refluxed
for 16 hours. After cooling, the mixture was partitioned between
EtOAc and water, the organic layer was washed with water, brine and
dried over Na.sub.2SO.sub.4. The organic layer was concentrated to
give the crude which was purified by prep-HPLC to obtained 150 mg
of the product.
[0918] .sup.1H NMR (CHLOROFORM-d) 7.54-7.63 (m, 1H), 6.97 (d, J=1.3
Hz, 1H), 6.70 (d, J=1.0 Hz, 1H), 4.91 (s, 0.5H), 4.54 (d, J=12.8
Hz, 0.5H), 4.23-4.39 (m, 2.5H), 3.96 (s, 3H), 3.79-3.85 (m, 0.5H),
3.68-3.78 (m, 2H), 3.49-3.60 (m, 0.5H), 3.39 (s, 3H), 3.26-3.36 (m,
1H), 3.04-3.20 (m, 1.5H), 2.64-2.82 (m, 1H), 2.50-2.63 (m, 1H),
2.00-2.04 (m, 1), 1.38 (d, J=6.5 Hz, 1H), 1.28 (d, J=5.5 Hz, 2H),
1.13-1.21 (m, 2H), 0.97-1.06 (m, 2H)
[0919] LC-MS: m/z 470.2 (M+H).sup.+
Compound 624
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2',6'--
divinyl-[3,4'-bipyridine]-5-carbonitrile
[0920] The mixture of
(R)-2',6'-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)-[3,4'-bipyridine]-5-carbonitrile (50 mg, 0.105 mmol),
Potassium vinyltrifluoroborate (50 mg, 0.316 mmol),
Pd(dppf)Cl.sub.2 (4 mg, 0.0043 mmol), CsF (50 mg, 0.316 mmol) in
dioxane/H.sub.2O was stirred at 100.degree. C. for 16 hours, the
mixture was partitioned between EtOAc and water, the organic was
washed with water, brine and concentrated to give the crude which
was purified by column to give 25 mg of the product.
[0921] .sup.1H NMR (CHLOROFORM-d) 7.63 (s, 1H), 7.24 (s, 1H), 7.28
(s, 1H), 6.77-6.98 (m, 2H), 6.30 (s, 1H), 6.34 (s, 1H), 5.55 (d,
J=10.8 Hz, 2H), 4.09 (s, 0.5H), 4.53 (d, J=12.3 Hz, 0.5H),
4.21-4.36 (m, 2.5H), 3.68-3.85 (m, 3H), 3.50-3.61 (m, 0.5H), 3.38
(s, 4H), 3.03-3.15 (m, 1H), 2.70 (dd, J=15.7, 6.4 Hz, 1H),
2.51-2.59 (m, 1H), 1.90-2.12 (m, 1H), 1.36-1.42 (m, 1H), 1.22-1.30
(m, 2H), 1.18 (s, 2H), 0.94-1.05 (m, 2H)
[0922] LC-MS: m/z 458.2 (M+H).sup.+
Compound 634 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
2-vinylquinazolin-5-yl)nicotinonitrile
[0923] .sup.1H NMR (CHLOROFORM-d) .delta. 9.15 (d, J=11.3 Hz, 1H),
8.03 (d, J=8.3 Hz, 1H), 7.93 (t, J=7.8 Hz, 1H), 7.64 (d, J=3.3 Hz,
1H), 7.50 (dd, J=10.3, 7.3 Hz, 1H), 7.04 (dd, J=17.2, 10.7 Hz, 1H),
6.78 (d, J=17.1 Hz, 1H), 5.85 (d, J=10.5 Hz, 1H), 4.64-4.76 (m,
1H), 4.42-4.49 (m, 1H), 3.88 (d, J=13.6 Hz, 0.5H), 3.73 (d, J=5.8
Hz, 2H), 3.61 (d, J=9.8 Hz, 0.5H), 3.39-3.50 (m, 0.5H), 3.37 (s,
3H), 3.05-3.25 (m, 2H), 2.85-3.10 (m, 0.5H), 2.50-2.85 (m, 2H),
2.18-2.33 (m, 1H), 1.99-2.15 (m, 1H), 0.99-1.22 (m, 6H), 0.82-0.94
(m, 5H)
[0924] LC-MS: m/z 511.3 (M+H).sup.+
Compound 635 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinazolin-5-yl)nicotinonitrile
[0925] .sup.1H NMR (CHLOROFORM-d) .delta. 9.15 (d, J=7.8 Hz, 1H),
8.04 (d, J=8.5 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.66 (d, J=1.5 Hz,
1H), 7.43-7.56 (m, 1H), 7.04 (dd, J=17.3, 10.5 Hz, 1H), 6.78 (d,
J=17.1 Hz, 1H), 5.85 (d, J=10.5 Hz, 1H), 4.33-4.80 (m, 2.5H),
4.07-4.22 (m, 0.5H), 3.85-4.02 (m, 1H), 3.60-3.81 (m, 3H), 3.37 (s,
3H), 2.98-3.26 (m, 2H), 2.37-2.76 (m, 2H), 1.98-2.28 (m, 1H),
1.51-1.61 (m, 1H), 1.11-1.26 (m, 2H), 0.86 (d, J=7.8 Hz, 2H),
0.40-0.55 (m, 4H)
[0926] LC-MS: m/z 509.3 (M+H).sup.+
Compound 636 (General Procedure 1, Step I)
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-vinylquinazolin-5-yl)nicotinonitrile
[0927] .sup.1H NMR (CHLOROFORM-d) .delta. 9.16 (d, J=8.0 Hz, 1H),
8.04 (d, J=8.5 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.62-7.72 (m, 1H),
7.44-7.56 (m, 1H), 7.05 (dd, J=17.3, 10.5 Hz, 1H), 6.78 (d, J=17.1
Hz, 1H), 5.75-5.95 (m, 1H), 4.49-4.66 (m, 2.5H), 4.05-4.25 (m, 1H),
3.75-3.88 (m, 1H), 3.06-3.32 (m, 2.5H), 2.29 (s, 1H), 1.50-1.57 (m,
1H), 1.34-1.47 (m, 1H), 1.14-1.22 (m, 2H), 0.98-1.09 (m, 2H),
0.77-0.91 (m, 4H), 0.39-0.67 (m, 4H)
[0928] LC-MS: m/z 491.2 (M+H).sup.+
Compound 645 (General procedure 1, Step I)
[0929]
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin--
1-yl)-5-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile (Core
synthesis method 1 using 4-chloro-2-vinyl-1,8-naphthyridine as
starting material)
[0930] In a sealed tube was added 120 mg of
4-chloro-2-vinyl-1,8-naphthyridine, 242 mg of 8-3 (0.5 mmol), 230
mg of CsF (1.5 mmol), 41 mg of Pd(dppf).sub.2Cl.sub.2 (0.05 mmol)
and 10 mL of Dioxane, then the mixture was heated in a microwave
reactor (100.degree. C., 30 minutes), when LC-MS indicated the
product formation. Then the resulting mixture was filtered, the
filtrated was concentrated, purified by Prep-TLC (Petroleum
ether:Ethyl acetate=2:1) to give 45 mg of title compound. .sup.1H
NMR (CHLOROFORM-d) .delta. 9.17 (dd, J=4.3, 1.8 Hz, 1H), 8.03 (td,
J=8.7, 1.8 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H), 7.61 (d, J=3.5 Hz, 1H),
7.48 (dd, J=8.3, 4.3 Hz, 1H), 7.15 (dd, J=17.7, 10.9 Hz, 1H), 6.57
(dd, J=17.6, 1.8 Hz, 1H), 5.83 (d, J=11.0 Hz, 1H), 4.60 (d, J=12.3
Hz, 2H), 4.49 (d, J=12.8 Hz, 1H), 4.15 (br. s., 0.5H), 3.91 (br.
s., 0.5H), 3.65-3.85 (m, 3H), 3.40 (s, 4H), 3.27 (d, J=12.0 Hz,
2H), 2.67 (br. s., 2H), 1.20 (d, J=4.5 Hz, 2H), 0.82-0.98 (m, 2H),
0.66 (br. s., 1H), 0.59 (br. s., 1H), 0.49 (d, J=5.0 Hz, 2H)
[0931] LC-MS: m/z 509.1 (M+H).sup.+
Compound 629 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(-
2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile
[0932] .sup.1H NMR (CHLOROFORM-d) .delta. 8.99-9.21 (m, 1H), 7.99
(dd, J=12.4, 8.4 Hz, 1H), 7.50-7.72 (m, 2H), 7.45 (dt, J=7.8, 3.7
Hz, 1H), 7.11 (dd, J=17.4, 10.9 Hz, 1H), 6.53 (d, J=17.6 Hz, 1H),
5.79 (d, J=10.8 Hz, 1H), 4.56-4.78 (m, 1.5H), 4.35-4.56 (m, 2H),
3.74-3.99 (m, 2.5H), 3.37-3.60 (m, 1H), 3.06-3.28 (m, 2H),
2.92-3.06 (m, 1H), 2.53-2.83 (m, 3H), 2.12 (dt, J=10.0, 6.5 Hz,
1H), 1.43-1.55 (m, 1H), 0.98-1.15 (m, 4H), 0.72-0.97 (m, 5H)
[0933] LC-MS: m/z 497.3 (M+H).sup.+
Compound 625 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inyl-1,8-naphthyridin-4-yl)nicotinonitrile
[0934] .sup.1H NMR (CHLOROFORM-d) .delta. 9.05-9.19 (m, 1H), 7.98
(ddd, J=6.1, 4.3, 2.1 Hz, 1H), 7.63-7.68 (m, 1H), 7.55-7.61 (m,
1H), 7.41-7.47 (m, 1H), 7.03-7.17 (m, 1H), 6.52 (d, J=17.6 Hz, 1H),
5.72-5.84 (m, 1H), 4.89 (br. s., 0.5H), 4.54 (d, J=12.5 Hz, 1H),
4.39 (d, J=13.8 Hz, 1H), 4.29 (d, J=19.8 Hz, 2H), 4.20 (br. s.,
1H), 3.82-4.00 (m, 2.5H), 3.01-3.24 (m, 2H), 2.46-2.76 (m, 3H),
1.06-1.19 (m, 2H), 0.75-0.94 (m, 3H)
[0935] LC-MS: m/z 469.2 (M+H).sup.+
Compound 626 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile
[0936] .sup.1H NMR (CHLOROFORM-d) .delta. 9.12 (S, 1h), 7.99 (br.
s., 1H), 7.52-7.69 (m, 2H), 7.36-7.50 (m, 1H), 7.00-7.19 (m, 1H),
6.53 (d, J=17.6 Hz, 1H), 5.78 (d, J=10.8 Hz, 1H), 4.71 (br. s.,
1.5H), 4.35-4.52 (m, 2H), 3.58-3.81 (m, 3.5H), 3.37 (d, J=3.0 Hz,
4H), 3.18 (dd, J=13.6, 3.5 Hz, 2H), 2.52-2.82 (m, 2H), 1.08 (dt,
J=12.0, 5.7 Hz, 4H), 0.87 (d, J=6.8 Hz, 6H)
[0937] LC-MS: m/z 511.2 (M+H).sup.+
Compound 599 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inyl-1,8-naphthyridin-4-yl)nicotinonitrile
[0938] .sup.1H NMR (CHLOROFORM-d) .delta. 9.14 (dd, J=4.1, 1.9 Hz,
1H), 7.98 (br. s., 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.45 (dd,
J=8.3, 4.3 Hz, 1H), 7.11 (d, J=10.8 Hz, 1H), 6.44-6.62 (m, 1H),
5.80 (d, J=10.8 Hz, 1H), 4.94 (br. S., 0.5H), 4.55 (br. s., 0.5H),
4.42 (br. s., 3H), 3.75 (d, J=6.3 Hz, 3H), 3.39 (s, 4H), 3.15 (br.
s., 2H), 2.63 (br. s., 2H), 1.10-1.22 (m, 3H), 0.72-0.97 (m,
4H)
[0939] LC-MS: m/z 483.1 (M+H).sup.+
Compound 596 (General Procedure 1, Step I)
(R)-2'-cyclopropyl-6'-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-vi-
nyl-2,3'-bipyridine-5'-carbonitrile
[0940] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.67 (d, J=5.3 Hz, 1H),
7.89 (s, 1H), 7.50 (s, 3H), 6.63-6.82 (m, 1H), 6.04 (d, J=17.6 Hz,
1H), 5.57 (d, J=11.0 Hz, 1H), 4.91 (br. s., 0.5H), 4.51 (br. s.,
1H), 4.34 (br. s., 3H), 3.65-3.83 (m, 2.5H), 3.33-3.44 (m, 4H),
3.29 (br. s., 1H), 2.71 (br. s., 1H), 2.62 (br. s., 2H), 1.33-1.43
(m, 3H), 1.15-1.25 (m, 4H)
[0941] LC-MS: m/z 431.2 (M+H).sup.+
Compound 612 (General Procedure 1, Step I)
(R)-5-(1-acryloyl-2,5-dihydro-1H-pyrrol-3-yl)-2-(4-(cyclopropanecarbonyl)--
3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile
[0942] 1H NMR (CHLOROFORM-d) .delta. 7.48-7.56 (m, 1H), 6.31-6.57
(m, 2H), 5.97 (d, J=2.0 Hz, 1H), 5.65-5.88 (m, 1H), 4.01-4.90 (m,
8H), 3.02-3.81 (m, 3H), 2.09-2.34 (m, 1H), 1.75 (br. s., 2H),
1.25-1.37 (m, 3H), 1.09-1.22 (m, 2H), 0.95-1.09 (m, 4H), 0.67-0.94
(m, 2H)
[0943] LC-MS: m/z 432.2 (M+H).sup.+
Compound 620 (General Procedure 1, Step I)
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-6'-vin-
yl-3,3'-bipyridine-5-carbonitrile
[0944] .sup.1H NMR (CHLOROFORM-d) .delta. 8.63 (d, J=2.0 Hz, 1H),
7.66-7.74 (m, 1H), 7.58-7.65 (m, 1H), 7.40-7.50 (m, 1H), 6.87 (dd,
J=17.6, 10.8 Hz, 1H), 6.27 (dd, J=17.6, 1.0 Hz, 1H), 5.54 (dd,
J=10.8, 1.0 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d, J=13.1 Hz,
0.5H), 4.17-4.41 (m, 2.5H), 3.66-3.88 (m, 2.5H), 3.54 (t, J=11.2
Hz, 0.5H), 3.37 (s, 3H), 3.28 (t, J=9.8 Hz, 1H), 2.99-3.20 (m,
1.5H), 2.52-2.81 (m, 2H), 1.94-2.06 (m, 1H), 1.33-1.41 (m, 1.5H),
1.24-1.29 (m, 1.5H), 1.14-1.23 (m, 2H), 0.91-1.04 (m, 2H)
[0945] LC-MS: m/z 432.1 (M+H).sup.+
Compound 619 (General Procedure 1, Step I)
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-2'-vin-
yl-3,3'-bipyridine-5-carbonitrile
[0946] .sup.1H NMR (CHLOROFORM-d) .delta. 8.54-8.72 (m, 1H),
7.45-7.58 (m, 2H), 7.18-7.34 (m, 1H), 6.53-6.69 (m, 1H), 6.38-6.47
(m, 1H), 5.43 (d, J=10.8 Hz, 1H), 4.90 (br. s., 0.5H), 4.52 (d,
J=13.1 Hz, 0.5H), 4.14-4.39 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.54
(d, J=4.8 Hz, 0.5H), 3.37 (s, 3H), 3.23-3.33 (m, 1H), 2.99-3.21 (m,
1.5H), 2.51-2.80 (m, 2H), 1.55-1.69 (m, 1H), 1.39 (br. s., 1.5H),
1.29 (br. s., 1.5H), 1.04-1.19 (m, 2H), 0.79-1.00 (m, 2H)
[0947] LC-MS: m/z 432.2 (M+H).sup.+
Compound 630 (General Procedure 1, Step I)
(R)-5-(1-acryloyl-1,2,3,6-tetrahydropyridin-4-yl)-2-(4-(cyclopropanecarbon-
yl)-3-methylpiperazin-1-yl)-6-cyclopropylnicotinonitrile
[0948] 1H NMR (CHLOROFORM-d) .delta. 7.45 (s, 1H), 6.64 (td,
J=16.1, 10.7 Hz, 1H), 6.29-6.42 (m, 1H), 5.67-5.86 (m, 2H),
4.00-5.00 (m, 6H), 3.85-3.93 (m, 1H), 3.79 (t, J=5.3 Hz, 1H),
3.00-3.63 (m, 3H), 2.39-2.52 (m, 2H), 1.96-2.12 (m, 1H), 1.75 (br.
s., 1H), 1.28-1.51 (m, 3H), 1.08-1.17 (m, 2H), 0.94-1.08 (m, 4H),
0.76-0.86 (m, 2H)
[0949] LC-MS: m/z 446.0 (M+H).sup.+
Compound 557 (General Procedure 1, Step I)
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-methyl-1,8-naphthyridin-4-yl)nicotinonitrile
[0950] .sup.1H NMR (CHLOROFORM-d) .delta. 0.39-0.53 (m, 1H) 0.56
(d, J=4.52 Hz, 3H) 0.79-0.94 (m, 4H) 0.94-1.14 (m, 3H) 1.22 (br.
s., 2H) 1.27 (br. s., 2H) 1.33 (br. s., 2H) 3.01 (s, 3H) 4.53 (d,
J=12.55 Hz, 2.5H) 7.46 (s, 1H) 7.58 (br. s., 1H) 7.67 (s, 1H) 8.14
(br. s., 1H) 9.22 (br. s., 1H)
[0951] LC-MS: m/z 479.3 (M+H).sup.+
Compound 552 (General Procedure 2, Step M)
(R)-tert-butyl
5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)pip-
erazin-1-yl)pyridin-3-yl)-1H-indazole-1-carboxylate
[0952] 70 mg of
(R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(1H-indazol-5-yl)nico-
tinonitrile (NB247-78) (0.18 mmol), 83 mg of HATU (0.22 mmol), 37
mg of TEA in 10 mL of DCM was added 23 mg of
3,3,3-trifluoropropanoic acid (0.18 mmol), then the mixture was
stirred at room temperature for 2 hours, concentrated, purified by
Prep-TLC(Petroleum ether:Ethyl acetate=1:1) to give 31.5 mg of
title compound. .sup.1H NMR (CHLOROFORM-d) 7.98 (br. s., 1H), 7.77
(s, 1H), 7.42-7.62 (m, 2H), 7.15 (d, J=7.0 Hz, 1H), 4.56 (d, J=13.1
Hz, 2H), 4.13 (br. s., 0.5H), 3.84 (br. s., 1.5H), 3.35 (d, J=10.0
Hz, 2H), 3.23 (br. s., 2H), 3.12 (br. s., 1H), 1.94 (s, 1H),
1.15-1.32 (m, 5H), 0.94 (dd, J=7.8, 3.3 Hz, 2H), 0.52 (d, J=5.3 Hz,
2H)
[0953] LC-MS: m/z 495.2 (M+H).sup.+
Compound 537 (General Procedure 2, Step M)
(R)-5-(benzo[d]thiazol-6-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifl-
uoropropanoyl)piperazin-1-yl)nicotinonitrile
[0954] .sup.1H NMR (CHLOROFORM-d) .delta. 9.07 (s, 1H), 8.22 (d,
J=8.5 Hz, 1H), 7.99 (d, J=1.5 Hz, 1H), 7.71 (s, 1H), 7.57 (dd,
J=8.4, 1.6 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H), 4.42 (d, J=12.8 Hz,
1H), 3.98-4.21 (m, 0.5H), 3.67-3.95 (m, 1.5H), 3.26-3.38 (m, 2H),
3.15-3.26 (m, 2H), 3.09 (t, J=11.3 Hz, 1H), 2.04-2.12 (m, 1H), 1.42
(d, J=14.3 Hz, 1H), 1.17-1.24 (m, 2H), 0.95-1.03 (m, 2H), 0.67 (br.
s., 1H), 0.57 (br. s., 1H), 0.45-0.53 (m, 2H)
[0955] LC-MS: m/z 512.1 (M+H).sup.+
Compound 536 (General Procedure 2, Step M)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(2-methyl-1-oxo-1,2-dihydroisoquinolin-4-yl)nicotinonitrile
[0956] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.45-8.58 (m, 1H),
7.59-7.69 (m, 2H), 7.47-7.59 (m, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.07
(d, J=1.8 Hz, 1H), 4.53 (d, J=13.1 Hz, 1H), 4.43 (d, J=12.0 Hz,
1H), 4.12 (br. s., 0.5H), 3.78 (br. s., 1H), 3.67 (s, 3H), 3.33 (q,
J=9.8 Hz, 2H), 3.16-3.26 (m, 1H), 3.03-3.16 (m, 0.5H), 1.92 (br.
s., 1H), 1.69-1.80 (m, 1H), 1.20-1.28 (m, 2H), 1.07-1.19 (m, 2H),
0.81-0.95 (m, 2H), 0.67 (br. s., 1H), 0.57 (br. s., 1H), 0.43-0.54
(m, 2H)
[0957] LC-MS: m/z 536.2 (M+H).sup.+
Compound 580 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inyl-1,7-naphthyridin-4-yl)nicotinonitrile
[0958] 1H NMR (CHLOROFORM-d) d: 9.56 (s, 1H), 8.59 (d, J=5.8 Hz,
1H), 7.74 (s, 1H), 7.64-7.70 (m, 1H), 7.44-7.52 (m, 1H), 7.11 (dd,
J=17.7, 10.9 Hz, 1H), 6.44 (dd, J=17.7, 1.6 Hz, 1H), 5.83 (d,
J=11.0 Hz, 1H), 4.95 (br. s., 0.5H), 4.58 (d, J=11.3 Hz, 0.5H),
4.42 (d, J=11.3 Hz, 1.5H), 4.31 (br. s., 1H), 3.86 (d, J=13.1 Hz,
0.5H), 3.72-3.81 (m, 2H), 3.55-3.68 (m, 0.5H), 3.4 (s, 3H)
3.34-3.39 (m, 0.5H), 3.04-3.30 (m, 2H), 2.53-2.83 (m, 2H),
1.47-1.55 (m, 1H), 1.37-1.46 (m, 1.5H), 1.29-1.37 (m, 1.5H), 1.20
(t, J=4.9 Hz, 2H), 0.84-0.96 (m, 2H)
[0959] LC-MS: m/z 483.2 (M+H).sup.+
Compound 609 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inyl-1,7-naphthyridin-4-yl)nicotinonitrile
[0960] .sup.1H NMR (CHLOROFORM-d) .delta. 9.50-9.65 (m, 1H), 8.60
(d, J=6.0 Hz, 1H), 7.74-7.82 (m, 1H), 7.62-7.72 (m, 1H), 7.48-7.57
(m, 1H), 7.11 (dd, J=17.7, 10.9 Hz, 1H), 6.45 (dd, J=17.6, 1.8 Hz,
1H), 5.85 (d, J=11.0 Hz, 1H), 4.93 (br. s., 0.5H), 4.50-4.64 (m,
0.5H), 4.40-4.49 (m, 1H), 4.31-4.40 (m, 1H), 4.22 (br. s., 0.5H),
3.91-4.01 (m, 2H), 3.78 (d, J=11.3 Hz, 0.5H), 3.61 (d, J=11.8 Hz,
0.5H), 3.39 (d, J=13.6 Hz, 1H), 3.10-3.31 (m, 1.5H), 2.65-2.80 (m,
1H), 2.52-2.65 (m, 1H), 1.43-1.54 (m, 3H), 1.35 (t, J=5.6 Hz, 2H),
1.21 (dd, J=6.9, 3.6 Hz, 2H), 0.87-0.98 (m, 2H)
[0961] LC-MS: m/z 469.2 (M+H).sup.+
Compound 611 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile
[0962] .sup.1H NMR (CHLOROFORM-d) d: 9.57 (s, 1H), 8.60 (dd, J=5.6,
3.1 Hz, 1H), 7.75 (d, J=12.0 Hz, 1H), 7.66 (dd, J=4.8, 3.3 Hz, 1H),
7.45-7.55 (m, 1H), 7.04-7.17 (m, 1H), 6.44 (d, J=17.6 Hz, 1H), 5.84
(d, J=10.8 Hz, 1H), 4.61-4.81 (m, 1.5H), 4.42-4.56 (m, 1.5H), 3.92
(d, J=13.6 Hz, 0.5H), 3.70-3.83 (m, 2H), 3.44-3.56 (m, 0.5H),
3.37-3.43 (m, 3H), 3.08-3.31 (m, 2H), 2.90-3.05 (m, 0.5H),
2.55-2.85 (m, 2H), 1.49 (dd, J=7.4, 4.4 Hz, 1H), 1.14-1.32 (m, 2H),
1.11 (ddd, J=15.2, 6.5, 4.1 Hz, 4H), 0.83-0.98 (m, 5H)
[0963] LC-MS: m/z 511.3 (M+H).sup.+
Compound 542
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-vinylquinolin-4-yl)nicotinonitrile
##STR00848##
[0964] Step 1
[0965] To 10 mg PdCl2(dppf).CH.sub.2Cl.sub.2 in a reaction tube
under nitrogen were added 5 mL dioxane, 3 mL water, 150 mg (0.98
mmol) CsF, 75 mg (0.43 mmol) quinolin-4-ylboronic acid and 150 mg
(0.36 mmol)
(R)-5-bromo-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cy-
clopropylnicotinonitrile. The reaction solution was heated to
100.degree. C. for half hour under microwave irradiation. The
reaction was extracted with ethyl acetate, washed several times
with water and purified by TLC preparation (petroleum ether:ethyl
acetate=1:1) to give desired compound 50 mg (32%, yield). LC-MS:
m/z 438.22 (M+H).sup.+
Step 2
[0966] To a stirred solution of
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropy-
l-5-(quinolin-4-yl)nicotinonitrile (50 mg, 0.108 mmol) in 10 mL of
anhydrous CH.sub.2Cl.sub.2 was added 3-chlorobenzoperoxoic acid (37
mg, 0.216 mmol) portionwise over 1 min. The resulting mixture was
stirred at room temperature for 3 hours. Then saturated aqueous
Na2SO3 (10 mL) was added to the reaction. The reaction was
extracted with ethyl acetate to give desired compound
(R)-4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-2-cycl-
opropylpyridin-3-yl)quinoline 1-oxide 48 mg (93%). LC-MS: m/z
453.22 (M+H).sup.+
Step 3
[0967] To a solution of
(R)-4-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2-
-cyclopropylpyridin-3-yl)quinoline 1-oxide (35 mg, 0.07 mmol) in 20
mL of CHCl3 was added POCl.sub.3 (32 mg, 0.209) dropwise at room
temperature. The reaction mixture was then heated at reflux for 3
hours. After LC-MS showed completion of reaction, the mixture was
cooled to room temperature and poured into water and extracted with
methylene chloride. The combined organic layer was dried over anhy.
Na.sub.2SO.sub.4 and concentrated in vacuo to give the title
compound as a brown solid 30 mg (83.3%). LC-MS: m/z 472.18
(M+H).sup.+
Step 4 is Similar to Compound 390 Step 2: Compound 542
[0968] .sup.1H NMR (CHLOROFORM-d) d: 8.21 (d, J=8.3 Hz, 1H), 7.77
(t, J=7.5 Hz, 1H), 7.68 (d, J=1.0 Hz, 1H), 7.48-7.66 (m, 3H), 7.13
(dd, J=17.4, 10.9 Hz, 1H), 6.35 (d, J=17.6 Hz, 1H), 5.76 (d, J=11.0
Hz, 1H), 4.61 (d, J=12.5 Hz, 1.5H), 4.49 (d, J=12.3 Hz, 1.5H), 4.12
(br. s., 1H), 3.67-3.82 (m, 1H), 3.34 (br. s., 1.5H), 3.19 (br. s.,
1.5H), 1.58 (ddd, J=12.0, 7.8, 4.5 Hz, 1H), 1.14-1.35 (m, 4H),
1.00-1.13 (m, 2H), 0.76-0.93 (m, 4H), 0.71 (br. s., 1H), 0.38-0.63
(m, 3H)
[0969] LC-MS: m/z 490.6 (M+H).sup.+
Compound 543
(R)-5-(2-chloroquinolin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpip-
erazin-1-yl)-6-cyclopropylnicotinonitrile
[0970] The synthesis was similar to Compound 542.
[0971] .sup.1H NMR (CHLOROFORM-d) d: 8.12 (d, J=8.3 Hz, 1H),
7.76-7.84 (m, 1H), 7.61-7.68 (m, 2H), 7.53-7.61 (m, 1H), 7.38 (d,
J=1:8 Hz, 1H), 4.63 (d, J=12.5 Hz, 1H), 4.51 (d, J=12.5 Hz, 1H),
3.97-4.20 (m, 1H), 3.82 (br. s., 1H), 3.59-3.78 (m, 1H), 3.34 (br.
s., 1H), 3.20 (br. s., 1H), 1.74 (br. s., 2H), 1.50-1.59 (m, 1H),
1.14-1.26 (m, 2H), 0.97-1.14 (m, 2H), 0.79-0.97 (m, 4H), 0.70 (br.
s., 1H), 0.42-0.63 (m, 3H)
[0972] LC-MS: m/z 499.0 (M+H).sup.+
Compound 571
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinolin-4-yl)nicotinonitrile
[0973] The synthesis was similar to Compound 542.
[0974] 1H NMR (CHLOROFORM-d) d: 8.18 (d, J=8.5 Hz, 1H), 7.76 (t,
J=7.7 Hz, 1H), 7.69 (d, J=1.0 Hz, 1H), 7.46-7.64 (m, 3H), 7.11 (dd,
J=17.7, 10.9 Hz, 1H), 6.28-6.39 (m, 1H), 5.75 (d, J=11.0 Hz, 1H),
4.59 (d, J=13.1 Hz, 1H), 4.47 (d, J=13.1 Hz, 1H), 4.13 (d, J=8.3
Hz, 0.5H), 3.94 (br. s., 2H), 3.82 (br. s., 1H), 3.76 (br. s., 1H),
3.43 (br. s., 1H), 3.21-3.37 (m, 1.5H), 3.15 (d, J=11.5 Hz, 1H),
2.55-2.70 (m, 2H), 1.67 (br. s., 1H), 1.59 (tt, J=8.1, 4.3 Hz, 1H),
1.10-1.24 (m, 2H), 0.80-0.94 (m, 2H), 0.69 (br. s., 1H), 0.58 (br.
s., 1H), 0.51 (br. s., 2H)
[0975] LC-MS: m/z 494.2 (M+H).sup.+
Compound 574
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinolin-4-yl)nicotinonitrile
[0976] The synthesis was similar to Compound 542.
[0977] .sup.1H NMR (CHLOROFORM-d) .delta. 8.15 (d, J=8.5 Hz, 1H),
7.71-7.78 (m, 1H), 7.67 (d, J=1.0 Hz, 1H), 7.56-7.64 (m, 1H), 7.54
(d, J=4.5 Hz, 1H), 7.46-7.53 (m, 1H), 7.02-7.14 (m, 1H), 6.32 (dd,
J=17.6, 1.3 Hz, 1H), 5.73 (d, J=11.3 Hz, 1H), 4.71-4.74 (m, 0.5H),
4.53-4.66 (m, 1H), 4.45 (d, J=13.1 Hz, 1H), 4.06-4.24 (m, 0.5H),
3.91 (d, J=11.5 Hz, 0.5H), 3.68-3.84 (m, 3H), 3.39 (s, 3H), 3.26
(br. s., 1.5H), 3.07-3.21 (m, 1H), 2.61-2.85 (m, 2H), 1.53-1.64 (m,
1H), 1.32-1.44 (m, 1H), 1.11-1.24 (m, 2H), 0.80-0.94 (m, 2H),
0.48-0.78 (m, 1H)
[0978] LC-MS: m/z 508.1 (M+H).sup.+
Compound 591
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylypiperazin-1-yl)-5-(2--
vinylquinolin-4-yl)nicotinonitrile
[0979] The synthesis was similar to Compound 542.
[0980] .sup.1H NMR (CHLOROFORM-d) .delta. 8.18 (d, J=8.3 Hz, 1H),
7.76 (ddd, J=8.3, 6.8, 1.4 Hz, 1H), 7.68 (s, 1H), 7.57-7.63 (m,
1H), 7.48-7.57 (m, 2H), 7.10 (dd, J=17.7, 10.9 Hz, 1H), 6.34 (dd,
J=17.6, 1.8 Hz, 1H), 5.74 (d, J=11.0 Hz, 1H), 4.93 (br. s., 0.5H),
4.48-4.68 (m, 0.5H), 4.26-4.45 (m, 2H), 3.87-3.98 (m, 2H),
3.74-3.87 (m, 0.5H), 3.61 (t, J=12.3 Hz, 0.5H), 3.31-3.48 (m, 2H),
3.05-3.29 (m, 1H), 2.49-2.79 (m, 2H), 1.53-1.63 (m, 1H), 1.46 (dd,
J=6.5, 2.5 Hz, 1.5H), 1.32-1.40 (m, 1.5H), 1.15-1.23 (m, 2H),
0.80-0.93 (m, 2H)
[0981] LC-MS: m/z 468.2 (M+H).sup.+
Compound 592
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inylquinolin-4-yl)nicotinonitrile
[0982] The synthesis was similar to Compound 542.
[0983] .sup.1H NMR (CHLOROFORM-d) .delta. 8.19 (d, J=8.3 Hz, 1H),
7.76 (t, J=7.5 Hz, 1H), 7.65-7.68 (m, 1H), 7.58-7.64 (m, 1H),
7.48-7.57 (m, 2H), 7.11 (dd, J=17.7, 10.9 Hz, 1H), 6.34 (d, J=17.8
Hz, 1H), 5.75 (d, J=10.8 Hz, 1H), 4.95 (br. s., 0.5H), 4.50-4.70
(m, 0.5H), 4.24-4.47 (m, 2.5H), 3.71-3.89 (m, 2.5H), 3.59 (d, J=9.8
Hz, 0.5H), 3.31-3.45 (m, 4H), 3.07-3.28 (m, 1.5H), 2.67-2.85 (m,
1H), 2.54-2.67 (m, 1H), 1.52-1.62 (m, 1H), 1.33-1.49 (m, 3H),
1.11-1.21 (m, 2H), 0.78-0.93 (m, 2H)
[0984] LC-MS: m/z 482.2 (M+H).sup.+
Compound 553 (General Procedure 1, Step I)
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-methyl-1,7-naphthyridin-4-yl)nicotinonitrile
[0985] 1H NMR (CHLOROFORM-d) d: 9.53 (s, 1H), 8.59 (d, J=5.5 Hz,
1H), 7.65 (s, 1H), 7.42-7.50 (m, 2H), 4.63 (d, J=9.3 Hz, 1H), 4.51
(d, J=11.0 Hz, 2.5H), 3.08-3.48 (m, 4.5H), 2.87 (s, 3H), 1.59-1.68
(m, 1H), 1.46-1.53 (m, 1H), 1.22 (d, J=3.0 Hz, 1H), 1.05-1.11 (m,
2H), 0.92-0.98 (m, 2H), 0.87-0.92 (m, 2H), 0.84 (dd, J=7.9, 2.6 Hz,
2H), 0.70 (br. s., 1H), 0.42-0.63 (m, 3H)
[0986] LC-MS: m/z 479.6 (M+H).sup.+
Compound 551
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(2-vinylquinolin-5-yl)nicotinonitrile
[0987] The synthesis was similar to Compound 542.
[0988] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.18 (d, J=8.2
Hz, 1H), 7.91 (dd, J=12.5, 8.8 Hz, 1H), 7.79 (t, J=7.8 Hz, 1H),
7.64-7.71 (m, 1H), 7.57-7.64 (m, 1H), 7.46 (dd, J=6.9, 2.3 Hz, 1H),
6.97-7.17 (m, 1H), 6.34 (d, J=17.8 Hz, 1H), 5.75 (d, J=10.7 Hz,
1H), 4.56 (dd, J=13.0, 1.7 Hz, 1H), 4.45 (d, J=11.8 Hz, 1H), 4.15
(m, 0.5H), 3.87 (m, 1.5H), 3.26-3.44 (m, 2.5H), 3.01-3.20 (m,
2.5H), 1.42-1.52 (m, 1H), 1.07-1.21 (m, 2H), 0.79-0.92 (m, 3H),
0.66-0.76 (m, 2H), 0.46-0.56 (m, 2H)
[0989] LC-MS: m/z 532.2 (M+H).sup.+
Compound 570
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinolin-5-yl)nicotinonitrile
[0990] The synthesis was similar to Compound 542.
[0991] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.11-8.17 (m,
1H), 7.85-7.95 (m, 1H), 7.78 (t, J=7.3 Hz, 1H), 7.64-7.68 (m, 1H),
7.60 (dd, J=8.8, 1.5 Hz, 1H), 7.42-7.47 (m, 1H), 7.00-7.13 (m, 1H),
6.32 (d, J=17.6 Hz, 1H), 5.72 (d, J=11.0 Hz, 1H), 4.72 (m, 0.5H),
4.54 (d, J=12.5 Hz, 1H), 4.43 (d, J=12.8 Hz, 1H), 4.14 (d, J=7.8
Hz, 0.5H), 3.91 (d, J=11.8 Hz, 0.5H), 3.75 (t, J=5.6 Hz, 2.5H),
3.40 (s, 3H), 3.23 (d, J=8.0 Hz, 1H), 3.01-3.17 (m, 1H), 2.70-2.81
(m, 1H), 2.67 (m, 1H), 2.03 (d, J=5.5 Hz, 1H), 1.56 (td, J=7.8, 4.0
Hz, 1H), 1.11-1.20 (m, 3H), 0.78-0.86 (m, 2H), 0.58-0.66 (m, 2H),
0.42-0.52 (m, 2H)
[0992] LC-MS: m/z 508.2 (M+H).sup.+
Compound 569
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinolin-5-yl)nicotinonitrile
[0993] The synthesis was similar to Compound 542.
[0994] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.8.10-8.19 (m,
1H), 7.90 (dd, J=12.3, 8.8 Hz, 1H), 7.74-7.82 (m, 1H), 7.67 (s,
1H), 7.58-7.63 (m, 1H), 7.45 (ddd, J=7.0, 3.0, 1.0 Hz, 1H), 7.07
(dd, J=17.6, 10.9 Hz, 1H), 6.33 (d, J=17.5 Hz, 1H), 5.73 (d, J=11.0
Hz, 1H), 4.72 (d, J=9.5 Hz, 0.5H), 4.55 (d, J=13.0 Hz, 1H), 4.43
(d, J=12.5 Hz, 1H), 4.12 (d, J=7.2 Hz, 0.5H), 3.87-3.99 (m, 2H),
3.73-3.84 (m, 1H), 3.46 (m, 1H), 3.26 (m, 1.5H), 3.13 (d, J=10.5
Hz, 1H), 2.59-2.68 (m, 1.5H), 2.03 (d, J=6.0 Hz, 1H), 1.54-1.59 (m,
1H), 1.11-1.19 (m, 3H), 0.86-0.94 (m, 2H), 0.80-0.86 (m, 2H),
0.51-0.57 (m, 2H)
[0995] LC-MS: m/z 493.3 (M+H).sup.+
Compound 608
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2--
vinylquinolin-5-yl)nicotinonitrile
[0996] The synthesis was similar to Compound 542.
[0997] 1H NMR (400 MHz, CHLOROFORM-d) .delta.8.16-8.24 (m, 1H),
7.90-7.97 (m, 1H), 7.76-7.83 (m, 1H), 7.59-7.66 (m, 2H), 7.46 (d,
J=7.0 Hz, 1H), 7.12 (dd, J=17.6, 10.9 Hz, 1H), 6.35 (d, J=17.5 Hz,
1H), 5.76 (d, J=11.0 Hz, 1H), 4.95 (m, 0.5H), 4.58 (d, J=12.5 Hz,
0.5H), 4.19-4.44 (m, 2.5H), 3.67-3.91 (m, 1.5H), 3.40 (s, 3H),
3.15-3.26 (m, 1.5H), 2.67-2.82 (m, 1.5H), 2.03 (d, J=5.7 Hz, 1H),
1.55 (td, J=8.0, 4.1 Hz, 1H), 1.31-1.37 (m, 3H), 1.11-1.18 (m, 2H)
0.77-0.86 (m, 2H)
[0998] LC-MS: m/z 482.2 (M+H).sup.+
Compound 633 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inylquinolin-5-yl)nicotinonitrile
[0999] The synthesis was similar to Compound 542.
[1000] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta. 8.21 (d, J=8.2
Hz, 1H), 7.87-7.99 (m, 1H), 7.75-7.85 (m, 1H), 7.58-7.69 (m, 2H),
7.41-7.50 (m, 1H), 7.12 (dd, J=17.0, 11.0 Hz, 1H), 6.35 (d, J=17.5
Hz, 1H), 5.76 (d, J=11.0 Hz, 1H), 4.93 (m, 0.5H), 4.51-4.61 (m,
0.5H), 4.37 (d, J=12.8 Hz, 1H), 4.21-4.29 (m, 1H), 3.88-3.99 (m,
2H), 3.77 (d, J=12.0 Hz, 0.5H), 3.60 (t, J=12.3 Hz, 0.5H),
3.27-3.44 (m, 2H), 3.02-3.26 (m, 1H), 2.49-2.79 (m, 2H), 1.96-2.07
(m, 1H), 1.51-1.60 (m, 1H), 1.27 (s, 3H), 1.08-1.17 (m, 2H),
0.77-0.87 (m, 2H)
[1001] LC-MS: m/z 468.2 (M+H).sup.+
Compound 637
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inylquinazolin-4-yl)nicotinonitrile
[1002] The synthesis was similar to Compound 542.
[1003] .sup.1H NMR (CHLOROFORM-d) .delta. 8.07 (d, J=8.3 Hz, 1H),
7.85-7.96 (m, 2H), 7.81 (d, J=8.0 Hz, 1H), 7.57 (td, J=7.7, 1.0 Hz,
1H), 7.08 (dd, J=17.3, 10.5 Hz, 1H), 6.81 (dd, J=17.3, 1.8 Hz, 1H),
5.79-5.94 (m, 1H), 4.82-4.98 (m, 0.5H), 4.54 (d, J=12 Hz, 0.5H),
4.29-4.48 (m, 2H), 3.93 (br. s., 2H), 3.69-3.82 (m, 0.5H),
3.52-3.66 (m, 0.5H), 3.43-3.52 (m, 1H), 3.31-3.43 (m, 1H),
3.01-3.30 (m, 1.5H), 2.47-2.77 (m, 2H), 1.64-1.79 (m, 1H), 1.42 (d,
J=6.5 Hz, 1.5H), 1.32 (d, J=6.5 Hz, 1.5H), 1.11-1.24 (m, 2H), 0.90
(d, J=5.8 Hz, 2H)
[1004] LC-MS: m/z 469.2 (M+H).sup.+
Compound 334 (General Procedure 1, Step H)
(R)-6-cyclopropyl-5-(2-ethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-p-
iperazin-1-yl]-nicotinonitrile
[1005] .sup.1H NMR (METHANOL-d) .delta. 7.59 (s, 1H), 7.33-7.36 (d,
J=4.4 Hz, 2H), 7.24-7.27 (m, 1H), 7.12-7.13 (d, J=7.6 Hz, 1H),
4.40-4.46 (m, 1H), 4.14-4.23 (m, 2H), 3.92-3.96 (d, J=14.4 Hz,
0.5H), 3.34 (s, 3H), 3.14-3.19 (m, 2H), 3.34 (s, 4H), 2.99-3.14 (m,
0.5H), 2.60-2.81 (m, 2H), 2.46-2.50 (m, 2H), 1.64-1.69 (m, 1H),
1.37-1.41 (q, J=7.2 Hz, 1.3H), 1.26-1.30 (t, J=6.4 Hz, 1.7H),
1.02-1.11 (m, 5H), 0.82-0.91 (m, 2H); LC-MS: m/z 433.6 (M+H)
Compound 357 (General Procedure 1, Step H)
(R)-6-cyclopropyl-5-(2,6-dimethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-met-
hyl-piperazin-1-yl]-nicotinonitrile
[1006] .sup.1H NMR (METHANOL-d) .delta. 7.48 (s, 1H), 7.11-7.18 (m,
3H), 4.79 (s, 1H), 4.39-4.45 (m, 1H), 4.21-4.24 (d, J=12.8 Hz,
1.5H), 4.13-4.17 (d, J=13.2 Hz, 0.5H), 3.91-3.95 (d, J=13.6 Hz,
0.5H), 3.66-3.69 (t, J=5.2 Hz, 2H), 3.55-3.61 (t, J=7.2 Hz, 0.5H),
3.34 (s, 4H), 3.10-3.21 (m, 1H), 2.96-3.01 (m, 0.5H), 2.69-2.80 (m,
1H), 2.60-2.65 (m, 1H), 2.01-2.02 (d, J=2.8 Hz, 6H), 1.51-1.57 (m,
1H), 1.38-1.39 (d, J=6.4 Hz, 1.3H), 1.26-1.28 (d, J=6.8 Hz, 1.7H),
1.08-1.11 (m, 1H), 0.75-0.91 (m, 2H) LC-MS: m/z 433.2 (M+H)
Compound 344 (General Procedure 1, Step H)
(R)-6-cyclopropyl-5-(2-hydroxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3--
methyl-piperazin-1-yl]-nicotinonitrile
[1007] 1H NMR (METHANOL-d) .delta. 7.63 (s, 1H), 7.58-7.60 (d,
J=7.6 Hz, 1H), 7.40-7.44 (t, J=7.6 Hz, 1H), 7.33-7.36 (t, J=7.6 Hz,
1H), 7.16-7.18 (d, J=7.6 Hz, 1H), 4.78 (s, 1H), 4.36-4.49 (m, 3H),
4.13-4.24 (m, 2H), 3.91-3.95 (d, J=13.2 Hz, 0.5H), 3.66-6.69 (m,
2H), 3.54-3.61 (m, 0.5H), 3.33-3.34 (m, 4H), 3.25-3.28 (m, 0.5H),
3.13-3.15 (m, 1H), 2.96-3.02 (m, 0.5H), 2.69-2.81 (m, 1H),
2.60-2.65 (m, 1H), 1.62-1.68 (m, 1H), 1.37-1.39 (m, 1.5H),
1.25-1.28 (m, 1.5H), 1.11-1.12 (m, 2H), 0.83-0.92 (m, 2H); LC-MS:
m/z 435.2 (M+H)
Compound 328 (General Procedure 1, Step H)
(R)-2-cyclopropyl-2'-methoxy-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-
-1-yl]-[3,3']bipyridinyl-5-carbonitrile
[1008] .sup.1H NMR (METHANOL-d) .delta. 8.17-8.18 (dd, J=4.8 Hz,
1H), 7.65 (s, 1H), 7.61-7.63 (dd, J=7.2 Hz, 1H), 7.04-7.07 (dd,
J=7.2 Hz, 1H), 4.76-4.78 (m, 0.5H), 4.38-4.44 (m, 1H), 4.13-4.25
(m, 2H), 3.90 (s, 3H), 3.66-3.69 (t, J=5.6 Hz, 2H), 3.54-6.60 (m,
0.5H), 3.33 (s, 3H), 3.15-3.19 (m, 0.5H), 3.12-3.13 (m, 1H),
2.97-3.03 (m, 0.5H), 2.69-2.80 (m, 1H), 2.59-2.65 (m, 1H),
1.67-1.73 (m, 1H), 1.37-1.38 (d, J=6.4 Hz, 1H), 1.25-1.27 (d, J=6.8
Hz, 2H), 1.10-1.11 (m, 2H), 0.85-0.92 (m, 2H)
[1009] LC-MS: m/z 436.2 (M+H)
Compound 338 (General Procedure 1, Step H)
(R)-6-cyclopropyl-5-[2-(2-methoxy-ethyl)-phenyl]-2-[4-(3-methoxy-propionyl-
)-3-methyl-piperazin-1-yl]-nicotinonitrile
[1010] 1H NMR (METHANOL-d) .delta. 7.63 (s, 1H), 7.51-7.53 (d,
J=6.4 Hz, 1H), 7.39-7.42 (m, 2H), 7.22-7.23 (dd, J=6.8 Hz, 1H),
4.15-4.45 (m, 4H), 3.93-3.96 (m, 0.5H), 3.66-3.69 (m, 2H), 3.34 (s,
4H), 3.16-3.17 (d, J=4.0 Hz, 3H), 3.13-3.14 (m, 0.5H), 3.00-3.04
(m, 0.5H), 2.70-2.81 (m, 1H), 2.61-2.64 (m, 1H), 1.63-1.67 (m, 1H),
1.38-1.40 (m, 1H), 1.26-1.29 (m, 2H), 1.12-1.25 (m, 2H), 0.83-0.94
(m, 2H) LC-MS: m/z 449.2 (M+H)
Compound 360 (General Procedure 1, Step H)
(R)-5-(2-chloro-quinolin-3-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3--
methyl-piperazin-1-yl]-nicotinonitrile
[1011] 1H NMR (METHANOL-d) .delta. 8.38 (S, 1H), 8.00-8.02 (m, 2H),
7.85 (t, J=7.2 Hz, 2H), 7.81 (S, 1H), 7.68 (t, J=8.0 Hz, 1H), 4.8
(m, 1H), 4.4-4.5 (m, 1H), 4.2-4.4 (m, 1H), 3.95 (d, J=14.0 Hz,
0.5H), 3.67 (t, J=18.0 Hz, 2h), 3.54-3.60 (m, 0.5H), 3.32-3.45 (m,
4.5H), 3.22-3.25 (m, 1H), 3.09-3.22 (m, 0.5H), 2.71-2.79 (m, 1H),
2.60-2.65 (m, 1H), 1.63-1.69 (m, 1H), 1.39-1.41 (m, 1H), 1.30 (t,
J=6.8 Hz, 2H), 1.18-1.24 (m, 1H), 1.12-1.17 (m, 1H), 0.95-1.15 (m,
1H), 0.85-0.95 (m, 1H).
[1012] LC-MS: m/z 490.1 (M+H)+.
Compound 371 (General Procedure 1, Step H)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(2-
-methyl-2H-pyrazol-3-yl)-nicotinonitrile
[1013] 1H NMR (METHANOL-d) .delta. 7.77 (s, 1H), 7.55 (d, J=2.0 Hz,
1H), 6.36 (d, J=2.0 Hz, 1H), 4.78 (m, 0.5H), 4.21-4.44 (m, 3H),
3.94 (d, J=12.6 Hz, 0.5H), 3.66-3.69 (m, 4.5H), 3.54-3.62 (m,
0.5H), 3.33 (m, 3.5H), 2.70-2.82 (m, 1H), 2.59-2.65 (m, 1H),
1.68-1.74 (m, 1H), 1.36 (d, J=6.8 Hz, 1H), 1.27 (d, J=11.2 Hz, 2H),
1.14-1.24 (m, 2H), 0.97-1.02 (m, 2H). LC-MS: m/z 409.2
(M+H).sup.+.
Compound 345 (General Procedure 1, Step H)
(R)-6-cyclopropyl-5-(3,5-dimethyl-isoxazol-4-yl)-2-[4-(3-methoxy-propionyl-
)-3-methyl-piperazin-1-yl]-nicotinonitrile
[1014] 1H NMR (METHANOL-d) .delta. 7.70 (s, 1H), 4.77-4.80 (m,
0.5H), 4.42 (d, J=13.2 Hz, 1H), 4.17-4.28 (m, 2H), 3.94 (d, J=13.2
Hz, 0.5H), 3.68 (t, J=5.2 Hz, 2H), 3.51-3.62 (m, 1H), 3.31-3.33 (m,
3H), 3.14-3.24 (m, 1H), 3.01-3.08 (m, 0.5H), 2.71-2.80 (m, 1H),
2.59-2.70 (m, 1H), 2.30 (s, 3H), 2.14 (s, 3H), 1.75-1.82 (m, 1H),
1.38 (d, J=6.8 Hz, 1H), 1.25 (d, J=11.2 Hz, 2H), 1.15-1.20 (m, 2H),
0.98-1.02 (m, 2H). LC-MS: m/z 424.2 (M+H)+.
Compound 394 (General Procedure 1, Step H)
(R)-6-cyclopropyl-5-(1H-indol-2-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-pi-
perazin-1-yl]-nicotinonitrile
[1015] .sup.1H NMR (CHLOROFORM-d) .delta. 8.27 (s, 1H), 7.79 (s,
1H0, 7.64 (d, J=8.0 Hz, 1H), 7.23 (t, J=8.0 Hz, 1H), 7.16 (t, J=7.6
Hz, 1H), 6.65 (t, J=1.2 Hz, 1H), 4.89 (s, 0.5H), 4.52 (d, J=13.2
Hz, 0.5H), 4.23-4.35 (m, 2.5H), 3.72-3.77 (m, 2.5H), 3.54-3.60 (m,
0.5H), 3.37 (s, 3H), 3.26-3.32 (m, 1H), 3.04-3.17 (m, 1H),
2.55-2.72 (m, 2H), 2.36-2.43 (m, 1H), 1.37 (d, J=5.6 Hz, 1H), 1.26
(d, J=6.8 Hz, 2H), 1.18-1.20 (m, 2H), 1.03-1.04 (m, 2H). LC-MS: m/z
444.2 (M+H).sup.+.
Compound 361 (General Procedure 1, Step I)
(R)-5-(1H-benzoimidazol-5-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-m-
ethyl-piperazin-1-yl]-nicotinonitrile
[1016] .sup.1H NMR (METHANOL-d) 8.226 (s, 1H), 7.764 (s, 1H),
7.697-7.614 (m, 2H), 7.333-7.313 (d, J=8 Hz, 2H), 4.775-4.856 (m,
0.5H), 4.459-4.389 (m, 1H), 4.268-4.147 (m, 2H), 3.968-3.929 (m,
0.5H), 3.688-3.567 (m, 3H), 3.342 (s, 3H), 3.193-3.022 (m, 2H),
2.814-2.626 (m, 2H), 2.125-2.076 (m, 1H), 1.402-1.274 (m, 3H),
1.175 (s, 2H), 1.54-0.928 (m, 2H). LC-MS: m/z 445.1
(M+H).sup.+.
Compound 352 (General Procedure 1, Step I)
(R)-5-benzothiazol-5-yl-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl--
piperazin-1-yl]-nicotinonitrile
[1017] 1H NMR (METHANOL-d) 9.301 (s, 1H), 8.163-8.142 (d, J=8.4 Hz,
1H), 8.102-8.099 (d, J=1.2, 1H), 7.807 (s, 1H), 7.559-7.535 (dd,
J1=9.6 Hz, J2=1.6 Hz, 1H), 4.792 (m, 0.5H), 4.453-4.418 (m, 1H),
4.282-4.170 (m, 2H), 3.959-3.926 (m, 0.5H), 3.682-3.667 (m, 2H),
3.616-3.561 (m, 0.5H), 3.338 (s, 3H), 3.212-3.004 (m, 2H),
2.806-2.594 (m, 2H), 2.085-2.022 (m, 1H), 1.392-1.262 (m, 3H),
1.211-1.176 (m, 2H), 1.000-0.900 (m, 2H). LC-MS: m/z 462.1
(M+H)+.
Compound 364 (General Procedure 1, Step I)
(R)-5-benzothiazol-6-yl-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl--
piperazin-1-yl]-nicotinonitrile
[1018] 1H NMR (METHANOL-d) 9.292 (s, 1H), 8.131 (s, 2H), 7.806 (s,
1H), 7.624-7.606 (d, J=7.2 Hz, 1H), 4.775-4.856 (m, 0.5H),
4.412-4.172 (m, 3H), 3.960-3.931 (m, 0.5H), 3.555-3.688 (m, 3H),
3.345 (s, 3H), 3.188-3.038 (m, 2H), 2.762-2.640 (m, 2H),
2.047-2.035 (m, 1H), 1.379-1.266 (m, 3H), 1.192 (s, 2H), 0.965 (s,
2H). LC-MS: m/z 462.0 (M+H)+.
Compound 417 (General Procedure 1, Step I)
(R)-5-(2-amino-benzothiazol-6-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-
-3-methyl-piperazin-1-yl]-nicotinonitrile
[1019] 1H NMR (CHLOROFORM-d) 7.844 (s, 1H), 7.719-7.715 (d, J=1.6
Hz, 1H), 7.547 (s, 2H), 7.402-7.381 (d, J=8.4 Hz, 1H), 7.266-7.242
(d, J=9.6, 1H), 4.631-4.664 (m, 0.5H), 4.297-4.017 (m, 3H),
3.869-3.838 (m, 0.5H), 3.564-3.453 (m, 3H), 3.349-3.228 (m, 3H),
3.109-2.929 (m, 2H), 2.669-2.500 (m, 2H), 2.081-2.058 (m, 1H),
1.236 (s, 1H), 1.135-1.079 (m, 4H), 0.964-0.936 (m, 2H). LC-MS: m/z
477.1 (M+H)+.
Compound 370 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-te-
trazolo[1,5-a]pyridin-6-yl-nicotinonitrile
[1020] 1H NMR (METHANOL-d) 9.213-9.215 (d, J=0.8 Hz, 1H),
8.131-8.154 (d, J=9.2 Hz, 1H), 7.917-7.947 (m, 2H), 4.784 (s,
0.5H), 4.220-4.782 (m, 3H), 3.973-3.939 (d, J=13.6 Hz, 0.5H), 3.680
(s, 0.5H), 3.051-3.40 (m, 6H), 2.595-2.821 (m, 2H), 1.973-2.033 (m,
1H), 1.231-1.369 (m, 5H), 0.90-1.120 (s, 2H). LC-MS: m/z 447.1
(M+H)+.
Compound 367 (General Procedure 1, Step I)
(R)-6-cyclopropyl-5-isoquinolin-8-yl-2-[4-(3-methoxy-propionyl)-3-methyl-p-
iperazin-1-yl]-nicotinonitrile
[1021] 1H NMR (METHANOL-d) 9.342-9.356 (d, J=5.6 Hz, 1H),
8.626-8.642 (d, J=6.4 Hz, 1H), 8.530-8.546 (d, J=6.4 Hz 1H),
8.347-8.368 (d, J=8.4 Hz 1H), 8.263-8.284 (d, J=8.4 Hz 1H),
7.976-7.994 (d, J=7.2 Hz, 1H), 7.912 (s, 1H), 4.814 (s, 0.5H),
4.265-4.808 (m, 3H), 3.968-4.002 (m, 2.5H), 3.151-3.441 (m, 5H),
2.622-2.804 (m, 2H), 1.182-1.496 (m, 5H), 0.801-0.981 (m, 2H).
LC-MS: m/z 456.1 (M+H).sup.+.
Compound 373 (General Procedure 1, Step I)
(R)-6-cyclopropyl-5-(1H-indol-7-yl)-2-[4-(3-methoxy-propionyl)-3-methyl-pi-
perazin-1-yl]-nicotinonitrile
[1022] 1H NMR (METHANOL-d) 7.759 (s, 1H), 7.579-7.599 (d, J=8 Hz,
1H), 7.218 (s, 1H), 7.080-7.099 (d, J=7.6 Hz 1H), 7.000-7.018 (d,
J=7.2 Hz 1H), 6.506-6.513 (d, J=7.2 Hz, 1H), 4.417-4.466 (dd, J=8
Hz, 1H), 4.191-4.261 (m, 3H), 3.940-3.976 (d, J=1.44 Hz, 0.5H),
3.603-3.642 (m, 3H), 2.617-3.346 (m, 7H), 1.717-1.828 (m, 1H),
1.155-1.421 (m, 5H), 0.832-0.851 (dd, J=4.4 HZ, 2H). LC-MS: m/z
444.2 (M+H)+.
Compound 353 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-qu-
inolin-6-yl-nicotinonitrile
[1023] .sup.1H NMR (METHANOL-d) 9.170-9.183 (d, J=5.2 Hz, 1H),
9.076-9.097 (d, J=8.4 Hz, 1H), 8.304-8.333 (t, 2H), 8.194-8.216 (d,
J=8.8 Hz 1H), 8017-8.050 (m, 1H), 7.918 (s, 1H), 4.787 (s, 0.5H),
4.214-4.447 (m, 3H), 3.974-4.214 (d, J=96 Hz, 0.5H), 3.336-3.397
(m, 3H), 3.076-3.3.250 (m, 5H), 2.599-2.811 (m, 2H), 2.023-2.043
(m, 1H), 1.363-1.379 (d, J=6.4 Hz 1H), 1.244-1.263 (d, J=7.6 Hz
4H), 0.99-1.026 (m, 2H). LC-MS: m/z 456.1 (M+H)+.
Compound 374 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(1-
H-pyrrolo[2,3-b]pyridin-5-yl)-nicotinonitrile
[1024] .sup.1H NMR (METHANOL-d) 8.313 (s, 1H), 8.280 (s, 1H), 7.831
(s, 1H), 7.563-7.572 (d, J=3.6 Hz 1H), 6.682-6.690 (d, J=3.2 Hz
1H), 4.795 (s, 0.5H), 4.183-4.455 (m, 3H), 3.929-3.969 (m, 0.5H),
3.568-3.687 (m, 3H), 3.179-3.342 (m, 4H), 3.046-3.078 (m, 1H),
2.609-2.810 (m, 2H), 2.020 (s, 1H), 1.194-1.392 (m, 5H),
0.964-0.991 (m, 2H). LC-MS: m/z 445.2 (M+H)+.
Compound 395 (General Procedure 1, Step I)
(R)-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazi-
n-1-yl]-pyridin-3-yl}-thiazol-2-yl)-carbamic acid tert-butyl
ester
[1025] .sup.1H NMR (CHLOROFORM-d) 8.282 (s, 1H), 7.884-7.889 (d,
J=2 Hz, 1H), 6.947-6.951 (d, J=1.6 Hz, 1H), 4.888 (s, 0.5H),
4.493-4.524 (d, J=12.4 Hz, 0.5H), 4.205-4.371 (m, J=44.8 Hz, 2.5H),
3.719-3.790 (m, J=28.4 Hz, 2.5H), 3.499-3.550 (m, J=20.4, 0.5H),
3.367-3.372 (d, J=2 Hz, 3H), 3.218-3.246 (t, J=11.2 Hz, 1H),
3.006-3.118 (m, J=44.8 Hz, 1.5H), 2.544-2.745 (m, J=80.4 Hz, 2H),
2.404-2.465 (m, J=24.4 Hz, 1H), 1.532 (s, 9H), 1.243-1.355 (q,
J=44.8 Hz, 3H), 1.153-1.158 (d, J=2 Hz, 2H), 0.969-0.985 (t, J=6.4
Hz, 2H). LC-MS: m/z 527.2 (M+H)+.
Compound 418 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(2-
-methyl-1-oxo-1,2-dihydro-isoquinolin-4-yl)-nicotinonitrile
[1026] 1H NMR (CHLOROFORM-d) 8.506-8.526 (d, J=8.0 Hz, 1H),
7.617-7.658 (t, J=16.4 Hz, 1H), 7.596 (s, 1H), 7.529-7.569 (t, J=16
Hz, 1H), 7.209-7.240 (t, J=12.4 Hz, 1H), 7.036 (s, 1H), 4.916 (s,
0.5H), 4.534-4.642 (m, J=43.2 Hz, 3H), 4.208-4.351 (m, J=57.2 Hz,
3H), 3.836-3.869 (m, J=13.2 Jz, 0.5H), 3.681-3.739 (t, J=23.2 Hz,
2H), 3.589 (s, 3H), 3.287-3.371 (m, J=33.6 Hz, 1H), 3.155-3.192 (m,
1.5H), 2.594-2.773 (m, 2H), 1.678-1.740 (m, J=24.8 Hz, 1H),
1.301-1.423 (d, J=48.8 Hz, 3H), 1.089-1.143 (m, 2H), 0.809-0.909
(m, 2H). LC-MS: m/z 486.2 (M+H)+.
Compound 354 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(4-
-morpholin-4-yl-phenyl)-nicotinonitrile
[1027] 1H NMR (CHLOROFORM-d) 7.665 (s, 1H), 7.348-7.327 (d, J=8.4
Hz, 2H), 7.129-7.107 (d, J=8.8 Hz, 2H), 4.824-4.780 (m, 1H),
4.440-4.408 (m, 1H), 4.220-4.109 (m, 2H), 3.884-3.860 (m, 4H),
3.693-3.520 (m, 3H), 3.361-3.4 (s, 3H), 3.230-3.298 (m, 4.5H),
3.183-2.988 (m, 1.5H), 2.798-2.600 (m, 2H), 2.115-2.076 (m, 1H),
1.382-1.253 (m, 3H), 1.162-1.128 (m, 2H), 0.986-0.957 (m, 2H).
LC-MS: m/z 490.2 (M+H)+.
Compound 396 (General Procedure 1, Step I)
(R)-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-6'-p-
iperazin-1-yl-[3,3']bipyridinyl-5-carbonitrile
[1028] 1H NMR (CHLOROFORM-d) 8.201-8.207 (d, J=2.4 Hz, 1H), 7.531
(s, 2H), 6.718-6.739 (d, J=8.4 Hz, 1H), 4.867 (m, 1H), 4.477-4.507
(m, 4H), 4.149-4.302 (m, 3H), 4.17-4.39 (m, 3H), 3.601-3.807 (m,
6H), 3.494-3.549 (m, 1H), 3.349 (s, 3H), 2.992-3.213 (m, 6H),
2.531-2.734 (m, 2H), 1.974-2.030 (m, 1H), 1.352-1.367 (d, J=6 Hz,
1H), 1.235-1.265 (t, 2H), 0.967-0.992 (m, 2H). LC-MS: m/z 490.2
(M+H)+.
Compound 406 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-[3-
-(1H-pyrazol-4-yl)-phenyl]-nicotinonitrile
[1029] 1H NMR (CHLOROFORM-d) 8.030 (s, 2H), 7.735 (s, 1H),
7.589-7.613 (m, 2H), 7.423-7.462 (m, 1H), 7.242-7.269 (m, 1H),
4.781 (m, 0.5H), 4.376-4.441 (m, 1H), 4.131-4.243 (m, 2H),
3.908-3.940 (d, J=12.8 Hz, 1H), 3.660-3.675 (m, 2H), 3.540-3.602
(m, 0.5H), 3.334 (s, 3H), 3.253-3.262 (d, J=3.6 Hz, 0.5H),
3.122-3.183 (t, 1H), 2.966-3.022 (t, 0.5H), 2.631-2.810 (m, 1H),
2.586-2.615 (m, 1H), 2.061-2.124 (m, 1H), 1.362-1.379 (d, J=6.8 Hz,
1H), 1.249-1.266 (d, J=6.8 Hz, 2H), 1.165-1.182 (m, 2H),
0.900-0.970 (m, 2H) 137. LC-MS: m/z 471.2 (M+H)+.
Compound 363 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-[3-
-(1H-pyrazol-3-yl)-phenyl]-nicotinonitrile
[1030] .sup.1H NMR (CHLOROFORM-d) 7.820-7.824 (d, J=1.6 Hz, 1H),
7.767-7.795 (t, 2H), 7.686-7.692 (d, J=2.4 Hz, 1H), 7.490-7.528 (t,
1H), 7.374-7.393 (d, J=7.6 Hz, 1H), 6.720-6.725 (d, J=2 Hz, 1H),
4.790 (m, 0.5H), 4.396-4.452 (m, 1H), 4.153-4.264 (m, 2H),
3.920-3.953 (d, J=13.2 Hz, 0.5H), 3.608-3.680 (m, 2H), 3.554-3.582
(t, 0.5H), 3.337 (s, 3H), 3.220 (m, 0.5H), 3.140-3.197 (t, 1H),
2.986-3.043 (t, 0.5H), 2.751-2.803 (m, 1H), 2.591-2.729 (m, 1H),
2.069-2.120 (m, 1H), 1.372-1.388 (d, J=6.4 Hz, 1H), 1.259-1.276 (d,
J=6.8 Hz, 2H), 1.156-1.191 (m, 2H), 0.982 (m, 2H). LC-MS: m/z 471.4
(M+H)+.
Compound 436 (General Procedure 1, Step I)
(R)-6-cyclopropyl-5-imidazo[1,2-a]pyridin-6-yl-2-[4-(3-methoxy-propionyl)--
3-methyl-piperazin-1-yl]-nicotinonitrile
[1031] .sup.1H NMR (CHLOROFORM-d) 8.126 (s, 1H), 7.952 (bs, 1H),
7.681-7.684 (d, J=1.2 Hz, 1H), 7.621 (s, 1H), 7.547 (s, 1H),
7.257-7.280 (d, J=13.6 Hz, 1H), 4.823 (br, 0.5H), 4.436-4.467 (d,
J=12.4 Hz, 0.5H), 4.149-4.278 (m, 3H)), 3.649-3.717 (m, 2.5H),
3.446-3.501 (m, 0.5H), 3.299 (s, 3H), 3.219-3.254 (m, 1H),
3.019-3.121 (m, 2H), 2.628-2.646 (m, 1H), 2.501-2.531 (m, 1H),
1.842-1.897 (m, 1H), 1.293-1.308 (d, J=6 Hz, 1.5H), 1.183-1.204 (d,
J=8.4 Hz, 1.5H), 1.097-1.115 (m, 2H), 0.902-0.933 (m, 2H). LC-MS:
m/z 445.1 (M+H)+.
Compound 437 (General Procedure 1, Step I)
(R)-5-benzo[1,2,5]oxadiazol-4-yl-6-cyclopropyl-2-[4-(3-methoxy-propionyl)--
3-methyl-piperazin-1-yl]-nicotinonitrile
[1032] 1H NMR (CHLOROFORM-d) 7.785-7.808 (d, J=9.2 Hz, 1H), 7.646
(s, 1H), 7.433-7.473 (d, J=16 Hz, 1H), 7.335-7.353 (dd, J=7.2 Hz,
1H), 4.835 (m, 0.5H), 4.441 (m, 0.5H), 4.201-4.320 (m, 3H)),
3.669-3.725 (m, 2.5H), 3.478-3.487 (m, 0.5H), 3.312 (s, 3H),
3.103-3.106 (m, 1H), 3.402-3.705 (m, 2H), 2.596-2.654 (m, 1H),
2.484-2.537 (m, 1H), 1.769-1.800 (m, 1H), 1.308 (m, 1.5H),
1.204-1.219 (d, J=6 Hz, 1.5H), 1.127-1.145 (m, 2H), 0.870-0.889 (m,
2H). LC-MS: m/z 447.1 (M+H)+.
Compound 438 (General Procedure 1, Step I)
(R)-6-cyclopropyl-5-(1H-indazol-4-yl)-2-[4-(3-methoxy-propionyl)-3-methyl--
piperazin-1-yl]-nicotinonitrile
[1033] .sup.1H NMR (CHLOROFORM-d) 7.887 (bs, 1H), 7.646 (s, 1H),
7.462-7.483 (d, J=8.4 Hz, 1H), 7.391-7.429 (t, J=15.2 Hz, 1H),
7.055-7.071 (d, J=6.4 Hz, 1H), 4.859 (m, 0.5H), 4.465-4.500 (d,
J=14 Hz, 0.5H), 4.166-4.281 (m, 3H)), 3.671-3.733 (m, 2.5H),
3.486-3.510 (m, 0.5H), 3.312 (s, 3H), 3.200-3.252 (m, 1H),
2.992-3.103 (m, 2H), 2.614-2.670 (m, 1H), 2.527-2.557 (m, 1H),
1.819-1.840 (m, 1H), 1.340-1.355 (d, J=6 Hz, 1.5H), 1.238-1.253 (d,
J=6 Hz, 1.5H), 1.101-1.117 (m, 2H), 0.819-0.846 (m, 2H). LC-MS: m/z
445.1 (M+H).sup.+.
Compound 473 (General Procedure 1, Step I)
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-5-(2-
-oxo-2,3-dihydro-benzooxazol-5-yl)-nicotinonitrile
[1034] 1H NMR (CHLOROFORM-d) 8.492 (s, 1H), 7.568-7.569 (d, J=0.4
Hz, 1H), 7.277 (s, 1H), 7.121-7.125 (t, 1H), 7.064-7.068 (d, J=1.6
Hz, 1H), 6.720-6.725 (d, J=2 Hz, 1H), 4.897 (m, 0.5H), 4.510-4.549
(m, 0.5H), 4.175 (m, 2.5H), 3.780 (m, 2.5H), 3.543 (t, 0.5H), 3.369
(s, 3H), 3.246-3.273 (m, 1H), 3.113-3.119 (m, 1H), 3.019-3.048 (t,
0.5H), 2.649-2.759 (m, 1H), 2.556-2.609 (m, 1H), 1.998-2.006 (m,
1H), 1.268-1.387 (m, 3H), 1.129-1.155 (m, 2H), 0.928-0.955 (m, 2H).
LC-MS: m/z 462.1 (M+H)+.
Compound 474 (General Procedure 1, Step I)
(R)-6-cyclopropyl-5-(1-methoxy-isoquinolin-4-yl)-2-[4-(3-methoxy-propionyl-
)-3-methyl-piperazin-1-yl]-nicotinonitrile
[1035] .sup.1H NMR (CHLOROFORM-d) 8.350-8.325 (d, J=10 Hz, 1H),
7.913 (s, 1H), 7.660-7.415 (m, 4H), 4.915 (s, 0.5H), 4.562-4.530
(m, 0.5H), 4.278-4.228 (m, 2.5H), 4.261 (s, 3H), 3.797-3.553 (m,
3H), 3.797 (s, 3H), 3.577-3.044 (m, 2.5H), 2.750-2.568 (m, 2H),
1.633-1.625 (m, 1H), 1.429-1.322 (m, 3H), 1.137-1.093 (m, 2H),
0.842-0.765 (m, 2H). LC-MS: m/z 486.1 (M+H).sup.+.
Compound 299
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(4-fluorophenyl)-4-methylnicotinonitrile
[1036] .sup.1H NMR (CHLOROFORM-d) .delta. 7.10-7.16 (m, 4H),
4.62-4.65 (m, 0.5H), 4.23 (d, J=12.8 Hz, 1H), 4.15 (d, J=12.5 Hz,
1H), 4.04 (d, J=8.3 Hz, 0.5H), 3.61-3.88 (m, 3.5H), 3.31-3.38 (m,
3H), 3.25 (br. s., 0.5H), 3.02-3.17 (m, 1H), 2.89-3.02 (m, 1H),
2.51-2.73 (m, 2H), 2.09-2.18 (m, 3H), 1.53-1.59 (m, 1H), 1.33-1.44
(m, 1H), 0.99-1.08 (m, 2H), 0.75-0.86 (m, 2H), 0.29-0.63 (m,
4H)
[1037] LC-MS: m/z 463.4 (M+H).sup.+
Compound 300
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(4-fluorophenyl)-4-methylnicotinonitrile
[1038] .sup.1H NMR (CHLOROFORM-d) .delta. 7.19 (d, J=7.3 Hz, 4H),
4.70 (br. s., 0.5H), 4.30 (d, J=13.1 Hz, 1H), 4.18-4.27 (m, 1H),
4.12 (d, J=8.3 Hz, 0.5H), 3.81-3.94 (m, 1H), 3.66-3.78 (m, 1H),
3.32 (q, J=9.8 Hz, 2H), 3.08-3.21 (m, 1H), 2.97-3.08 (m, 1H),
2.14-2.25 (m, 3H), 1.58-1.67 (m, 1H), 1.50 (br. s., 1H), 1.04-1.14
(m, 2H), 0.81-0.89 (m, 2H), 0.65 (br. s., 1H), 0.56 (br. s., 1H),
0.37-0.52 (m, 2H)
[1039] LC-MS: m/z 487.2 (M+H).sup.+
Compound 627
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-met-
hyl-5-(6-vinylpyrimidin-4-yl)nicotinonitrile
[1040] 1H NMR (CHLOROFORM-d) .delta. 9.30 (d, J=1.1 Hz, 1H), 9.30
(d, J=1.1 Hz, 1H), 7.32 (t, J=4.5 Hz, 1H), 6.82 (dd, J=17.4, 10.7
Hz, 1H), 6.64-6.49 (m, 1H), 5.81 (dd, J=14.9, 4.1 Hz, 1H), 4.93 (d,
J=17.7 Hz, 1H), 4.53 (d, J=13.3 Hz, 1H), 4.20 (dd, J=33.1, 13.9 Hz,
2H), 3.77 (dd, J=18.0, 11.5 Hz, 2H), 3.57 (dd, J=12.8, 9.6 Hz, 1H),
3.39 (s, 3H), 3.34-2.95 (m, 3H), 2.82-2.49 (m, 2H), 2.26 (s, 3H),
2.88-1.49 (m, 8H), 1.57 (ddd, J=12.5, 8.0, 4.5 Hz, 1H), 1.45-1.37
(m, 2H), 1.33-1.28 (m, 2H), 1.14 (dt, J=7.4, 3.5 Hz, 2H), 0.96-0.81
(m, 3H).
[1041] LC-MS: m/z 447.2 (M+H).sup.+
Compound 628
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-met-
hyl-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1042] 1H NMR (CHLOROFORM-d) .delta. 8.70 (d, J=4.9 Hz, 1H), 7.23
(s, 1H), 7.08 (d, J=4.1 Hz, 1H), 6.88 (dd, J=17.4, 10.8 Hz, 1H),
6.30 (d, J=17.4 Hz, 1H), 5.58 (d, J=10.9 Hz, 1H), 4.92 (s, 1H),
4.53 (t, J=14.2 Hz, 1H), 4.29-4.08 (m, 3H), 3.76 (t, J=6.3 Hz, 2H),
3.57 (dd, J=23.8, 17.1 Hz, 1H), 3.40 (s, 3H), 3.31-2.95 (m, 3H),
2.68 (ddd, J=33.7, 17.4, 11.1 Hz, 2H), 2.20 (d, J=8.0 Hz, 3H), 1.57
(ddd, J=12.5, 8.1, 4.6 Hz, 1H), 1.41 (d, J=6.3 Hz, 2H), 1.36-1.25
(m, 4H), 1.10 (s, 2H), 0.94-0.74 (m, 3H).
[1043] LC-MS: m/z 446.2 (M+H).sup.+
Compound 411
(R)-5-(4-aminophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)-4-methylnicotinonitrile
[1044] 1H NMR (CHLOROFORM-d) d: 6.97-7.10 (m, 2H), 6.87-6.97 (m,
J=8.0 Hz, 2H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H), 4.23
(br. s., 0.5H), 3.95-4.18 (m, 2H), 3.71-3.83 (m, 2.5H), 3.58 (m,
0.5H) 3.40 (s, 3H), 3.11-3.27 (m, 1.5H), 2.88-3.10 (m, 1H),
2.53-2.82 (m, 2H), 2.16-2.28 (m, 3H), 1.68-1.78 (m, 1H), 1.38-1.47
(m, 1.5H), 1.33 (d, J=6.5 Hz, 1.5H), 0.98-1.13 (m, 2H), 0.75-0.93
(m, 2H)
[1045] LC-MS: m/z 433.5 (M+H).sup.+
Compound 278
(R)-6-cyclopropyl-5-(6-methoxynaphthalen-2-yl)-2-(4-(3-methoxypropanoyl)--
3-methylpiperazin-1-yl)-4-methylnicotinonitrile
[1046] .sup.1H NMR (CHLOROFORM-d) .delta. 7.83 (d, J=8.3 Hz, 1H),
7.71-7.78 (m, 1H), 7.60 (s, 1H), 7.25-7.32 (m, 1H), 7.17-7.24 (m,
2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H), 4.05-4.21 (m,
2.5H), 3.91-4.00 (m, 3H), 3.69-3.87 (m, 2.5H), 3.52-3.69 (m, 0.5H),
3.33-3.46 (m, 3H), 3.13-3.29 (m, 1.5H), 2.97-3.11 (m, 1H),
2.65-2.83 (m, 1H), 2.60 (dd, J=13.1, 6.5 Hz, 1H), 2.17-2.28 (m,
3H), 1.61-1.74 (m, 1H), 1.39-1.49 (m, 1.5H), 1.33 (d, J=6.5 Hz,
1.5H), 0.99-1.17 (m, 2H), 0.69-0.84 (m, 2H)
[1047] LC-MS: m/z 499.1 (M+H).sup.+
Compound 282
(R)-6-cyclopropyl-5-(2-fluorobiphenyl-4-yl)-2-(4-(3-methoxypropanoyl)-3-m-
ethylpiperazin-1-yl)-4-methylnicotinonitrile
[1048] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (d, J=8.0 Hz, 2H),
7.44-7.57 (m, 3H), 7.37-7.44 (m, 1H), 7.00-7.10 (m, 2H), 4.91 (br.
s., 0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.04-4.32 (m, 2.5H),
3.69-3.89 (m, 2.5H), 3.58 (t, J=10.8 Hz, 0.5H), 3.34-3.42 (m, 3H),
3.12-3.30 (m, 1.5H), 2.93-3.12 (m, 1H), 2.64-2.82 (m, 1H), 2.59
(dd, J=13.3, 6.5 Hz, 1H), 2.25 (s, 3H), 1.66-1.76 (m, 1H), 1.41 (d,
J=6.3 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.04-1.15 (m, 2H), 0.87
(dt, J=7.5, 3.7 Hz, 2H)
[1049] LC-MS: m/z 513.1 (M+H).sup.+
Compound 318 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(3-methyl-pyridyl-5-yl)-2-[4-(3-methoxy-propionyl)-3-m-
ethyl-piperazin-1-yl]-nicotinonitrile
[1050] 1H NMR (METHANOL-d) .delta. 8.79 (s, 1H), 8.70 (s, 1H), 8.40
(d, J=0.4 Hz, 1H), 4.77-4.79 (m, 0.5H), 4.42 (d, J=14.4 Hz, 1H),
4.22-4.24 (m, 1.5H), 4.14 (d, J=13.2 Hz, 0.5H), 3.94 (d, J=13.2 Hz,
0.5H), 3.68 (t, J=6.0 Hz, 2H), 3.55-3.62 (m, 0.5H), 3.31-3.33 (m,
3H), 3.13-3.22 (m, 1H), 3.00-3.06 (m, 0.5H), 2.68-2.82 (m, 1H),
2.58-2.63 (m, 4H), 2.22 (s, 3H), 1.47-1.54 (m, 1H), 1.37 (d, J=6.8
Hz, 1H), 1.26 (d, J=11.2 Hz, 2H), 1.13-1.17 (m, 2H), 0.91-0.94 (m,
2H)
[1051] LC-MS: m/z 434.2 (M+H)+.
Compound 319 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(4-methanesulfonyl-phenyl)-2-[4-(3-methoxy-propionyl)--
3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1052] .sup.1H NMR (METHANOL-d) d 8.07 (d, J=8.4 Hz, 2H), 7.52 (d,
J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12
(m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,
0.5H), 3.43 (s, 3H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m,
0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),
1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85
(m, 2H)
[1053] LC-MS: m/z 497.2 (M+H).sup.+
Compound 320 (General Procedure 6, Step G')
(R)-2-cyclopropyl-2'-methoxy-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-
-1-yl]-4-methyl-[3,3']bipyridinyl-5-carbonitrile
[1054] 1H NMR (METHANOL-d) .delta. 8.22 (dd, J1=2.0 Hz, J2=4.8 Hz,
1H), 7.54 (dd, J1=2.0 Hz, J2=7.2 Hz, 1H), 7.07-7.10 (m, 1H), 4.78
(s, 0.5H), 4.38-4.45 (m, 1H), 4.01-4.13 (m, 2H), 3.88-3.94 (m,
3.5H), 3.66-3.69 (m, 2H), 3.55-3.61 (m, 0.5H), 3.33 (s, 3H),
3.09-3.25 (m, 2H), 2.91-2.97 (m, 0.5H), 2.69-2.78 (m, 1H),
2.60-2.64 (m, 1H), 2.12 (s, 3H), 1.49-1.52 (m, 1H), 1.40 (d, J=6.4
Hz, 1.3H), 1.28 (dd, J1=2.4 Hz, J2=6.4 Hz, 1.7H), 0.99-1.10 (m,
2H), 0.80-0.83 (m, 2H)
[1055] LC-MS: m/z 450.2 (M+H).sup.+
Compound 321 (General Procedure 6, Step G')
(R)-5-(3-cyano-4-fluoro-phenyl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-
-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1056] 1H NMR (METHANOL-d) .delta. 7.71 (dd, J1=2.0 Hz, J2=6.4 Hz,
1H), 7.60-7.64 (m, 1H), 7.50 (t, J=9.2 Hz, 1H), 4.77-4.79 (m,
0.5H), 4.38-4.44 (m, 1H), 4.05-4.16 (m, 2H), 3.93 (d, J=13.6 Hz,
0.5H), 3.67-369 (m, 2H), 3.57-3.58 (m, 0.5H), 3.33 (s, 3H),
3.21-3.28 (m, 1H), 3.11-3.15 (m, 1H), 2.96-2.97 (m, 0.5H),
2.69-2.77 (m, 1H), 2.59-2.65 (m, 1H), 2.17 (s, 3H), 1.50-1.54 (m,
1H), 1.38 (d, J=6.4 Hz, 1.3H), 1.26 (d, J=6.8 Hz, 1.7H), 1.09-1.10
(m, 2H), 0.84-0.89 (m, 2H)
[1057] LC-MS: m/z 462.1 (M+H).sup.+
Compound 322 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(3-methoxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3--
methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1058] 1H NMR (METHANOL-d) .delta. 7.47 (t, J=7.6 Hz, 1H), 7.38 (d,
J=8.0 Hz, 1H), 7.20 (s, 1H), 7.15 (d, J=7.6 Hz, 1H), 4.79 (s,
0.5H), 4.50 (s, 2H), 4.37-4.45 (m, 1H), 4.01-4.12 (m, 2H), 3.93 (d,
J=13.6 Hz, 0.5H), 3.66-3.69 (m, 2H), 3.55-3.62 (m, 0.6H), 3.39 (s,
3H), 3.33 (s, 3H), 3.04-3.29 (m, 2H), 2.90-2.97 (m, 0.5H),
2.59-2.81 (m, 2H), 2.15 (s, 3H), 1.62-1.66 (m, 1H), 1.42 (d, J=6.4
Hz, 1.4H), 1.31 (d, J=6.4 Hz, 1.6H), 1.02-1.09 (m, 2H), 0.77-0.84
(m, 2H)
[1059] LC-MS: m/z 463.2 (M+H).sup.+
Compound 323 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(3-fluoro-4-methoxy-phenyl)-2-[4-(3-methoxy-propionyl)-
-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1060] 1H NMR (METHANOL-d) .delta. 7.19 (t, J=8.4 Hz, 1H),
6.95-6.99 (m, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),
4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H),
3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m,
0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),
1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85
(m, 2H)
[1061] LC-MS: m/z 467.2 (M+H).sup.+
Compound 324 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(2-fluoro-3-methoxy-phenyl)-2-[4-(3-methoxy-propionyl)-
-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1062] 1H NMR (METHANOL-d) .delta. 7.25-7.34 (m, 2H), 6.75-6.79 (m,
1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H),
3.88-3.97 (m, 3.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34
(s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m,
3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H)
[1063] LC-MS: m/z 467.2 (M+H)+.
Compound 325 (General Procedure 6, Step G')
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-me-
thyl-5-(1-methyl-1H-indol-5-yl)-nicotinonitrile
[1064] 1H NMR (METHANOL-d) .delta. 7.45 (d, J=8.4 Hz, 1H), 7.35 (s,
1H), 7.21 (s, 1H), 6.96 (d, J=8.4 Hz, 1H), 4.75-4.85 (m, 0.5H),
4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m,
2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H),
2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m,
2H), 0.78-0.85 (m, 2H).
[1065] LC-MS: m/z 472.2 (M+H)+.
Compound 326 (General Procedure 6, Step G')
(R)--N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piper-
azin-1-yl]-4-methyl-pyridin-3-yl}-phenyl)-acetamide
[1066] 1H NMR (METHANOL-d) .delta. 7.66 (d, J=8.8 Hz, 2H), 7.16 (d,
J=8.8 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12
(m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,
0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H),
2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 2.15 (s, 3H),
1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85
(m, 2H).
[1067] LC-MS: m/z 476.2 (M+H)+.
Compound 327 (General Procedure 6, Step G')
(R)-3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-
-1-yl]-4-methyl-pyridin-3-yl}-N-methyl-benzamide
[1068] 1H NMR (METHANOL-d) .delta. 7.87 (d, J=8.0 Hz, 1H), 7.69 (s,
1H), 7.56-7.62 (m, 1H), 7.41 (d, J=8.0 Hz, 1H) 4.75-4.85 (m, 0.5H),
4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m,
2H), 2.87-2.98 (m, 3.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H),
2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m,
2H), 0.78-0.85 (m, 2H).
[1069] LC-MS: m/z 476.2 (M+H)+.
Compound 329 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(3-methanesulfonyl-phenyl)-2-[4-(3-methoxy-propionyl)--
3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1070] 1H NMR (METHANOL-d) .delta. 8.02 (d, J=7.6 Hz, 1H), 7.85 (s,
1H), 7.75-7.79 (m, 1H), 7.61 (d, J=7.6 Hz, 1H) 4.75-4.85 (m, 0.5H),
4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m,
5H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H),
2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m,
2H), 0.78-0.85 (m, 2H).
[1071] LC-MS: m/z 497.1 (M+H)+.
Compound 330 (General Procedure 6, Step G')
(R)--N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piper-
azin-1-yl]-4-methyl-pyridin-3-yl}-benzyl)-methanesulfonamide
[1072] .sup.1H NMR (METHANOL-d) .delta. 7.51 (d, J=8.0 Hz, 2H),
7.22 (d, J=8.0 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H),
4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H),
3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m,
3.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),
1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85
(m, 2H).
[1073] LC-MS: m/z 526.2 (M+H)+.
Compound 331 (General Procedure 6, Step G')
(R)-4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-
-1-yl]-4-methyl-pyridin-3-yl}-N-methyl-benzenesulfonamide
[1074] .sup.1H NMR (METHANOL-d) .delta. 7.95 (d, J=8.4 Hz, 2H),
7.47 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),
4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H),
3.52-3.62 (m, 0.5H), 3.43 (s, 3H), 3.16-3.25 (m, 1.5H), 2.87-2.98
(m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 4H), 2.18 (s, 3H),
1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85
(m, 2H).
[1075] LC-MS: m/z 512.2 (M+H).sup.+.
Compound 332 (General Procedure 6, Step G')
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-me-
thyl-5-[3-(pyrrolidine-1-carbonyl)-phenyl]-nicotinonitrile
[1076] 1H NMR (METHANOL-d) .delta. 7.57-7.59 (m, 2H), 7.40 (s, 1H),
7.34-7.37 (m, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),
4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H),
3.45-3.62 (m, 4.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m,
0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),
1.88-1.99 (m, 4H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09
(m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 516.2 (M+H).sup.+.
Compound 333 (General Procedure 6, Step G')
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-me-
thyl-5-[4-(pyrrolidine-1-carbonyl)-phenyl]-nicotinonitrile
[1077] .sup.1H NMR (METHANOL-d) .delta. 7.65 (d, J=8.4 Hz, 2H),
7.33 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),
4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H),
3.52-3.62 (m, 4.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m,
0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H),
1.88-1.99 (m, 4H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09
(m, 2H), 0.78-0.85 (m, 2H).
[1078] LC-MS: m/z 516.2 (M+H)+.
Compound 335 (General Procedure 6, Step G')
(R)--N-(3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piper-
azin-1-yl]-4-methyl-pyridin-3-yl}-benzyl)-methanesulfonamide
[1079] .sup.1H NMR (METHANOL-d) .delta. 7.42-7.50 (m, 2H), 7.26 (s,
1H), 7.22 (d, J=7.2 Hz, 1H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m,
1H), 4.31 (s, 2H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m,
2H), 2.87-2.98 (m, 0.5H), 2.87 (s, 3H), 2.68-2.85 (m, 1H),
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m,
3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 526.2
(M+H).sup.+.
Compound 336 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(4-cyclopropylmethoxy-phenyl)-2-[4-(3-methoxy-propiony-
l)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1080] .sup.1H NMR (METHANOL-d) .delta. 7.11 (d, J=8.4 Hz, 2H),
7.01 (d, J=8.4 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H),
3.88-4.12 (m, 5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s,
3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.21-1.41 (m,
4H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H), 0.61-0.69 (m, 2H),
0.35-0.41 (m, 2H).
[1081] LC-MS: m/z 489.2 (M+H)+.
Compound 337 (General Procedure 6, Step G')
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-me-
thyl-5-(4-propoxy-phenyl)-nicotinonitrile
[1082] 1H NMR (METHANOL-d) .delta. 7.10 (d, J=8.8 Hz, 2H), 7.01 (d,
J=8.8 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.98-4.12
(m, 4H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,
0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H),
2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.78-1.89 (m,
2H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 5H),
0.78-0.85 (m, 2H).
[1083] LC-MS: m/z 477.2 (M+H)+.
Compound 340 (General Procedure 6, Step G')
(R)--N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piper-
azin-1-yl]-4-methyl-pyridin-3-yl}-benzyl)-acetamide
[1084] 1H NMR (METHANOL-d) .delta. 7.41 (d, J=8.0 Hz, 2H), 7.19 (d,
J=8.0 Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12
(m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m,
0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H),
2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 2.01 (s, 3H),
1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85
(m, 2H).
[1085] LC-MS: m/z 490.1 (M+H)+.
Compound 346 (General Procedure 6, Step G')
(R)-5-(4-fluoro-pyridyl-3-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-m-
ethyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1086] 1H NMR (METHANOL-d) .delta. 8.10-8.09 (d, J=2.4 Hz, 1H),
7.89-7.85 (m, 1H), 7.23-7.20 (m, 1H), 4.79-4.78 (d, J=1.2 Hz,
0.5H), 4.44-4.41 (d, J=14 Hz, 1H), 4.18-4.01 (m, 2H), 3.95-3.92 (d,
J=13.6 Hz, 0.5H), 3.68-3.67 (d, J=5.6 Hz, 2H), 3.62-3.56 (t, J=11.6
Hz, 0.5H), 3.33 (s, 3H), 3.26-3.24 (m, 1H), 3.20-3.11 (m, 1H),
3.01-2.98 (m, 0.5H), 2.80-2.69 (m, 1H), 2.64-2.59 (m, 1H), 2.19 (s,
3H), 1.56-1.54 (m, 1H), 1.39-1.37 (d, J=6.4 Hz, 1H), 1.27-1.26 (d,
J=6.8 Hz, 1H), 1.11-1.09 (t, J=3.6 Hz, 2H), 0.89-0.87 (m, 2H).
LC-MS: m/z 438.1 (M+H)+.
Compound 347 (General Procedure 6, Step G')
(R)-5-(4-cyano-phenyl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-p-
iperazin-1-yl]-4-methyl-nicotinonitrile
[1087] 1H NMR (METHANOL-d) .delta. 7.87-7.85 (d, J=8.4 Hz, 2H),
7.47-7.45 (d, J=8 Hz, 2H), 4.79 (s, 1H), 4.45-4.39 (m, 1H),
4.16-4.05 (m, 2H), 3.95-3.92 (d, J=13.2 Hz, 0.5H), 3.69-3.66 (t,
J=11.6 Hz, 2H), 3.62-3.55 (m, 0.5H), 3.33 (s, 3H), 3.27-3.08 (m,
2H), 2.99-2.94 (m, 0.5H), 2.81-2.69 (m, 1H), 2.64-2.59 (m, 1H),
2.16 (s, 3H), 1.55-1.49 (m, 1H), 1.39-1.28 (m, 3H), 1.12-1.09 (m,
1H), 0.89-0.86 (m, 2H). LC-MS: m/z 444.1 (M+H)+.
Compound 348 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(2-methoxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3--
methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1088] 1H NMR (METHANOL-d) .delta. 7.53-7.55 (m, 1H), 7.40-7.45 (m,
2H), 7.11-7.14 (m, 1H), 4.79 (s, 0.5H), 4.42 (t, J=14.4 Hz, 1H),
4.04-4.15 (m, 4H), 3.93 (d, J=12.8 Hz, 0.5H), 3.59-3.69 (m, 2.5H),
3.33 (s, 3H), 3.20 (d, J=4.8 Hz, 4H), 2.95-3.18 (m, 1H), 2.71-2.76
(m, 1H), 2.60-2.65 (m, 1H), 2.08 (s, 3H), 1.40-1.5 (m, 2.3H),
1.27-1.38 (m, 1.7H), 1.02-1.09 (m, 2H), 0.75-0.82 (m, 2H).
[1089] LC-MS: m/z 463.2 (M+H)+.
Compound 349 (General Procedure 6, Step G')
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-me-
thyl-5-(2-methyl-2H-pyrazol-3-yl)-nicotinonitrile
[1090] 1H NMR (METHANOL-d) d 7.60 (s, 1H), 6.33 (s, 1H), 4.75-4.85
(m, 0.5H), 4.35-4.48 (m, 1H), 4.21-4.38 (m, 2H), 3.88-3.95 (m,
0.5H), 3.65-3.72 (m, 2H), 3.63 (s, 3H), 3.52-3.62 (m, 0.5H), 3.34
(s, 3H), 3.03-3.25 (m, 1H), 2.97-3.08 (m, 0.5H), 2.68-2.85 (m, 1H),
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m,
3H), 1.05-1.19 (m, 2H), 0.78-0.95 (m, 2H). LC-MS: m/z 423.2
(M+H).sup.+.
Compound 350 (General Procedure 6, Step G')
(R)--N-(3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piper-
azin-1-yl]-4-methyl-pyridin-3-yl}-phenyl)-methanesulfonamide
[1091] 1H NMR (METHANOL-d) d 7.45-7.48 (m, 1H), 7.30 (d, J=7.6 Hz,
1H), 7.11 (s, 1H), 7.02 (d, J=7.6 Hz, 1H), 4.75-4.85 (m, 0.5H),
4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m,
2H), 2.98 (s, 3H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),
2.57-2.63 (m, 1H), 2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m,
3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 512.1
(M+H).sup.+.
Compound 351 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(3,5-dimethyl-isoxazol-4-yl)-2-[4-(3-methoxy-propionyl-
)-3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1092] 1H NMR (METHANOL-d) d 4.75-4.85 (m, 0.5H), 4.35-4.48 (m,
1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H),
3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m,
0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.24 (s, 3H), 2.21 (s,
3H), 2.08 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.12
(m, 2H), 0.85-0.95 (m, 2H).
[1093] LC-MS: m/z 438.2 (M+H).sup.+.
Compound 358 (General Procedure 6, Step G')
(R)-5-(1-benzyl-1H-pyrazol-4-yl)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)--
3-methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1094] 1H NMR (METHANOL-d) 7.742 (s, 1H), 7.499 (s, 1H),
4.365-7.255 (m, 5H), 5.410 (s, 2H), 4.773 (s, 0.5H), 4.429-4.359
(m, 1H), 4.109-4.004 (m, 2H), 3.924-3.891 (m, 0.5H), 3.683-3.655
(m, 2H), 3.592-3.535 (m, 0.5H), 3.328 (s, 3H), 3.255-3.041 (m, 2H),
2.954-2.898 (m, 0.5H), 2.801-2.588 (m, 2H), 2.260 (s, 3H),
1.909-1.869 (m, 1H), 1.375-1.246 (m, 3H), 1.071 (s, 2H), 0.90-0.80
(m, 2H). LC-MS: m/z 499.2 (M+H).sup.+.
[1095] Compound 359 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(2-ethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3-methyl-p-
iperazin-1-yl]-4-methyl-nicotinonitrile
[1096] 1H NMR (METHANOL-d) .delta. 7.40-7.37 (m, 2H), 7.35-7.27 (m,
1H), 7.07-7.04 (m, 1H), 4.80-4.79 (d, J=2.4 Hz, 0.5H), 4.46-4.38
(m, 1H), 4.14-4.04 (m, 2H), 3.95-3.92 (d, J=12.8 Hz, 0.5H),
3.68-3.63 (m, 2H), 3.60 (m, 0.5H), 3.34 (s, 3H), 3.26-3.06 (m, 2H),
2.97-2.94 (d, J=12 Hz, 0.5H), 2.80-2.60 (m, 2H), 2.42-2.30 (m, 2H),
2.09 (s, 3H), 1.55-1.50 (m, 1H), 1.43-1.39 (m, 1H), 1.32-1.27 (m,
1H), 1.08-1.03 (m, 5.5H) 0.82-0.80 (m, 2H). LC-MS: m/z 447.2
(M+H)+.
Compound 362 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(3-dimethylamino-phenyl)-2-[4-(3-methoxy-propionyl)-3--
methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1097] 1H NMR (METHANOL-d) .delta. 7.53 (t, J=8.0 Hz, 1H), 7.27 (d,
J=8.4 Hz, 1H), 7.09 (s, 1H), 7.02 (d, J=7.2 Hz, 1H), 4.78 (s, 1H),
4.38-4.45 (m, 1H), 4.03-4.14 (m, 2H), 3.91-3.95 (m, 0.5H),
3.65-3.70 (m, 2H), 3.53-3.62 (m, 0.5H), 3.34 (s, 4H), 3.21-3.31 (m,
1.5H), 3.16 (s, 7H), 2.96-2.98 (m, 0.5H), 2.71-2.79 (m, 1H),
2.62-2.65 (m, 1H), 2.19 (s, 3H), 1.61-1.67 (m, 1H), 1.38-1.40 (d,
J=6.4 Hz, 1.3H), 1.27-1.28 (d, J=6.4 Hz, 1.7H), 1.07-1.09 (m, 2H),
0.81-0.84 (m, 2H). LC-MS: m/z 462.1 (M+H)+.
Compound 365 (General Procedure 6, Step G')
(R)-6-cyclopropyl-2-[4-(3-methoxy-propionyl)-3-methyl-piperazin-1-yl]-4-me-
thyl-5-(1-methyl-1H-pyrazol-4-yl)-nicotinonitrile
[1098] .sup.1H NMR (METHANOL-d) d 7.64 (s, 1H), 7.44 (s, 1H),
4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 3.88-4.12 (m, 5.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m,
2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H),
2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m,
2H), 0.78-0.85 (m, 2H). LC-MS: m/z 423.1 (M+H)+.
Compound 366 (General Procedure 6, Step G')
(R)-3-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-
-1-yl]-4-methyl-pyridin-3-yl}-benzoic acid methyl ester
[1099] .sup.1H NMR (METHANOL-d) d 8.06 (d, J=8.0 Hz, 1H), 7.87 (s,
1H), 7.58-7.63 (m, 1H), 7.48 (d, J=8.0 Hz, 1H), 4.75-4.85 (m,
0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H), 3.88-3.97 (m, 3.5H),
3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34 (s, 3H), 3.03-3.25 (m,
2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H),
2.16 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m,
2H), 0.78-0.85 (m, 2H). LC-MS: m/z 477.1 (M+H)+.
Compound 369 (General Procedure 6, Step G')
(R)-2-cyclopropyl-2'-fluoro-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin--
1-yl]-4-methyl-[3,3']bipyridinyl-5-carbonitrile
[1100] 1H NMR (METHANOL-d) .delta. 8.31-8.30 (d, J=4.4 Hz, 1H),
7.90-7.86 (t, J=8.4 Hz, 1H), 7.48-7.45 (m, 1H), 4.82-4.79 (m,
0.5H), 4.45-4.37 (m, 0.5H), 4.20-4.10 (m, 2H), 3.95-3.92 (d, J=12.8
Hz, 0.5H), 3.68-3.67 (m, 2H), 3.62-3.56 (t, J=12 Hz, 0.5H),
3.34-3.33 (m, 3.5H), 3.18-3.16 (d, J=10.8 Hz, 1H), 3.01 (m, 1H),
2.80-2.71 (m, 1H), 2.65-2.61 (m, 1H), 2.2 (s, 3H), 1.52-1.49 (m,
1H), 1.39-1.38 (d, J=2.8 Hz, 1H), 1.28-1.27 (d, J=6.4 Hz, 1H),
1.13-0.90 (m, 1H), 0.90-0.88 (m, 1H). LC-MS: m/z 438.2
(M+H).sup.+.
Compound 372 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(2-hydroxymethyl-phenyl)-2-[4-(3-methoxy-propionyl)-3--
methyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1101] 1H NMR (CHLOROFORM-d) .delta. 7.61-7.59 (d, J=7.6 Hz, 1H),
7.46-7.37 (m, 2H), 7.10-7.08 (d, J=7.2 Hz, 1H), 4.90 (s, 0.5H),
4.53-4.34 (M, 2.5H), 4.22-4.05 (m, 2.5H), 3.79-3.71 (m, 2.5H),
3.60-3.54 (M, 0.5H), 3.48 (S, 1H), 3.37 (S, 3H), 3.19-3.14 (M,
1.5H), 3.03-2.98 (m, 1H), 2.75-2.66 (M, 1H), 2.60-2.55 (m, 1H),
2.11 (s, 3H), 1.48-1.44 (m, 2H), 1.31-1.30 (d, J=4.8 Hz, 1.5H),
1.10-1.07 (m, 2H). LC-MS: m/z 449.1 (M+H).sup.+.
Compound 380 (General Procedure 6, Step G')
(R)--N-(4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piper-
azin-1-yl]-4-methyl-pyridin-3-yl}-phenyl)-methanesulfonamide
[1102] 1H NMR (METHANOL-d) d 7.36 (d, J=8.4 Hz, 2H), 7.21 (d, J=8.4
Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 1H), 4.05-4.12 (m, 2H),
3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.43
(s, 3H), 3.16-3.25 (m, 1.5H), 3.03 (s, 3H), 2.87-2.98 (m, 0.5H),
2.68-2.85 (m, 1H), 2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m,
1H), 1.34-1.41 (m, 3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H).
LC-MS: m/z 512.2 (M+H)+.
Compound 393 (General Procedure 6, Step G')
(R)-4-{5-cyano-2-cyclopropyl-6-[4-(3-methoxy-propionyl)-3-methyl-piperazin-
-1-yl]-4-methyl-pyridin-3-yl}-benzenesulfonamide
[1103] 1H NMR (METHANOL-d) d 8.02 (d, J=8.4 Hz, 2H), 7.43 (d, J=8.4
Hz, 2H), 4.75-4.85 (m, 0.5H), 4.35-4.48 (m, 3H), 4.05-4.12 (m, 2H),
3.88-3.97 (m, 0.5H), 3.65-3.72 (m, 2H), 3.52-3.62 (m, 0.5H), 3.34
(s, 3H), 3.03-3.25 (m, 2H), 2.87-2.98 (m, 0.5H), 2.68-2.85 (m, 1H),
2.57-2.63 (m, 1H), 2.18 (s, 3H), 1.62-1.69 (m, 1H), 1.34-1.41 (m,
3H), 1.05-1.09 (m, 2H), 0.78-0.85 (m, 2H). LC-MS: m/z 498.1
(M+H).sup.+.
Compound 405 (General Procedure 6, Step G')
(R)-6-cyclopropyl-5-(2,3-difluoro-phenyl)-2-[4-(3-methoxy-propionyl)-3-met-
hyl-piperazin-1-yl]-4-methyl-nicotinonitrile
[1104] 1H NMR (METHANOL-d) .delta. 7.26-7.39 (m, 2H), 7.07 (t,
J=6.8 Hz, 1H), 4.72 (s, 0.5H), 4.41-4.45 (m, 1H), 4.07-4.19 (m,
2H), 3.93 (d, J=13.6 Hz, 0.5H), 3.66-3.69 (m, 2H), 3.56-3.62 (m,
0.5H), 3.33 (s, 3H), 3.20-3.28 (m, 1H), 3.14-3.17 (m, 1H),
2.96-3.02 (m, 0.5H), 2.60-2.81 (m, 2H), 2.18 (s, 3H), 1.55-1.61 (m,
1H), 1.38 (d, J=6.4 Hz, 1.3H), 1.27 (d, J=6.8 Hz, 1.7H), 1.06-1.1
(m, 2H), 0.82-0.89 (m, 2H). LC-MS: m/z 455.1 (M+H).sup.+.
Compound 589
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-
-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1105] It was obtained by the same procedure of Compound 527.
[1106] .sup.1H NMR (CHLOROFORM-d) .delta. 8.70 (d, J=5.0 Hz, 1H),
7.26 (s, 1H), 7.10 (d, J=3.8 Hz, 1H), 6.90 (dd, J=17.4, 10.9 Hz,
1H), 6.32 (d, J=17.3 Hz, 1H), 5.61 (d, J=11.3 Hz, 1H), 4.60-4.76
(m, 0.5H), 4.34 (d, J=12.8 Hz, 1H), 4.26 (d, J=12.8 Hz, 1H), 4.08
(d, J=9.0 Hz, 0.5H), 3.92 (br. s., 2H), 3.78 (br. s., 1H),
3.39-3.56 (m, 1H), 3.23 (br. s., 1H), 3.15 (d, J=11.8 Hz, 1H), 3.05
(br. s., 1H), 2.61 (br. s., 2H), 2.17-2.29 (m, 3H), 1.55-1.60 (m,
1H), 1.38-1.47 (m, 1H), 1.27-1.33 (br. s., 1H), 1.12 (br. s., 2H),
0.64 (br. s., 2H), 0.33-0.54 (m, 2H)
[1107] LC-MS: m/z 458.3 (M+H).sup.+
Compound 674
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(6-vinylpyridazin-4-yl)nicotinonitrile
##STR00849##
[1108] Step
1(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-
-5-(6-hydroxypyridazin-4-yl)nicotinonitrile
[1109] A mixture of
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)--
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (200
mg, 0.42 mmol), 5-chloropyridazin-3-ol (109 mg, 0.625 mmol), CsF
(127 mg, 0.84 mmol) and Pd(dppf)Cl.sub.2 (17 mg) in dioxane and
water was heated at 100.degree. C. for 2 hrs. The reaction mixture
was concentrated and the residue was purified by pre-TLC to afford
120 mg of title compound.
[1110] LC-MS: m/z 449.2 (M+H).sup.+
Step 2
(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl-
)piperazin-1-yl)pyridin-3-yl)pyridazin-3-yl
trifluoromethanesulfonate
[1111] A solution of
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)--
5-(6-hydroxypyridazin-4-yl)nicotinonitrile (120 mg, 0.27 mmol),
Tf.sub.2O (100 mg, 0.48 mmol) and TEA (0.1 mL) in DCM was stirred
for 1 hr. The reaction mixture was washed with water, dried and
concentrated. The residue was purified by pre-TLC to afford 60 mg
of title compound.
[1112] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.41 (d, J=1.5 Hz, 1H),
7.71 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 4.71 (d, J=12.8 Hz, 1.5H),
4.58 (d, J=11.5 Hz, 1H), 4.14 (brs, 0.5H), 3.93 (br. s., 0.5H),
3.75 (br. s., 2.5H), 3.39 (s, 3H), 3.21-3.36 (m, 3H), 2.54-2.83 (m,
2H), 1.86-1.96 (m, 1H), 1.08-1.28 (m, 5H), 0.48-0.63 (m, 4H).
[1113] LC-MS: m/z 580.7 (M+H).sup.+
Step 3
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin--
1-yl)-5-(6-vinylpyridazin-4-yl)nicotinonitrile (Compound 674)
[1114] A mixture of
(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyppipera-
zin-1-yl)pyridin-3-yl)pyridazin-3-yl trifluoromethanesulfonate (25
mg, 0.043 mmol), Potassium vinyltrifluoroborate (12 mg, 0.083
mmol), TEA (20 mg, 0.215 mmol) and Pd(dppf)Cl.sub.2(3.5 mg) in
i-PrOH and water was heated at 100.degree. C. for 2 hrs. The
reaction mixture was concentrated and the residue was purified by
pre-TLC to afford 11 mg of title compound.
[1115] .sup.1H NMR (CHLOROFORM-d) .delta.9.21 (br. s., 1H), 7.68
(s, 1H), 7.61 (s, 1H), 7.13 (dd, J=17.6, 11.0 Hz, 1H), 6.37 (d,
J=17.6 Hz, 1H), 5.79 (d, J=11.0 Hz, 1H), 4.63 (d, J=12.8 Hz, 1.5H),
4.50 (d, J=12.3 Hz, 1H), 4.05-4.18 (m, 0.5H), 3.90 (d, J=11.0 Hz,
0.5H), 3.63-3.83 (m, 2.5H), 3.38 (s, 3H), 3.18-3.33 (m, 2H), 3.15
(br. s., 1H), 2.71-2.64 (m, 2H), 1.89-1.99 (m, 1H), 1.29-1.40 (m,
3H), 1.07 (dd, J=7.4, 2.9 Hz, 2H), 0.61-0.44 (m, 4H).
[1116] LC-MS: m/z 459.0 (M+H).sup.+
Compound 675
(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)pipera-
zin-1-yl)pyridin-3-yl)pyridazin-3-yl trifluoromethanesulfonate
[1117] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.41 (d, J=1.5 Hz, 1H),
7.71 (s, 1H), 7.51 (d, J=1.8 Hz, 1H), 4.71 (d, J=12.8 Hz, 1.5H),
4.58 (d, J=11.5 Hz, 1H), 4.14 (brs, 0.5H), 3.93 (br. s., 0.5H),
3.75 (br. s., 2.5H), 3.39 (s, 3H), 3.21-3.36 (m, 3H), 2.54-2.83 (m,
2H), 1.86-1.96 (m, 1H), 1.08-1.28 (m, 5H), 0.48-0.63 (m, 4H).
[1118] LC-MS: m/z 580.7 (M+H).sup.+
Compound 687
(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2--
cyclopropylpyridin-3-yl)pyridazin-3-yl
trifluoromethanesulfonate
[1119] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.42 (br. s., 1H), 7.72
(s, 1H), 7.52 (s, 1H), 4.73 (d, J=12.8 Hz, 1.5H), 4.60 (d, J=12.0
Hz, 1H), 4.33 (brs, 0.5H), 4.05 (brs, 0.5H), 3.76 (br. s., 1H),
3.24-3.40 (m, 2.5H), 1.89-1.97 (m, 1H), 1.72 (br. s., 1H),
1.29-1.34 (m, 3H), 0.99-1.20 (m, 4H), 0.78-0.90 (m, 2H), 0.41-0.66
(m, 4H).
[1120] LC-MS: m/z 563.0 (M+H).sup.+
Compound 766
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-5-(5-vinylpyridazin-3-yl)nicotinonitrile
##STR00850##
[1121] Step
1(R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(5-vinylpyridazin-3--
yl)nicotinonitrile
[1122] A stirred solution of (R)-tert-butyl
4-(3-cyano-6-cyclopropyl-5-(5-vinylpyridazin-3-yl)pyridin-2-yl)-2-cyclopr-
opylpiperazine-1-carboxylate (100 mg, 0.2 mmol) in TFA (2 mL) was
stirred at room temperature overnight. When LC-MS showed completion
of the reaction, the mixture was evaporated under reduced pressure
and the residue was dissolved in DCM, washed with Sat. NaHCO3, and
brine. The organic layer was evaporated under reduced pressure to
give crude product which was used without further purification (70
mg)
Step 2. Compound 766
[1123] To a stirred 2-(oxetan-2-yl)acetic acid (20 mg) in
CH.sub.2Cl.sub.2 was added HATU (72 mg, 0.19 mmol) followed by
DIPEA, the mixture was stirred at room temperature for 1 hr, then
(R)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-yl)-5-(5-vinylpyridazin-3-y-
l)nicotinonitrile (70 mg) was added. The mixture was stirred at
room temperature overnight. It was quenched with water, extracted
with CH.sub.2Cl.sub.2. The organic layer was washed with Sat.
NaHCO3, brine and dried over Na2SO4, evaporated and purified by
prepTLC to give product.
[1124] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.23 (br. s., 1H), 7.97
(s, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H),
6.20 (d, J=17.6 Hz, 1H), 5.76 (d, J=10.9 Hz, 1H), 5.11-5.36 (m,
1H), 4.48-4.77 (m, 4H), 4.08 (d, J=8.5 Hz, 0.5H), 3.95 (d, J=13.2
Hz, 0.5H), 3.75 (d, J=11.2 Hz, 0.5H), 3.32 (br. s., 1H), 3.05-3.27
(m, 2H), 2.98 (dd, J=14.8, 6.0 Hz, 1.5H), 2.79-2.90 (m, 2H), 2.54
(d, J=7.9 Hz, 1H), 2.12-2.26 (m, 1H), 1.25 (dd, J=6.6, 3.7 Hz, 3H),
0.94-1.12 (m, 2H), 0.51-0.72 (m, 2H), 0.35-0.49 (m, 2H)
[1125] LC-MS: m/z 471.6 (M+H).sup.+
Compound 769
(R,E)-6-cyclopropyl-2-(3-cyclopropyl-4-(5-hydroxypent-2-enoyl)piperazin-1--
yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1126] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.27 (d, J=2.1 Hz, 1H),
7.43 (d, J=2.1 Hz, 1H), 6.87 (dt, J=14.8, 7.3 Hz, 1H), 6.73 (dd,
J=17.8, 11.0 Hz, 1H), 6.26-6.48 (m, 1H), 6.21 (d, J=17.6 Hz, 1H),
5.77 (d, J=10.9 Hz, 1H), 4.42 (d, J=12.9 Hz, 1H), 4.33 (d, J=12.6
Hz, 1H), 3.89-4.21 (m, 1H), 3.79 (t, J=6.0 Hz, 2H), 3.38 (br. s.,
1H), 3.23 (d, J=10.0 Hz, 1H), 3.08 (td, J=12.5, 2.9 Hz, 1H), 2.50
(q, J=6.2 Hz, 2H), 2.18-2.29 (m, 3H), 1.36-1.50 (m, 2H), 1.15 (br.
s., 2H), 0.88 (dd, J=7.6, 3.2 Hz, 2H), 0.65 (br. s., 1H), 0.51 (br.
s., 1H), 0.44 (br. s., 2H)
[1127] LC-MS: m/z 485.6 (M+H).sup.+
Compound 768
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1128] .sup.1H NMR (CHLOROFORM-d) .delta.:9.28 (d, J=2.1 Hz, 1H),
7.43 (d, J=2.1 Hz, 1H), 6.74 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d,
J=17.9 Hz, 1H), 5.71-5.86 (m, 1H), 5.27 (quin, J=6.7 Hz, 1H),
4.64-4.76 (m, 1H), 4.49-4.63 (m, 1H), 4.41 (d, J=12.6 Hz, 1H),
4.23-4.37 (m, 1H), 4.07 (d, J=8.2 Hz, 1H), 3.92 (d, J=12.6 Hz, 1H),
3.69-3.86 (m, 1H), 3.20-3.36 (m, 1H), 2.93-3.20 (m, 3H), 2.74-2.93
(m, 2H), 2.46-2.66 (m, 1H), 2.18-2.30 (m, 3H), 1.78 (br. s., 1H),
1.41-1.51 (m, 2H), 1.33-1.41 (m, 1H), 1.10-1.20 (m, 2H), 0.89 (dd,
J=7.8, 3.1 Hz, 2H), 0.58-0.72 (m, 1H), 0.53 (br. s., 1H), 0.45 (d,
J=5.6 Hz, 2H)
[1129] LC-MS: m/z 485.6 (M+H).sup.+
[1130] Compound 767
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-
-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1131] .sup.1H NMR (CHLOROFORM-d) .delta.:9.28 (s, 1H), 7.44 (d,
J=2.1 Hz, 1H), 7.28 (s, 1H), 6.74 (dd, J=17.6, 10.9 Hz, 1H), 6.21
(d, J=17.6 Hz, 1H), 5.78 (d, J=10.9 Hz, 1H), 4.37-4.47 (m, 1H),
4.26-4.36 (m, 1H), 4.01-4.13 (m, 1H), 3.83-3.98 (m, 2H), 3.65-3.83
(m, 1H), 3.13-3.29 (m, 2H), 2.98-3.13 (m, 1H), 2.46-2.68 (m, 2H),
2.19-2.29 (m, 3H), 1.84-2.10 (m, 1H), 1.42-1.55 (m, 1H), 1.15 (br.
s., 1H), 0.81-0.95 (m, 3H), 0.63 (br. s., 1H), 0.53 (br. s., 1H),
0.32-0.48 (m, 2H)
[1132] LC-MS: m/z 459.6 (M+H).sup.+
Compound 749
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-
-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile
[1133] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.21 (d, J=2.1 Hz, 1H),
7.70 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.15 (dd, J=17.8, 11.0 Hz,
1H), 6.39 (d, J=17.9 Hz, 1H), 5.81 (d, J=10.9 Hz, 1H), 4.64 (d,
J=13.2 Hz, 1H), 4.52 (d, J=12.9 Hz, 1H), 4.10 (d, J=9.7 Hz, 1H),
3.85-3.99 (m, 2H), 3.71-3.83 (m, 1H), 3.07-3.36 (m, 3H), 2.42-2.71
(m, 2H), 1.88-2.02 (m, 1H), 1.20-1.40 (m, 3H), 1.01-1.12 (m, 2H),
0.45-0.78 (m, 4H)
[1134] LC-MS: m/z 473.3 (M+H).sup.+
Compound 724
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(5-
-vinylpyridazin-3-yl)nicotinonitrile
[1135] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.22 (s, 1H), 7.93-8.03
(m, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H),
6.20 (d, J=17.6 Hz, 1H), 5.76 (d, J=10.9 Hz, 1H), 4.65 (d, J=13.2
Hz, 1H), 4.52 (d, J=12.6 Hz, 1H), 4.16 (m, 1H), 3.80-4.02 (m, 2H),
3.58-3.74 (m, 1H), 3.45 (s, 3H), 3.26 (d, J=10.3 Hz, 2H), 3.12 (t,
J=10.6 Hz, 1H), 2.11-2.32 (m, 1H), 1.23-1.30 (m, 3H), 0.98-1.08 (m,
2H), 0.41-0.72 (m, 4H)
[1136] LC-MS: m/z 445.2 (M+H).sup.+
Compound 723
(R)-tert-butyl(6-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropa-
noyl)piperazin-1-yl)pyridin-3-yl)pyridazin-4-yl)carbamate
[1137] The mixture of
((R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-
-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (67
mg, 0.157 mmol), tert-butyl (6-chloropyridazin-4-yl)carbamate (30
mg, 0.131 mmol), Pd(dppf)Cl.sub.2 (5 mg, 0.007 mmol) and CsF (40
mg, 0.216 mmol) in dioxane/H.sub.2O was stirred at 100.degree. C.
for 16 hours. The mixture was diluted with EtOAc (30 mL) and
filtered. The filtrated was partitioned between EtOAc (30 mL) and
water (10 mL), the organic layer was washed with water (10 mL),
brine and dried over Na.sub.2SO.sub.4 and concentrated to give the
crude which was purified by prep-TLC to give 20 mg of the
product.
[1138] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.08 (s, 1H), 8.29 (s,
1H), 7.98 (s, 1H), 7.60 (br. s., 1H), 4.64 (d, J=12.9 Hz, 1H), 4.52
(d, J=12.3 Hz, 1H), 4.08 (d, J=8.5 Hz, 1H), 3.93 (s, 2H), 3.66-3.84
(m, 1H), 3.25 (m, 3H), 2.50-2.61 (m, 2H), 1.56 (s, 9H), 1.21-1.28
(m, 3H), 1.07 (s, 2H), 0.41-0.80 (m, 4H)
[1139] LC-MS: m/z 534.3 (M+H).sup.+
Compound 716
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(5-vinylpyridazin-3-yl)nicotinonitrile
[1140] .sup.1H NMR (CHLOROFORM-d) .delta.9.23 (s, 1H), 7.98 (s,
1H), 7.61 (d, J=2.1 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20
(d, J=17.6 Hz, 1H), 5.71-5.84 (m, 1H), 4.64 (d, J=12.9 Hz, 1H),
4.51 (d, J=12.6 Hz, 1H), 4.01-4.16 (m, 1H), 3.92 (s, 2H), 3.65-3.83
(m, 1H), 3.05-3.25 (d, J=11.2 Hz, 2H), 2.50-2.68 (m, 2H), 2.12-2.30
(m, 1H), 1.19-1.27 (m, 3H), 1.00-1.11 (m, 2H), 0.39-0.62 (m,
1H)
[1141] LC-MS: m/z 445.2 (M+H).sup.+
Compound 715
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(6-
-vinylpyridazin-4-yl)nicotinonitrile
[1142] .sup.1H NMR (CHLOROFORM-d) .delta.9.20 (s, 1H), 7.68 (s,
1H), 7.61 (s, 1H), 7.11 (dd, J=17.8, 11.0 Hz, 1H), 6.36 (d, J=17.9
Hz, 1H), 5.77 (d, J=11.2 Hz, 1H), 4.64 (d, J=12.9 Hz, 1H), 4.50 (d,
J=12.6 Hz, 1H), 4.15 (s, 2H), 3.80-4.12 (m, 1H), 3.60-3.66 (m, 1H),
3.44 (s, 3H), 3.26 (dd, J=13.2, 3.5 Hz, 1H), 3.07-3.18 (m, 1H),
1.87-2.04 (m, 1H), 1.19-1.29 (m, 3H), 1.06 (dd, J=7.9, 2.9 Hz, 2H),
0.47-0.65 (m, 4H)
[1143] LC-MS: m/z 445.2 (M+H).sup.+
Compound 696
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1144] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.23 (d, J=2.1 Hz, 1H),
7.98 (s, 1H), 7.63 (d, J=2.1 Hz, 1H), 6.75 (dd, J=17.6, 10.9 Hz,
1H), 6.21 (d, J=17.6 Hz, 1H), 5.78 (d, J=10.9 Hz, 1H), 4.66 (d,
J=12.9 Hz, 2.5H), 3.98-4.54 (m, 1H), 3.51-3.88 (m, 1H), 3.00-3.45
(m, 1H), 2.16-2.28 (m, 1H), 1.72 (s, 1H), 1.17-1.30 (m, 3H),
0.95-1.11 (m, 4H), 0.77-0.87 (m, 2H), 0.39-0.64 (m, 1H)
[1145] LC-MS: m/z 441.2 (M+H).sup.+
Compound 686
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(6-vinylpyridazin-4-yl)nicotinonitrile
[1146] The mixture of
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)--
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (100
mg, 0.235 mmol), 5-chloro-3-vinylpyridazine (30 mg, 0.213 mmol),
Pd(dppf)Cl.sub.2 (8 mg, 0.011 mmol) and CsF (98 mg, 0.640 mmol) in
dioxane/H.sub.2O was stirred at 100.degree. C. for 16 hours. The
mixture was diluted with EtOAc (30 mL) and filtered. The filtrate
was partitioned between EtOAc (30 mL) and water (10 mL), the
organic layer was washed with water (10 mL), brine, dried over
Na.sub.2SO.sub.4 and concentrated to give the crude which was
purified by prep-TLC to give 25 mg of the product.
[1147] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.21 (d, J=2.1 Hz, 1H),
7.70 (s, 1H), 7.64 (d, J=2.1 Hz, 1H), 7.15 (dd, J=17.8, 11.0 Hz,
1H), 6.39 (d, J=17.9 Hz, 1H), 5.81 (d, J=10.9 Hz, 1H), 4.64 (d,
J=13.2 Hz, 1H), 4.52 (d, J=12.9 Hz, 1H), 4.10 (d, J=9.7 Hz, 1H),
3.87-4.01 (m, 2H), 3.71-3.87 (m, 1H), 3.07-3.36 (m, 3H), 2.46-2.70
(m, 2H), 1.81-2.03 (m, 1H), 1.20-1.34 (m, 3H), 1.03-1.13 (m, 2H),
0.60-0.69 (m, 1H), 0.46-0.57 (m, 4H)
[1148] LC-MS: m/z 445.2 (M+H).sup.+
Compound 671
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(6-hydroxypyridazin-4-yl)nicotinonitrile
[1149] .sup.1H NMR (CHLOROFORM-d) .delta.: 12.36 (br. s., 1H), 7.95
(d, J=2.0 Hz, 1H), 7.65 (s, 1H), 7.00 (d, J=2.0 Hz, 1H), 4.63 (d,
J=13.1 Hz, 1H), 4.50 (d, J=12.8 Hz, 1H), 4.01-4.19 (m, 1H),
3.89-3.98 (m, 2H), 3.60-3.85 (m, 1H), 3.01-3.29 (m, 3H), 2.60 (dd,
J=11.8, 6.0 Hz, 2H), 1.87-2.05 (m, 1H), 1.14-1.26 (m, 3H),
0.31-1.14 (m, 4H).
[1150] LC-MS: m/z 435.2 (M+H).sup.+
Compound 673
(R)-6'-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1--
yl)-[3,4'-bipyridine]-2',5-dicarbonitrile
##STR00851##
[1152] The mixture of
(R)-2',6'-dichloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)-[3,4'-bipyridine]-5-carbonitrile (40 mg, 0.084 mmol),
CuCN (15 mg, 0.169 mmol), CuI (1 mg) in NMP (2 mL) was stirred at
230.degree. C. for 2 hours. After cooling to room temperature, the
mixture was partitioned between EtOAc (30 mL) and water (10 mL),
the organic layer was washed with water (10 mL), brine and dried
over Na2SO4, concentrated to give the crude which was purified by
prep-TLC to give 20 mg of the product.
[1153] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.72 (d, J=1.0 Hz, 1H),
7.59-7.66 (m, 2H), 4.91 (s, 0.5H), 4.54 (d, J=10.3 Hz, 0.5H),
4.24-4.48 (m, 2.5H), 3.69-3.79 (m, 2H), 3.51-3.62 (m, 0.5H),
3.33-3.44 (m, 4H), 3.18-3.29 (m, 1.5H), 3.10-3.25 (m, 1.5H),
2.63-2.82 (m, 1H), 2.52-2.63 (m, 1H), 1.82-1.95 (m, 1H), 1.36 (d,
J=6.5 Hz, 1H), 1.23-1.28 (m, 4H), 1.04-1.15 (m, 2H)
[1154] LC-MS: m/z 465.2 (M+H).sup.+
Compound 672
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-6'-vin-
yl-[3,4'-bipyridine]-2',5-dicarbonitrile
##STR00852##
[1156] The mixture of
(R)-6'-chloro-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)-[3,4'-bipyridine]-2',5-dicarbonitrile (10 mg, 0.0215 mmol),
Potassium vinyltrifluoroborate (5 mg, 0.032 mmol), Pd(dppf)Cl.sub.2
(1 mg, 0.001 mmol) and CsF (10 mg, 0.064 mmol) in dioxane/H.sub.2O
was stirred at 100.degree. C. for 16 hours. The mixture was diluted
with EtOAc (30 mL) and filtered. The filtrated was partitioned
between EtOAc (30 mL) and water (10 mL), the organic layer was
washed with water (10 mL), brine and dried over Na.sub.2SO.sub.4
and concentrated to give the crude which was purified by prep-TLC
to give 5 mg of the product.
[1157] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.63 (s, 2H), 7.52-7.59
(m, 1H), 6.86 (dd, J=17.4, 10.7 Hz, 1H), 6.42 (d, J=17.6 Hz, 1H),
5.71 (d, J=10.8 Hz, 1H), 4.92 (s, 0.5H), 4.54 (d, J=9.5 Hz, 0.5H),
4.25-4.46 (m, 2.5H), 3.71-3.86 (m, 3.5H), 3.35-3.42 (m, 3.5H),
3.03-3.29 (m, 1.5H), 2.63-2.82 (m, 1H), 2.53-2.62 (m, 1H),
1.83-1.96 (m, 1H), 1.34-1.40 (m, 2H), 1.20-1.26 (m, 3H), 1.00-1.11
(m, 2H).
[1158] LC-MS: m/z 457.2 (M+H).sup.+
Compound 653
(R)-2-cyclopropyl-2'-(3-hydroxyprop-1-en-2-yl)-6-(4-(3-methoxypropanoyl)-3-
-methylpiperazin-1-yl)-[3,4'-bipyridine]-5-carbonitrile
##STR00853##
[1159] Step
1(R)-2-cyclopropyl-2'-hydroxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-
-1-yl)-[3,4'-bipyridine]-5-carbonitrile
[1160] A mixture of
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(4,-
4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (100 mg,
0.22 mmol), 4-bromopyridin-2-ol (38 mg, 0.22 mmol), CsF (66 mg,
0.44 mmol) and Pd(dppf)Cl.sub.2 (5 mg) in dioxane and water was
heated at 100.degree. C. for 0.5 hr. The reaction mixture was
concentrated and the residue was purified by pre-TLC to afford 52
mg of title compound.
[1161] LC-MS: m/z 422.1 (M+H).sup.+
Step 2
(R)-5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperaz-
in-1-yl)-[3,4'-bipyridin]-2'-yl trifluoromethanesulfonate
[1162] A solution of
(R)-2-cyclopropyl-2'-hydroxy-6-(4-(3-methoxypropanoyl)-3-methylpiperazin--
1-yl)-[3,4'-bipyridine]-5-carbonitrile (100 mg, 0.24 mmol),
Tf.sub.2O (40 mg) and TEA (1 drop) in DCM (5 ml) was stirred for 1
hr. The reaction mixture was washed with water, dried and
concentrated. The residue was purified by pre-TLC to afford 60 mg
of title compound.
[1163] LC-MS: m/z 554.1 (M+H).sup.+
Step 3
(R)-2-cyclopropyl-2'-(3-hydroxyprop-1-en-2-yl)-6-(4-(3-methoxypropa-
noyl)-3-methylpiperazin-1-yl)-[3,4'-bipyridine]-5-carbonitrile
Compound 653
[1164] A mixture of
(R)-5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)-[3,4'-bipyridin]-2'-yl trifluoromethanesulfonate (150 mg, 0.27
mmol), prop-2-en-1-ol (31 mg, 0.54 mmol), TEA (30 mg, 0.30 mmol),
Pd(OAc).sub.2(15 mg, 0.0675 mmol), and Dppf (72 mg, 0.13 mmol) in
DMF (10 mL) was heated at 100.degree. C. for 2 hrs. The reaction
mixture was diluted with DCM and washed with water and brine, dried
and concentrated and the residue was purified by prep-TLC and
prep-HPLC to afford 16 mg of title compound.
[1165] .sup.1H NMR (CHLOROFORM-d) .delta.8.62 (d, J=5.3 Hz, 1H),
7.69 (s, 1H), 7.65 (s, 1H), 7.31 (dd, J=5.0, 1.3 Hz, 1H), 5.87 (s,
1H), 5.60 (s, 1H), 4.92 (brs, 0.5H), 4.65 (s, 2H), 4.54 (d, J=12.5
Hz, 0.5H), 4.20-4.46 (m, 2.5H), 3.68-3.88 (m, 2.5H), 3.49-3.65 (m,
0.5H), 3.39 (s, 3H), 3.33 (d, J=13.3 Hz, 1H), 3.01-3.27 (m, 1.5H),
2.64-2.85 (m, 1H), 2.51-2.64 (m, 1H), 1.96-2.08 (m, 1H), 1.39 (d,
J=6.5 Hz, 1.5H), 1.25-1.36 (m, 1.5H), 1.17-1.25 (m, 2H), 0.95-1.09
(m, 2H).
[1166] LC-MS: m/z 462.1 (M+H).sup.+
Compound 765
6-cyclopropyl-2-((R)-3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-m-
ethyl-5-(2-vinylquinoxalin-5-yl)nicotinonitrile
[1167] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.00 (s, 1H), 8.09-8.21
(m, 1H), 7.80-7.91 (m, 1H), 7.53-7.66 (m, 1H), 7.00-7.13 (m, 1H),
6.51 (d, J=17.6 Hz, 1H), 5.85 (d, J=11.2 Hz, 1H), 4.71 (d, J=10.0
Hz, 0.5H), 4.47 (d, J=10.3 Hz, 0.5H), 4.40 (d, J=13.5 Hz, 1H),
4.23-4.35 (m, 1H), 3.85 (d, J=13.5 Hz, 0.5H), 3.71-3.81 (m, 2H),
3.59 (d, J=10.3 Hz, 0.5H), 3.46-3.55 (m, 0.5H), 3.40 (d, J=5.0 Hz,
3H), 3.05-3.14 (m, 2H), 3.02 (d, J=9.7 Hz, 1H), 2.55-2.83 (m, 3H),
2.28-2.44 (m, 1H), 2.15-2.28 (m, 1H), 2.04-2.10 (m, 3H), 1.02-1.12
(m, 6H), 0.84-0.95 (m, 2H), 0.72-0.81 (m, 1H), 0.59-0.70 (m,
1H)
[1168] LC-MS: m/z 525.6 (M+H).sup.+
Compound 760
2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1169] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.70 (d, J=4.4 Hz, 1H),
7.25 (s, 1H), 7.09 (d, J=3.5 Hz, 1H), 6.90 (dd, J=17.5, 10.7 Hz,
1H), 6.32 (d, J=17.3 Hz, 1H), 5.60 (d, J=10.9 Hz, 1H), 5.22-5.34
(m, 1H), 4.65-4.77 (m, 1H), 4.52-4.63 (m, 1H), 4.22-4.41 (m, 2H),
4.09 (d, J=8.2 Hz, 1H), 3.91 (br. s., 1H), 3.38 (s, 1H), 3.14 (br.
s., 1H), 2.94-3.09 (m, 2H), 2.68-2.94 (m, 3H), 2.49-2.63 (m, 1H),
2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12 (br. s., 2H), 0.88 (dd,
J=7.6, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.55 (br. s., 1H), 0.34-0.51
(m, 2H)
[1170] LC-MS: m/z 484.7 (M+H).sup.+
Compound 761
2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((S)-oxetan-2-yl)acetyl)piperazin--
1-yl)-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1171] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.70 (d, J=4.4 Hz, 1H),
7.25 (s, 1H), 7.09 (d, J=3.5 Hz, 1H), 6.90 (dd, J=17.5, 10.7 Hz,
1H), 6.32 (d, J=17.3 Hz, 1H), 5.60 (d, J=10.9 Hz, 1H), 5.22-5.34
(m, 1H), 4.65-4.77 (m, 1H), 4.52-4.63 (m, 1H), 4.22-4.41 (m, 2H),
4.09 (d, J=8.2 Hz, 1H), 3.91 (br. s., 1H), 3.38 (s, 1H), 3.14 (br.
s., 1H), 2.94-3.09 (m, 2H), 2.68-2.94 (m, 3H), 2.49-2.63 (m, 1H),
2.14-2.28 (m, 3H), 1.27 (s, 1H), 1.12 (br. s., 2H), 0.88 (dd,
J=7.6, 2.9 Hz, 2H), 0.62 (br. s., 1H), 0.55 (br. s., 1H), 0.34-0.51
(m, 2H)
[1172] LC-MS: m/z 484.7 (M+H).sup.+
Compound 664
(R)-2-cyclopropyl-6-(4-(1-hydroxycyclopropanecarbonyl)-3-methylpiperazin-1-
-yl)-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1173] .sup.1H NMR (CHLOROFORM-d) .delta.:8.64 (d, J=5.0 Hz, 1H),
7.64 (s, 1H), 7.40 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd,
J=17.6, 10.8 Hz, 1H), 6.27 (d, J=17.6 Hz, 1H), 5.57 (d, J=11.3 Hz,
1H), 4.87 (br. s., 1H), 4.50 (d, J=11.8 Hz, 1H), 4.39 (d, J=12.8
Hz, 1H), 4.32 (d, J=11.5 Hz, 1H), 3.32 (dd, J=13.1, 2.8 Hz, 1H),
3.21-3.66 (m, 2H), 1.99-2.07 (m, 1H), 1.30-1.50 (m, 3H), 1.21 (dt,
J=7.2, 3.5 Hz, 2H), 1.11-1.17 (m, 1H), 0.91-1.09 (m, 5H).
[1174] LC-MS: m/z 430.2 (M+H).sup.+
Compound 739
(R)-methyl
4-(4-(2'-chloro-5-cyano-2-cyclopropyl-3,4'-bipyridin-6-yl)-2-cy-
clopropylpiperazin-1-yl)-4-oxobutanoate
[1175] .sup.1H NMR (CHLOROFORM-d) .delta.:8.48 (d, J=5.0 Hz, 1H),
7.63 (s, 1H), 7.41 (s, 1H), 7.30 (d, J=4.4 Hz, 1H), 4.59 (d, J=12.3
Hz, 1H), 4.46 (d, J=12.0 Hz, 1H), 4.06 (br. s., 1H), 3.81-3.94 (m,
1H), 3.72 (s, 3H), 3.06-3.36 (m, 1.5H), 2.84 (br. s., 1.5H), 2.71
(d, J=7.9 Hz, 3H), 2.50-2.66 (m, 1H), 1.91-2.07 (m, 1H), 1.33 (br.
s., 1H), 1.27 (br. s., 1H), 1.14-1.25 (m, 2H), 1.05 (dd, J=7.5, 3.4
Hz, 2H), 0.61 (br. s., 1H), 0.54 (br. s., 1H), 0.45 (d, J=4.1 Hz,
2H).
[1176] LC-MS: m/z 494.2 (M+H).sup.+
Compound 738
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-hydroxyacetyl)piperazin-1-yl)-2'-v-
inyl-3,4'-bipyridine-5-carbonitrile
[1177] .sup.1H NMR (CHLOROFORM-d) .delta.:8.55-8.78 (m, 1H), 7.66
(s, 1H), 7.39 (br. s., 1H), 7.17-7.26 (m, 1H), 6.88 (dd, J=17.3,
10.9 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H),
4.56 (d, J=12.9 Hz, 1H), 4.43 (d, J=12.9 Hz, 1H), 4.22 (br. s.,
1H), 4.18 (br. s., 1H), 4.01 (br. s., 0.5H), 3.68 (br. s., 1.5H),
3.34-3.53 (m, 1H), 3.24 (d, J=10.9 Hz, 1H), 3.09 (t, J=11.3 Hz,
1H), 2.00-2.07 (m, 1H), 1.32 (br. s., 1H), 1.27 (br. s., 1H), 1.21
(br. s., 2H), 1.02 (br. s., 2H), 0.66 (br. s., 1H), 0.57 (br. s.,
1H), 0.48 (br. s., 1H).
[1178] LC-MS: m/z 430.2 (M+H).sup.+
Compound 747
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(4-methoxybutanoyl)piperazin-1-yl)-2'-
-vinyl-3,4'-bipyridine-5-carbonitrile
[1179] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.67 (d, J=4.7 Hz, 1H),
7.66 (s, 1H), 7.46 (br. s., 1H), 7.31 (br. s., 1H), 6.95 (dd,
J=17.3, 10.9 Hz, 1H), 6.38 (d, J=17.3 Hz, 1H), 5.66 (d, J=10.6 Hz,
1H), 4.58 (d, J=12.9 Hz, 1H), 4.46 (d, J=12.3 Hz, 1H), 3.70-4.12
(br. s., 2H), 3.46 (br. s., 2H), 3.36 (s, 3H), 3.23 (br. s., 1H),
3.11 (br. s., 1H), 2.49 (br. s., 2H), 1.89-2.14 (m, 4H), 1.27-1.31
(m, 1H), 1.18-1.25 (m, 2H), 1.00-1.08 (m, 2H), 0.59 (d, J=15.6 Hz,
2H), 0.47 (d, J=5.0 Hz, 2H).
[1180] LC-MS: m/z 472.5 (M+H).sup.+
Compound 753
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(4-hydroxybutanoyl)piperazin-1-yl)-2'-
-vinyl-3,4'-bipyridine-5-carbonitrile
[1181] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.64 (d, J=5.0 Hz, 1H),
7.64 (s, 1H), 7.39 (s, 1H), 7.18-7.27 (m, 1H), 6.87 (dd, J=17.3,
10.9 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H),
4.55 (d, J=12.9 Hz, 1H), 4.42 (d, J=12.6 Hz, 1H), 4.09 (d, J=7.9
Hz, 0.5H), 3.86 (d, J=13.2 Hz, 0.5H), 3.73 (br. s., 2H), 3.05-3.32
(m, 2H), 2.97 (s, 1H), 2.89 (s, 1H), 2.57 (br. s., 3H), 2.00-2.08
(m, 1H), 1.91-1.98 (m, 2H), 1.28 (d, J=17.3 Hz, 1H), 1.21 (br. s.,
2H), 1.01 (dd, J=7.6, 3.2 Hz, 2H), 0.61 (br. s., 1H), 0.54 (br. s.,
1H), 0.30-0.50 (m, 2H).
[1182] LC-MS: m/z 458.6 (M+H).sup.+
Compound 726
(R)-2-cyclopropyl-6-(3-isopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-2'-vin-
yl-3,4'-bipyridine-5-carbonitrile
[1183] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.64 (d, J=5.0 Hz, 1H),
7.58-7.66 (m, 1H), 7.37 (s, 1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.87
(dd, J=17.5, 10.7 Hz, 1H), 6.21-6.33 (m, 1H), 5.50-5.60 (m, 1H),
4.54-4.71 (m, 1H), 4.33-4.49 (m, 1.5H), 4.02-4.22 (m, 2H), 3.87 (d,
J=13.8 Hz, 0.5H), 3.33-3.50 (m, 4H), 3.03-3.23 (m, 2.5H), 2.21 (d,
J=7.6 Hz, 0.5H), 1.96-2.16 (m, 2H), 1.11-1.24 (m, 2H), 0.94-1.11
(m, 5H), 0.84-0.92 (m, 3H).
[1184] LC-MS: m/z 446.1 (M+H).sup.+
Compound 721
(R)-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-2'--
vinyl-3,4'-bipyridine-5-carbonitrile
[1185] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.66 (d, J=5.0 Hz, 1H),
7.64 (d, J=2.3 Hz, 1H), 7.40 (s, 1H), 7.25 (dd, J=5.1, 1.6 Hz, 1H),
6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.23-6.35 (m, 1H), 5.55-5.63 (m,
1H), 4.58-4.74 (m, 1.5H), 4.38-4.50 (m, 1.5H), 3.87-4.00 (m, 2H),
3.78 (d, J=13.8 Hz, 1H), 3.39-3.55 (m, 1H), 3.05-3.24 (m, 2H),
2.56-2.66 (m, 2H), 2.20-2.30 (m, 1H), 1.98-2.06 (m, 2H), 1.25-1.33
(m, 6H), 0.84-0.95 (m, 4H)
[1186] LC-MS: m/z 446.1 (M+H).sup.+
Compound 719
(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3--
hydroxypropanoyl)piperazin-1-yl)nicotinonitrile
##STR00854##
[1187] Step
1(R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4--
(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile
##STR00855##
[1189] To a solution of 4,6-dichloropyrimidin-2-amine (270 mg, 0.58
mmol) in a mixture of dimethoxyethane (5 mL) and a 2M aqueous
sodium carbonate solution (0.8 mL) were added
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)--
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (100
mg, 0.22 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg,
0.1 eq) under nitrogen atmosphere, and the mixture was heated for 2
hours at 100.degree. C. After cooling to ambient temperature, the
separated organic layer was evaporated under reduced pressure. The
residue was taken up into ethyl acetate, washed in turn with a 10%
aqueous potassium carbonate solution and brine, and dried over
sodium sulfate. After evaporation, the residue was chromatographed
on silica gel eluding with 5%-20% ethyl acetate in petroleum ether
to give
(R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(-
3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (140 mg
crude).
[1190] LC-MS: m/z 468.2 (M+H).sup.+
Step 2: Compound 719
(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3--
hydroxypropanoyl)piperazin-1-yl)nicotinonitrile
[1191] A mixture of above
(R)-5-(2-amino-6-chloropyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(-
3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (60 mg, 0.13
mmol), potassium vinylfluoborate (25 mg, 0.2 mmol),
Pd(PPh.sub.3).sub.4 (3 mg, 0.1 eq), and CsF (40 mg, 0.26 mmol) were
suspended in 5 mL of dioxane and 1 mL of water, the resulting
mixture was refluxed for 1 h. After the reaction was complete, the
reaction mixture was concentrated in vacuo, and the residue was
purified by column chromatography to afford 40 mg of title compound
as yellow solid. (70% yield)
[1192] LC-MS: m/z 460.2 (M+H).sup.+
[1193] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.92 (s, 1H), 6.87 (s,
1H), 6.65 (dd, J=17.3, 10.6 Hz, 1H), 6.39 (d, J=17.5 Hz, 1H), 5.69
(d, J=10.7 Hz, 1H), 5.44 (br. s., 2H), 4.61 (d, J=13.2 Hz, 1H),
4.48 (d, J=12.1 Hz, 1H), 4.07 (d, J=7.5 Hz, 1H), 3.87-3.98 (m, 2H),
3.63-3.84 (m, 2H), 3.17-3.31 (m, 2H), 3.00-3.17 (m, 1H), 2.50-2.66
(m, 2H), 2.30-2.45 (m, 1H), 1.17-1.28 (m, 3H), 0.97-1.13 (m, 2H),
0.61 (br. s., 1H), 0.54 (br. s., 1H), 0.46 (br. s., 2H).
[1194] LC-MS: m/z 460.2 (M+H).sup.+
Compound 663
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(6-vinylpyrimidin-4-yl)nicotinonitrile
[1195] .sup.1H NMR (CHLOROFORM-d) .delta.:9.19-9.32 (m, 1H), 8.01
(s, 1H), 7.46-7.59 (m, 1H), 6.82 (dd, J=17.3, 10.8 Hz, 1H),
6.51-6.63 (m, 1H), 5.80 (d, J=11.3 Hz, 1H), 5.32 (s, 1H), 4.66 (d,
J=13.1 Hz, 1H), 4.53 (d, J=12.8 Hz, 1H), 4.08 (d, J=9.8 Hz, 1H),
3.88-3.97 (m, 2H), 3.67-3.82 (m, 2H), 3.32 (br. s., 1H), 3.20-3.29
(m, 2H), 3.02-3.20 (m, 2H), 2.49-2.66 (m, 2H), 2.34-2.45 (m, 1H),
1.22-1.29 (m, 3H), 1.02-1.10 (m, 2H), 0.63 (d, J=7.8 Hz, 1H), 0.55
(br. s., 1H), 0.47 (br. s., 2H).
[1196] LC-MS: m/z 445.2 (M+H).sup.+
Compound 701
(R)-5-(2-amino-6-(2-aminoethyl)pyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-
-3-cyclopropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile
[1197] .sup.1H NMR (CHLOROFORM-d) .delta. 7.97-8.12 (m, 1H), 7.51
(br. s., 1H), 6.21 (br. s., 2H), 4.71 (d, J=12.8 Hz, 1H), 4.57 (d,
J=11.0 Hz, 1H), 4.06 (s, 1H), 3.52 (br. s., 3H), 3.31 (br. s., 3H),
3.22 (br. s., 2H), 2.38 (br. s., 1H), 1.71 (br. s., 1H), 1.19-1.28
(m, 3H), 0.96-1.14 (m, 4H), 0.75-0.87 (m, 2H), 0.62 (br. s., 1H),
0.51 (br. s., 2H), 0.38-0.48 (m, 1H).
[1198] LC-MS: m/z 473.3 (M+H).sup.+
Compound 759
(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-6-cyclopropyl-2-(3-cyclopropyl-4-(2--
methoxyacetyl)piperazin-1-yl)nicotinonitrile
[1199] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.95 (s, 1H), 6.88 (s,
1H), 6.66 (dd, J=17.5, 10.7 Hz, 1H), 6.47 (d, J=17.6 Hz, 1H), 5.71
(d, J=11.2 Hz, 1H), 5.27 (br. s., 2H), 4.64 (d, J=13.2 Hz, 2H),
4.50 (d, J=12.6 Hz, 2H), 4.16 (br. s., 3H), 4.01 (br. s., 1H), 3.90
(br. s., 1H), 3.65 (d, J=17.0 Hz, 1H), 3.46 (s, 3H), 3.18-3.32 (m,
2H), 3.02-3.18 (m, 1H), 2.32-2.47 (m, 1H), 1.18-1.32 (m, 3H),
1.00-1.11 (m, 2H), 0.63 (br. s., 2H), 0.46 (br. s., 2H)
[1200] LC-MS: m/z 460.2 (M+H).sup.+
Compound 727
(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclo-
propyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile
[1201] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.51 (br. s., 1H), 6.66
(dd, J=16.7, 10.6 Hz, 1H), 6.35 (d, J=16.7 Hz, 1H), 5.88 (br. s.,
1H), 5.66-5.83 (m, 1H), 4.44 (d, J=12.6 Hz, 1H), 4.25-4.38 (m, 2H),
4.19 (br. s., 1H), 3.98-4.10 (m, 1H), 3.91 (br. s., 2H), 3.84 (br.
s., 1H), 3.60-3.79 (m, 3H), 3.08-3.25 (m, 2H), 2.89-3.08 (m, 1H),
2.47-2.65 (m, 2H), 2.40 (br. s., 2H), 2.01-2.08 (m, 1H), 1.27 (br.
s., 1H), 1.14 (br. s., 2H), 0.98-1.10 (m, 2H), 0.62 (br. s., 1H),
0.53 (br. s., 1H), 6.34-0.50 (m, 2H).
[1202] LC-MS: m/z 476.6 (M+H).sup.+
Compound 728
(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclo-
propyl-4-(2-methoxyacetyl)piperazin-1-yl)nicotinonitrile
[1203] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.44-7.56 (m, 1H),
6.49-6.74 (m, 1H), 6.35 (d, J=16.7 Hz, 1H), 5.88 (br. s., 1H),
5.67-5.82 (m, 1H), 4.46 (d, J=12.9 Hz, 1H), 4.25-4.39 (m, 2H),
4.07-4.23 (m, 3H), 3.98 (d, J=8.5 Hz, 1H), 3.84 (t, J=5.1 Hz, 1H),
3.73 (t, J=5.4 Hz, 1H), 3.45 (s, 3H), 3.10-3.21 (m, 1H), 3.02 (t,
J=11.9 Hz, 1H), 2.39 (br. s., 2H), 2.00-2.16 (m, 1H), 1.69 (br. s.,
1H), 1.30-1.37 (m, 1H), 1.14 (br. s., 2H), 0.97-1.09 (m, 2H), 0.64
(br. s., 1H), 0.51 (br. s., 1H), 0.45 (br. s., 1H).
[1204] LC-MS: m/z 476.6 (M+H).sup.+
Compound 680
(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(4-(3-me-
thoxypropanoyl)-3-methylpiperazin-1-yl)-4-methylnicotinonitrile
[1205] .sup.1H NMR (CHLOROFORM-d) .delta.: 6.65 (d, J=10.0 Hz, 1H),
6.36 (d, J=16.8 Hz, 1H), 5.65-5.84 (m, 2H), 4.90 (br. s., 0.5H),
4.52 (d, J=13.1 Hz, 0.5H), 4.25-4.38 (m, 0.5H), 4.01-4.25 (m, 4H),
3.87-4.01 (m, 1H), 3.67-3.86 (m, 4H), 3.39 (s, 3H), 3.09-3.22 (m,
1H), 2.95-3.09 (m, 1H), 2.54-2.71 (m, 2H), 2.36-2.48 (m, 5H), 2.03
(br. s., 1H), 1.20-1.35 (m, 4H), 0.84-1.08 (m, 4H).
[1206] LC-MS: m/z 478.6 (M+H).sup.+
Compound 745
(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclo-
propyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-methylnicotinonitrile
[1207] .sup.1H NMR (CHLOROFORM-d) .delta.: 6.67 (dd, J=16.3, 10.4
Hz, 1H), 6.36 (d, J=16.1 Hz, 1H), 5.65-5.85 (m, 2H), 4.13-4.34 (m,
3H), 4.03-4.11 (m, 1H), 3.95 (d, J=18.8 Hz, 1H), 3.78-3.89 (m, 1H),
3.62-3.78 (m, 4H), 3.38 (s, 3H), 3.27 (br. s., 1H), 3.10 (br. s.,
1H), 2.98 (br. s., 1H), 2.36-2.47 (m, 5H), 1.96-2.08 (m, 1H),
1.23-1.39 (m, 3H), 0.81-1.07 (m, 4H), 0.60 (br. s., 1H), 0.52 (br.
s., 1H), 0.43 (br. s., 2H).
[1208] LC-MS: m/z 504.6 (M+H).sup.+
Compound 755
(R)-5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-(3-cyclo-
propyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-methylnicotinonitrile
##STR00856##
[1210] .sup.1H NMR (CHLOROFORM-d) .delta.: 6.67 (dd, J=16.7, 10.9
Hz, 1H), 6.36 (d, J=16.7 Hz, 1H), 5.64-5.85 (m, 1H), 4.10-4.38 (m,
3H), 4.04 (br. s., 1H), 3.98 (br. s., 1H), 3.91 (br. s., 2H),
3.61-3.83 (m, 3H), 3.04-3.34 (m, 2H), 2.59 (br. s., 1H), 2.52 (d,
J=10.3 Hz, 1H), 2.37-2.48 (m, 5H), 2.06 (br. s., 1H), 1.34-1.50 (m,
1H), 1.16 (br. s., 1H), 0.93-1.10 (m, 3H), 0.62 (br. s., 1H),
0.27-0.56 (m, 3H)
[1211] LC-MS: m/z 490.6 (M+H).sup.+
Compound 762
(R)-1'-acryloyl-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-isopropylpiperaz-
in-1-yl)-4-methyl-1',2',5',6'-tetrahydro-[3,3'-bipyridine]-5-carbonitrile
[1212] .sup.1H NMR (CHLOROFORM-d) .delta.: 6.36 (d, J=16.7 Hz, 1H),
5.68-5.98 (m, 2H), 4.33 (d, J=11.7 Hz, 1H), 4.22 (d, J=13.2 Hz,
2H), 4.04 (br. s., 1H), 3.92 (t, J=5.0 Hz, 3H), 3.64-3.78 (m, 2H),
3.47 (d, J=7.9 Hz, 1H), 2.96-3.09 (m, 2H), 2.52-2.65 (m, 2H),
2.38-2.48 (m, 5H), 2.04 (br. s., 2H), 0.95-1.07 (m, 6H), 0.83-0.95
(m, 4H)
[1213] LC-MS: m/z 492.6 (M+H).sup.+
Compound 649
2-cyclopropyl-6-((3R)-3-methyl-4-(2-(oxetan-2-yl)acetyl)piperazin-1-yl)-2'-
-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1214] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.60 (m, 1H), 7.64 (s,
1H), 7.37 (s, 1H), 7.19-7.27 (m, 1H), 6.88 (dd, J=17.4, 10.9 Hz,
1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=11.0 Hz, 1H), 5.17-5.42
(m, 1H), 4.89 (m, 0.5H), 4.73 (q, J=7.0 Hz, 1H), 4.46-4.62 (m,
1.5H), 4.34 (m, 2H), 4.28 (d, J=13.3 Hz, 0.5H), 3.85 (t, J=13.3 Hz,
0.5H), 3.50-3.67 (m, 0.5H), 3.21-3.32 (m, 1H), 2.99-3.20 (m, 1.5H),
2.76-2.94 (m, 3H), 2.46-2.60 (m, 1H), 1.87-2.09 (m, 1H), 1.24-1.32
(m, 3H), 1.14-1.23 (m, 2H), 0.93-1.10 (m, 3H).
[1215] LC-MS: m/z 444.0 (M+H).sup.+
Compound 648
2-cyclopropyl-6-((R)-3-methyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-
-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1216] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.65 (d, J=5.0 Hz, 1H),
7.63 (s, 1H), 7.38 (s, 1H), 7.13-7.27 (m, 1H), 6.88 (dd, J=17.4,
10.9 Hz, 1H), 6.13-6.40 (m, 1H), 5.56 (d, J=11.5 Hz, 1H), 5.18-5.34
(m, 1H), 4.81-5.03 (m, 0.5H), 4.65-4.79 (m, 1H), 4.48-4.65 (m,
1.5H), 4.30-4.42 (m, 2H), 4.26 (d, J=12.8 Hz, 0.5H), 3.86 (d,
J=13.3 Hz, 0.5H), 3.49-3.66 (m, 0.5H), 3.23-3.40 (m, 1H), 3.01-3.20
(m, 1.5H), 2.71-3.01 (m, 3H), 2.37-2.64 (m, 1H), 1.90-2.10 (m, 1H),
1.24-1.34 (m, 3H), 1.13-1.24 (m, 2H), 0.93-1.09 (m, 2H)
[1217] LC-MS: m/z 444.0 (M+H).sup.+
Compound 654
(R)-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1218] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.70 (d, J=4.8 Hz, 1H),
7.23 (s, 1H), 7.07 (d, J=4.8 Hz, 1H), 6.88 (dd, J=17.4, 10.9 Hz,
1H), 6.30 (d, J=17.3 Hz, 1H), 5.58 (d, J=11.3 Hz, 1H), 4.90 (br.
s., 0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.07-4.26 (m, 2.5H), 3.93
(br. s., 2H), 3.66-3.79 (m, 0.5H), 3.58 (t, J=11.0 Hz, 0.5H), 3.46
(br. s., 1H), 3.13-3.29 (m, 1.5H), 2.95-3.13 (m, 1H), 2.47-2.75 (m,
2H), 2.22 (s, 3H), 1.74 (br. s., 1H), 1.50-1.63 (m, 1H), 1.37-1.46
(m, 1.5H), 1.33 (d, J=6.8 Hz, 1.5H), 1.01-1.14 (m, 2H), 0.79-0.95
(m, 2H).
[1219] LC-MS: m/z 431.5 (M+H).sup.+
Compound 655
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinyl-1,8-naphthyridin-4-yl)nicotinonitrile
[1220] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.94-8.05 (m, 1H), 7.69
(d, J=1.3 Hz, 1H), 7.60 (d, J=3.5 Hz, 1H), 7.43-7.48 (m, 1H), 7.14
(dd, J=17.6, 10.8 Hz, 1H), 6.55 (dd, J=17.6, 1.8 Hz, 1H), 5.81 (d,
J=11.0 Hz, 1H), 4.60 (d, J=13.1 Hz, 1.5H), 4.48 (d, J=13.1 Hz, 1H),
4.13 (d, J=6.0 Hz, 0.5H), 3.86-3.99 (m, 2H), 3.82 (br. s., 1.5H),
3.28 (br. s., 1.5H), 3.15 (dd, J=15.7, 8.2 Hz, 2H), 2.56-2.68 (m,
2H), 1.13-1.23 (m, 2H), 0.80-0.97 (m, 3H), 0.68 (br. s., 1H), 0.59
(br. s., 1H), 0.51 (br. s., 2H).
[1221] LC-MS: m/z 495.1 (M+H).sup.+
Compound 650
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(-
2-vinylquinazolin-5-yl)nicotinonitrile
[1222] .sup.1H NMR (CHLOROFORM-d) .delta.9.20 (d, J=11.0 Hz, 1H),
8.14 (d, J=8.5 Hz, 1H), 7.96-8.04 (m, 1H), 7.68 (dd, J=4.4, 2.9 Hz,
1H), 7.49-7.59 (m, 1H), 7.06-7.23 (m, 1H), 6.86 (d, J=17.1 Hz, 1H),
5.94 (d, J=10.5 Hz, 1H), 4.62-4.80 (m, 1.5H), 4.43-4.54 (m, 1.5H),
3.87-4.03 (m, 2H), 3.73-3.86 (m, 1H), 2.91-3.31 (m, 3H), 2.54-2.67
(m, 2H), 2.09-2.25 (m, 1H), 1.54 (td, J=8.0, 4.1 Hz, 1H), 1.11 (dd,
J=13.7, 6.4 Hz, 4H), 0.79-0.94 (m, 6H).
[1223] LC-MS: m/z 497.3 (M+H).sup.+
Compound 652
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inylquinazolin-5-yl)nicotinonitrile
[1224] .sup.1H NMR (CHLOROFORM-d) .delta.9.17 (d, J=3.3 Hz, 1H),
8.08 (d, J=8.5 Hz, 1H), 7.97 (dd, J=8.4, 7.2 Hz, 1H), 7.68 (s, 1H),
7.52 (d, J=7.0 Hz, 1H), 7.08 (dd, J=17.3, 10.5 Hz, 1H), 6.74-6.90
(m, 1H), 5.89 (dd, J=10.5, 1.5 Hz, 1H), 4.93 (br. s., 0.5H), 4.57
(d, J=12.5 Hz, 0.5H), 4.28-4.47 (m, 2H), 4.21 (br. s., 0.5H), 3.94
(s, 2H), 3.71-3.84 (m, 0.5H), 3.50-3.68 (m, 0.5H), 3.29-3.44 (m,
1H), 3.06-3.26 (m, 2H), 2.49-2.78 (m, 2H), 1.50-1.62 (m, 1H), 1.45
(t, J=7.2 Hz, 1H), 1.35 (t, J=6.4 Hz, 2H), 1.14-1.22 (m, 2H),
0.83-0.98 (m, 2H)
[1225] LC-MS: m/z 469.2 (M+H).sup.+
Compound 651
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinazolin-5-yl)nicotinonitrile
[1226] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.08 (d, J=8.3 Hz, 1H),
7.97 (td, J=7.8, 1.3 Hz, 1H), 7.69 (d, J=1.5 Hz, 1H), 7.47-7.56 (m,
1H), 7.09 (dd, J=17.1, 10.5 Hz, 1H), 6.82 (d, J=17.1 Hz, 1H), 5.90
(dd, J=10.7, 1.6 Hz, 1H), 4.61 (dd, J=13.1, 7.3 Hz, 1H), 4.41-4.55
(m, 1H), 4.12 (d, J=6.5 Hz, 1H), 3.94 (s, 2H), 3.67-3.82 (m, 1H),
3.10-3.40 (m, 3H), 2.49-2.68 (m, 2H), 1.56 (td, J=8.1, 4.1 Hz, 1H),
1.32-1.41 (m, 1H), 1.14-1.24 (m, 2H), 0.84-0.95 (m, 2H), 0.51-0.69
(m, 4H)
[1227] LC-MS: m/z 495.2 (M+H).sup.+
Compound 657
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinoxalin-5-yl)nicotinonitrile
[1228] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.00 (s, 1H), 8.08-8.18
(m, 1H), 7.79-7.90 (m, 1H), 7.65-7.76 (m, 2H), 7.07 (dd, J=17.8,
11.0 Hz, 1H), 6.51 (d, J=17.6 Hz, 1H), 5.84 (d, J=11.0 Hz, 1H),
4.51 (d, J=13.1 Hz, 1H), 4.40 (d, J=12.8 Hz, 1H), 4.13 (q, J=7.0
Hz, 1.5H), 3.86-3.99 (m, 2.5H), 3.76 (d, J=19.8 Hz, 2H), 3.37 (d,
J=7.8 Hz, 1H), 3.22-3.33 (m, 1H), 3.17 (d, J=12.3 Hz, 1H), 3.09
(br. s., 1H), 2.55-2.69 (m, 2H), 1.58-1.69 (m, 1H), 1.17-1.37 (m,
3H), 1.08 (br. s., 2H), 0.83 (br. s., 2H), 0.66 (br. s., 1H), 0.55
(br. s., 1H), 0.48 (d, J=5.8 Hz, 3H).
[1229] LC-MS: m/z 495.1 (M+H).sup.+
Compound 740
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(6-vinyl-1H-pyrrolo[2,3-b]pyridin-4-yl)nicotinonitrile
[1230] .sup.1H NMR (CHLOROFORM-d) .delta.: 10.15 (br. s., 1H),
7.69-7.87 (m, 1H), 7.36-7.45 (m, 1H), 7.23 (s, 1H), 6.97 (dd,
J=17.3, 11.2 Hz, 1H), 6.43 (d, J=3.2 Hz, 1H), 6.28 (d, J=17.3 Hz,
1H), 5.56 (d, J=10.9 Hz, 1H), 4.58 (d, J=12.9 Hz, 1H), 4.45 (d,
J=12.6 Hz, 1H), 4.12 (d, J=8.5 Hz, 1H), 3.94 (br. s., 2H),
3.63-3.87 (m, 2H), 3.13-3.27 (m, 2H), 2.54-2.69 (m, 2H), 1.95-2.02
(m, 1H), 1.54-1.74 (m, 1H), 1.22 (br. s., 2H), 0.97 (dd, J=7.6, 3.5
Hz, 2H), 0.67 (br. s., 1H), 0.57 (br. s., 1H), 0.50 (br. s.,
2H)
[1231] LC-MS: m/z 483.6 (M+H).sup.+
Compound 735
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinyl-1,7-naphthyridin-5-yl)nicotinonitrile
[1232] .sup.1H NMR (CHLOROFORM-d) .delta.9.53 (s, 1H), 8.54 (d,
J=3.2 Hz, 1H), 7.88-8.00 (m, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.69 (s,
1H), 7.09 (dd, J=17.8, 11.0 Hz, 1H), 6.41 (d, J=17.6 Hz, 1H), 5.81
(d, J=11.2 Hz, 1H), 4.59 (d, J=13.2 Hz, 1H), 4.47 (d, J=12.6 Hz,
1H), 4.1-4.2 (m, 0.5H), 3.93 (br. s., 2H), 3.82 (m, 1.5H), 3.44 (m,
1H), 3.05-3.35 (m, 3H), 2.54-2.70 (m, 2H), 1.47-1.64 (m, 2H),
1.13-1.23 (m, 2H), 0.90-0.96 (m, 2H), 0.68 (br. s., 1H), 0.58 (br.
s., 1H), 0.51 (br. s., 2H)
[1233] LC-MS: m/z 495.2 (M+H).sup.+
Compound 744
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(1-methyl-6-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yl)nicotinonitrile
[1234] .sup.1H NMR (CHLOROFORM-d) .delta.7.90 (s, 1H), 7.77 (s,
1H), 7.21 (s, 1H), 6.99 (dd, J=17.5, 10.7 Hz, 1H), 6.41 (d, J=17.3
Hz, 1H), 5.58-5.73 (m, 1H), 4.60 (d, J=13.2 Hz, 1H), 4.48 (d,
J=12.6 Hz, 1H), 4.20 (s, 3H), 4.11 (d, J=8.8 Hz, 1H), 3.93 (br. s.,
2H), 3.65-3.85 (m, 1H), 3.44 (br. s., 1H), 3.18-3.36 (m, 2H), 3.13
(d, J=10.0 Hz, 1H), 2.46-2.70 (m, 2H), 1.88-2.01 (m, 1H), 1.31-1.42
(m, 1H), 1.24 (dt, J=7.0, 3.5 Hz, 2H), 0.93-1.04 (m, 2H), 0.66 (br.
s., 1H), 0.57 (br. s., 1H), 0.32-0.53 (m, 2H)
[1235] LC-MS: m/z 498.2 (M+H).sup.+
Compound 670
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinazolin-4-yl)nicotinonitrile
[1236] .sup.1H NMR (CHLOROFORM-d) .delta. 8.09 (d, J=8.3 Hz, 1H),
7.86-7.97 (m, 2H), 7.82 (d, J=8.0 Hz, 1H), 7.58 (td, J=7.7, 1.0 Hz,
1H), 7.09 (dd, J=17.2, 10.4 Hz, 1H), 6.82 (dd, J=17.3, 1.8 Hz, 1H),
5.76-5.93 (m, 1H), 4.65 (d, J=13.1 Hz, 1H), 4.52 (d, J=12.8 Hz,
1H), 4.11 (d, J=9.3 Hz, 0.5H), 3.93 (br. s., 2H), 3.7-3.85 (m,
1.5H), 3.48 (br. s., 1H), 3.26 (d, J=13.1 Hz, 2H), 3.17 (m, 1H),
2.52-2.68 (m, 2H), 1.88 (br. s., 1H), 1.66-1.80 (m, 1H), 0.81-0.99
(m, 4H), 0.62-0.79 (m, 1H), 0.57 (br. s., 1H), 0.50 (d, J=5.8 Hz,
2H)
[1237] LC-MS: m/z 495.2 (M+H).sup.+
Compound 669
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-vinylquinazolin-4-yl)nicotinonitrile
[1238] .sup.1H NMR (CHLOROFORM-d) .delta.8.08 (d, J=8.5 Hz, 1H),
7.87-7.97 (m, 2H), 7.83 (d, J=8.3 Hz, 1H), 7.54-7.66 (m, 1H), 7.08
(dd, J=17.2, 10.4 Hz, 1H), 6.74-6.90 (m, 1H), 5.78-5.94 (m, 1H),
4.66 (d, J=11.3 Hz, 1H), 4.46-4.62 (m, 1H), 4.15-4.35 (m, 1H),
3.53-3.77 (m, 1H), 3.48 (d, J=4.5 Hz, 1H), 3.30 (m, 1H), 3.19 (m,
1H), 1.60-1.83 (m, 2H), 1.43 (br. s., 1H), 1.16-1.29 (m, 2H), 1.04
(d, J=18.8 Hz, 2H), 0.77-0.97 (m, 4H), 0.59-0.77 (m, 1H), 0.37-0.59
(m, 3H)
[1239] LC-MS: m/z 491.2 (M+H).sup.+
Compound 720
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinylquinolin-7-yl)nicotinonitrile
[1240] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.15-8.23 (m, 1H),
8.08-8.15 (m, 1H), 7.88 (d, J=8.3 Hz, 1H), 7.72-7.79 (m, 1H), 7.66
(d, J=8.6 Hz, 1H), 7.56 (dd, J=8.1, 1.6 Hz, 1H), 7.07 (dd, J=17.6,
10.9 Hz, 1H), 6.34 (d, J=17.7 Hz, 1H), 5.73 (d, J=11.0 Hz, 1H),
4.69 (d, J=9.4 Hz, 0.5H), 4.54 (d, J=13.2 Hz, 1H), 4.42 (d, J=12.6
Hz, 1H), 4.10 (d, J=8.3 Hz, 0.5H), 3.93 (br. s., 2H), 3.69-3.86 (m,
1H), 3.16-3.36 (m, 2H), 2.99-3.16 (m, 1H), 2.48-2.69 (m, 2H),
2.11-2.20 (m, 1H), 1.16-1.31 (m, 3H), 0.93-1.05 (m, 2H), 0.66 (br.
s., 1H), 0.56 (br. s., 1H), 0.39-0.52 (m, 2H)
[1241] LC-MS: m/z 494.9 (M+H).sup.+
Compound 709
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-vinylquinolin-7-yl)nicotinonitrile (Exemplified by procedure
COMPOUND 720)
[1242] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.17 (d, J=8.5 Hz, 1H),
8.11 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.74 (s, 1H), 7.65 (d, J=8.5
Hz, 1H), 7.56 (dd, J=8.3, 1.5 Hz, 1H), 7.06 (dd, J=17.7, 10.9 Hz,
1H), 6.33 (d, J=17.8 Hz, 1H), 5.71 (d, J=10.8 Hz, 1H), 4.56 (d,
J=12.8 Hz, 1H), 4.43 (d, J=12.3 Hz, 1H), 4.09 (m, 1H), 3.72 (m,
1H), 3.29 (br. s., 2H), 3.12 (br. s., 1H), 2.10-2.20 (m, 1H), 1.73
(br. s., 1H), 1.44 (br. s., 1H), 1.18-1.25 (m, 2H), 1.06 (t, J=4.4
Hz, 1H), 0.94-1.04 (m, 3H), 0.81 (dd, J=7.8, 2.3 Hz, 2H), 0.67 (br.
s., 1H), 0.41-0.58 (m, 3H).
[1243] LC-MS: m/z 490.9 (M+H).sup.+
Compound 746
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-
-methyl-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile
[1244] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.58 (br. s., 1H), 8.57
(br. s., 1H), 7.67 (d, J=7.3 Hz, 1H), 7.21-7.34 (m, 2H), 7.10 (dd,
J=17.6, 10.9 Hz, 1H), 6.42 (dd, J=17.6, 2.6 Hz, 1H), 5.82 (d,
J=10.9 Hz, 1H), 4.38-4.49 (m, 1H), 4.34 (d, J=12.6 Hz, 1H), 4.14
(d, J=7.0 Hz, 1H), 3.89 (br. s., 1H), 3.69-3.82 (m, 2H), 3.40 (s,
3H), 3.23 (d, J=13.8 Hz, 2H), 3.02-3.17 (m, 1H), 2.72 (br. s., 1H),
2.67 (br. s., 1H), 2.11 (d, J=1.8 Hz, 3H), 1.45 (br. s., 1H),
1.06-1.18 (m, 2H), 0.79-0.90 (m, 1H), 0.69-0.79 (m, 2H), 0.64 (br.
s., 1H), 0.57 (br. s., 1H), 0.41-0.55 (m, 2H).
[1245] LC-MS: m/z 522.3 (M+H).sup.+
Compound 741
(R)-6-cyclopropyl-2-(3-isopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(2-v-
inyl-1,7-naphthyridin-4-yl)nicotinonitrile
[1246] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.58 (s, 1H), 8.60 (br.
s., 1H), 7.79 (d, J=10.9 Hz, 1H), 7.63-7.71 (m, 1H), 7.50-7.63 (m,
1H), 7.12 (dd, J=17.6, 10.9 Hz, 1H), 6.47 (d, J=17.6 Hz, 1H),
5.83-5.94 (m, 1H), 4.63-4.80 (m, 1.5H), 4.37-4.58 (m, 2H),
4.04-4.26 (m, 2H), 3.93 (d, J=13.5 Hz, 1H), 3.10-3.33 (m, 2H),
2.09-2.30 (m, 0.5H), 1.92-2.08 (m, 1H), 1.11 (dd, J=16.3, 6.6 Hz,
4H), 0.85-0.98 (m, 6H).
[1247] LC-MS: m/z 496.3 (M+H).sup.+
Compound 717
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(2-
-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile
[1248] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.56 (s, 1H), 8.59 (d,
J=5.6 Hz, 1H), 7.72 (d, J=3.2 Hz, 1H), 7.68 (s, 1H), 7.45 (dd,
J=9.5, 5.7 Hz, 1H), 7.10 (dd, J=17.8, 11.0 Hz, 1H), 6.42 (dd,
J=17.6, 2.1 Hz, 1H), 5.72-5.90 (m, 1H), 4.63 (d, J=13.2 Hz, 1H),
4.45-4.55 (m, 1H), 4.18 (br. s., 2H), 4.06 (br. s., 1H), 3.96 (br.
s., 1H), 3.60-3.85 (m, 1H), 3.44-3.49 (m, 3H), 3.23-3.34 (m, 1H),
3.16 (br. s., 1H), 1.97 (br. s., 1H), 1.48-1.56 (m, 1H), 1.22 (dd,
J=7.9, 3.8 Hz, 2H), 0.86-0.94 (m, 2H), 0.70 (br. s., 1H), 0.57 (br.
s., 1.5H), 0.51 (br. s., 1.5H).
[1249] LC-MS: m/z 494.6 (M+H).sup.+
Compound 689
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile
[1250] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.58 (br. s., 1H), 8.61
(br. s., 1H), 7.77 (d, J=3.0 Hz, 1H), 7.64-7.73 (m, 1H), 7.54 (br.
s., 1H), 7.12 (dd, J=17.6, 10.8 Hz, 1H), 6.45 (dd, J=17.7, 2.1 Hz,
1H), 5.85 (d, J=11.0 Hz, 1H), 4.64 (d, J=10.0 Hz, 1H), 4.52 (d,
J=12.0 Hz, 1H), 4.25 (br. s., 1H), 3.69-3.81 (br. s., 1H), 3.38 (d,
J=15.3 Hz, 1.5H), 3.21 (br. s., 1.5H), 1.75 (br. s., 1H), 1.50 (br.
s., 1H), 1.26-1.37 (m, 1H), 1.23 (br. s., 2H), 0.99-1.14 (m, 2H),
0.87-0.96 (m, 2H), 0.84 (dd, J=7.8, 2.3 Hz, 2H), 0.71 (br. s., 1H),
0.52-0.62 (m, 2H), 0.43-0.52 (m, 1H).
[1251] LC-MS: m/z 490.6 (M+H).sup.+
Compound 688
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile
[1252] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.59 (s, 1H), 8.60 (d,
J=5.5 Hz, 1H), 7.80 (d, J=2.8 Hz, 1H), 7.69 (d, J=1.3 Hz, 1H),
7.54-7.63 (m, 1H), 7.12 (dd, J=17.6, 10.8 Hz, 1H), 6.48 (dd,
J=17.7, 2.1 Hz, 1H), 5.88 (d, J=11.0 Hz, 1H), 4.63 (d, J=12.5 Hz,
1H), 4.52 (d, J=7.5 Hz, 1H), 4.13 (d, J=9.3 Hz, 1H), 3.87-3.99 (m,
2H), 3.67-3.87 (m, 1H), 3.30 (br. s., 2H), 3.18 (br. s., 1H),
2.57-2.68 (m, 2H), 1.43-1.54 (m, 1H), 1.32-1.41 (m, 1H), 1.19-1.26
(m, 2H), 0.87-0.97 (m, 2H), 0.67 (br. s., 1H), 0.60 (br. s., 1H),
0.40-0.55 (m, 2H).
[1253] LC-MS: m/z 494.6 (M+H).sup.+
Compound 658
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile
[1254] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.57 (s, 1H), 8.59 (d,
J=5.5 Hz, 1H), 7.76 (d, J=3.5 Hz, 1H), 7.68 (d, J=1.3 Hz, 1H),
7.49-7.60 (m, 1H), 7.11 (dd, J=17.6, 11.0 Hz, 1H), 6.45 (dd,
J=17.6, 1.8 Hz, 1H), 5.85 (d, J=11.3 Hz, 1H), 4.55-4.68 (m, 1H),
4.50 (dd, J=12.8, 2.3 Hz, 1H), 4.15 (br. s., 0.5H), 3.92 (br. s.,
0.5H), 3.66-3.84 (m, 3H), 3.40 (s, 3H), 3.30 (br. s., 1H), 3.22
(br. s., 1H), 3.15 (d, J=7.5 Hz, 1H), 2.66 (br. s., 1H), 2.56 (br.
s., 1H), 1.46-1.54 (m, 1H), 1.32 (d, J=16.1 Hz, 1H), 1.19-1.24 (m,
2H), 0.84-0.99 (m, 2H), 0.66 (br. s., 1H), 0.60 (br. s., 1H), 0.49
(br. s., 2H).
[1255] LC-MS: m/z 508.6 (M+H).sup.+
Compound 681
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(-
2-vinyl-1,7-naphthyridin-4-yl)nicotinonitrile
[1256] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.55 (s, 1H), 8.59 (dd,
J=5.3, 3.0 Hz, 1H), 7.73 (d, J=11.5 Hz, 1H), 7.67 (dd, J=4.5, 2.8
Hz, 1H), 7.45 (dd, J=12.5, 5.5 Hz, 1H), 7.10 (ddd, J=17.6, 10.9,
1.1 Hz, 1H), 6.42 (d, J=17.6 Hz, 1H), 5.82 (d, J=10.8 Hz, 1H),
4.61-4.79 (m, 1H), 4.41-4.60 (m, 2H), 3.86-4.01 (m, 2H), 3.82 (d,
J=13.6 Hz, 0.5H), 3.53-3.60 (m, 0.5H), 3.10-3.30 (m, 2H), 3.01 (d,
J=12.8 Hz, 0.5H), 2.73-2.84 (m, 0.5H), 2.56-2.68 (m, 2H), 2.09-2.37
(m, 1H), 1.47-1.55 (m, 1H), 1.05-1.17 (m, 4H), 0.80-1.01 (m,
6H).
[1257] LC-MS: m/z 496.6 (M+H).sup.+
Compound 710
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(1-vinylisoquinolin-7-yl)nicotinonitrile
[1258] 1H NMR (CHLOROFORM-d) .delta. 8.61 (d, J=5.8 Hz, 1H), 8.30
(s, 1H), 7.95 (d, J=8.3 Hz, 1H), 7.80 (d, J=8.0 Hz, 1H), 7.74 (s,
1H), 7.65-7.72 (m, 1H), 7.58-7.65 (m, 1H), 6.64 (d, J=16.1 Hz, 1H),
5.84 (d, J=10.3 Hz, 1H), 4.58 (d, J=11.5 Hz, 1H), 4.46 (d, J=11.8
Hz, 1H), 4.01-4.31 (m, 1H), 3.61-3.89 (m, 1H), 3.33 (d, J=17.3 Hz,
1.5H), 3.15 (br. s., 1.5H), 2.02-2.09 (m, 1H), 1.42-1.47 (m, 1H),
1.34 (d, J=8.5 Hz, 1H), 1.25-1.30 (m, 3H), 1.06-1.11 (m, 1H),
0.98-1.02 (m, 2H), 0.90 (t, J=6.7 Hz, 1H), 0.80-0.84 (m, 2H), 0.68
(br. s., 1H), 0.52-0.56 (m, 1H), 0.46-0.49 (m, 1H)
[1259] LC-MS: m/z 492.0 (M+H).sup.+
Compound 685
(R)-5-((2-chloropyridin-4-yl)methyl)-2-(4-(cyclopropanecarbonyl)-3-cyclopr-
opylpiperazin-1-yl)-6-cyclopropylnicotinonitrile
[1260] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.33 (d, J=5.0 Hz, 1H),
7.49 (s, 1H), 7.12 (s, 1H), 6.98-7.06 (m, 1H), 4.47 (d, J=12.5 Hz,
1H), 4.30-4.50 (m, 2.5H), 4.20-4.30 (m, 1H), 4.04 (s, 1H),
3.60-3.90 (s, 1H), 2.90-3.45 (m, 1H), 2.01 (s, 1H), 1.80-1.91 (m,
1H), 1.72 (s, 1H), 1.09-1.17 (m, 2H), 0.93-1.09 (m, 4H), 0.74-0.86
(m, 2H), 0.37-0.65 (m, 4H)
[1261] LC-MS: m/z 462.2 (M+H).sup.+
Compound 684
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-((2-vinylpyridin-4-yl)methyl)nicotinonitrile
[1262] .sup.1H NMR (CHLOROFORM-d): 8.50 (d, J=5.0 Hz, 1H), 7.47 (s,
1H), 7.12 (s, 1H), 6.89-6.99 (m, 1H), 6.80 (dd, J=17.6, 10.8 Hz,
1H), 6.16-6.29 (m, 1H), 5.44-5.57 (m, 1H), 4.25-4.60 (m, 2.5H),
4.12-4.20 (m, 1H), 4.03 (s, 2H), 3.49-3.90 (m, 1H), 2.95-3.29 (m,
2.5H), 1.85-1.98 (m, 1H), 1.71 (s, 1H), 1.35-1.45 (m, 1H),
1.07-1.17 (m, 2H), 0.92-1.07 (m, 4H), 0.76-0.82 (m, 2H), 0.30-0.63
(m, 4H)
[1263] LC-MS: m/z 454.2 (M+H).sup.+
Compound 708
(R)-5-((2-chloropyridin-4-yl)methyl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-h-
ydroxypropanoyl)piperazin-1-yl)nicotinonitrile
[1264] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.34 (d, J=5.3 Hz, 1H),
7.49 (s, 1H), 7.11 (s, 1H), 7.03 (d, J=5.0 Hz, 1H), 4.39-4.52 (m,
2H), 4.33 (d, J=12.3 Hz, 1H), 4.04 (s, 2H), 3.85-3.97 (m, 2H),
3.66-3.81 (m, 1H), 3.01-3.22 (m, 3H), 2.51-2.65 (m, 2H), 1.79-1.92
(m, 1H), 1.31-1.39 (m, 1H), 1.08-1.15 (m, 2H), 0.93-1.03 (m, 2H),
0.46-0.63 (m, 4H)
[1265] LC-MS: m/z 466.2 (M+H).sup.+
Compound 697
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-((2-vinylpyridin-4-yl)methyl)nicotinonitrile
[1266] A mixture of
(R)-5-((2-chloropyridin-4-yl)methyl)-6-cyclopropyl-2-(3-cyclopropyl-4-(3--
hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (80 mg, 0.172
mmol), potassium vinyltrifluoroborate (46 mg, 0.343 mmol),
Pd(dppf)Cl.sub.2 (7 mg, 0.009 mmol) and CsF (79 mg, 0.515 mmol) in
dioxane/H.sub.2O was stirred at 100.degree. C. for 16 hours. The
mixture was diluted with EtOAc (30 mL) and filtered. The filtrated
was partitioned between EtOAc (30 mL) and water (10 mL), the
organic layer was washed with water (10 mL), brine and dried over
Na.sub.2SO.sub.4 and concentrated to give the crude which was
purified by prep-TLC to give 25 mg of the product.
[1267] .sup.1H NMR (CHLOROFORM-d): 8.47 (d, J=5.0 Hz, 1H), 7.46 (s,
1H), 7.10 (s, 1H), 6.87-6.97 (m, 1H), 6.76 (dd, J=17.3, 10.8 Hz,
1H), 6.18 (dd, J=17.6, 1.0 Hz, 1H), 5.41-5.53 (m, 1H), 4.39 (d,
J=12.8 Hz, 1H), 4.27 (d, J=12.5 Hz, 1H), 4.01 (m, 2H), 3.80-3.92
(m, 2H), 3.51-3.79 (m, 2H), 2.99-3.18 (m, 3H), 2.42-2.66 (m, 2H),
1.85-1.97 (m, 1H), 1.30-1.40 (m, 1H), 1.03-1.12 (m, 2H), 0.88-1.00
(m, 2H), 0.30-0.59 (m, 4H)
[1268] LC-MS: m/z 458.3 (M+H).sup.+
Compound 698 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((2--
vinyl-1,7-naphthyridin-4-yl)amino)nicotinonitrile
[1269] .sup.1H NMR (CHLOROFORM-d) .delta.: 9.48 (s, 1H), 8.59 (d,
J=5.8 Hz, 1H), 7.90 (br. s., 1H), 7.68-7.77 (m, 1H), 7.35-7.48 (m,
1H), 6.91 (dd, J=17.4, 10.9 Hz, 1H), 6.56 (s, 1H), 6.26 (d, J=17.6
Hz, 1H), 5.67 (d, J=11.0 Hz, 1H), 4.86-4.98 (m, 0.5H), 4.51-4.62
(d, 0.5H) 4.14-4.38 (m, 3H), 3.94 (br. s., 2H), 3.70-3.81 (m,
0.5H), 3.59 (t, J=10.8 Hz, 0.5H), 3.27-3.41 (m, 1H), 3.01-3.24 (m,
2H), 2.48-2.78 (m, 2H), 1.97-2.09 (m, 1H), 1.44 (d, J=6.5 Hz,
1.5H), 1.34 (d, J=6.8 Hz, 1.5H), 1.10-1.20 (m, 2H), 0.94-1.06 (m,
2H).
[1270] LC-MS: m/z 483.2 (M+H).sup.+
Compound 679 (General Procedure 7)
(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-me-
thoxypropanoyl)piperazin-1-yl)nicotinonitrile
[1271] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.06 (d, J=5.4 Hz, 1H),
7.60 (s, 1H), 6.57-6.47 (m, 2H), 6.08 (s, 1H), 4.75-4.64 (m, 0.5H),
4.49 (t, J=11.8 Hz, 1H), 4.37 (t, J=10.9 Hz, 1H), 4.14-4.09 (m,
0.5H), 3.89 (ddd, J=7.5, 3.5, 2.5 Hz, 0.5H), 3.81-3.64 (m, 2.5H),
3.39 (s, 3H), 3.31-3.17 (m, 1.5H), 3.10 (td, J=12.8, 3.4 Hz, 1H),
2.69 (ddd, J=22.8, 14.8, 9.9 Hz, 2H), 2.52 (dd, J=20.7, 9.1 Hz,
0.5H), 2.06 (ddd, J=7.5, 4.5, 1.6 Hz, 1H), 1.28 (m, J=4.7 Hz, 1H),
1.15 (m, 2H), 1.08-0.99 (m, 2H), 0.72-0.52 (m, 2H), 0.52-0.39 (m,
2H).
[1272] LC-MS: m/z NB250-076-2 481.1 (M+H).sup.+
Compound 678 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-((2-vinylpyridin-4-yl)amino)nicotinonitrile
[1273] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.26 (d, J=5.7 Hz, 1H),
7.62 (s, 1H), 6.72 (dd, J=17.4, 10.8 Hz, 1H), 6.58 (s, 1H), 6.46
(d, J=4.1 Hz, 1H), 6.20 (d, J=17.4 Hz, 1H), 5.94 (s, 1H), 5.49 (d,
J=10.8 Hz, 1H), 4.70 (dd, J=14.5, 4.5 Hz, 0.5H), 4.46 (t, J=11.4
Hz, 1H), 4.33 (d, J=10.6 Hz, 1H), 4.13-4.07 (m, 0.5H), 3.92-3.85
(m, 0.5H), 3.83-3.62 (m, 2.5H), 3.39 (s, 3H), 3.31-3.16 (m, 1.5H),
3.09 (td, J=13.2, 3.7 Hz, 1H), 2.82-2.58 (m, 2H), 2.58-2.45 (m,
0.5H), 2.10 (dt, J=4.5, 3.0 Hz, 1H), 1.28 (s, 1H), 1.18-1.10 (m,
2H), 1.02 (ddd, J=9.9, 6.4, 3.2 Hz, 2H), 0.73-0.53 (m, 2H),
0.53-0.39 (m, 2H).
[1274] LC-MS: m/z 473.2 (M+H).sup.+
Compound 661 (General Procedure 7)
(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl-
)-3-methylpiperazin-1-yl)nicotinonitrile
[1275] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.06 (d, J=5.8 Hz, 1H),
7.60 (s, 1H), 6.54 (s, 1H), 6.51 (dd, J=5.8, 2.0 Hz, 1H), 6.15 (s,
1H), 4.90 (s, 0.5H), 4.54 (d, J=13.4 Hz, 0.5H), 4.35-4.16 (m,
2.5H), 3.93 (s, 2H), 3.74 (d, J=13.4 Hz, 0.5H), 3.58 (d, J=11.0 Hz,
0.5H), 3.30 (dd, J=10.8, 6.4 Hz, 1H), 3.15 (t, J=12.2 Hz, 1H),
3.08-3.01 (m, 0.5H), 2.74-2.51 (m, 2H), 2.07 (ddd, J=12.6, 8.0, 4.7
Hz, 1H), 1.42 (d, J=6.6 Hz, 1.5H), 1.32 (d, J=6.7 Hz, 1.5H), 1.13
(dt, J=7.2, 3.6 Hz, 2H), 1.05 (ddd, J=10.3, 6.6, 3.5 Hz, 2H).
[1276] LC-MS: m/z 441.0 (M+H).sup.+
Compound 677 (General Procedure 7)
(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hy-
droxypropanoyl)piperazin-1-yl)nicotinonitrile
[1277] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.01 (d, J=5.7 Hz, 1H),
7.59 (s, 1H), 6.49 (d, J=1.8 Hz, 1H), 6.46 (dd, J=5.7, 2.0 Hz, 1H),
6.41 (s, 1H), 4.66 (d, J=13.6 Hz, 0.5H), 4.45 (d, J=12.9 Hz, 1H),
4.33 (d, J=12.7 Hz, 1H), 4.06 (d, J=9.3 Hz, 0.5H), 3.91 (s, 2H),
3.80 (d, J=13.2 Hz, 0.5H), 3.72 (d, J=11.6 Hz, 0.5H), 3.56 (m,
0.5H), 3.27-3.01 (m, 2.5H), 2.59 (dd, J=17.2, 5.2 Hz, 1.5H),
2.11-2.04 (m, 1H), 1.98 (m, 0.5H), 1.43-1.27 (m, 1H), 1.18-1.09 (m,
2H), 1.07-0.98 (m, 2H), 0.63 (m, J=7.2, 4.7 Hz, 1H), 0.58-0.28 (m,
3H).
[1278] LC-MS: m/z 467.0 (M+H).sup.+
Compound 676 (General Procedure 6)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-((2-vinylpyridin-4-yl)amino)nicotinonitrile
[1279] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.20 (d, J=6.1 Hz, 1H),
7.63 (s, 1H), 6.73 (dd, J=17.5, 10.9 Hz, 1H), 6.69 (d, J=3.2 Hz,
1H), 6.63 (d, J=3.1 Hz, 1H), 6.29 (d, J=17.5 Hz, 1H), 5.57 (d,
J=10.9 Hz, 1H), 4.69 (d, J=11.0 Hz, 0.5H), 4.46 (d, J=13.0 Hz, 1H),
4.35 (d, J=13.1 Hz, 1H), 4.10 (d, J=7.7 Hz, 0.5H), 3.92 (d, J=3.9
Hz, 2H), 3.74 (ddd, J=21.2, 17.7, 8.0 Hz, 1.5H), 3.30-3.17 (m,
1.5H), 3.13-3.03 (m, 1H), 2.69-2.48 (m, 2H), 2.15-2.06 (m, 1H),
1.28 (d, J=5.0 Hz, 1H), 1.14 (dt, J=7.3, 3.6 Hz, 2H), 1.08-0.98 (m,
2H), 0.76-0.62 (m, 1H), 0.62-0.32 (m, 3H).
[1280] LC-MS: m/z 459.0 (M+H).sup.+
Compound 718 (General Procedure 7)
(R)-5-((2-chloropyridin-4-yl)amino)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-me-
thoxyacetyl)piperazin-1-yl)nicotinonitrile
[1281] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.06 (d, J=5.7 Hz, 1H),
7.60 (s, 1H), 6.50 (d, J=2.1 Hz, 1H), 6.46 (dd, J=5.7, 2.2 Hz, 1H),
5.79 (s, 1H), 4.43 (dd, J=52.6, 11.8 Hz, 2.5H), 4.16 (s, 2H), 4.00
(s, 1.5H), 3.67 (d, J=24.8 Hz, 1H), 3.46 (s, 3H), 3.21 (dd, J=13.0,
3.4 Hz, 1H), 3.09 (t, J=11.3 Hz, 1H), 2.07 (ddd, J=12.7, 8.0, 4.7
Hz, 1H), 1.38 (s, 1H), 1.15 (dt, J=7.5, 3.7 Hz, 2H), 1.08-1.00 (m,
2H), 0.67 (s, 1H), 0.63-0.39 (m, 3H).
[1282] LC-MS: m/z 467.2 (M+H).sup.+
Compound 711 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-((-
2-vinylpyridin-4-yl)amino)nicotinonitrile
[1283] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.26 (d, J=5.7 Hz, 1H),
7.62 (s, 1H), 6.71 (dd, J=17.4, 10.8 Hz, 1H), 6.59 (d, J=2.2 Hz,
1H), 6.45 (dd, J=5.7, 2.3 Hz, 1H), 6.18 (dd, J=17.4, 1.0 Hz, 1H),
6.01 (s, 1H), 5.47 (dd, J=10.8, 0.9 Hz, 1H), 4.81-4.26 (m, 2.6H),
4.16 (s, 2H), 3.95 (d, J=43.6 Hz, 1.5H), 3.70 (s, 1H), 3.46 (s,
3H), 3.20 (dd, J=13.0, 3.4 Hz, 1H), 3.07 (t, J=11.4 Hz, 1H),
2.15-2.07 (m, 1H), 1.41 (s, 1H), 1.19-1.10 (m, 2H), 1.02 (ddd,
J=10.2, 6.6, 3.4 Hz, 2H), 0.67 (s, 1H), 0.61-0.37 (m, 3H).
[1284] LC-MS: m/z NB295-002-01 459.1 (M+H).sup.+
Compound 743
(R)-6-cyclopropyl-2-(3-isopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-((2--
vinylpyridin-4-yl)amino)nicotinonitrile
[1285] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.24 (d, J=5.8 Hz, 1H),
7.60 (d, J=3.1 Hz, 1H), 6.72 (dd, J=17.4, 10.8 Hz, 1H), 6.61 (s,
1H), 6.51 (d, J=4.3 Hz, 1H), 6.37 (s, 1H), 6.23 (d, J=17.5 Hz, 1H),
5.52 (d, J=10.9 Hz, 1H), 4.68-4.47 (m, 1.5H), 4.37 (t, J=12.7 Hz,
1.5H), 4.28 (d, J=13.4 Hz, 0.5H), 4.22-4.13 (m, 1H), 4.08 (d,
J=13.5 Hz, 0.5H), 3.88 (d, J=13.6 Hz, 0.5H), 3.56 (d, J=10.6 Hz,
0.5H), 3.47 (d, J=2.5 Hz, 3H), 3.42 (dd, J=13.3, 2.9 Hz, 0.5H),
3.24-2.95 (m, 2.5H), 2.19-2.04 (m, 2H), 1.28 (d, J=4.7 Hz, 1H),
1.19-1.11 (m, 1H), 1.07 (d, J=6.5 Hz, 3H), 1.05-0.97 (m, 2H), 0.91
(dd, J=15.7, 6.8 Hz, 3H).
[1286] LC-MS: m/z NB295-018-01 461.4 (M+H).sup.+
Compound 731
(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropyl-
-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile
##STR00857## ##STR00858##
[1287] Step 1:
(R)-tert-butyl-4-(5-(2-chloropyridin-4-ylamino)-3-cyano-6-cyclopropylpyri-
din-2-yl)-2-cyclopropylpiperazine-1-carboxylate
[1288] To a solution of (R)-tert-butyl
4-(5-bromo-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyclopropylpiperazine-1-c-
arboxylate (1.5 g, 3.363 mmol) and 2-chloropyridin-4-amine (518.6
mg, 4.036 mmol) in 1,4-dioxane (20 mL) was added Pd(OAc).sub.2 (76
mg, 0.34 mmol), BINAP (314.3 mg, 0.505 mmol) and Cs.sub.2CO.sub.3
(2.2 g, 6.726 mmol) at r.t. under N.sub.2. The resulting mixture
was heated and stirred at 155.degree. C. under N.sub.2 in microwave
for 1 h. The solvent was removed in vacuum and the residue was
purified via column chromatography (petroleum ether: EtOAc) to
afford the title compound (1.1 g, 66.2%) as a yellow solid.
[1289] LC-MS: m/z 495.0 (M+H).sup.+
Step 2: (R)-tert-butyl
4-(5-((2-chloropyridin-4-yl)(methyl)amino)-3-cyano-6-cyclopropylpyridin-2-
-yl)-2-cyclopropylpiperazine-1-carboxylate
[1290] To a solution of (R)-tert-butyl
4-(5-(2-chloropyridin-4-ylamino)-3-cyano-6-cyclopropylpyridin-2-yl)-2-cyc-
lopropylpiperazine-1-carboxylate (550 mg, 1.1 mmol) in anhydrous
THF (10 mL) was added NaH (89 mg, 2.22 mmol) and iodomethane (2
drops) at r.t. The reaction mixture was stirred at r.t. for 3 hrs.
The reaction mixture was quenched by water at 0.degree. C. The
mixture was extracted with EtOAc (15 mL.times.2). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4.
The organic phase was filtered and the filtrate was concentrated in
vacuum to give out the title compound (crude, 567 mg) as a yellow
solid.
[1291] LC-MS: m/z 509.1 (M+H).sup.+
Step 3:
(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyc-
lopropylpiperazin-1-yl)nicotinonitrile
[1292] To a solution of (R)-tert-butyl
4-(5-((2-chloropyridin-4-yl)(methyl)amino)-3-cyano-6-cyclopropylpyridin-2-
-yl)-2-cyclopropylpiperazine-1-carboxylate (567 mg, 1.1 mmol) in
anhydrous DCM (5 mL) was added TFA (5 mL) at r.t. The reaction
mixture was stirred at r.t. for 2 hrs. The solvent was removed in
vacuum and the residue was adjusted to pH>7.0. The residue
mixture was extracted with EtOAc (15 mL.times.2). The combined
organic layer was washed with brine, dried over Na.sub.2SO.sub.4.
The organic phase was filtered and the filtrate was concentrated in
vacuum to give out the title compound (crude, 432 mg) as a yellow
solid.
[1293] LC-MS: m/z 409.1 (M+H).sup.+
Step 4:
(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyc-
lopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile
[1294] To a solution of
(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropy-
lpiperazin-1-yl)nicotinonitrile (410 mg, 1.0 mmol) in DMF (8 mL)
was added sodium 3-hydroxypropanoate (203.5 mg, 1.5 mmol), HATU
(572.3 mg, 1.5 mmol) and DIPEA (194 mg, 1.5 mmol) at r.t. The
reaction mixture was stirred at r.t. for 3 hrs. The solvent was
removed in vacuum and the residue was purified via silica gel
column chromatography (DCM: MeOH) to afford the title compound (270
mg, 56.3%) as a pale yellow solid.
[1295] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.03 (d, J=5.8 Hz, 1H),
7.56 (s, 1H), 6.45 (s, 1H), 6.35 (d, J=3.5 Hz, 1H), 4.70 (d, J=11.2
Hz, 0.5H), 4.51 (d, J=13.0 Hz, 1H), 4.39 (d, J=13.4 Hz, 1H), 4.10
(d, J=9.2 Hz, 0.5H), 3.93 (d, J=4.5 Hz, 2H), 3.86-3.65 (m, 1.5H),
3.40 (s, 1H), 3.30 (s, 3H), 3.28-3.15 (m, 1.5H), 3.15-3.01 (m, 1H),
2.69-2.44 (m, 2H), 1.89-1.78 (m, 1H), 1.28 (d, J=5.0 Hz, 1H), 1.13
(s, 2H), 1.01 (d, J=11.8 Hz, 2H), 0.82-0.65 (m, 1H), 0.64-0.32 (m,
3H)
[1296] LC-MS: m/z 481.0 (M+H).sup.+
Step 5: Compound 731
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(methyl(2-vinylpyridin-4-yl)amino)nicotinonitrile
[1297] To a solution of
(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(3-cyclopropy-
l-4-(3-hydroxypropanoyl)piperazin-1-yl)nicotinonitrile (270 mg,
0.563 mmol) in isopropanol (10 mL) and H.sub.2O (3 mL) was added
Vinyltrifluoroboric acid potassium salt (113.1 mg, 0.844 mmol),
Pd(dppf)Cl.sub.2 (49.0 mg, 0.06 mmol) and DIPEA (145.3 mg, 1.126
mmol) at r.t. under N.sub.2. The reaction mixture was heated and
stirred at reflux under N.sub.2 overnight. The solvent was removed
in vacuum and the residue was purified via silica gel column
chromatography (DCM: MeOH) to afford the title compound (121 mg,
45.5%) as a pale yellow solid.
[1298] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.25 (d, J=5.9 Hz, 1H),
7.58 (s, 1H), 6.71 (dd, J=17.4, 10.7 Hz, 1H), 6.46 (s, 1H), 6.33
(s, 1H), 6.20 (d, J=17.3 Hz, 1H), 5.45 (d, J=11.2 Hz, 1H), 4.69 (d,
J=13.4 Hz, 0.4H), 4.49 (d, J=13.0 Hz, 1H), 4.37 (d, J=12.7 Hz, 1H),
4.10 (d, J=8.6 Hz, 0.6H), 3.92 (s, 2H), 3.86-3.65 (m, 1.5H), 3.42
(s, 1H), 3.31 (s, 3H), 3.22 (m, 1.5H), 3.15-3.00 (m, 1H), 2.69-2.45
(m, 2H), 1.88 (ddd, J=12.7, 8.1, 4.7 Hz, 1H), 1.40-1.31 (m, 1H),
1.12 (s, 2H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).
[1299] LC-MS: m/z 473.4 (M+H).sup.+
Compound 699
(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(4-(3-methoxyp-
ropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile
##STR00859##
[1301] To a solution of
(R)-5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-
-3-methylpiperazin-1-yl)nicotinonitrile (675 mg, 1.487 mmol) in
anhydrous THF (15 mL) was added iodomethane (0.5 mL) and NaH (119
mg, 2.974 mmol) at r.t. The reaction mixture was stirred at r.t.
for 3 hrs. The reaction mixture was quenched by water at 0.degree.
C. The mixture was extracted with EtOAc (15 mL.times.2). The
combined organic layer was washed with brine, dried over
Na.sub.2SO.sub.4. The organic phase was filtered and the filtrate
was concentrated in vacuum. The residue was purified via silica gel
column chromatography (DCM: MeOH) to afford the title compound (350
mg, 50.3%) as a white solid.
[1302] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.04 (d, J=5.7 Hz, 1H),
7.54 (s, 1H), 6.42 (d, J=44.6 Hz, 2H), 4.92 (s, 0.5H), 4.55 (d,
J=13.0 Hz, 0.5H), 4.40-4.25 (m, 2H), 4.22 (d, J=13.9 Hz, 0.5H),
3.83 (d, J=13.7 Hz, 0.5H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (t, J=11.5
Hz, 0.5H), 3.39 (s, 3H), 3.37-3.33 (m, 0.5H), 3.31 (s, 3H),
3.28-2.97 (m, 2H), 2.85-2.65 (m, 1H), 2.64-2.51 (m, 1H), 1.80 (ddd,
J=12.5, 8.0, 4.6 Hz, 1H), 1.36 (dd, J=41.2, 6.2 Hz, 3H), 1.12 (s,
2H), 1.07-0.93 (m, 2H).
[1303] LC-MS: m/z 469.2 (M+H).sup.+
Compound 690 (General Procedure 6)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(met-
hyl(2-vinylpyridin-4-yl)amino)nicotinonitrile
##STR00860##
[1305] To a solution of
(R)-5-((2-chloropyridin-4-yl)(methyl)amino)-6-cyclopropyl-2-(4-(3-methoxy-
propanoyl)-3-methylpiperazin-1-yl)nicotinonitrile (330 mg, 0.71
mmol) in isopropanol (30 mL) and H.sub.2O (3 mL) was added
Vinyltrifluoroboric acid potassium salt (142.1 mg, 1.06 mmol),
Pd(dppf)Cl.sub.2 (58.0 mg, 0.071 mmol) and DIPEA (182 mg, 1.41
mmol) at r.t. under N.sub.2. The reaction mixture was heated and
stirred at reflux under N.sub.2 overnight. The solvent was removed
in vacuum and the residue was purified via silica gel column
chromatography (DCM: MeOH) to afford the title compound (89 mg,
27.5%) as a white solid.
[1306] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.24 (d, J=5.9 Hz, 1H),
7.55 (s, 1H), 6.71 (dd, J=17.4, 10.8 Hz, 1H), 6.46 (s, 1H), 6.33
(s, 1H), 6.20 (d, J=17.3 Hz, 1H), 5.46 (d, J=11.0 Hz, 1H), 4.91 (s,
0.5H), 4.54 (d, J=13.1 Hz, 0.5H), 4.34-4.16 (m, 2.5H), 3.89-3.68
(m, 2.5H), 3.56 (t, J=11.5 Hz, 0.5H), 3.39 (s, 3H), 3.31 (s, 3H),
3.29 (s, 1H), 3.10 (m, 1.5H), 2.80-2.52 (m, 2H), 1.88-1.83 (m, 1H),
1.41 (d, J=6.3 Hz, 1.5H), 1.30 (d, J=6.6 Hz, 1.5H), 1.10 (m, 2H),
0.97 (m, 2H).
[1307] LC-MS: m/z 461.2 (M+H).sup.+
Compound 660 (General Procedure 6)
(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)pyridin-3-ylamino)picolinonitrile
[1308] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.32 (d, J=5.8 Hz, 1H),
7.59 (s, 1H), 7.01 (s, 1H), 6.72 (d, J=3.8 Hz, 1H), 6.62 (s, 1H),
4.92 (s, 0.5H), 4.55 (d, J=12.7 Hz, 0.5H), 4.30 (t, J=11.2 Hz, 2H),
4.22 (d, J=12.7 Hz, 0.5H), 3.83 (d, J=13.8 Hz, 0.5H), 3.76 (t,
J=6.3 Hz, 2H), 3.57 (t, J=11.5 Hz, 0.5H), 3.39 (s, 3H), 3.33 (d,
J=12.5 Hz, 1H), 3.21-3.04 (m, 1.5H), 2.73 (ddd, J=22.1, 14.2, 6.5
Hz, 1H), 2.64-2.53 (m, 1H), 2.05-1.99 (m, 1H), 1.40 (d, J=6.3 Hz,
1.5H), 1.30 (d, J=6.7 Hz, 1.5H), 1.18-1.10 (m, 2H), 1.09-0.98 (m,
2H).
[1309] LC-MS: m/z 446.0 (M+H).sup.+
Compound 659 (General Procedure 6)
(R)-4,4'-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazi-
n-1-yl)pyridin-3-ylazanediyl)dipicolinonitrile
[1310] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.62 (d, J=5.5 Hz, 2H),
7.53 (s, 1H), 7.28-7.20 (m, 4H), 4.95 (s, 0.5H), 4.58 (d, J=10.0
Hz, 0.5H), 4.37 (dd, J=42.6, 13.4 Hz, 2.5H), 3.89 (d, J=13.8 Hz,
0.5H), 3.77 (t, J=6.3 Hz, 2H), 3.66-3.57 (m, 0.5H), 3.44 (s, 0.5H),
3.40 (s, 3H), 3.35-3.13 (m, 1.5H), 2.87-2.67 (m, 1H), 2.62 (dd,
J=13.7, 7.4 Hz, 1H), 1.68 (d, J=4.3 Hz, 1H), 1.44 (d, J=6.6 Hz,
1.5H), 1.34 (d, J=6.3 Hz, 1.5H), 1.11 (dt, J=6.9, 3.5 Hz, 2H),
0.97-0.88 (m, 2H).
[1311] LC-MS: m/z 548.1 (M+H).sup.+
Compound 729 (General Procedure 6)
(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)pyridin-3-ylamino)picolinamide
[1312] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.24 (d, J=5.7 Hz, 1H),
7.98 (s, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 6.62 (dd, J=5.6, 2.3 Hz,
1H), 6.03 (s, 1H), 5.65 (s, 1H), 4.92 (s, 0.5H), 4.55 (d, J=13.9
Hz, 0.5H), 4.27 (t, J=11.1 Hz, 2H), 4.19 (d, J=13.0 Hz, 0.5H), 3.82
(d, J=13.0 Hz, 0.5H), 3.76 (t, J=6.2 Hz, 2H), 3.57 (t, J=11.5 Hz,
0.5H), 3.40 (s, 3H), 3.34-3.23 (m, 1H), 3.15 (t, J=12.1 Hz, 1H),
3.10-3.00 (m, 0.5H), 2.84-2.65 (m, 1H), 2.60 (m, 1H), 2.07 (ddd,
J=12.6, 8.0, 4.6 Hz, 1H), 1.41 (d, J=6.2 Hz, 1.5H), 1.31 (d, J=6.7
Hz, 1.5H), 1.13 (dt, J=7.4, 3.6 Hz, 2H), 1.00 (td, J=6.6, 3.4 Hz,
2H).
[1313] LC-MS: m/z 464.1 (M+H).sup.+
Compound 742 (General Procedure 6)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-
-methyl-5-(2-vinylpyridin-4-ylamino)nicotinonitrile
[1314] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.24 (d, J=5.7 Hz, 1H),
6.70 (dd, J=17.4, 10.8 Hz, 1H), 6.49 (s, 1H), 6.35 (s, 1H), 6.19
(d, J=17.4 Hz, 1H), 5.79 (s, 1H), 5.48 (d, J=10.9 Hz, 1H), 4.68 (d,
J=12.8 Hz, 0.5H), 4.51-4.38 (m, 0.5H), 4.34 (d, J=12.9 Hz, 1H),
4.26 (d, J=12.6 Hz, 1H), 4.08 (d, J=9.0 Hz, 0.5H), 3.93 (s, 2H),
3.82-3.70 (m, 1H), 3.31 (dd, J=19.9, 7.5 Hz, 0.5H), 3.24-3.12 (m,
1H), 3.11-2.97 (m, 1H), 2.56 (m, 2H), 2.39 (s, 3H), 2.11 (ddd,
J=12.6, 8.0, 4.7 Hz, 1H), 1.35-1.25 (m, 1H), 1.10 (s, 2H), 0.97
(dd, J=7.9, 3.2 Hz, 2H), 0.78-0.34 (m, 4H).
[1315] LC-MS: m/z 473.4 (M+H).sup.+
Compound 748 (General Procedure 6)
5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-
-oxetan-2-yl)acetyl)piperazin-1-yl)nicotinonitrile
[1316] To a solution of
(R)-5-(2-chloropyridin-4-ylamino)-6-cyclopropyl-2-(3-cyclopropylpiperazin-
-1-yl)nicotinonitrile (300 mg, 0.761 mmol) in DMF (3 mL) was added
(R)-2-(oxetan-2-yl)acetic acid (115 mg, 0.99 mmol), HATU (436.0 mg,
1.142 mmol) and DIPEA (196.4 mg, 1.53 mmol) at r.t. The reaction
mixture was stirred at r.t. for 3 hs. The solvent was removed in
vacuum and the residue was purified via silica gel column
chromatography (DCM: MeOH) to afford the title compound (182 mg,
48.5%) as a pale yellow solid.
[1317] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.06 (d, J=5.7 Hz, 1H),
7.60 (s, 1H), 6.50 (d, J=1.8 Hz, 1H), 6.47 (dd, J=5.7, 2.0 Hz, 1H),
5.80 (s, 1H), 5.27 (dt, J=13.0, 6.5 Hz, 1H), 4.72 (dd, J=14.0, 8.0
Hz, 1H), 4.65-4.43 (m, 2H), 4.37 (d, J=13.2 Hz, 1H), 4.09 (d, J=7.2
Hz, 0.5H), 3.95 (d, J=15.5 Hz, 0.5H), 3.80-3.67 (m, 1H), 3.28 (ddd,
J=9.8, 9.1, 5.3 Hz, 1H), 3.16 (d, J=11.2 Hz, 6.5H), 3.13-3.03 (m,
1H), 2.98 (dd, J=15.2, 6.8 Hz, 1H), 2.93-2.78 (m, 2H), 2.78-2.66
(m, 0.5H), 2.66-2.47 (m, 1H), 2.10-2.02 (m, 1H), 1.28 (d, J=4.9 Hz,
1H), 1.15 (dt, J=7.3, 3.5 Hz, 2H), 1.04 (dt, J=7.0, 3.2 Hz, 2H),
0.77-0.38 (m, 4H).
[1318] LC-MS: m/z 494.0 (M+H).sup.+
Compound 662
(R)--N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin--
1-yl)pyridin-3-yl)--N-(2-vinylpyridin-4-yl)acetamide
##STR00861##
[1320] A solution of
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2--
vinylpyridin-4-ylamino)nicotinonitrile (200 mg, 0.448 mmol) in
acetic anhydride (5 mL) was heated and stirred at 135.degree. C.
overnight. The solvent was removed in vacuum and the residue was
purified via reverse phase silica gel column chromatography
(MeOH:H.sub.2O) to afford the title compound (16 mg, 7.3%) as a
pale yellow solid.
[1321] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.52 (d, J=5.5 Hz, 1H),
7.57 (s, 1H), 7.36 (d, J=5.3 Hz, 1H), 7.03 (d, J=5.2 Hz, 1H), 6.78
(dd, J=17.4, 10.8 Hz, 1H), 6.23 (d, J=17.3 Hz, 1H), 5.52 (d, J=10.9
Hz, 1H), 4.92 (s, 1H), 4.55 (d, J=11.4 Hz, 1H), 4.40-4.23 (m, 3H),
3.84 (d, J=12.8 Hz, 1H), 3.76 (t, J=6.3 Hz, 2H), 3.57 (t, J=11.0
Hz, 1H), 3.39 (s, 3H), 3.35 (s, 1H), 3.17 (dt, J=24.0, 11.2 Hz,
2H), 2.73 (ddd, J=23.2, 13.8, 6.3 Hz, 1H), 2.59 (dd, J=13.3, 7.2
Hz, 1H), 2.20-2.06 (m, 3H), 2.01 (dt, J=12.8, 6.2 Hz, 1H), 1.40 (d,
J=5.9 Hz, 2H), 1.29 (d, J=6.7 Hz, 2H), 1.16 (d, J=4.3 Hz, 3H), 1.03
(d, J=7.5 Hz, 1H).
[1322] LC-MS: m/z 489.3 (M+H).sup.+
Compound 758 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-(-
(4-vinylpyridin-2-yl)amino)nicotinonitrile
[1323] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.12 (d, J=5.4 Hz, 1H),
7.82 (d, J=5.7 Hz, 1H), 6.83 (d, J=5.4 Hz, 1H), 6.59 (dd, J=17.6,
10.8 Hz, 1H), 6.40 (s, 2H), 5.90 (d, J=17.5 Hz, 1H), 5.47 (d,
J=10.9 Hz, 1H), 4.71 (d, J=12.5 Hz, 0.5H), 4.45 (dd, J=16.5, 9.9
Hz, 1.5H), 4.33-4.22 (m, 1H), 3.85 (d, J=13.3 Hz, 0.5H), 3.82-3.70
(m, 2H), 3.57 (d, J=10.5 Hz, 0.5H), 3.49-3.41 (m, 0.5H), 3.39 (d,
J=3.3 Hz, 3H), 3.05 (dddd, J=21.0, 19.1, 13.7, 2.9 Hz, 2H),
2.82-2.54 (m, 2H), 2.27 (dd, J=16.7, 6.8 Hz, 0.5H), 2.18 (ddd,
J=12.8, 8.2, 4.8 Hz, 1H), 1.35-1.27 (m, 1H), 1.18-0.97 (m, 7H),
0.91 (d, J=6.8 Hz, 1.5H), 0.86 (d, J=6.8 Hz, 1.5H).
[1324] LC-MS: m/z 475.6 (M+H).sup.+
Compound 764 (General Procedure 7)
6-cyclopropyl-2-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1--
yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1325] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.10 (d, J=5.3 Hz, 1H),
7.81 (d, J=8.1 Hz, 1H), 6.82 (d, J=5.4 Hz, 1H), 6.69 (s, 1H), 6.58
(dd, J=17.6, 10.8 Hz, 1H), 6.39 (s, 1H), 5.89 (d, J=17.5 Hz, 1H),
5.46 (d, J=10.9 Hz, 1H), 5.32-5.24 (m, 1H), 4.83-4.61 (m, 1.5H),
4.56 (dtd, J=7.7, 5.8, 1.8 Hz, 1H), 4.48 (d, J=13.5 Hz, 0.5H),
4.46-4.39 (m, 1H), 4.27 (d, J=11.9 Hz, 1H), 3.88 (d, J=13.4 Hz,
0.5H), 3.56 (d, J=10.0 Hz, 0.5H), 3.45 (dd, J=13.4, 3.2 Hz, 0.5H),
3.13-2.92 (m, 3H), 2.92-2.75 (m, 2H), 2.65-2.44 (m, 1H), 2.31-2.24
(m, 0.5H), 2.21-2.10 (m, 2H), 1.16-1.07 (m, 2H), 1.05 (dd, J=6.5,
3.0 Hz, 3H), 1.04-0.98 (m, 2H), 0.92 (d, J=6.8 Hz, 1H), 0.86 (d,
J=6.8 Hz, 2H).
[1326] LC-MS: m/z 487.6 (M+H).sup.+
Compound 763 (General Procedure 7)
[1327] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.08 (d, J=5.6 Hz, 1H),
7.81 (s, 1H), 6.87 (d, J=5.6 Hz, 1H), 6.59 (dd, J=17.5, 10.9 Hz,
1H), 6.43 (s, 1H), 5.94 (d, J=17.6 Hz, 1H), 5.53 (d, J=10.9 Hz,
1H), 5.31-5.22 (m, 1H), 4.77-4.68 (m, 1H), 4.59-4.51 (m, 1H), 4.41
(s, 1H), 4.29-4.31 (m, 1 H), 4.10-4.03 (m, 1H), 3.96-3.89 (m,
0.5H), 3.74-3.76 (m, 1H), 3.10-3.41 (m, 3H), 2.83-2.90 (m, 2.5H),
2.54-2.55 (m, 1H), 2.18-2.20 (m, 1H), 1.35-1.36 (m, 1H), 1.14-1.16
(m, 2H), 1.04-1.06 (m, 2H), 0.38-0.49 (m, 4H).
[1328] LC-MS: m/z 485.6 (M+H).sup.+
Compound 756 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1329] To a solution of
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)--
5-((4-vinylpyridin-2-yl)amino)nicotinonitrile (180 mg, 0.46 mmol)
in 10 mL DMF was added sodium 3-hydroxypropanoate (104 mg, 0.92
mmol), and triethylamine (1 mL), HATU (350 mg, 0.92 mmol). The
resulting reaction mixture was stirred at r.t. for overnight. After
TLC showed the complete conversion of starting material to product,
the reaction mixture was concentrated and purified by Prep-HPLC
(50% EtOAc/petroleum ether) to get 100 mg title compound.
[1330] .sup.1H NMR (CHLOROFORM-d) .delta.8.11 (d, 1H), 7.86 (s,
1H), 7.65 (s, 1H), 6.82 (dd, 1H), 6.53-6.62 (m, 1H), 6.40 (s, 1H),
5.89 (d., 1H), 5.45 (s, 1H), 4.75 (m, 0.5H), 4.37-4.32 (dd, 2H),
3.92 (m, 0.5H), 3.39-3.05 (m, 3H), 2.61-2.60 (m, 2H), 2.20-1.69 (m,
1H), 1.28-1.26 (m, 1H), 1.40-1.00 (m, 4H), 0.47-0.45 (m, 4H).
[1331] LC-MS: m/z 4 459 (M+H).sup.+
Compound 656
(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-
-yl)pyridin-3-yl)-N-methoxy-N-methylbenzamide
##STR00862##
[1333] To a solution of
(R)-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin--
1-yl)pyridin-3-yl)benzoic acid (450 mg, 1 mmol) and
N,O-dimethylhydroxylammonium chloride (146 mg, 1.5 mmol) in DCM (10
mL) was added HATU(570 mg, 1.5 mmol) and DIPEA (516 mg, 4 mmol).
The resulting mixture was stirred at r.t. for 2 h. The organic
phase was washed with 1N HCl (10 mL.times.3), sat. NaHCO.sub.3 (20
mL.times.1) and brine, dried over Na.sub.2SO.sub.4 and concentrated
under vacuum to give 390 mg of the title compound as a white
solid.
[1334] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.71-7.85 (m, J=8.3 Hz,
2H), 7.64 (s, 1H), 7.39-7.50 (m, J=8.3 Hz, 2H), 4.92 (br. s.,
0.5H), 4.54 (d, J=12.3 Hz, 0.5H), 4.13-4.39 (m, 2.5H), 3.78-3.87
(m, 0.5H), 3.76 (br. s., 2H), 3.63 (s, 3H), 3.58 (d, J=10.3 Hz,
0.5H), 3.35-3.46 (m, 6H), 3.23-3.34 (m, 1H), 3.13 (br. s., 1H),
3.06 (d, J=12.5 Hz, 0.5H), 2.73 (br. s., 1H), 2.61 (br. s., 1H),
2.00-2.12 (m, 1H), 1.35-1.47 (m, 1.5H), 1.24-1.35 (m, 1.5H),
1.12-1.24 (m, 2H), 0.87-1.02 (m, 2H)
[1335] LC-MS: m/z 492.6 (M+H).sup.+
Compound 714 (General Procedure 7)
(R)-5-(bis(4-ethynylpyridin-2-yl)amino)-6-cyclopropyl-2-(4-(3-methoxypropa-
noyl)-3-methylpiperazin-1-yl)nicotinonitrile
[1336] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.29 (d, J=5.1 Hz, 2H),
7.59 (s, 1H), 7.12 (br. s., 2H), 7.03 (dd, J=5.1, 1.1 Hz, 2H), 4.92
(br. s., 0.5H), 4.54 (d, J=13.2 Hz, 0.5H), 4.14-4.36 (m, 2.5H),
3.76 (t, J=6.2 Hz, 2.5H), 3.49-3.66 (m, 0.5H), 3.39 (s, 3H),
3.20-3.35 (m, 3H), 3.14 (d, J=11.3 Hz, 1H), 3.06 (d, J=11.3 Hz,
0.5H), 2.65-2.84 (m, 1H), 2.52-2.65 (m, 1H), 1.86-1.99 (m, 1H),
1.22-1.38 (m, 3H), 0.95-1.08 (m, 2H), 0.68-0.82 (m, 2H)
[1337] LC-MS: m/z 546.6 (M+H).sup.+
Compound 713 (General Procedure 7)
(R)-6-cyclopropyl-5-(4-ethynylpyridin-2-ylamino)-2-(4-(3-methoxypropanoyl)-
-3-methylpiperazin-1-yl)nicotinonitrile
[1338] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.12 (d, J=5.4 Hz, 1H),
7.78 (s, 1H), 6.82 (dd, J=5.4, 1.1 Hz, 1H), 6.61 (br. s., 1H), 6.52
(s, 1H), 4.92 (br. s., 0.5H), 4.54 (d, J=13.4 Hz, 0.5H), 4.07-4.32
(m, 2.5H), 3.68-3.87 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.39 (s, 3H),
3.18-3.33 (m, 2H), 2.92-3.17 (m, 1.5H), 2.64-2.83 (m, 1H),
2.53-2.64 (m, 1H), 2.08-2.22 (m, 1H), 1.41 (d, J=6.2 Hz, 1.5H),
1.31 (d, J=6.4 Hz, 1.5H), 1.07-1.18 (m, 2H), 0.96-1.07 (m, 2H)
[1339] LC-MS: m/z 445.5 (M+H).sup.+
Compound 750 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-methoxyacetyl)piperazin-1-yl)-5-(4-
-ethynylpyridin-2-ylamino)nicotinonitrile
[1340] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.00 (d, J=5.9 Hz, 1H),
7.71 (s, 1H), 6.88 (dd, J=5.9, 1.2 Hz, 1H), 6.64 (s, 1H), 4.51 (d,
J=13.2 Hz, 1H), 4.37 (d, J=12.9 Hz, 1H), 4.17 (br. s., 2H), 4.01
(br. s., 0.5H), 3.89 (br. s., 0.5H), 3.71 (br. s., 0.5H), 3.40-3.52
(m, 4.5H), 3.22 (d, J=9.7 Hz, 1H), 3.02-3.16 (m, 1H), 2.09-2.20 (m,
1H), 1.03-1.22 (m, 4H), 0.67 (br. s., 2H), 0.47 (br. s., 4H)
[1341] LC-MS: m/z 457.5 (M+H).sup.+
Compound 647 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((4--
vinylpyridin-2-yl)amino)nicotinonitrile
[1342] To a solution of
(R)-5-amino-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile (140 mg, 0.41 mmol) and 2-chloro-4-vinylpyridine
(57 mg, 0.41 mmol) in 1,4-dioxane (15 mL) was added Pd2(dba)3 (56
mg, 0.061 mmol) and Xantphos (59 mg, 0.1 mmol) and Cs2CO3 (267 mg,
0.82 mmol) and the mixture was heated at 110.degree. C. under N2.
for 16 h. After TLC showed the complete conversion of starting
material to product, the reaction mixture was concentrated and
purified by column chromatography (DCM:MeOH=20:1) to afford 25 mg
of title compound COMPOUND 647 and 20 mg compound COMPOUND 646.
[1343] .sup.1H NMR (CHLOROFORM-d) .delta.: 7.94-7.93 (d, 1H), 7.68
(s, 1H), 6.84-6.82 (d, 1H), 6.58-6.51 (q, 1H), 6.38 (s, 1H),
5.95-5.90 (d, 1H), 5.55-5.52 (d, 1H), 4.87 (s, 0.5H), 4.54-4.51 (d,
0.5H); 4.48-4.13 (m, 3H) 3.79-3.70 (m, 2H) 3.44-3.35 (m, 1H) 3.25
(s, 3H), 3.11-2.98 (m, 3H), 2.77-2.56 (m, 2H), 2.17-2.12 (m, 1H),
1.38-1.13 (m, 3H), 1.09-1.00 (m, 2H), 0.99-0.98 (m, 2H).
[1344] LC-MS: m/z 447 (M+H).sup.+
Compound 646 (General Procedure 7)
(R)-5-(bis(4-vinylpyridin-2-yl)amino)-6-cyclopropyl-2-(4-(3-methoxypropano-
yl)-3-methylpiperazin-1-yl)nicotinonitrile
[1345] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.15-8.14 (d, 1H), 7.58
(s, 1H), 7.26-7.23 (d, 1H), 6.97-6.94 (dd, 1H), 6.79-6.72 (q, 1H),
6.03-5.98 (dd, 1H), 5.58 (s, 1H), 5.36-5.33 (dd, 1H), 4.88 (s,
0.5H), 4.54-4.51 (d, 0.5H); 4.20-4.09 (dd, 2H) 3.93 (s, 2H)
3.75-3.52 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.50 (m, 2H), 2.18-2.10
(m, 1H), 1.41-1.26 (m, 3H), 1.43-1.30 (m, 2H), 1.13-1.11 (m, 2H),
1.03-1.09 (m, 2H).
[1346] LC-MS: m/z 433 (M+H).sup.+
Compound 706 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1347] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.13 (d, 1H), 7.85 (s,
1H), 6.83 (dd, 1.2 Hz, 1H), 6.58 (dd, 10.7 Hz, 1H), 6.41 (s, 1H),
6.33 (br. s., 1H), 5.90 (d, 1H), 5.46 (d, 0.5H), 4.36 (d, 1H), 4.26
(d, Hz, 1H), 4.00-4.15 (m, 0.5H), 3.87 (d, 0.5H), 3.74 (t, 3H),
3.39 (s, 3H), 3.74-3.04 (m, 3H), 2.48-2.77 (m, 2H), 2.14-2.25 (m,
1H), 1.39 (br. s., 1H), 1.14 (t, 2H), 0.98-1.06 (m, 2H), 0.62-0.46
(d, 4H).
[1348] LC-MS: m/z 473 (M+H).sup.+
Compound 754 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-5-(-
2-vinylpyridin-4-ylamino)nicotinonitrile
[1349] .sup.1H NMR (DMSO-d.sub.6) .delta.: 8.08-8.20 (m, 1H), 7.92
(d, J=5.3 Hz, 1H), 6.67-6.84 (m, 2H), 6.64 (br. s., 1H), 6.25 (d,
J=16.7 Hz, 1H), 5.63 (br. s., 1H), 4.56 (t, J=5.3 Hz, 1.5H),
4.08-4.52 (m, 4.5H), 3.94 (d, J=13.5 Hz, 1H), 3.59-3.72 (m, 3.5H),
3.07-3.20 (m, 2H), 1.91-2.11 (m, 3H), 0.91-1.06 (m, 8H), 0.74 (d,
J=6.7 Hz, 3H)
[1350] LC-MS: m/z 461.6 (M+H).sup.+
Compound 707 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((4--
vinylpyridin-2-yl)amino)nicotinonitrile
[1351] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.11 (d, 1H), 7.84 (s,
1H), 7.28 (s, 1H), 6.74-6.92 (m, 1H), 6.67 (br. s., 1H), 6.58 (dd,
10.8 Hz, 1H), 6.41 (s, 1H), 5.90 (d, 1H), 5.47 (d, 1H), 4.89 (br.
s., 0.5H), 4.53 (d, 0.5H), 4.07-4.36 (m, 2H), 3.93 (br. s., 2H),
3.72-3.65 (m, 1H), 2.98-3.27 (m, 2.5H), 2.44-2.74 (m, 2.5H),
2.14-2.44 (m, 1H), 1.83-2.11 (m, 1.5H), 1.21-1.50 (m, 1.5H),
0.96-1.20 (m, 2H), 0.90 (t, 2H).
[1352] LC-MS: m/z 433 (M+H).sup.+
Compound 725 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-
-methyl-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1353] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.07 (d, J=5.3 Hz, 1H),
6.88 (br. s., 1H), 6.79 (dd, J=5.3, 1.2 Hz, 1H), 6.41-6.57 (m, 1H),
6.10 (s, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.43 (d, J=10.9 Hz, 1H),
4.71-4.62 (m, 2-0.5H), 4.16-4.34 (m, 2H), 4.07 (d, J=8.8 Hz, 0.5H),
3.92 (br. s., 3H), 3.77 (br. s., 1H), 3.21-3.12 (d, 2H), 2.54-2.68
(m, 2H), 2.41 (s, 3H), 2.14-2.31 (m, 1H), 1.03-1.13 (m, 2H),
0.89-1.01 (m, 2H), 0.32-0.57 (m, 4H).
[1354] LC-MS: m/z 473 (M+H).sup.+
Compound 682 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2--
methoxypyridin-4-yl)amino)nicotinonitrile
[1355] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.33 (s, 1H), 7.82 (s,
1H), 7.57 (s, 1H), 6.41-6.41 (d, 1H), 6.06 (s, 1H), 5.05 (m, 0.5H),
4.51-4.58 (m, 0.5H), 4.14 (s, 3H), 4.12 (m, 0.5H), 3.85 (m, 2H),
3.54-3.52 (m, 0.5H); 3.28 (s, 3H) 3.12-3.03 (m, 2H), 2.72-2.70 (m,
2H), 2.57-2.55 (m, 1H), 1.38-1.36 (m, 1.5H), 1.32 (m, 1.5H),
1.26-1.25 (m, 2H), 1.09-1.05 (m, 2H).
[1356] LC-MS: m/z 451 (M+H).sup.+
Compound 683 (General Procedure 7)
(R)-methyl
4-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)pyridin-3-yl)amino)picolinate
[1357] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.35 (s, 1H), 7.60 (s,
1H), 7.44 (s, 1H), 6.82 (s, 1H), 5.32-5.31 (m, 0.5H), 4.28-4.26 (m,
0.5H), 4.25-4.22 (m, 3H), 3.96 (s, 3H), 4.12 (m, 3H), 3.37 (s, 3H),
3.03-3.28 (m, 2H), 2.61-2.58 (m, 2H) 2.05-2.03 (m, 1H), 1.40-1.38
(m, 1.5H), 1.33-1.29 (m, 1.5H), 1.27-1.25 (m, 2H), 1.11-0.99 (m,
2H).
[1358] LC-MS: m/z 479 (M+H).sup.+
Compound 736 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((4--
vinylpyrimidin-2-yl)amino)nicotinonitrile
[1359] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.36 (d, 1H), 8.30 (s,
1H), 7.02-7.13 (m, 1H), 6.75 (d, 1H), 6.63 (dd, 10.6 Hz, 1H), 6.40
(d, 1H), 5.67 (d, 1H), 4.91 (br. s., 0.5H), 4.54 (d, 0.5H), 4.23
(br. s., 0.5H), 4.00-4.17 (m, 2H), 3.66-3.82 (m, 2H), 3.37-3.42 (m,
4H), 2.93-3.23 (m, 2H), 2.53-2.79 (m, 2H), 2.08-2.20 (m, 1H),
1.38-1.45 (m, 1.5H), 1.31 (d, 1.5H), 1.09-1.17 (m, 2H), 1.03 (dd,
2H).
[1360] LC-MS: m/z 448 (M+H).sup.+
Compound 705 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inyl-1,8-naphthyridin-4-ylamino)nicotinonitrile
[1361] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.99 (br. s., 1H), 8.55
(d, J=7.8 Hz, 1H), 7.64 (s, 1H), 7.39 (dd, J=8.3, 4.3 Hz, 1H), 6.82
(dd, J=17.1, 10.8 Hz, 1H), 6.38 (br. s., 1H), 6.30 (d, J=17.6 Hz,
1H), 5.59 (d, J=10.8 Hz, 1H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.6
Hz, 0.5H), 4.26 (d, J=11.3 Hz, 2H), 4.16 (d, J=13.3 Hz, 1H),
3.70-3.89 (m, 3H), 3.50-3.09 (m, 7H), 3.04 (d, J=12.3 Hz, 1H),
2.52-2.82 (m, 2.5H), 1.98-2.13 (m, 1.5H), 1.28-1.44 (m, 5H),
0.93-1.02 (m, 2H)
[1362] LC-MS: m/z 498.1 (M+H).sup.+
Compound 702
(R)--N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin--
1-yl)pyridin-3-yl)-N-(pyridin-4-yl)acryl amide
##STR00863##
[1363] Step 1:
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(py-
ridin-4-ylamino)nicotinonitrile
[1364] To a solution of
(R)-5-bromo-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile (406 mg, 1 mmol) and pyridin-4-amine (94 mg, 1
mmol) in 1,4-dioxane (5 mL) was added Pd(dba).sub.3 (136 mg, 0.15
mmol) and X-phos (72 mg, 0.15 mmol) and Cs.sub.2CO.sub.3 (752 mg, 2
mmol) at room temperature under N.sub.2. The resulting mixture was
heated and stirred at 120.degree. C. under N.sub.2 in microwave for
1.5 h. The solvent was removed in vacuum and the residue was
purified by column chromatography (MeOH/DCM=1/15) afforded 168 mg
of title compound as a yellow solid.
[1365] LC-MS: m/z 471.4 (M+H).sup.+
Step 2: Compound 702
(R)--N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin--
1-yl)pyridin-3-yl)-N-(pyridin-4-yl)acryl amide
[1366] To a solution of
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(py-
ridin-4-ylamino)nicotinonitrile (41 mg, 0.1 mmol) and
N,N-Diisopropylethylamine (26 mg, 0.2 mmol) in 5 mL of DCM was
added Acryloyl chloride (10 mg, 0.1 mmol) at room temperature. The
reaction mixture was then stirred at room temperature for 3 h.
After LC-MS showed the completion of reaction, the mixture was
poured into water and extracted with methylene chloride. The
combined organic layer was dried over anhy. Na.sub.2SO.sub.4 and
concentrated in vacuo. Column chromatography (MeOH/DCM=1/15)
afforded 12.6 mg of title compound as a colorless oil.
[1367] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.60 (d, J=4.8 Hz, 2H),
7.53 (s, 1H), 7.28 (s, 2H), 6.58 (d, J=16.7 Hz, 1H), 6.16 (d, J=5.1
Hz, 1H), 5.82 (d, J=10.5 Hz, 1H), 4.92 (m, 0.5H), 4.56 (m, 0.5H),
4.20-4.42 (m, 2H), 3.69-3.91 (m, 2H), 3.58 (m, 1H), 3.37-3.41 (m,
3H), 3.36 (br. s., 1H), 3.14 (br. s., 2H), 2.59 (d, J=5.9 Hz, 2H),
1.82-1.94 (m, 1H), 1.37-1.44 (m, 2H), 1.20-1.36 (m, 5H).
[1368] LC-MS: m/z 475.5 (M+H).sup.+
Compound 712
(R)--N-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin--
1-yl)pyridin-3-yl)-N-(quinolin-4-yl)acryl amide
[1369] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.96 (d, J=4.5 Hz, 1H),
8.26 (d, J=8.5 Hz, 1H), 7.93-8.03 (m, 1H), 7.84 (t, J=7.5 Hz, 1H),
7.70 (d, J=7.3 Hz, 1H), 7.44 (br. s., 1H), 7.30 (br. s., 1H), 6.61
(d, J=16.8 Hz, 1H), 6.16 (d, J=5.10 Hz, 1H), 5.82 (d, J=10.48 Hz,
1H), 4.88 (m, J=10.48 Hz, 0.5H), 4.52 (m, J=6.48 Hz, 0.5H), 4.27
(t, J=12.9 Hz, 2H), 3.74 (t, J=6.1 Hz, 2H), 3.52 (m, J=9.1 Hz, 1H),
3.37 (s, 3H), 3.29 (d, J=10.8 Hz, 1H), 3.12 (br. s., 2H), 2.72 (t,
J=9.8 Hz, 1H), 2.58 (t, J=5.8 Hz, 1H), 2.23 (t, J=7.7 Hz, 1H),
1.31-1.40 (m, 2H), 1.21-1.31 (m, 3H), 1.14 (br. s., 2H).
[1370] LC-MS: m/z 525.5 (M+H).sup.+
Compound 732 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-v-
inylquinolin-7-ylamino)nicotinonitrile
[1371] To a solution of
(R)-5-amino-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-y-
l)nicotinonitrile (34 mg, 0.1 mmol) and 7-bromo-2-vinylquinoline
(23 mg, 0.1 mmol) in 1,4-dioxane (1 mL) was added Pd(dba).sub.3
(13.6 mg, 0.015 mmol) and X-phos (7.2 mg, 0.15 mmol) and
Cs.sub.2CO.sub.3 (75.2 mg, 0.2 mmol) at room temperature under
N.sub.2. The resulting mixture was heated and stirred at
120.degree. C. under N.sub.2 in microwave for 1.5 h. The solvent
was removed in vacuum and the residue was purified by column
chromatography (MeOH/DCM=1/15) afforded 17.2 mg of title compound
as a colorless oil.
[1372] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.08 (d, J=8.2 Hz, 1H),
7.68 (d, J=8.8 Hz, 1H), 7.64 (s, 1H), 7.44 (d, J=8.5 Hz, 1H), 7.31
(br. s., 1H), 7.03-7.18 (m, 2H), 6.32 (d, J=17.6 Hz, 1H), 6.18 (br.
s., 1H), 5.74 (d, J=10.9 Hz, 1H), 4.92 (m, 0.5H), 4.54 (m, 0.5H),
4.09-4.33 (m, 2H), 3.71-3.86 (m, 2H), 3.57 (br. s., 1H), 3.40 (s,
3H), 3.25 (t, J=11.4 Hz, 1H), 3.13 (br. s., 2H), 2.75 (br. s., 1H),
2.53-2.64 (m, 1H), 2.14-2.27 (m, 1H), 1.40-1.47 (m, 1H), 1.24-1.35
(m, 2H), 1.12 (t, J=3.7 Hz, 2H), 0.97 (dd, J=7.9, 3.5 Hz, 2H).
[1373] LC-MS: m/z 497.4 (M+H).sup.+
Compound 665
(R)-methyl-4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipe-
razin-1-yl)pyridin-3-yl)benzoate
[1374] 1H NMR (CHLOROFORM-d) .delta. 8.12 (d, J=7.5 Hz, 2H), 7.63
(br. s., 1H), 7.48 (d, J=7.5 Hz, 2H), 4.47-4.61 (d, J=12.5 Hz,
0.5H), 4.19-4.37 (m, 2.5H), 3.96 (br. s., 3H), 3.75 (br. s., 2H),
3.47-3.61 (m, 1H), 3.38 (br. s., 3H), 3.28 (br. s., 1H), 3.01-3.18
(m, 1H), 2.65-2.79 (m, 1H), 2.60 (br. s., 1H), 1.96-2.10 (m, 1H),
1.72-1.91 (m, 1H), 1.38 (br. s., 1H), 1.28 (br. s., 2H), 1.18 (br.
s., 2H), 0.97 (br. s., 2H)
[1375] LC-MS: m/z 463.2 (M+H).sup.+
Compound 704 (General Procedure 8)
(R)-5-((2-chloropyridin-4-yl)oxy)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)--
3-methylpiperazin-1-yl)nicotinonitrile
[1376] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.29 (d, J=5.7 Hz, 1H),
7.47 (s, 1H), 6.83-6.77 (m, 2H), 4.90-4.91 (m, 1H), 4.53-4.55 (m,
1H), 4.20 (t, J=12.8 Hz, 3H), 3.92 (s, 2H), 3.79-3.70 (m, 1H), 3.55
(d, J=10.9 Hz, 1H), 3.31-3.20 (m, 1H), 3.14-2.99 (m, 1H), 2.55 (s,
2H), 2.01 (t, J=4.6 Hz, 1H), 1.87 (d, J=3.4 Hz, 1H), 1.43 (d, J=6.4
Hz, 1H), 1.32 (d, J=6.4 Hz, 2H), 1.12 (dd, J=7.9, 3.1 Hz, 2H), 1.03
(dt, J=7.9, 3.1 Hz, 2H).
[1377] LC-MS: m/z 442.1 (M+H).sup.+
Compound 695 (General Procedure 8)
(R)-5-((2-chloropyridin-4-yl)oxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-meth-
oxypropanoyl)piperazin-1-yl)nicotinonitrile
[1378] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.29 (d, J=5.6 Hz, 1H),
7.46 (s, 1H), 6.83-6.76 (m, 2H), 4.69-4.72 (m, 0.5H), 4.40 (d,
J=12.6 Hz, 1H), 4.28 (d, J=12.7 Hz, 1H), 4.13 (dd, J=14.3, 7.2 Hz,
1H), 3.88 (d, J=12.0 Hz, 1H), 3.78-3.64 (m, 3H), 3.38 (s, 3H), 3.18
(d, J=13.1 Hz, 1H), 3.04 (d, J=26.4 Hz, 1H), 2.74-2.57 (m, 2H),
2.48-2.50 (m, 0.5H), 1.98-2.04 (m, 1H), 1.35 (t, J=10.7 Hz, 1H),
1.13 (dd, J=7.4, 3.1 Hz, 2H), 1.02 (dt, J=7.9, 3.1 Hz, 2H), 0.59
(d, J=30.2 Hz, 2H), 0.45-0.48 (m, 2H).
[1379] LC-MS: m/z 482.1 (M+H).sup.+
Compound 694 (General Procedure 8)
(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydrox-
ypropanoyl)piperazin-1-yl)nicotinonitrile
[1380] A mixture of
(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropylpiperazin-1-
-yl)nicotinonitrile (3, general procedure 8 scheme) (0.35 g, 0.88
mol), sodium 3-hydroxypropanoate (0.10 g, 0.88 mol), HATU (0.5 g,
1.32 mmol) and 0.23 g DIEA (1.76 mmol) was stirred in 8 mL DMF for
4 hrs. Then the mixture was quenched by adding 6 mL water and
extracted with EtOAc (15 mL.times.2), the organic phase was
combined and concentrated to give a yellow oil, which was further
purified by silica gel chromatography (DCM:MeOH=20:1) to give 0.10
g of product as yellow solid (52% yield).
[1381] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.30 (d, J=5.6 Hz, 1H),
7.48-7.49 (m, 0.5H), 6.81 (dt, J=5.6, 2.0 Hz, 2H), 4.70 (s, 1H),
4.41 (d, J=13.0 Hz, 1H), 4.29 (d, J=13.0 Hz, 1H), 4.12 (dd, J=18.6,
7.4 Hz, 1H), 3.93 (s, 2H), 3.84-3.67 (m, 1H), 3.18 (d, J=12.8 Hz,
1H), 3.13-2.99 (m, 1H), 2.61 (s, 2H), 2.32-2.22 (m, 0.5H), 2.02 (t,
J=4.6 Hz, 1H), 1.35 (s, 1H), 1.29 (d, J=9.4 Hz, 3H), 1.14 (dd,
J=7.4, 3.0 Hz, 2H), 1.04 (dt, J=7.9, 3.1 Hz, 2H), 0.66-0.67 (m,
2H), 0.46-0.51 (m, 2H).
[1382] LC-MS: m/z 468.1 (M+H).sup.+
Compound 692 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-(2-vinylpyridin-4-yloxy)nicotinonitrile
[1383] A mixture of
(R)-5-(2-chloropyridin-4-yloxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydro-
xy propanoyl)piperazin-1-yl)nicotinonitrile (4) 0.35 g, (0.75
mmol), potassium trifluoro(vinyl)borate (0.15 g, 1.1 mmol),
PdCl.sub.2dppf (80 mg, 0.075 mmol) and DIEA (0.24 mL, 1.5 mmol) was
heated in isopropanol at reflux at 85.degree. C. under nitrogen for
5 hrs. The mixture was then concentrated under reduced pressure to
give a yellow solid which was further purified by silica
chromatography (PE/EA/MeOH=150/120/8) to give 0.19 g of product as
a white solid (55% yield).
[1384] .sup.1H NMR (CHLOROFORM-d) .delta.:8.47 (d, J=5.6 Hz, 1H),
7.48-7.49 (m, 0.5H), 6.86 (d, J=2.3 Hz, 1H), 6.77 (dd, J=17.4, 10.8
Hz, 1H), 6.66 (dd, J=5.6, 2.4 Hz, 1H), 6.22 (dd, J=17.4, 0.9 Hz,
1H), 5.53 (dd, J=10.8, 0.8 Hz, 1H), 4.68 (d, J=11.7 Hz, 1H), 4.38
(d, J=12.9 Hz, 1H), 4.30-4.22 (m, 1H), 4.15-4.04 (m, 1H), 3.92 (s,
2H), 3.75 (d, J=20.7 Hz, 1H), 3.47 (d, J=21.7 Hz, 1H), 3.25-3.12
(m, 1H), 3.09-2.95 (m, 1H), 2.60 (s, 2H), 2.32-2.22 (m, 0.5H),
2.11-2.05 (m, 1H), 1.37 (d, J=20.5 Hz, 1H), 1.27 (d, J=2.0 Hz, 1H),
1.16-1.10 (m, 2H), 1.01 (ddd, J=10.1, 6.7, 3.3 Hz, 2H), 0.65 (t,
J=33.7 Hz, 2H), 0.45-0.48 (m, 2H).
[1385] LC-MS: m/z 460.1 (M+H).sup.+
Compound 693 (General Procedure 8)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-(2-vinylpyridin-4-yloxy)nicotinonitrile
[1386] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.46 (d, J=5.6 Hz, 1H),
7.46 (s, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.77 (dd, J=17.4, 10.8 Hz,
1H), 6.66 (dd, J=5.6, 2.4 Hz, 1H), 6.22 (d, J=17.4 Hz, 1H), 5.53
(d, J=10.9 Hz, 1H), 4.54-4.71 (m, 0.5H), 4.37 (d, J=12.4 Hz, 1H),
4.26 (d, J=12.6 Hz, 1H), 4.11 (s, 1H), 3.88 (d, J=11.9 Hz, 1H),
3.80-3.68 (m, 3H), 3.38 (s, 3H), 3.20 (t, J=23.2 Hz, 1H), 3.05 (s,
1H), 2.68 (dd, J=15.1, 12.2 Hz, 2H), 2.47-2.53 (m, 0.5H), 2.06 (dd,
J=8.6, 3.9 Hz, 1H), 1.38-1.28 (m, 1H), 1.13 (dd, J=7.4, 3.1 Hz,
2H), 1.01 (dt, J=7.9, 3.2 Hz, 2H), 0.73-0.51 (m, 2H), 0.43-0.46 (m,
2H).
[1387] LC-MS: m/z 476.1 (M+H).sup.+
Compound 668 (General Procedure 8)
(R)-5-((2-chloropyridin-4-yl)oxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)--
3-methylpiperazin-1-yl)nicotinonitrile
[1388] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.33 (s, 1H), 7.47 (s,
1H), 6.85 (s, 2H), 4.93-5.05 (m, 0.5H), 4.56-4.58 (m, 0.5H),
4.33-4.09 (m, 3H), 3.88-3.68 (m, 3H), 3.57 (s, 1H), 3.40 (s, 3H),
3.30 (s, 1H), 3.10 (dd, J=36.0, 11.2 Hz, 1H), 2.82-2.48 (m, 1H),
1.42 (d, J=6.5 Hz, 2H), 1.36-1.29 (m, 2H), 1.14 (s, 2H), 1.03-1.05
(m, 2H).
[1389] LC-MS: m/z 456.0 (M+H).sup.+
Compound 666 (General Procedure 8)
(R)-5-((6-chloropyrimidin-4-yl)oxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl-
)-3-methylpiperazin-1-yl)nicotinonitrile
[1390] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.33 (s, 1H), 7.47 (s,
1H), 6.85 (s, 2H), 4.92-4.96 (m, 0.5H), 4.55-4.58 (m, 0.5H),
4.33-4.09 (m, 3H), 3.88-3.68 (m, 2H), 3.57 (s, 1H), 3.40 (s, 3H),
3.30 (s, 1H), 3.10 (dd, J=36.0, 11.2 Hz, 1H), 2.82-2.48 (m, 1H),
1.42 (d, J=6.5 Hz, 2H), 1.36-1.29 (m, 2H), 1.14 (s, 2H), 1.03 (d,
J=4.1 Hz, 2H).
[1391] LC-MS: m/z 449.0 (M+H).sup.+
Compound 734 (General Procedure 8)
(R)-5-((4-chloropyridin-2-yl)oxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydr-
oxypropanoyl)piperazin-1-yl)nicotinonitrile
[1392] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.07 (d, J=6.0 Hz, 1H),
7.54 (s, 1H), 7.09-7.05 (m, 2H), 4.60-4.68 (m, 1H), 4.31-4.35 (m,
1H), 4.21 (d, J=13.0 Hz, 1H), 4.07 (d, J=9.8 Hz, 1H), 3.92 (s, 2H),
3.74 (d, J=11.5 Hz, 1H), 3.48 (d, J=24.4 Hz, 1H), 3.21-3.07 (m,
1H), 3.03 (d, J=10.9 Hz, 1H), 2.58 (d, J=17.5 Hz, 2H), 2.15-2.00
(m, 1H), 1.44 (s, 1H), 1.13 (dd, J=7.3, 3.6 Hz, 2H), 0.98 (dt,
J=6.8, 2.7 Hz, 2H), 0.65 (s, 2H), 0.45-0.48 (m, 2H).
[1393] LC-MS: m/z 469.2 (M+H).sup.+
Compound 733 (General Procedure 8)
(R)-5-((4-chloropyridin-2-yl)oxy)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydr-
oxypropanoyl)piperazin-1-yl)nicotinonitrile
[1394] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.10 (d, J=5.3 Hz, 1H),
7.53 (s, 1H), 7.07 (dd, J=5.3, 1.1 Hz, 1H), 6.97 (s, 1H), 6.70 (dd,
J=17.6, 10.9 Hz, 1H), 6.01 (d, J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz,
1H), 4.69-4.71 (m, 0.5H), 4.28 (d, J=12.4 Hz, 1H), 4.18 (d, J=12.5
Hz, 1H), 4.09 (d, J=8.0 Hz, 1H), 3.80-3.90 (m, 0.5H), 3.72 (dd,
J=13.7, 7.8 Hz, 3H), 3.39 (d, J=5.9 Hz, 3H), 3.27 (s, 1H), 3.09 (d,
J=12.5 Hz, 1H), 2.97 (s, 1H), 2.73-2.59 (m, 2H), 2.18-2.10 (m, 1H),
1.12 (d, J=4.0 Hz, 2H), 0.96 (ddd, J=9.2, 8.5, 5.1 Hz, 3H), 0.89
(dd, J=13.9, 6.8 Hz, 2H), 0.62 (s, 2H), 0.45-0.47 (m, 2H).
[1395] LC-MS: m/z 474.2 (M+H).sup.+
Compound 832 (General Procedure 8)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2--
vinylpyridin-4-yl)oxy)nicotinonitrile
##STR00864##
[1397] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.47 (d, J=5.6 Hz, 1H),
7.44 (d, J=3.5 Hz, 1H), 6.88 (s, 1H), 6.84-6.74 (m, 1H), 6.69 (d,
J=3.5 Hz, 1H), 6.28 (d, J=17.4 Hz, 1H), 5.58 (d, J=10.7 Hz, 1H),
4.89-4.91 (m, 0.5H), 4.50-4.54 (m, 0.5H), 4.23-4.06 (m, 2H),
3.82-3.68 (m, 2H), 3.50-3.53 (m, 0.5H), 3.37 (s, 3H), 3.26 (d,
J=12.7 Hz, 1H), 3.05-3.10 (m, 1.5H), 2.78-2.52 (m, 2H), 2.05-1.93
(m, 1H), 1.39 (d, J=6.0 Hz, 1H), 1.32-1.25 (m, 3H), 1.14-1.08 (m,
2H), 0.99 (dt, J=11.5, 3.3 Hz, 2H).
[1398] LC-MS: m/z 448.0 (M+H).sup.+
Compound 703 (General Procedure 8)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2--
vinylpyridin-4-yl)methoxy)nicotinonitrile
[1399] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.61 (d, J=5.0 Hz, 1H),
7.39 (s, 1H), 7.21-7.26 (m, 1H), 7.18 (s, 1H), 6.85 (dd, J=17.4,
10.9 Hz, 1H), 6.26 (dd, J=17.4, 1.1 Hz, 1H), 5.47-5.61 (m, 1H),
5.06 (s, 2H), 4.88 (br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.21
(d, J=6.8 Hz, 0.5H), 3.85-4.05 (m, 2H), 3.67-3.81 (m, 2.5H), 3.54
(d, J=6.8 Hz, 0.5H), 3.37 (s, 3H), 3.04-3.18 (m, 1.5H), 2.84-3.04
(m, 1H), 2.63-2.80 (m, 1H), 2.44-2.63 (m, 2H), 1.22-1.36 (m, 3H),
1.03-1.17 (m, 4H)
[1400] LC-MS: m/z 461.6 (M+H).sup.+
Compound 789
5-(1-acryloyl-1,2,5,6-tetrahydropyridin-3-yl)-6-cyclopropyl-2-((R)-3-cyclo-
propyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1-yl)-4-methylnicotinonitril-
e
[1401] 1H NMR (CHLOROFORM-d) 6.67 (dd, J=16.7, 10.6 Hz, 1H), 6.35
(dd, J=16.7, 7.0 Hz, 1H), 5.64-5.85 (m, 2H), 5.26 (m, 6.6 Hz, 1H),
4.66-4.79 (m, 1H), 4.56 (br. s., 1H), 4.23-4.39 (m, 2H), 4.18 (d,
J=12.6 Hz, 1H), 3.95-4.11 (m, 2H), 3.90 (d, J=17.9 Hz, 1H),
3.63-3.83 (m, 2H), 3.27 (br. s., 1H), 3.08 (br. s., 1H), 2.96 (d,
J=10.3 Hz, 2H), 2.79-2.92 (m, 2H), 2.53 (d, J=7.9 Hz, 1H),
2.31-2.48 (m, 5H), 2.04 (dd, J=13.4, 6.0 Hz, 1H), 1.44 (d, J=8.2
Hz, 1H), 1.15 (br. s., 1H), 0.85-1.07 (m, 3H), 0.60 (br. s., 1H),
0.52 (br. s., 1H), 0.44 (br. s., 2H)
[1402] LC-MS: m/z 516.6 (M+H)
Compound 778
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-5-(1-methyl-6-vinyl-1H-pyrazolo[3,4-b]pyridin-4-yl)nicotinonitrile
[1403] .sup.1H NMR (CHLOROFORM-d) 7.86-7.94 (s, 1H), 7.71-7.81 (s,
1H), 7.22 (s, 1H), 6.99 (dd, J=17.6, 10.9 Hz, 1H), 6.28-6.48 (m,
1H), 5.66 (dd, J=10.9, 0.9 Hz, 1H), 5.28 (t, J=6.7 Hz, 1H),
4.68-4.78 (m, 1H), 4.54-4.68 (m, 2H), 4.48 (d, J=14.1 Hz, 1H), 4.21
(s, 3H), 3.75-4.17 (m, 2H), 2.77-3.35 (m, 6H), 2.45-2.65 (m, 1H),
1.85-2.01 (m, 2H), 1.18-1.25 (m, 2H), 0.95-1.05 (m, 2H), 0.61-0.81
(m, 1H), 0.57 (br. s., 1H), 0.48 (br. s., 2H)
[1404] LC-MS: m/z 524.2 (M+H).sup.+
Compound 777
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-
-methyl-5-((2-vinylpyridin-4-yl)oxy)nicotinonitrile
[1405] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.48 (d, J=5.7 Hz,
1H), 6.93-6.75 (m, 2H), 6.65 (d, J=3.7 Hz, 1H), 6.30 (d, J=17.4 Hz,
1H), 5.60 (d, J=10.7 Hz, 1H), 4.60-4.71 (m, 0.5H), 4.27-4.28 (m,
1H), 4.23-4.14 (m, 1H), 4.10-4.15 (m, 0.5H), 3.92-3.93 (m, 2H),
3.78-3.79 (m, 1H), 3.44-3.45 (m, 1H), 3.26-3.10 (m, 1H), 3.04-3.05
(m, 1H), 2.61-2.62 (m, 2H), 2.31 (s, 3H), 2.01-1.94 (m, 1H),
1.44-1.45 (m, 1H), 1.13-1.07 (m, 2H), 1.01-0.94 (m, 2H), 0.91-0.86
(m, 1H), 0.65-0.66 (m, 1H), 0.46-0.52 (m, 2H). MS (ES) M+H expected
474.0, found 474.6
Compound 833
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-((5-vinylpyridazin-3-yl)amino)nicotinonitrile
##STR00865##
[1407] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (s, 1H), 7.76
(s, 1H), 6.58 (dd, J=17.6, 11.0 Hz, 2H), 6.05 (d, J=17.6 Hz, 1H),
5.66 (d, J=11.0 Hz, 1H), 4.65-4.70 (m, 0.5H), 4.43-4.46 (m, 1H),
4.33 (d, J=12.4 Hz, 1H), 4.16-4.07 (m, 1H), 3.87-3.88 (m, 0.5H),
3.71-3.74 (m, 3H), 3.39 (s, 3H), 3.20 (s, 1H), 3.07-3.09 (m, 1H),
2.65-2.66 (m, 2H), 2.55-2.47 (m, 1H), 2.18 (d, J=10.1 Hz, 1H),
1.30-1.25 (m, 1H), 1.15 (s, 2H), 1.07-0.98 (m, 2H), 0.50-0.60 (m,
2H), 0.45-0.47 (m, 2H). MS (ES) M+H expected 474.0, found 474.6
Compound 792
(R)-5-(4-cyanopyridin-2-ylamino)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-metho-
xypropanoyl)piperazin-1-yl)nicotinonitrile
[1408] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.: 8.31 (d, J=5.0
Hz, 1H), 7.80-7.69 (m, 1H), 6.94 (dd, J=1.3, 5.1 Hz, 1H), 6.59 (s,
1H), 6.51 (s, 1H), 4.34 (d, J=12.6 Hz, 2H), 4.14-3.65 (m, 4H), 3.39
(s, 3H), 2.61-3.23 (m, 5H), 2.15-2.05 (m, 1H), 1.20-1.11 (m, 2H),
1.04 (td, J=3.0, 7.8 Hz, 2H), 0.45 (d, J=5.3 Hz, 5H) LC_MS
(M+1).sup.+472.5
Compound 783
4-(5-cyano-2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl-
)piperazin-1-yl)pyridin-3-ylamino)picolinonitrile
[1409] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.: 8.30 (d, J=5.9
Hz, 1H), 7.59 (s, 1H), 6.92 (d, J=2.3 Hz, 1H), 6.77-6.62 (m, 2H),
5.27 (t, J=6.7 Hz, 1H), 4.75-4.65 (m, 1H), 4.62-4.51 (m, 1H), 4.47
(d, J=12.6 Hz, 1H), 4.37 (d, J=12.6 Hz, 1H), 4.07 (d, J=7.9 Hz,
1H), 3.65-3.75 (m, 1H), 3.30-3.04 (m, 2H), 2.98 (s, 1H), 2.92-2.72
(m, 3H), 2.62-2.44 (m, 1H), 2.05-1.98 (m, 1H), 1.08-0.99 (m, 2H),
0.93-0.80 (m, 4H), 0.63 (br. s., 1H), 0.52 (br. s., 1H), 0.48-0.36
(m, 1H)
[1410] LC_MS (M+1).sup.+484.6
Compound 774
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((S)-oxetan-2-yl)acetyl)piperazin--
1-yl)-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile
[1411] .sup.1H NMR (CHLOROFORM-d) .delta. 8.23 (d, J=5.9 Hz, 1H),
7.62 (s, 1H), 6.72 (dd, J=17.4, 10.9 Hz, 1H), 6.63 (s, 1H), 6.55
(s, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.54 (d, J=10.7 Hz, 1H),
5.34-5.22 (m, 1H), 4.73 (dd, J=14.6, 8.2 Hz, 1H), 4.56 (dt, J=9.1,
5.8 Hz, 1H), 4.47 (d, J=12.9 Hz, 1H), 4.34 (d, J=13.2 Hz, 1H), 4.09
(d, J=10.0 Hz, 0.5H), 3.89 (d, J=13.3 Hz, 0.5H), 3.80-0.64 (m, 1H),
3.42-3.15 (m, 2H), 3.15-2.78 (m, 3H), 2.75-2.34 (m, 2H), 2.10 (ddd,
J=12.7, 8.1, 4.7 Hz, 1H), 1.29 (dd, J=6.7, 4.8 Hz, 1H), 1.18-1.10
(m, 2H), 1.03 (dd, J=7.7, 3.2 Hz, 2H), 0.81-0.53 (m, 2H), 0.52-0.38
(m, 2H).
[1412] LC-MS: m/z NB295-063-01 485.1 (M+H).sup.+
Compound 791
(R,E)-6-cyclopropyl-2-(4-(5-hydroxypent-2-enoyl)-3-isopropylpiperazin-1-yl-
)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1413] .sup.1H NMR (CHLOROFORM-d) .delta. 8.10 (d, J=5.3 Hz, 1H),
7.81 (s, 1H), 6.90 (tt, J=14.6, 7.3 Hz, 1H), 6.82 (d, J=5.3 Hz,
1H), 6.79-6.63 (m, 1H), 6.58 (dd, J=17.6, 10.8 Hz, 1H), 6.41 (d,
J=14.1 Hz, 2H), 5.89 (d, J=17.5 Hz, 1H), 5.46 (d, J=10.8 Hz, 1H),
4.76-4.64 (m, 0.5H), 4.55-4.37 (m, 1.5H), 4.26 (t, J=11.6 Hz, 1H),
4.18 (d, J=5.2 Hz, 0.5H), 3.95 (d, J=13.7 Hz, 0.5H), 3.81 (t, J=6.0
Hz, 2H), 3.67 (d, J=9.3 Hz, 0.5H), 3.54-3.42 (m, 0.5H), 3.29-3.16
(m, 0.5H), 3.16-2.96 (m, 2.5H), 2.52 (dd, J=13.0, 6.4 Hz, 2H),
2.36-2.24 (m, 0.5H), 2.24-2.11 (m, 1.5H), 1.18-1.08 (m, 2H), 1.07
(d, J=6.5 Hz, 3H), 1.04-0.98 (m, 2H), 0.93-0.84 (m, 3H).
[1414] LC-MS: m/z NB295-055-02 487.7 (M+H).sup.+
Compound 790
(R)-6-cyclopropyl-2-(4-(5-hydroxypent-2-enoyl)-3-isopropylpiperazin-1-yl)--
5-(2-vinylquinoxalin-5-yl)nicotinonitrile
[1415] .sup.1H NMR (400 MHz, CHLOROFORM-d) .delta.: 9.02 (s, 1H),
8.19-8.09 (m, 1H), 7.91-7.80 (m, 1 H), 7.76-7.67 (m, 2H), 7.08 (dd,
J=11.2, 17.6 Hz, 1H), 6.98-6.82 (m, 0.5H), 6.57-6.37 (m, 1.5H),
5.97-5.73 (m, 2H), 4.70-4.35 (m, 3.5H), 4.23-4.16 (m, 1H),
3.86-3.75 (m, 1.5H), 3.60-3.42 (m, 1H), 3.32-3.05 (m, 4H),
2.58-2.48 (m, 1H), 2.37-2.18 (m, 1H), 1.32-1.23 (m, 2H), 1.16-1.05
(m, 3H), 0.98-0.72 (m, 6H)
[1416] LC_MS (M+1).sup.+523.7
Compound 794
2-cyclopropyl-6-((R)-3-cyclopropyl-4-(3-((R)-oxetan-2-yl)propanoyl)piperaz-
in-1-yl)-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1417] .sup.1H NMR (CHLOROFORM-d) .delta. 8.63 (d, J=5.3 Hz, 1H),
7.63 (s, 1H), 7.38 (s, 1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.86 (dd,
J=17.3, 10.9 Hz, 1H), 6.26 (d, J=17.3 Hz, 1H), 5.55 (d, J=10.9 Hz,
1H), 4.86 (s, 1H), 4.60-4.74 (m, 1H), 4.46-4.60 (m, 2H), 4.40 (d,
J=12.9 Hz, 1H), 4.07 (s, 1H), 3.82 (s, 1H), 3.69 (s, 1H), 3.12-3.42
(m, 2H), 2.99-3.10 (m, 1H), 2.48-2.63 (m, 3H), 1.96-2.24 (m, 3H),
1.19 (m, 2H), 0.93-1.02 (m, 2H), 0.33-0.54 (m, 4H)
[1418] LC-MS: m/z 484.3 (M+H).sup.+
Compound 785
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-4-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile
[1419] .sup.1H NMR (CHLOROFORM-d) .delta. 9.01 (d, J=1.8 Hz, 1H),
7.50 (d, J=2.1 Hz, 1H), 7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.36 (d,
J=17.9 Hz, 1H), 5.79 (d, J=11.2 Hz, 1H), 5.27 (t, J=6.7 Hz, 1H),
4.66-4.79 (m, 1H), 4.51-4.63 (m, 1H), 4.41 (d, J=12.6 Hz, 1H), 4.09
(d, J=7.6 Hz, 1H), 3.95 (d, J=12.6 Hz, 1H), 3.79 (d, J=10.9 Hz,
1H), 2.92-3.32 (m, 4H), 2.84-2.92 (m, 1H), 2.46-2.61 (m, 1H), 2.24
(s, 3H), 2.04 (dd, J=15.1, 7.5 Hz, 1H), 1.43-1.50 (m, 1H),
1.09-1.19 (m, 2H), 0.83-0.91 (m, 2H), 0.35-0.62 (m, 4H)
[1420] LC-MS: m/z 485.3 (M+H).sup.+
Compound 786
6-cyclopropyl-2-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1--
yl)-4-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile
[1421] .sup.1H NMR (CHLOROFORM-d) .delta. 9.01 (s, 1H), 7.50 (s,
1H), 7.12 (dd, J=17.9, 11.2 Hz, 1H), 6.36 (d, J=17.9 Hz, 1H), 5.78
(d, J=11.2 Hz, 1H), 5.23-5.31 (m, 1H), 4.64-4.78 (m, 1H), 4.39-4.63
(m, 3H), 4.34 (d, J=12.6 Hz, 1H), 3.91 (d, J=13.5 Hz, 1H),
3.43-3.65 (m, 1H), 2.92-3.17 (m, 4H), 2.82-2.91 (m, 1H), 2.44-2.66
(m, 1H), 2.22 (s, 3H), 2.07-2.17 (m, 1H), 1.91-2.04 (m, 1H),
1.38-1.58 (m, 1H), 1.00-1.15 (m, 3H), 0.85-0.94 (m, 6H)
[1422] LC-MS: m/z 487.3 (M+H).sup.+
Compound 776
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-4-
-methyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile
[1423] .sup.1H NMR (CHLOROFORM-d) .delta. 9.01 (d, J=1.8 Hz, 1H),
7.50 (d, J=1.8 Hz, 1H), 7.13 (dd, J=17.8, 11.0 Hz, 1H), 6.37 (d,
J=17.6 Hz, 1H), 5.80 (d, J=11.2 Hz, 1H), 4.41 (d, J=13.2 Hz, 1H),
4.32 (d, J=12.9 Hz, 1H), 4.09 (d, J=7.0 Hz, 1H), 3.93 (s, 2H),
3.68-3.84 (m, 2H), 3.13-3.37 (m, 2H), 3.09 (d, J=8.5 Hz, 1H),
2.54-2.67 (m, 2H), 2.24 (s, 3H), 1.45-1.49 (m, 1H), 1.07-1.19 (m,
2H), 0.92 (dd, J=12.5, 6.3 Hz, 2H), 0.47-0.67 (m, 4H)
[1424] LC-MS: m/z 459.2 (M+H).sup.+
Compound 793
6-cyclopropyl-2-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1--
yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1425] .sup.1H NMR (CHLOROFORM-d) .delta. 9.27 (br. s., 1H), 7.43
(br. s., 1H), 6.73 (dd, J=17.6, 11.2 Hz, 1 H), 6.20 (d, J=17.6 Hz,
1H), 5.77 (d, J=10.9 Hz, 1H), 5.28 (m, 1H), 4.63-4.78 (m, 1H),
4.30-4.60 (m, 3.5H), 3.87 (d, J=13.2 Hz, 0.5H), 3.41-3.61 (m, 1H),
2.88-3.18 (m, 4H), 2.72-2.88 (m, 2H), 2.41-2.65 (m, 1H), 2.22 (s,
3H), 2.01-2.16 (m, 1H), 1.38-1.51 (m, 1H), 1.12 (d, J=16.4 Hz, 2H),
0.98-1.05 (m, 3H), 0.75-0.98 (m, 6H)
[1426] LC-MS: m/z 487.1 (M+H)
Compound 784
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-4-m-
ethyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1427] .sup.1H NMR (CHLOROFORM-d) .delta. 9.28 (d, J=2.1 Hz, 1H),
7.44 (d, J=2.1 Hz, 1H), 6.75 (dd, J=17.6, 10.9 Hz, 1H), 6.21 (d,
J=17.6 Hz, 1H), 5.79 (d, J=11.2 Hz, 1H), 4.40-4.55 (m, 1.5H), 4.35
(d, J=11.2 Hz, 1H), 3.94 (t, J=4.8 Hz, 2H), 3.67-3.81 (m, 0.5H),
3.41-3.57 (m, 1H), 3.01-3.21 (m, 3H), 2.57-2.66 (m, 2H), 2.28 (s,
3H), 1.63-1.67 (m, 1H), 1.12-1.16 (m, 2H), 1.01-1.09 (m, 3H),
0.79-0.98 (m, 6H)
[1428] LC-MS: m/z 461.1 (M+H)
Compound 780
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((S)-oxetan-2-yl)acetyl)piperazin--
1-yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1429] .sup.1H NMR (CHLOROFORM-d) .delta. 9.27 (d, J=2.1 Hz, 1H),
7.43 (d, J=2.3 Hz, 1H), 6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.20 (d,
J=17.6 Hz, 1H), 5.77 (d, J=10.9 Hz, 1H), 5.20-5.29 (m, 1H),
4.68-4.78 (m, 1H), 4.51-4.68 (m, 1H), 4.43 (d, J=12.9 Hz, 1H), 4.33
(d, J=12.0 Hz, 1H), 4.07 (d, J=9.1 Hz, 0.5H), 3.81-3.93 (m, 0.5H),
3.69-3.81 (m, 0.5H), 3.09-3.28 (m, 3.5H), 2.81-3.01 (m, 3H), 2.55
(m, 1H), 2.30 (s, 3H), 1.82 (br. s., 1H), 1.41-1.54 (m, 1H), 1.15
(br. s., 2H), 0.88 (m, 2H), 0.43-0.72 (m, 4H)
[1430] LC-MS: m/z 485.1 (M+H)
Compound 779
(R)-5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl-
)-[3,4'-bipyridin]-2'-yl trifluoromethanesulfonate
[1431] .sup.1H NMR (CHLOROFORM-d) .delta. 8.49 (d, J=5.0 Hz, 1H),
7.65 (s, 1H), 7.46 (dd, J=5.1, 1.3 Hz, 1H), 7.23-7.28 (m, 1H), 4.92
(br. s., 0.5H), 4.55 (d, J=10.3 Hz, 0.5H), 4.23-4.47 (m, 2.5H),
3.68-3.88 (m, 2.5H), 3.49-3.65 (m, 0.5H), 3.31-3.45 (m, 4H),
3.05-3.29 (m, 1.5H), 2.64-2.80 (m, 1H), 2.53-2.64 (m, 1H),
1.90-2.03 (m, 1H), 1.38 (d, J=6.2 Hz, 1.5H), 1.18-1.33 (m, 3.5H),
1.02-1.13 (m, 2H)
[1432] LC-MS: m/z 554.1 (M+H)
Compound 773
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-4-m-
ethyl-5-(6-vinylpyridazin-4-yl)nicotinonitrile
[1433] .sup.1H NMR (CHLOROFORM-d) .delta. 9.02 (s, 1H), 7.52 (s,
1H), 7.14 (dd, J=17.6, 11.2 Hz, 1H), 6.37 (d, J=17.9 Hz, 1H), 5.80
(d, J=11.2 Hz, 1H), 4.65-4.76 (m, 0.5H), 4.40-4.55 (m, 1.5H), 4.34
(t, J=10.4 Hz, 1H), 3.86-4.01 (m, 2H), 3.77 (d, J=13.5 Hz, 0.5H),
3.42-3.57 (m, 1H), 2.96-3.21 (m, 3H), 2.53-2.69 (m, 2H), 2.20 (s,
3H), 1.42-1.50 (m, 1H), 1.10-1.16 (m, 2H), 1.00-1.08 (m, 3H),
0.83-1.00 (m, 6H)
[1434] LC-MS: m/z 461.1 (M+H)
Compound 771
(R)-tert-butyl
4-(3-cyano-6-cyclopropyl-4-methyl-5-(5-vinylpyridazin-3-yl)pyridin-2-yl)--
2-cyclopropylpiperazine-1-carboxylate
[1435] .sup.1H NMR (CHLOROFORM-d) .delta. 9.28 (d, J=2.1 Hz, 1H),
7.44 (d, J=2.1 Hz, 1H), 6.75 (dd, J=17.8, 11.0 Hz, 1H), 6.15-6.26
(m, 1H), 5.79 (d, J=10.9 Hz, 1H), 4.41 (d, J=12.9 Hz, 1H), 4.31 (d,
J=12.6 Hz, 1H), 4.08 (d, J=14.4 Hz, 1H), 3.36-3.55 (m, 2H), 3.24
(dd, J=12.9, 3.5 Hz, 1H), 3.07 (td, J=12.5, 3.5 Hz, 1H), 2.24 (s,
3H), 1.54 (s, 9H), 1.41-1.47 (m, 1H), 1.31-1.39 (m, 1H), 1.16 (br.
s., 2H), 0.79-0.96 (m, 2H), 0.42-0.66 (m, 3H), 0.28-0.42 (m,
1H)
[1436] LC-MS: m/z 487.1 (M+H)
Compound 772
(R)-tert-butyl
4-(3-cyano-6-cyclopropyl-4-methyl-5-(6-vinylpyridazin-4-yl)pyridin-2-yl)--
2-cyclopropylpiperazine-1-carboxylate
[1437] .sup.1H NMR (CHLOROFORM-d) .delta. .sup.1H NMR
(CHLOROFORM-d): 9.27 (d, J=2.1 Hz, 1H), 7.44 (d, J=2.1 Hz, 1H),
6.74 (dd, J=17.8, 11.0 Hz, 1H), 6.21 (d, J=17.6 Hz, 1H), 5.77 (d,
J=10.9 Hz, 1H), 4.41 (d, J=12.9 Hz, 1H), 4.30 (d, J=12.6 Hz, 1H),
4.02-4.22 (m, 1H), 3.36-3.53 (m, 2H), 3.18-3.30 (m, 1H), 3.07 (td,
J=12.4, 3.4 Hz, 1H), 2.23 (s, 3H), 1.49 (s, 9H), 1.42-1.48 (m, 1H),
1.31-1.38 (m, 1H), 1.09-1.21 (m, 2H), 0.87 (dd, J=7.8, 3.1 Hz, 2H),
0.42-0.65 (m, 3H), 0.30-0.42 (m, 1H)
[1438] LC-MS: m/z 487.1 (M+H)
Compound 769
(R,E)-6-cyclopropyl-2-(3-cyclopropyl-4-(5-hydroxypent-2-enoyl)piperazin-1--
yl)-4-methyl-5-(5-vinylpyridazin-3-yl)nicotinonitrile
[1439] .sup.1H NMR (CHLOROFORM-d) .delta. 9.27 (d, J=2.1 Hz, 1H),
7.43 (d, J=2.1 Hz, 1H), 6.87 (dt, J=14.8, 7.3 Hz, 1H), 6.73 (dd,
J=17.8, 11.0 Hz, 1H), 6.26-6.49 (m, 1H), 6.21 (d, J=17.6 Hz, 1H),
5.77 (d, J=10.9 Hz, 1H), 4.42 (d, J=12.9 Hz, 1H), 4.33 (d, J=12.6
Hz, 1H), 4.04-4.21 (m, 1H), 3.79 (t, J=6.0 Hz, 3H), 3.38 (br. s.,
1H), 3.23 (d, J=10.0 Hz, 1H), 3.08 (td, J=12.5, 2.9 Hz, 1H), 2.50
(q, J=6.2 Hz, 2H), 2.27 (s, 3H), 1.35-1.52 (m, 2H), 1.15 (br. s.,
2H), 0.88 (dd, J=7.6, 3.2 Hz, 2H), 0.65 (br. s., 1H), 0.51 (br. s.,
1H), 0.44 (br. s., 2H)
[1440] LC-MS: m/z 485.1 (M+H)
Compound 770
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(4-hydroxybutanoyl)piperazin-1-yl)-4--
methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1441] .sup.1H NMR (CHLOROFORM-d) 8.69 (d, J=5.0 Hz, 1H), 7.23 (s,
1H), 7.07 (d, J=5.0 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.29
(d, J=17.3 Hz, 1H), 5.57 (dd, J=10.7, 1.0 Hz, 1H), 4.33 (d, J=12.9
Hz, 1H), 4.25 (d, J=12.6 Hz, 1H), 4.09 (d, J=7.6 Hz, 0.5H),
3.79-3.92 (m, 1H), 3.65-3.79 (m, 2.5H), 3.31 (br. s., 0.5H), 3.14
(d, J=12.0 Hz, 1H), 2.99-3.11 (m, 1.5H), 2.58 (br. s., 2H),
2.17-2.26 (m, 3H), 1.90-2.00 (m, 2H), 1.51-1.62 (m, 1H), 1.43 (d,
J=10.3 Hz, 1H), 1.02-1.16 (m, 2H), 0.87 (dd, J=7.9, 2.9 Hz, 2H),
0.62 (br. s., 1H), 0.54 (br. s., 1H), 0.31-0.50 (m, 2H)
[1442] LC-MS: m/z 472.5 (M+H).sup.+
Compound 781
2-cyclopropyl-6-((R)-3-isopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin-1--
yl)-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1443] 1H NMR (CHLOROFORM-d) 8.70 (d, J=5.0 Hz, 1H), 7.21-7.28 (m,
1H), 7.09 (br. s., 1H), 6.89 (dd, J=17.3, 10.9 Hz, 1H), 6.30 (d,
J=17.3 Hz, 1H), 5.59 (d, J=10.9 Hz, 1H), 5.26-5.33 (m, 1H),
4.67-4.78 (m, 1.5H), 4.56 (dt, J=9.1, 5.9 Hz, 1H), 4.38-4.48 (m,
1.5H), 4.29 (d, J=12.3 Hz, 1H), 3.89 (d, J=13.5 Hz, 0.5H),
3.45-3.61 (m, 1H), 2.92-3.15 (m, 3.5H), 2.78-2.91 (m, 2H),
2.44-2.65 (m, 1H), 2.26 (br. s., 0.5H), 2.19-2.23 (m, 3H),
2.11-2.18 (m, 0.5H), 1.56 (td, J=8.0, 4.5 Hz, 1H), 1.12 (br. s.,
1H), 1.04 (d, J=6.5 Hz, 4H), 0.93 (d, J=6.7 Hz, 1H), 0.83-0.90 (m,
4H)
[1444] LC-MS: m/z 486.6 (M+H).sup.+
Compound 795
(R,E)-2-cyclopropyl-6-(4-(5-hydroxypent-2-enoyl)-3-isopropylpiperazin-1-yl-
)-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1445] .sup.1H NMR (CHLOROFORM-d) 8.68 (d, J=5.0 Hz, 1H), 7.23 (d,
J=9.7 Hz, 1H), 7.07 (br. s., 1H), 6.81-6.94 (m, 2H), 6.40 (d,
J=15.3 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H),
4.35-4.52 (m, 1.5H), 4.28 (d, J=9.4 Hz, 1H), 3.94 (d, J=12.9 Hz,
0.5H), 3.80 (t, J=5.9 Hz, 2H), 3.68 (d, J=9.7 Hz, 0.5H), 3.52 (t,
J=11.9 Hz, 0.5H), 3.05-3.18 (m, 2H), 2.51 (q, J=6.4 Hz, 2H),
2.25-2.32 (m, 1H), 2.20 (s, 3H), 2.05 (d, J=7.3 Hz, 1H), 1.51-1.61
(m, 1H), 1.10 (br. s., 1H), 1.04 (d, J=6.5 Hz, 4H), 0.93 (d, J=6.7
Hz, 1H), 0.76-0.95 (m, 4H)
[1446] LC-MS: m/z 486.6 (M+H).sup.+
Compound 782
(R)-6-(4-(2-cyclopentylacetyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl--
4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1447] 1H NMR (CHLOROFORM-d) 8.69 (d, J=5.0 Hz, 1H), 7.24 (s, 1H),
7.08 (d, J=4.4 Hz, 1H), 6.88 (dd, J=17.3, 10.9 Hz, 1H), 6.29 (d,
J=17.6 Hz, 1H), 5.57 (d, J=10.9 Hz, 1H), 4.34 (d, J=12.9 Hz, 1H),
4.26 (d, J=12.0 Hz, 1H), 4.13 (q, J=7.2 Hz, 1H), 3.70-3.91 (br. s.,
1.5H), 3.23-3.39 (m, 0.5H), 3.09-3.21 (m, 1H), 3.03 (t, J=10.7 Hz,
1H), 2.33-2.51 (m, 2H), 2.24-2.32 (m, 1H), 2.17-2.24 (m, 3H),
1.80-1.95 (m, 2H), 1.61-1.72 (m, 2H), 1.50-1.61 (m, 3H), 1.43 (d,
J=12.6 Hz, 1H), 1.14-1.24 (m, 2H), 1.11 (br. s., 2H), 0.82-0.91 (m,
2H), 0.51-0.75 (m, 2H), 0.44 (d, J=5.0 Hz, 2H)
[1448] LC-MS: m/z 496.7 (M+H).sup.+
COMPOUND 788
(R)-2-cyclopropyl-6-(3-isopropyl-4-(4-methoxybutanoyl)piperazin-1-yl)-4-me-
thyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1449] 1H NMR (CHLOROFORM-d) 8.68 (d, J=5.0 Hz, 1H), 7.23 (d, J=8.8
Hz, 1H), 7.07 (br. s., 1H), 6.87 (dd, J=17.3, 10.9 Hz, 1H),
6.23-6.33 (m, 1H), 5.48-5.66 (m, 1H), 4.69 (d, J=10.9 Hz, 0.5H),
4.37-4.48 (m, 1.5H), 4.23-4.31 (m, 1H), 3.82 (d, J=13.8 Hz, 0.5H),
3.41-3.53 (m, 3H), 3.22-3.38 (m, 3H), 2.92-3.15 (m, 3H), 2.39-2.56
(m, 2H), 2.25-2.33 (m, 0.5H), 2.17-2.24 (m, 3H), 2.09-2.17 (m,
0.5H), 1.90-2.00 (m, 2H), 1.52-1.60 (m, 1H), 1.09-1.15 (m, 1H),
1.03 (dd, J=6.5, 2.6 Hz, 4H), 0.91 (d, J=6.7 Hz, 1H), 0.80-0.89 (m,
4H)
[1450] LC-MS: m/z 488.7 (M+H).sup.+
Compound 787
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-cyclopropylacetyl)piperazin-1-yl)--
4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1451] 1H NMR (CHLOROFORM-d) 8.71 (d, J=5.0 Hz, 1H), 7.26 (br. s.,
1H), 7.09 (d, J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz, 1H), 6.25
(d, J=17.6 Hz, 1H), 5.57 (d, J=11.2 Hz, 1H), 4.34 (d, J=12.9 Hz,
1H), 4.25 (d, J=12.6 Hz, 1H), 4.04-4.16 (m, 0.5H), 3.68-3.86 (m,
1.5H), 3.16 (br. s., 1.5H), 3.03 (br. s., 1H), 2.36 (br. s., 1.5H),
2.26 (d, J=7.3 Hz, 2H), 2.20 (s, 3H), 1.50-1.59 (m, 1H), 1.05-1.11
(m, 3H), 0.86 (dd, J=7.9, 3.2 Hz, 2H), 0.55-0.61 (m, 4H), 0.44 (br.
s., 1H), 0.16-0.23 (m, 3H)
[1452] LC-MS: m/z 468.6 (M+H).sup.+
Compound 408
6-cyclopropyl-5-(isoquinolin-4-yl)-2-((R)-4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)-4-methylnicotinonitrile
[1453] .sup.1H NMR (CHLOROFORM-d) .delta. 9.36 (s, 1H), 8.41 (br.
s., 1H), 8.07-8.19 (m, 1H), 7.65-7.76 (m, 2H), 7.46 (t, J=9.0 Hz,
1H), 4.96 (br. s., 0.5H), 4.58 (br. s., 0.5H), 4.11-4.38 (m, 2.5H),
3.73-3.89 (m, 2.5H), 3.58-3.64 (m, 0.5H), 3.41 (s, 3H), 3.04-3.32
(m, 2.5H), 2.56-2.84 (m, 2H), 2.10 (s, 3H), 1.42-1.51 (m, 1H),
1.31-1.41 (m, 3H), 1.03-1.14 (m, 2H), 0.63-0.83 (m, 2H)
[1454] LC-MS: m/z 470.4 (M+H).sup.+
Compound 410
6-cyclopropyl-5-(isoquinolin-5-yl)-2-((R)-4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)-4-methylnicotinonitrile
[1455] .sup.1H NMR (CHLOROFORM-d) .delta. 9.48 (br. s., 1H), 8.58
(br. s., 1H), 8.13 (d, J=8.3 Hz, 1H), 7.78 (t, J=7.7 Hz, 1H), 7.64
(d, J=7.0 Hz, 1H), 7.32 (d, J=10.3 Hz, 1H), 4.96 (br. s., 0.5H),
4.58 (d, J=12.3 Hz, 0.5H), 4.08-4.36 (m, 2.5H), 3.71-3.93 (m,
2.5H), 3.56-3.70 (m, 0.5H), 3.41 (s, 3H), 3.19-3.36 (m, 1.5H),
3.01-3.14 (m, 1H), 2.56-2.78 (m, 2H), 2.02-2.10 (m, 3H), 1.81 (br.
s., 1H), 1.42-1.50 (m, 3H), 1.05-1.15 (m, 2H), 0.61-0.81 (m,
2H)
[1456] LC-MS: m/z 470.6 (M+H).sup.+
Compound 470
(R)--N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl-
)-2-cyclopropyl-4-methylpyridin-3-yl)phenyl)ethenesulfonamide
[1457] .sup.1H NMR (CHLOROFORM-d) .delta. 7.44 (t, J=7.8 Hz, 1H),
7.13-7.23 (m, 1H), 6.96-7.12 (m, 2H), 6.48-6.67 (m, 2H), 6.32 (d,
J=16.3 Hz, 1H), 6.02 (d, J=10.0 Hz, 1H), 4.58 (br. s., H), 4.34 (d,
J=12.5 Hz, 1H), 4.26 (d, J=12.3 Hz, 1H), 3.76 (br. s., 2H), 3.23
(br. s., 1H), 3.07 (br. s., 1H), 2.19 (s, 3H), 1.73 (br. s., 1H),
1.32 (d, J=11.5 Hz, 2H), 0.96-1.15 (m, 4H), 0.74-0.88 (m, 4H), 0.67
(br. s., 1H), 0.37-0.60 (m, 3H)
[1458] LC-MS: m/z 532.7 (M+H).sup.+
Compound 271
(R)-5-(3-chloro-4-fluorophenyl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)-4-methylnicotinonitrile
[1459] .sup.1H NMR (CHLOROFORM-d) .delta. 7.22-7.30 (m, 2H), 7.08
(ddd, J=8.2, 4.6, 2.0 Hz, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=13.6
Hz, 0.5H), 4.00-4.29 (m, 2.5H), 3.66-3.85 (m, 2.5H), 3.49-3.65 (m,
0.5H), 3.38 (s, 3H), 3.01-3.25 (m, 2.5H), 2.63-2.84 (m, 1H),
2.48-2.63 (m, 1H), 2.18 (s, 3H), 1.51-1.61 (m, 1H), 1.31-1.40 (m,
2H), 1.01-1.14 (m, 2H), 0.80-0.90 (m, 2H)
[1460] LC-MS: m/z 471.2 (M+H).sup.+
Compound 568
2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(3-hydroxybutanoyl)piperazin-1-yl)-2-
'-vinyl-3,4'bipyridine-5-carbonitrile
[1461] 1H NMR (CHLOROFORM-d) .delta. 8.65 (d, J=4.8 Hz, 1H), 7.65
(s, 1H), 7.39 (s, 1H), 7.24 (d, J=4.3 Hz, 1H), 6.88 (dd, J=17.4,
10.9 Hz, 1H), 6.28 (d, J=17.3 Hz, 1H), 5.57 (d, J=10.8 Hz, 1H),
4.49-4.79 (m, 2H), 4.43 (d, J=12.5 Hz, 1H), 4.17-4.33 (m, 2H),
3.96-4.17 (m, 1H), 3.79 (br. s., 1H), 3.71 (d, J=11.8 Hz, 1H),
3.02-3.31 (m, 2H), 2.53 (d, J=9.8 Hz, 1H), 2.48 (m, 1H), 2.04 (m,
1H), 1.32 (br. s., 3H), 0.82-1.12 (m, 3H), 0.72 (br. s., 1H), 0.63
(br. s., 1H), 0.55 (br. s., 1H), 0.22-0.51 (m, 2H)
[1462] LC-MS: m/z 458.2 (M+H).sup.+
Compound 558
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-
-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1463] 1H NMR (CHLOROFORM-d) .delta. 8.59 (d, J=4.8 Hz, 1H), 7.16
(s, 1H), 7.00 (d, J=4.8 Hz, 1H), 6.78 (dd, J=17.3, 10.8 Hz, 1H),
6.19 (d, J=17.6 Hz, 1H), 5.46 (dd, J=10.8, 1.0 Hz, 1H), 4.60 (d,
J=10.5 Hz, 0.5H), 4.26 (d, J=12.8 Hz, 1H), 4.17 (d, J=12.5 Hz, 1H),
3.96-4.06 (m, 0.5H), 3.80 (d, J=12.3 Hz, 1H), 3.59-3.74 (m, 3H),
3.18-3.37 (m, 4H), 3.04-3.14 (m, 1H), 2.90-3.01 (m, 1H), 2.37-2.67
(m, 2H), 2.08-2.18 (m, 3H), 1.39-1.56 (m, 1H), 0.98-1.10 (m, 2H),
0.78 (dd, J=7.9, 3.1 Hz, 2H), 0.51 (br. s., 1H), 0.44 (br. s., 1H),
0.29-0.40 (m, 2H)
[1464] LC-MS: m/z 472.4 (M+H).sup.+
Compound 598
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-(-
prop-1-en-2-yl)pyrimidin-4-yl)nicotinonitrile
[1465] 1H NMR (CHLOROFORM-d) .delta. 9.22 (s, 1H), 7.98 (s, 1H),
7.61-7.76 (m, 1H), 6.18 (s, 1H), 5.54 (s, 1H), 4.88 (br. s., 1H),
4.51 (d, J=9.8 Hz, 1H), 4.18-4.47 (m, 3H), 3.63-3.93 (m, 3H),
3.41-3.63 (m, 1H), 3.36 (s, 4H), 2.97-3.24 (m, 2H), 2.49-2.79 (m,
2H), 2.28-2.47 (m, 1H), 2.22 (s, 3H), 1.34 (d, J=6.3 Hz, 2H),
1.14-1.30 (m, 4H), 1.04 (dd, J=7.9, 2.9 Hz, 2H)
[1466] LC-MS: m/z 447.2 (M+H).sup.+
Compound 478
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-4-methyl-5-(1H-pyrazol-4-yl)nicotinonitrile
[1467] .sup.1H NMR (CHLOROFORM-d) .delta. 7.61 (s, 2H), 4.59 (s,
1H), 4.33 (d, J=12.5 Hz, 1H), 4.24 (d, J=12.5 Hz, 1H), 3.98-4.15
(m, 1H), 3.84 (s, 1H), 3.22 (d, J=15.1 Hz, 1H), 3.05 (s, 1H), 2.31
(s, 3H), 1.83-1.98 (m, 1H), 1.73 (s, 1H), 1.37-1.60 (m, 1H),
0.98-1.15 (m, 4H), 0.74-0.92 (m, 4H), 0.34-0.65 (m, 4H).
[1468] LC-MS: m/z 416.2 (M+H).sup.+
Compound 463
(R)--N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl-
)-2-cyclopropyl-4-methylpyridin-3-yl)phenyl)-N-(vinylsulfonyl)ethenesulfon-
amide
[1469] .sup.1H NMR (CHLOROFORM-d) .delta. 7.47-7.60 (m, 1H),
7.31-7.40 (m, 2H), 7.00-7.14 (m, 2H), 6.28 (s, 1H), 6.32 (s, 1H),
6.17 (d, J=9.8 Hz, 2H), 4.34 (d, J=12.8 Hz, 1H), 4.26 (d, J=12.5
Hz, 2H), 3.85 (s, 1H), 3.06 (br. s., 2H), 1.85 (br. s., 1H), 1.72
(br. s., 1H), 1.58 (td, J=8.2, 4.1 Hz, 2H), 0.95-1.18 (m, 4H),
0.72-0.95 (m, 5H), 0.65 (br. s., 1H), 0.32-0.59 (m, 3H)
[1470] LC-MS: m/z 622.2 (M+H).sup.+
Compound 535
(R)-5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)-
piperazin-1-yl)pyridin-3-yl)quinoline-2-carbonitrile
[1471] .sup.1H NMR (CHLOROFORM-d) .delta. 8.27 (d, J=8.5 Hz, 1H),
8.11 (dd, J=11.5, 8.8 Hz, 1H), 7.94 (t, J=7.8 Hz, 1H), 7.53-7.78
(m, 3H), 4.59 (dt, J=13.1, 2.3 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H),
4.04-4.34 (m, 1H), 3.81 (br. s., 1H), 3.21-3.51 (m, 3H), 3.15 (d,
J=11.5 Hz, 2H), 1.68 (br. s., 2H), 1.37-1.48 (m, 3H), 1.14-1.36 (m,
13H), 0.77-1.04 (m, 4H), 0.71 (br. s., 1H), 0.60 (br. s., 1H),
0.31-0.57 (m, 2H)
[1472] LC-MS: m/z 513.2 (M+H).sup.+
Compound 563
(R)-5-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-2--
cyclopropylpyridin-3-yl)quinoline-2-carbonitrile
[1473] .sup.1H NMR (CHLOROFORM-d) .delta. 8.25 (d, J=8.8 Hz, 1H),
8.13 (dd, J=10.3, 9.0 Hz, 1H), 7.85-8.04 (m, 1H), 7.56-7.76 (m,
3H), 4.59 (d, J=12.0 Hz, 1H), 4.47 (d, J=12.5 Hz, 2H), 4.13 (q,
J=7.0 Hz, 1H), 3.72 (br. s., 1H), 3.42 (d, J=10.0 Hz, 1H),
3.09-3.36 (m, 2H), 1.66-1.86 (m, 1H), 1.52-1.66 (m, 1H), 1.36-1.52
(m, 2H), 1.00-1.30 (m, 8H), 0.75-1.00 (m, 6H), 0.71 (d, J=7.8 Hz,
1H), 0.34-0.63 (m, 4H)
[1474] LC-MS: m/z 489.2 (M+H).sup.+
Compound 610
(R)-2-(4-(cyclopropanecarbonyl)-3-methylpiperazin-1-yl)-6-cyclopropyl-5-(1-
-propioloyl-2,5-dihydro-1H-pyrrol-3-yl)nicotinonitrile
[1475] .sup.1H NMR (CHLOROFORM-d) d: 7.53 (d, J=1.0 Hz, 1H), 6.00
(dt, J=19.1, 2.0 Hz, 1H), 4.61-4.91 (m, 2H), 4.52-4.61 (m, 1H),
4.40-4.52 (m, 2H), 4.19-4.40 (m, 2H), 3.50 (s, 1H), 3.43 (d, J=6.0
Hz, 1H), 3.02-3.32 (m, 3H), 2.09-2.31 (m, 2H), 1.75 (br. s., 2H),
1.37-1.48 (m, 1H), 1.11-1.37 (m, 7H), 0.95-1.11 (m, 2H), 0.66-0.95
(m, 2H).
[1476] LC-MS: m/z 430.2 (M+H).sup.+
Compound 450
(R)--N-(3-(5-cyano-6-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-y-
l)-2-cyclopropylpyridin-3-yl)phenyl)propionamide
[1477] .sup.1H NMR (CHLOROFORM-d) d: 7.70 (d, J=6.0 Hz, 2H), 7.61
(s, 1H), 7.48 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.13 (d,
J=7.5 Hz, 1H), 4.50 (d, J=11.8 Hz, 1H), 4.38 (d, J=12.3 Hz, 1H),
3.73 (d, J=7.0 Hz, 1H), 3.25 (br. s., 1H), 3.07 (br. s., 1H),
2.38-2.51 (m, 2H), 1.98-2.22 (m, 1H), 1.73 (br. s., 1H), 1.21-1.45
(m, 6H), 1.16 (dt, J=7.8, 3.6 Hz, 3H), 0.87-1.11 (m, 5H), 0.76-0.86
(m, 2H), 0.65 (br. s., 1H), 0.29-0.59 (m, 3H).
[1478] LC-MS: m/z 484.3 (M+H).sup.+
Compound 834 (General Procedure 2, Step M)
6-cyclopropyl-2-((R)-3-cyclopropyl-4-((1S,2S)-2-ethoxycyclopropanecarbonyl-
)piperazin-1-yl)-5-(isoquinolin-5-yl)nicotinonitrile
##STR00866##
[1480] .sup.1H NMR (DEUTERIUM OXIDE) 9.35 (s, 1H), 8.54 (dd, J=5.9,
1.9 Hz, 1H), 8.07 (d, J=8.0 Hz, 1H), 7.69-7.75 (m, 1H), 7.64-7.68
(m, 2H), 7.44 (dd, J=12.5, 6.0 Hz, 1H), 4.46-4.59 (m, 2.5H),
4.08-4.18 (m, 1H), 3.86 (br. s., 0.5H), 3.53-3.74 (m, 3H),
3.21-3.32 (m, 2H), 1.87-2.06 (m, 2H), 1.49-1.58 (m, 1H), 1.33 (d,
J=5.8 Hz, 1H), 1.14-1.28 (m, 7H), 0.81-0.90 (m, 2H), 0.65 (br. s.,
1H), 0.36-0.59 (m, 3H).
[1481] LC-MS: m/z 508.2 (M+H).sup.+
COMPOUND 730
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)--
5-(methyl(2-vinylpyridin-4-yl)amino)nicotinonitrile
[1482] .sup.1H NMR (CHLOROFORM-d) .delta. 8.25 (d, J=5.9 Hz, 1H),
7.58 (s, 1H), 6.71 (dd, J=17.4, 10.7 Hz, 1H), 6.46 (s, 1H), 6.33
(s, 1H), 6.20 (d, J=17.3 Hz, 1H), 5.45 (d, J=11.2 Hz, 1H), 4.69 (d,
J=13.4 Hz, 0.4H), 4.49 (d, J=13.0 Hz, 1H), 4.37 (d, J=12.7 Hz, 1H),
4.10 (d, J=8.6 Hz, 0.6H), 3.92 (s, 2H), 3.86-3.65 (m, 1.5H), 3.42
(s, 1H), 3.31 (s, 3H), 3.22 (m, 1.5H), 3.15-3.00 (m, 1H), 2.69-2.45
(m, 2H), 1.88 (ddd, J=12.7, 8.1, 4.7 Hz, 1H), 1.40-1.31 (m, 1H),
1.12 (s, 2H), 0.99 (s, 2H), 0.81-0.34 (m, 4H).
[1483] LC-MS: m/z 473.4 (M+H).sup.+
Compound 835
(R)-4-cyclopropyl-2-(3-cyclopropyl-4-(4-methoxybutanoyl)piperazin-1-yl)-5--
(2-vinylpyridin-4-yl)benzonitrile
##STR00867##
[1485] .sup.1H NMR (CHLOROFORM-d) 8.64 (d, J=5.0 Hz, 1H), 7.46 (s,
1H), 7.34-7.42 (m, 1H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd,
J=17.6, 10.9 Hz, 1H), 6.54 (s, 1H), 6.21-6.33 (m, 1H), 5.55 (dd,
J=10.9, 0.9 Hz, 1H), 4.63-4.77 (m, 0.3H), 4.01-4.18 (m, 0.7H),
3.80-3.94 (m, 1H), 3.41-3.82 (m, 4H), 3.35 (s, 3H), 3.18-3.35 (m,
1H), 2.97-3.05 (m, 1H), 2.79-2.93 (m, 1H), 2.46 (d, J=7.3 Hz, 2H),
1.81-1.99 (m, 4H), 0.94-1.07 (m, 2H), 0.72-0.83 (m, 2H), 0.36-0.56
(m, 4H).
[1486] LC-MS: m/z 471.2 (M+H).sup.+
Compound 775
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-5-
-((5-vinylpyridazin-3-yl)amino)nicotinonitrile
[1487] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.76 (s, 1H), 7.76
(s, 1H), 6.58 (dd, J=17.6, 11.0 Hz, 2H), 6.05 (d, J=17.6 Hz, 1H),
5.66 (d, J=11.0 Hz, 1H), 4.65-4.70 (m, 0.5H), 4.43-4.46 (m, 1H),
4.33 (d, J=12.4 Hz, 1H), 4.16-4.07 (m, 1H), 3.87-3.88 (m, 0.5H),
3.71-3.74 (m, 3H), 3.39 (s, 3H), 3.20 (s, 1H), 3.07-3.09 (m, 1H),
2.65-2.66 (m, 2H), 2.55-2.47 (m, 1H), 2.18 (d, J=10.1 Hz, 1H),
1.30-1.25 (m, 1H), 1.15 (s, 2H), 1.07-0.98 (m, 2H), 0.50-0.60 (m,
2H), 0.45-0.47 (m, 2H).
[1488] LC-MS: m/z 474.6 (M+H).sup.+
Compound 836
(R)-tert-butyl(5-(5-cyano-2-cyclopropyl-6-(3-cyclopropyl-4-(3-hydroxypropa-
noyl)piperazin-1-yl)pyridin-3-yl)pyridazin-3-yl)carbamate
##STR00868##
[1490] The mixture of
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)--
5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)nicotinonitrile (268
mg, 0.627 mmol), tert-butyl (5-chloropyridazin-3-yl)carbamate (120
mg, 0.523 mmol), Pd(dppf)Cl.sub.2 (20 mg, 0.026 mmol) and CsF (159
mg, 1.045 mmol) in dioxane/H.sub.2O (8 mL/2 mL) was stirred at
100.degree. C. for 16 hours. The mixture was diluted with EtOAc (50
mL) and filtered. The filtrated was partitioned between EtOAc (50
mL) and water (30 mL), the organic layer was washed with water (30
mL), brine and dried over Na.sub.2SO.sub.4 and concentrated to give
the crude which was purified by prep-TLC to give 150 mg of the
product.
[1491] .sup.1H NMR (CHLOROFORM-d): 8.97 (d, J=2.1 Hz, 1H), 8.33 (d,
J=1.8 Hz, 1H), 8.24 (br. s., 1H), 7.70 (s, 1H), 4.62 (d, J=13.2 Hz,
1H), 4.49 (d, J=12.9 Hz, 1H), 4.08 (d, J=8.8 Hz, 1H), 3.92 (t,
J=4.5 Hz, 2H), 3.63-3.85 (m, 1H), 3.02-3.23 (m, 3H), 2.41-2.67 (m,
2H), 1.91-2.06 (m, 1H), 1.48-1.63 (m, 9H), 1.15-1.25 (m, 3H),
1.02-1.13 (m, 2H), 0.46-0.72 (m, 4H)
[1492] LC-MS: m/z 534.3 (M+H).sup.+
Compound 339 (General Procedure 9)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(qui-
nolin-3-ylamino)nicotinonitrile
[1493] .sup.1H NMR (MeOD): .delta. 8.797-8.790 (d, J=2.8 Hz, 1H),
8.059-8.037 (d, J=8.8 Hz, 1H), 7.985-7.962 (d, J=9.2 Hz, 1H),
7.926-7.920 (d, J=2.4 Hz, 1H), 7.861 (s, 1H), 7.795-7.710 (m, 2H),
4.797-4.783 (m, 0.5H), 4.451-4.416 (m, 1H), 4.227-4.112 (m, 2H),
3.972-3.932 (m, 0.5H), 3.694-3.613 (m, 2H), 3.608-3.577 (m, 0.5H),
3.334 (s, 3H), 3.284 (m, 0.5H), 3.211-3.137 (m, 1H), 3.045-3.007
(m, 0.5H), 2.852-2.704 (m, 1H), 2.700-2.578 (m, 1.5H), 2.240-2.177
(m, 1H), 1.401-1.384 (d, J=6.8 Hz, 1.5H), 1.284-1.267 (d, J=6.8 Hz,
1.5H), 1.188-1.170 (m, 2H), 0.992-0.965 (m, 2H);
[1494] LC-MS: m/z 471.5 (M+H).sup.+
Compound 355 (General Procedure 9)
(R)-6-cyclopropyl-5-((4-fluorophenyl)amino)-2-(4-(3-methoxypropanoyl)-3-me-
thylpiperazin-1-yl)nicotinonitrile
[1495] 1H NMR (MeOD): .delta. 7.543 (s, 1H), 6.936-6.893 (t, J=8.6
Hz, 2H), 6.723-6.690 (q, J=4.4 Hz, 2H), 4.798-4.781 (m, 0.5H),
4.443-4.361 (m, 1H), 4.050-3.898 (m, 2.5H), 3.675-3.509 (m, 2.5H),
3.336 (s, 3H), 3.254-2.877 (m, 2.5H), 2.792-2.588 (m, 2H),
2.260-2.196 (m, 1H), 1.402-1.255 (m, 3H), 1.115-1.097 (m, 2H),
0.992-0.968 (m, 2H);
[1496] LC-MS: m/z 438.5 (M+H).sup.+
Compound 356 (General Procedure 9)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(qui-
nolin-4-ylamino)nicotinonitrile
[1497] .sup.1H NMR (MeOD): .delta. 8.593-8.572 (d, J=8.4 Hz, 1H),
8.440-8.422 (d, J=7.2 Hz, 1H), 8.065-8.026 (m, 1H), 7.983-7.962 (d,
J=8.4 Hz, 1H), 7.931 (s, 1H), 7.854-7.813 (m, 2H), 6.552-6.535 (d,
J=6.8 Hz, 1H), 4.792-4.783 (m, 0.5H), 4.451-4.420 (m, 1H),
4.329-4.207 (m, 2H), 3.982-3.948 (m, 0.5H), 3.414-3.338 (m, 4H),
3.257-3.068 (m, 1.5H), 2.829-2.610 (m, 2H), 2.091-2.026 (m, 1H),
1.389-1.256 (m, 3H), 1.199-1.181 (m, 2H), 1.050-0.988 (m, 2H);
[1498] LC-MS: m/z 471.5 (M+H).sup.+
Compound 368 (General Procedure 9)
(R)-5-(4-acetylpiperazin-1-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-m-
ethylpiperazin-1-yl)nicotinonitrile
[1499] 1H NMR (MeOD): .delta. 7.558 (s, 1H), 4.763-4.752 (m, 0.5H),
4.429-4.346 (m, 1H), 4.052-3.883 (m, 3H), 3.747-3.668 (m, 6H),
3.328 (s, 3H), 3.182-3.119 (m, 2H), 3.061-2.886 (m, 4.5H),
2.781-2.677 (m, 1H), 2.623-2.562 (m, 2H), 2.142 (s, 3H),
1.375-1.358 (m, 1.5H), 1.261-1.244 (m, 1.5H), 1.109-1.036 (m,
4H);
[1500] LC-MS: m/z 455.5 (M+H).sup.+
Compound 375 (General Procedure 9)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-morp-
holinonicotinonitrile
[1501] .sup.1H NMR (MeOD): .delta. 7.551 (s, 1H), 4.762-4.748 (m,
0.5H), 4.428-4.352 (m, 1H), 4.039-3.975 (m, 2H), 3.941-3.827 (m,
5H), 3.681-3.667 (m, 2H), 3.574-3.501 (m, 1H), 3.327 (s, 3H),
3.173-3.116 (m, 2H), 3.046-2.991 (m, 1H), 2.940-2.882 (m, 4H),
2.744-2.522 (m, 2.5H), 1.378-1.361 (m, 1.5H), 1.264-1.247 (m,
1.5H), 1.097-1.012 (m, 4H);
[1502] LC-MS: m/z 414.5 (M+H).sup.+
Compound 376 (General Procedure 9)
(R)-ethyl
4-(5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)pyridin-3-yl)piperazine-1-carboxylate
[1503] 1H NMR (MeOD): .delta. 7.549 (s, 1H), 4.763-4.747 (m, 0.5H),
4.426-4.343 (m, 1H), 4.171-4.118 (m, 2H), 4.044-3.882 (m, 1.5H),
3.666-3.639 (m, 6H), 3.573-3.501 (m, 1H), 3.327 (s, 3H),
3.176-2.988 (m, 2H), 2.911-2.886 (m, 4.5H), 2.781-2.546 (m, 3H),
1.374-1.358 (m, 1.5H), 1.289-1.253 (m, 4.5H), 1.101-1.026 (m,
4H);
[1504] LC-MS: m/z 485.6 (M+H).sup.+
Compound 377 (General Procedure 9)
(R)-6-cyclopropyl-5-(4-(ethylsulfonyl)piperazin-1-yl)-2-(4-(3-methoxypropa-
noyl)-3-methylpiperazin-1-yl)nicotinonitrile
[1505] 1H NMR (MeOD): .delta. 7.587 (s, 1H), 4.765-4.749 (m, 0.5H),
4.426-4.348 (m, 1H), 4.055-3.882 (m, 1.5H), 3.669-3.457 (m, 7H),
3.329 (s, 3H), 3.152-3.066 (m, 4H), 3.004-2.888 (m, 4.5H),
2.742-2.538 (m, 3H), 1.373-1.335 (m, 4.5H), 1.261-1.245 (m, 1.5H),
1.094-1.036 (m, 4H);
[1506] LC-MS: m/z 505.6 (M+H).sup.+
Compound 378 (General Procedure 9)
(R)-6-cyclopropyl-5-(4-(cyclopropylmethyl)piperazin-1-yl)-2-(4-(3-methoxyp-
ropanoyl)-3-methylpiperazin-1-yl)nicotinonitrile
[1507] 1H NMR (MeOD): .delta. 7.598 (s, 1H), 4.768-4.752 (m, 0.5H),
4.431-4.355 (m, 1H), 4.068-3.892 (m, 2.5H), 3.688-3.660 (m, 2H),
3.572-3.507 (m, 1H), 3.333 (s, 3H), 3.101-2.930 (m, 9H),
2.903-2.871 (m, 1H), 2.787-2.586 (m, 4H), 2.544-2.493 (m, 1H),
1.378-1.362 (m, 1.5H), 1.264-1.248 (m, 1.5H), 1.124-1.044 (m, 5H),
0.698-0.652 (m, 2H), 0.357-0.268 (m, 2H);
[1508] LC-MS: m/z 467.6 (M+H).sup.+
Compound 379 (General Procedure 9)
(R)-5-(4-benzoylpiperazin-1-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)nicotinonitrile
[1509] 1H NMR (MeOD): .delta. 7.588 (s, 1H), 7.492-7.451 (m, 5H),
4.780-4.768 (m, 0.5H), 4.430-4.346 (m, 1H), 4.053-3.881 (m, 4.5H),
3.667-3.630 (m, 2.5H), 3.536-3.477 (m, 2H), 3.326 (m, 4H),
3.180-3.085 (m, 1.5H), 3.023-2.923 (m, 5H), 2.756-2.709 (m, 1H),
2.619-2.567 (m, 2H), 1.373-1.357 (m, 1.5H), 1.259-1.243 (m, 1.5H),
1.113-1.033 (m, 4H);
[1510] LC-MS: m/z 517.6 (M+H).sup.+
Compound 265 (General Procedure 6)
(R)-6-cyclopropyl-5-(3-fluorophenyl)-2-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)-4-methylnicotinonitrile
[1511] .sup.1H NMR (CHLOROFORM-d) .delta. 7.41-7.51 (m, 1H), 7.12
(td, J=8.5, 2.5 Hz, 1H), 7.01 (d, J=7.5 Hz, 1H), 6.95 (d, J=9.0 Hz,
1H), 4.92 (br. s., 0.5H), 4.55 (d, J=12.8 Hz, 0.5H), 4.02-4.22 (m,
2.5H), 3.70-3.92 (m, 2.5H), 3.53-3.67 (m, 0.5H), 3.40 (s, 3H),
2.92-3.31 (m, 2.5H), 2.61-2.84 (m, 21H), 2.16-2.25 (m, 3H),
1.57-1.65 (m, 1H), 1.43 (d, J=6.5 Hz, 1.5H), 1.33 (d, J=6.8 Hz,
1.5H), 1.08 (t, J=4.6 Hz, 2H), 0.79-0.90 (m, 2H)
[1512] LC-MS: m/z 437.4 (M+H).sup.+
Compound 264 (General Procedure 6)
6-cyclopropyl-5-(2,4-difluorophenyl)-2-((R)-4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)-4-methylnicotinonitrile
[1513] .sup.1H NMR (CHLOROFORM-d) .delta. 7.15-7.25 (m, 1H),
6.94-7.06 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d, J=13.3 Hz, 0.5H),
4.05-4.34 (m, 2.5H), 3.70-3.85 (m, 2.5H), 3.52-3.67 (m, 0.5H), 3.40
(s, 3H), 2.93-3.31 (m, 2.5H), 2.73 (td, J=15.3, 7.3 Hz, 1H),
2.54-2.64 (m, 1H), 2.21 (s, 3H), 1.54-1.61 (m, 1H), 1.39-1.45 (m,
1.5H), 1.32 (t, J=5.8 Hz, 1.5H), 1.01-1.18 (m, 2H), 0.83-0.93 (m,
2H)
[1514] LC-MS: m/z 455.4 (M+H).sup.+
Compound 263 (General Procedure 6)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-5-(4-(trifluoromethoxy)phenyl)nicotinonitrile
[1515] .sup.1H NMR (CHLOROFORM-d) .delta. 7.31-7.36 (m, J=8.0 Hz,
2H), 7.23-7.28 (m, J=8.3 Hz, 2H), 4.92 (br. s., 0.5H), 4.55 (d,
J=13.8 Hz, 0.5H), 4.00-4.22 (m, 2.5H), 3.68-3.87 (m, 2.5H),
3.53-3.67 (m, 0.5H), 3.36-3.44 (m, 3H), 3.12-3.31 (m, 1.5H),
2.94-3.12 (m, 1H), 2.64-2.83 (m, 1H), 2.61 (br. s., 1H), 2.16-2.22
(m, 3H), 1.52-1.63 (m, 1H), 1.39-1.47 (m, 1.5H), 1.32 (d, J=6.3 Hz,
1.5H), 1.03-1.15 (m, 2H), 0.78-0.90 (m, 2H)
[1516] LC-MS: m/z 503.3 (M+H).sup.+
Compound 272 (General Procedure 8)
(R)-benzyl
2-(5-cyano-2-isopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)pyridin-3-yloxy)ethylcarbamate
[1517] .sup.1H NMR (CHLOROFORM-d) .delta. 7.32-7.40 (m, 5H), 7.18
(s, 1H), 4.90 (br. s., 0.5H), 4.53 (d, J=12.5 Hz, 0.5H), 4.21 (br.
s., 0.5H), 4.06 (d, J=14.1 Hz, 1H), 3.95-4.01 (m, 2.5H), 3.68-3.79
(m, 3H), 3.53-3.67 (m, 2.5H), 3.30-3.44 (m, 5H), 3.07-3.25 (m, 2H),
2.89-3.07 (m, 1H), 2.51-2.79 (m, 2.5H), 1.40 (d, J=6.5 Hz, 1.5H),
1.30 (d, J=6.8 Hz, 1.5H), 1.11-1.20 (m, 7H)
[1518] LC-MS: m/z 524.3 (M+H).sup.+
Compound 270 (General Procedure 6)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-5-(thiophen-3-yl)nicotinonitrile
[1519] .sup.1H NMR (CHLOROFORM-d) .delta. 7.47 (dd, J=5.0, 3.0 Hz,
1H), 7.17 (dd, J=2.8, 1.3 Hz, 1H), 7.00 (dd, J=5.0, 1.3 Hz, 1H),
4.91 (br. s., 0.5H), 4.55 (d, J=10.8 Hz, 0.5H), 3.98-4.28 (m,
2.5H), 3.75 (q, J=6.0 Hz, 2.5H), 3.50-3.67 (m, 0.5H), 3.36-3.46 (m,
3H), 3.10-3.30 (m, 1.5H), 2.89-3.10 (m, 1H), 2.65-2.81 (m, 2H),
2.25 (s, 3H), 1.71-1.79 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H), 1.32 (d,
J=6.8 Hz, 1.5H), 1.05-1.12 (m, 2H), 0.81-0.90 (m, 2H)
[1520] LC-MS: m/z 425.3 (M+H).sup.+
Compound 269 (General Procedure 6)
(R)-5-(benzo[d][1,3]dioxol-5-yl)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-
-methylpiperazin-1-yl)-4-methylnicotinonitrile
[1521] .sup.1H NMR (CHLOROFORM-d) .delta. 6.91 (d, J=8.0 Hz, 1H),
6.60-6.74 (m, 2H), 6.01-6.11 (m, 2H), 4.92 (br. s., 0.5H), 4.55 (d,
J=13.6 Hz, 0.5H), 4.24 (br. s., 0.5H), 4.02-4.20 (m, 2H), 3.70-3.85
(m, 2.5H), 3.59 (t, J=11.7 Hz, 0.5H), 3.39 (s, 3H), 3.19 (t, J=13.7
Hz, 1.5H), 2.92-3.08 (m, 1H), 2.65-2.83 (m, 1H), 2.55-2.64 (m, 1H),
2.19-2.27 (m, 3H), 1.67-1.76 (m, 1H), 1.42 (d, J=6.5 Hz, 1.5H),
1.31-1.38 (m, 1.5H), 1.06 (t, J=5.3 Hz, 2H), 0.79-0.91 (m, 2H)
[1522] LC-MS: m/z 463.3 (M+H).sup.+
Compound 268 (General Procedure 6)
(R)-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-3,4'-bipyridine-5-carbonitrile
[1523] .sup.1H NMR (CHLOROFORM-d) .delta. 8.87 (br. s., 2H), 7.86
(br. s., 2H), 4.90-5.00 (m, 0.5H), 4.57 (br. s., 0.5H), 4.33 (d,
J=12.5 Hz, 2.5H), 3.71-3.82 (m, 2.5H), 3.58 (br. s., 0.5H), 3.40
(s, 3H), 3.09-3.28 (m, 2.5H), 2.68 (br. s., 1H), 2.61 (br. s., 1H),
2.23-2.28 (m, 3H), 1.62-1.66 (m, 1H), 1.32-1.38 (m, 3H), 1.20 (br.
s., 2H), 0.98 (br. s., 2H)
[1524] LC-MS: m/z 420.5 (M+H).sup.+
Compound 267 (General Procedure 6)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-4-meth-
yl-5-(naphthalen-2-yl)nicotinonitrile
[1525] .sup.1H NMR (CHLOROFORM-d) .delta. 7.84-8.00 (m, 3H), 7.71
(s, 1H), 7.53-7.60 (m, 2H), 7.34 (dd, J=8.4, 1.4 Hz, 1H), 4.94 (br.
s., 0.5H), 4.57 (d, J=13.3 Hz, 0.5H), 4.06-4.34 (m, 2.5H),
3.71-3.85 (m, 2.5H), 3.52-3.69 (m, 0.5H), 3.37-3.45 (m, 3H),
3.14-3.30 (m, 1.5H), 2.94-3.12 (m, 1H), 2.67-2.85 (m, 1H),
2.54-2.66 (m, 1H), 2.19-2.28 (m, 3H), 1.62-1.70 (m, 1H), 1.45 (d,
J=5.8 Hz, 1.5H), 1.35 (d, J=5.5 Hz, 1.5H), 1.03-1.16 (m, 2H),
0.74-0.84 (m, 2H)
[1526] LC-MS: m/z 469.4 (M+H).sup.+
Compound 559 (General Procedure 9)
(R)-6-cyclopropyl-5-(4-(ethylsulfonyl)piperazin-1-yl)-2-(3-methyl-4-(3,3,3-
-trifluoropropanoyl)piperazin-1-yl)nicotinonitrile
[1527] .sup.1H NMR (CHLOROFORM-d) .delta. 7.38 (s, 1H), 4.29 (d,
J=12.8 Hz, 1H), 4.18 (d, J=12.5 Hz, 1H), 4.09 (d, J=7.5 Hz, 0.5H),
3.70-3.81 (m, 1.5H), 3.46-3.55 (m, 4.5H), 3.30 (q, J=9.8 Hz, 2H),
2.92-3.14 (m, 8.5H), 2.38-2.53 (m, 1H), 1.38-1.49 (m, 3H),
1.29-1.36 (m, 1H), 1.02-1.17 (m, 4H), 0.42-0.67 (m, 4H)
[1528] LC-MS: m/z 555.2 (M+H).sup.+
Compound 529 (General Procedure 9)
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(4-(ethyl sulfonyl)piperazin-1-yl)nicotinonitrile
[1529] .sup.1H NMR (CHLOROFORM-d) .delta. 7.37 (s, 1H), 3.42-4.57
(m, 9H), 2.90-3.22 (m, 8H), 2.40-2.52 (m, 1H), 1.73 (br. s., 1H),
1.39-1.50 (m, 4H), 1.10-1.17 (m, 2H), 0.95-1.09 (m, 4H), 0.76-0.85
(m, 2H), 0.35-0.58 (m, 4H)
[1530] LC-MS: m/z 513.2 (M+H).sup.+
Compound 528 (General Procedure 9)
(R)-2-(4-(cyclopropanecarbonyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-
-5-(quinolin-4-ylamino)nicotinonitrile
[1531] .sup.1H NMR (CHLOROFORM-d) .delta. 8.55 (d, J=5.5 Hz, 1H),
8.05 (d, J=8.0 Hz, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.67-7.78 (m, 2H),
7.51-7.63 (m, 1H), 6.32 (d, J=5.3 Hz, 1H), 4.50 (d, J=12.3 Hz, 1H),
4.38 (d, J=12.3 Hz, 1H), 3.12-4.18 (m, 5H), 2.05-2.13 (m, 1H),
1.03-1.22 (m, 5H), 0.95-1.01 (m, 3H), 0.83 (dd, J=7.9, 2.4 Hz, 2H),
0.39-0.62 (m, 4H)
[1532] LC-MS: m/z 479.3 (M+H).sup.+
Compound 722 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3-hydroxypropanoyl)piperazin-1-yl)-5-
-((2-vinyl-1,7-naphthyridin-4-yl)amino)nicotinonitrile
[1533] .sup.1H NMR (CHLOROFORM-d) .delta. 9.48 (s, 1H), 8.58 (d,
J=5.9 Hz, 1H), 7.87 (br. s., 1H), 7.74 (s, 1H), 6.91 (dd, J=17.6,
10.9 Hz, 1H), 6.57 (s, 1H), 6.27 (d, J=17.6 Hz, 1H), 5.69 (d,
J=10.9 Hz, 1H), 4.52 (d, J=12.9 Hz, 1H), 4.40 (d, J=12.3 Hz, 1H),
4.11 (d, J=7.9 Hz, 1H), 3.94 (br. s., 2H), 3.64-3.88 (m, 1H), 3.33
(br. s., 1H), 3.24 (d, J=13.5 Hz, 1H), 3.03-3.19 (m, 1H), 2.48-2.69
(m, 2H), 1.98-2.09 (m, 1H), 1.37 (d, J=16.1 Hz, 1H), 1.10-1.22 (m,
2H), 0.95-1.08 (m, 2H), 0.66 (br. s., 1H), 0.57 (br. s., 1H), 0.49
(br. s., 2H)
[1534] LC-MS: m/z 430.2 (M+H).sup.+
Compound 819 (General Procedure 6)
(R)-6-(4-(2-cyclobutylacetyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropyl-4-
-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1535] 1H NMR (CHLOROFORM-d) .delta. 8.69 (d, J=4.7 Hz, 1H), 7.23
(br. s., 1H), 7.07 (d, J=4.4 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz,
1H), 6.29 (d, J=17.3 Hz, 1H), 5.57 (d, J=11.7 Hz, 1H), 4.34 (d,
J=12.9 Hz, 1H), 4.25 (d, J=12.0 Hz, 1H), 4.09 (br. s., 1H), 3.80
(br. s., 1H), 3.13 (br. s., 2H), 3.02 (br. s., 1H), 2.73 (dt,
J=15.6, 7.8 Hz, 1H), 2.51 (br. s., 2H), 2.21 (s, 3H), 2.10-2.20 (m,
2H), 1.67-1.97 (m, 5H), 1.50-1.66 (m, 1H), 1.43 (d, J=15.8 Hz, 1H),
1.11 (br. s., 2H), 0.83-0.93 (m, 2H), 0.61 (br. s., 1H), 0.52 (br.
s., 1H), 0.31-0.48 (m, 2H)
[1536] LC-MS: m/z 482.6 (M+H).sup.+
Compound 820 (General Procedure 6)
(R)-6-(4-(2-cyclobutylideneacetyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopro-
pyl-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1537] 1H NMR (CHLOROFORM-d) .delta. 8.70 (d, J=5.0 Hz, 1H), 7.25
(s, 1H), 7.09 (d, J=3.8 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz, 1H),
6.31 (d, J=17.3 Hz, 1H), 5.92 (br. s., 1H), 5.59 (d, J=11.2 Hz,
1H), 4.35 (d, J=12.9 Hz, 1H), 4.27 (d, J=12.6 Hz, 1H), 3.91-4.19
(m, 1H), 3.78 (br. s., 1H), 3.10-3.31 (m, 3H), 3.04 (td, J=12.4,
3.4 Hz, 1H), 2.84 (t, J=8.4 Hz, 2H), 2.43-2.55 (m, 1H), 2.22 (s,
3H), 1.98-2.17 (m, 2H), 1.53-1.63 (m, 1H), 1.45 (br. s., 1H),
1.04-1.18 (m, 2H), 0.82-0.96 (m, 2H), 0.64 (br. s., 1H), 0.50 (br.
s., 1H), 0.31-0.48 (m, 2H)
[1538] LC-MS: m/z 480.6 (M+H).sup.+
Compound 266 (General Procedure 6)
(R)-6-cyclopropyl-5-(3-fluoro-4-methylphenyl)-2-(4-(3-methoxypropanoyl)-3--
methylpiperazin-1-yl)-4-methylnicotinonitrile
[1539] .sup.1H NMR (CHLOROFORM-d) .delta. 7.25-7.31 (m, 1H),
6.85-6.92 (m, 2H), 4.91 (br. s., 0.5H), 4.54 (d, J=13.3 Hz, 0.5H),
4.00-4.23 (m, 2.5H), 3.68-3.87 (m, 2.5H), 3.51-3.63 (m, 0.5H), 3.39
(s, 3H), 3.10-3.27 (m, 1.5H), 2.94-3.09 (m, 1H), 2.64-2.82 (m, 1H),
2.55-2.64 (m, 1H), 2.32-2.39 (m, 3H), 2.20 (s, 3H), 1.60-1.70 (m,
1H), 1.39-1.47 (m, 1.5H), 1.30-1.35 (m, 1.5H), 1.07 (t, J=4.6 Hz,
2H), 0.83 (dt, J=7.5, 3.5 Hz, 2H)
[1540] LC-MS: m/z 451.4 (M+H).sup.+
Compound 277 (General Procedure 8)
6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(1-p-
henylethoxy)nicotinonitrile
[1541] .sup.1H NMR (CHLOROFORM-d) .delta. 7.28-7.42 (m, 5H), 6.97
(d, J=3.3 Hz, 1H), 5.15 (q, J=6.3 Hz, 1H), 4.85 (br. s., 0.5H),
4.48 (d, J=13.1 Hz, 0.5H), 4.15 (br. s., 0.5H), 3.76-3.94 (m, 2H),
3.64-3.76 (m, 2.5H), 3.41-3.57 (m, 0.5H), 3.36 (s, 3H), 2.96-3.13
(m, 1.5H), 2.77-2.96 (m, 1H), 2.61-2.77 (m, 1H), 2.48-2.61 (m, 2H),
1.67 (d, J=6.3 Hz, 3H), 1.26 (d, J=5.3 Hz, 3H), 0.97-1.15 (m,
4H)
[1542] LC-MS: m/z 449.2 (M+H).sup.+
Compound 279 (General Procedure 8)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyr-
idin-2-ylmethoxy)nicotinonitrile
[1543] .sup.1H NMR (CHLOROFORM-d) .delta. 8.64 (d, J=4.5 Hz, 1H),
7.82 (t, J=7.3 Hz, 1H), 7.51-7.62 (m, 1H), 7.29-7.39 (m, 1H), 7.23
(s, 1H), 5.22 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=12.8 Hz,
0.5H), 4.18 (br. s., 0.5H), 3.82-4.03 (m, 2H), 3.63-3.81 (m, 2.5H),
3.44-3.61 (m, 0.5H), 3.37 (s, 3H), 3.09 (t, J=13.2 Hz, 1.5H),
2.82-3.01 (m, 1H), 2.62-2.79 (m, 1H), 2.45-2.61 (m, 2H), 1.26 (d,
J=5.3 Hz, 3H), 0.99-1.16 (m, 4H)
[1544] LC-MS: m/z 436.2 (M+H).sup.+
Compound 280 (General Procedure 8)
(R)-6-cyclopropyl-5-(3-methoxybenzyloxy)-2-(4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)nicotinonitrile
[1545] .sup.1H NMR (CHLOROFORM-d) .delta. 7.32 (t, J=7.9 Hz, 1H),
7.18 (s, 1H), 6.93-7.05 (m, 2H), 6.89 (dd, J=8.0, 2.3 Hz, 1H), 5.02
(s, 2H), 4.87 (br. s., 0.5H), 4.51 (d, J=13.3 Hz, 0.5H), 4.18 (br.
s., 0.5H), 3.92 (t, J=12.7 Hz, 2H), 3.83 (s, 3H), 3.73 (t, J=6.1
Hz, 2.5H), 3.53 (d, J=8.0 Hz, 0.5H), 3.37 (s, 3H), 3.01-3.18 (m,
1.5H), 2.81-3.00 (m, 1H), 2.62-2.78 (m, 1H), 2.45-2.62 (m, 2H),
1.27-1.44 (m, 3H), 0.97-1.15 (m, 4H)
[1546] LC-MS: m/z 465.2 (M+H).sup.+
Compound 281 (General Procedure 8)
(R)-6-cyclopropyl-5-(4-methoxybenzyloxy)-2-(4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)nicotinonitrile
[1547] .sup.1H NMR (CHLOROFORM-d) .delta. 7.28-7.39 (m, J=8.8 Hz,
2H), 7.20 (s, 1H), 6.88-6.97 (m, J=8.8 Hz, 2H), 4.96 (s, 2H), 4.88
(d, J=7.8 Hz, 0.5H), 4.51 (d, J=13.3 Hz, 0.5H), 4.18 (br. s., 1H),
3.92 (t, J=12.5 Hz, 2H), 3.83 (s, 3H), 3.67-3.78 (m, 2.5H),
3.46-3.60 (m, 0.5H), 3.37 (s, 3H), 3.00-3.16 (m, 1.5H), 2.80-2.99
(m, 1H), 2.61-2.80 (m, 1H), 2.42-2.61 (m, 2H), 1.39 (d, J=6.5 Hz,
1.5H), 1.29 (d, J=6.8 Hz, 1.5H), 0.92-1.14 (m, 4H)
[1548] LC-MS: m/z 465.2 (M+H).sup.+
Compound 292 (General Procedure 8)
(R)-methyl
3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)pyridin-3-yloxy)methyl)benzoate
[1549] .sup.1H NMR (CHLOROFORM-d) .delta. 8.11 (s, 1H), 8.04 (d,
J=7.8 Hz, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.50 (t, J=7.7 Hz, 1H), 7.19
(s, 1H), 5.07 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=13.6 Hz,
0.5H), 4.18 (br. s., 0.5H), 3.94 (s, 3H), 3.83-4.02 (m, 2H),
3.64-3.80 (m, 2.5H), 3.52 (br. s., 0.5H), 3.37 (s, 3H), 3.09 (t,
J=13.6 Hz, 1.5H), 2.82-3.01 (m, 1H), 2.62-2.80 (m, 1H), 2.41-2.62
(m, 2H), 1.39 (d, J=6.5 Hz, 1.5H), 1.29 (d, J=6.8 Hz, 1.5H),
0.98-1.15 (m, 4H)
[1550] LC-MS: m/z 493.2 (M+H).sup.+
Compound 293 (General Procedure 8)
(R)-methyl
4-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpip-
erazin-1-yl)pyridin-3-yloxy)methyl)benzoate
[1551] .sup.1H NMR (CHLOROFORM-d) .delta. 8.01-8.14 (m, 2H),
7.44-7.56 (m, J=8.5 Hz, 2H), 7.18 (s, 1H), 5.10 (s, 2H), 4.88 (br.
s., 0.5H), 4.51 (d, J=13.6 Hz, 0.5H), 4.19 (br. s., 0.5H), 3.93 (s,
3H), 3.82-4.02 (m, 2H), 3.66-3.81 (m, 2.5H), 3.46-3.60 (m, 0.5H),
3.37 (s, 3H), 3.10 (t, J=13.7 Hz, 1.5H), 2.82-3.01 (m, 1H),
2.62-2.79 (m, 1H), 2.43-2.62 (m, 2H), 1.39 (d, J=6.5 Hz, 1.5H),
1.27-1.34 (m, 1.5H), 0.96-1.17 (m, 4H)
[1552] LC-MS: m/z 493.2 (M+H).sup.+
Compound 294 (General Procedure 8)
(R)-5-(3-cyanobenzyloxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)nicotinonitrile
[1553] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (s, 1H), 7.61-7.71
(m, 2H), 7.54 (t, J=7.9 Hz, 1H), 7.17 (s, 1H), 5.06 (s, 2H), 4.88
(br. s., 0.5H), 4.52 (d, J=13.6 Hz, 0.5H), 4.21 (br. s., 0.5H),
3.85-4.06 (m, 2H), 3.74 (br. s., 2.5H), 3.54 (br. s., 0.5H), 3.37
(s, 3H), 3.04-3.21 (m, 1.5H), 2.84-3.04 (m, 1H), 2.55-2.81 (m, 2H),
2.40-2.51 (m, 1H), 1.39 (d, J=5.5 Hz, 1.5H), 1.30 (d, J=6.3 Hz,
1.5H), 0.98-1.16 (m, 4H)
[1554] LC-MS: m/z 460.2 (M+H).sup.+
Compound 301 (General Procedure 8)
(R)-6-cyclopropyl-5-(4-(hydroxymethyl)benzyloxy)-2-(4-(3-methoxypropanoyl)-
-3-methylpiperazin-1-yl)nicotinonitrile
[1555] .sup.1H NMR (CHLOROFORM-d) .delta. 7.35-7.49 (m, 4H), 7.18
(s, 5.04 (s, 2H), 4.81-4.91 (m, 0.5H), 4.73 (s, 2H), 4.50 (d,
J=13.3 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.81-4.00 (m, 2H), 3.64-3.81
(m, 2.5H), 3.45-3.60 (m, 0.5H), 3.37 (s, 3H), 3.00-3.17 (m, 1.5H),
2.81-2.99 (m, 1H), 2.61-2.79 (m, 1H), 2.43-2.61 (m, 2H), 1.92-2.08
(m, 1H), 1.31-1.41 (m, 3H), 0.97-1.14 (m, 4H)
[1556] LC-MS: m/z 465.2 (M+H).sup.+
Compound 302 (General Procedure 8)
6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(2-m-
ethyl-1-phenylpropoxy)nicotinonitrile
[1557] .sup.1H NMR (CHLOROFORM-d) .delta. 7.27-7.39 (m, 5H), 6.87
(d, J=1.5 Hz, 1H), 4.84 (br. s., 0.5H), 4.66-4.74 (m, 1H), 4.47 (d,
J=13.3 Hz, 0.5H), 4.14 (br. s., 0.5H), 3.63-3.90 (m, 4.5H),
3.40-3.57 (m, 0.5H), 3.35 (s, 3H), 2.93-3.12 (m, 1.5H), 2.76-2.93
(m, 1H), 2.47-2.75 (m, 3H), 2.18 (dq, J=13.3, 6.6 Hz, 1H),
1.19-1.39 (m, 3H), 1.00-1.11 (m, 7H), 0.87-0.97 (m, 3H)
[1558] LC-MS: m/z 477.2 (M+H).sup.+
Compound 303 (General Procedure 8)
6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((S)-
-1-phenylethoxy)nicotinonitrile
[1559] .sup.1H NMR (CHLOROFORM-d) .delta. 7.27-7.42 (m, 5H),
6.91-7.00 (m, 1H), 5.15 (q, J=6.5 Hz, 1H), 4.85 (br. s., 0.5H),
4.48 (d, J=13.6 Hz, 0.5H), 4.15 (br. s., 0.5H), 3.78-3.95 (m, 2H),
3.61-3.77 (m, 2.5H), 3.43-3.57 (m, 0.5H), 3.36 (s, 3H), 2.96-3.13
(m, 1.5H), 2.85 (td, J=12.4, 2.8 Hz, 1H), 2.48-2.76 (m, 3H), 1.67
(d, J=6.5 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H), 1.21-1.28 (m, 1.5H),
0.97-1.13 (m, 4H)
[1560] LC-MS: m/z 449.2 (M+H).sup.+
Compound 304 (General Procedure 8)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyr-
idin-3-ylmethoxy)nicotinonitrile
[1561] .sup.1H NMR (CHLOROFORM-d) .delta. 8.70 (s, 1H), 8.63 (d,
J=3.8 Hz, 1H), 7.79 (dt, J=7.8, 1.9 Hz, 1H), 7.37 (dd, J=7.8, 4.8
Hz, 1H), 7.24 (s, 1H), 5.06 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d,
J=12.5 Hz, 0.5H), 4.20 (br. s., 0.5H), 3.83-4.04 (m, 2H), 3.63-3.83
(m, 2.5H), 3.53 (br. s., 0.5H), 3.37 (s, 3H), 3.03-3.17 (m, 1.5H),
2.84-3.02 (m, 1H), 2.62-2.78 (m, 1H), 2.51-2.62 (m, 1H), 2.39-2.51
(m, 1H), 1.36-1.43 (m, 2H), 1.27-1.34 (m, 2H), 0.91-1.15 (m,
4H)
[1562] LC-MS: m/z 436.2 (M+H).sup.+
Compound 307 (General Procedure 8)
6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((R)-
-1-phenylethoxy)nicotinonitrile
[1563] .sup.1H NMR (CHLOROFORM-d) .delta. 7.27-7.42 (m, 5H),
6.92-6.98 (m, 1H), 5.15 (q, J=6.4 Hz, 1H), 4.84 (br. s., 0.5H),
4.49 (d, J=13.6 Hz, 0.5H), 4.15 (br. s., 0.5H), 3.77-3.95 (m, 2H),
3.72 (t, J=6.3 Hz, 2.5H), 3.43-3.56 (m, 0.5H), 3.36 (s, 3H),
2.97-3.13 (m, 1.5H), 2.78-2.95 (m, 1H), 2.48-2.78 (m, 3H), 1.67 (d,
J=6.3 Hz, 3H), 1.36 (d, J=6.8 Hz, 1.5H), 1.26 (d, J=5.5 Hz, 1.5H),
0.97-1.14 (m, 4H)
[1564] LC-MS: m/z 449.2 (M+H).sup.+
Compound 308 (General Procedure 8)
6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(1-p-
henylpropoxy)nicotinonitrile
[1565] .sup.1H NMR (CHLOROFORM-d) .delta. 7.28-7.42 (m, 5H), 6.92
(d, J=2.3 Hz, 1H), 4.78-4.95 (m, 1.5H), 4.48 (d, J=13.3 Hz, 0.5H),
4.14 (br. s., 0.5H), 3.77-3.93 (m, 2H), 3.65-3.77 (m, 2.5H), 3.48
(br. s., 0.5H), 3.36 (s, 3H), 2.95-3.12 (m, 1.5H), 2.76-2.95 (m,
1H), 2.46-2.76 (m, 3H), 2.00-2.13 (m, 1H), 1.84-1.98 (m, 1H), 1.36
(d, J=6.8 Hz, 1.5H), 1.25-1.29 (m, 1.5H), 0.92-1.12 (m, 7H)
[1566] LC-MS: m/z 463.2 (M+H).sup.+
Compound 309 (General Procedure 8)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(pyr-
idin-4-ylmethoxy)nicotinonitrile
[1567] .sup.1H NMR (CHLOROFORM-d) .delta. 8.67 (d, J=5.8 Hz, 2H),
7.39 (d, J=5.8 Hz, 2H), 7.17 (s, 1H), 5.07 (s, 2H), 4.79-4.95 (m,
0.5H), 4.51 (d, J=13.6 Hz, 0.5H), 4.19 (br. s., 0.5H), 3.86-4.04
(m, 2H), 3.62-3.81 (m, 2.5H), 3.45-3.59 (m, 0.5H), 3.37 (s, 3H),
3.03-3.18 (m, 1.5H), 2.83-3.02 (m, 1H), 2.62-2.79 (m, 1H),
2.43-2.61 (m, 2H), 1.39 (d, J=6.8 Hz, 1.5H), 1.27-1.31 (m, 1.5H),
0.99-1.15 (m, 4H)
[1568] LC-MS: m/z 436.2 (M+H).sup.+
Compound 310 (General Procedure 8)
5-(1-(3-chlorophenyl)ethoxy)-6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-
-methylpiperazin-1-yl)nicotinonitrile
[1569] .sup.1H NMR (CHLOROFORM-d) .delta. 7.33-7.38 (m, 1H),
7.27-7.33 (m, 3H), 7.19-7.25 (m, 1H), 6.96 (d, J=4.5 Hz, 1H), 5.11
(q, J=6.3 Hz, 1H), 4.85 (br. s., 0.5H), 4.49 (d, J=13.6 Hz, 0.5H),
4.16 (br. s., 0.5H), 3.78-3.97 (m, 2H), 3.63-3.78 (m, 2.5H), 3.49
(br. s., 0.5H), 3.36 (s, 3H), 2.98-3.14 (m, 1.5H), 2.79-2.97 (m,
1H), 2.60-2.77 (m, 1H), 2.46-2.60 (m, 2H), 1.65 (d, J=6.3 Hz, 3H),
1.36 (d, J=6.5 Hz, 1.5H), 1.26 (d, J=7.8 Hz, 1.5H), 0.98-1.15 (m,
4H)
[1570] LC-MS: m/z 483.2 (M+H).sup.+
Compound 311 (General Procedure 8)
5-(1-(4-chlorophenyl)ethoxy)-6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-
-methylpiperazin-1-yl)nicotinonitrile
[1571] .sup.1H NMR (CHLOROFORM-d) .delta. 7.23-7.40 (m, 4H), 6.95
(d, J=3.8 Hz, 1H), 5.13 (q, J=6.1 Hz, 1H), 4.85 (br. s., 0.5H),
4.49 (d, J=13.1 Hz, 0.5H), 4.16 (br. s., 0.5H), 3.79-3.98 (m, 2H),
3.63-3.78 (m, 2.5H), 3.42-3.57 (m, 0.5H), 3.36 (s, 3H), 2.98-3.13
(m, 1.5H), 2.77-2.97 (m, 1H), 2.60-2.76 (m, 1H), 2.43-2.60 (m, 2H),
1.65 (d, J=6.3 Hz, 3H), 1.33-1.39 (m, 1.5H), 1.22-1.29 (m, 1.5H),
0.97-1.13 (m, 4H)
[1572] LC-MS: m/z 483.2 (M+H).sup.+
Compound 312 (General Procedure 8)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(3-n-
itrobenzyloxy)nicotinonitrile
[1573] .sup.1H NMR (CHLOROFORM-d) .delta. 8.33 (s, 1H), 8.24 (dd,
J=8.2, 1.2 Hz, 1H), 7.72-7.84 (m, 1H), 7.54-7.67 (m, 1H), 7.21 (s,
1H), 5.13 (s, 2H), 4.88 (br. s., 0.5H), 4.51 (d, J=13.7 Hz, 0.5H),
4.19 (br. s., 0.5H), 3.86-4.03 (m, 2H), 3.63-3.84 (m, 2.5H), 3.53
(br. s., 0.5H), 3.37 (s, 3H), 3.04-3.18 (m, 1.5H), 2.84-3.04 (m,
1H), 2.62-2.78 (m, 1H), 2.42-2.61 (m, 2H), 1.39 (d, J=6.7 Hz,
1.5H), 1.29 (d, J=6.7 Hz, 1.5H), 0.97-1.19 (m, 4H)
[1574] LC-MS: m/z 480.2 (M+H).sup.+
Compound 341 (General Procedure 8)
(R)-5-(3-aminobenzyloxy)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylp-
iperazin-1-yl)nicotinonitrile
[1575] .sup.1H NMR (CHLOROFORM-d) .delta. 7.13-7.24 (m, 2H), 6.79
(d, J=7.8 Hz, 1H), 6.74 (s, 1H), 6.67 (dd, J=8.0, 1.5 Hz, 1H), 4.95
(s, 2H), 4.87 (br. s., 0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.17 (br.
s., 0.5H), 3.81-3.98 (m, 2H), 3.73 (t, J=6.1 Hz, 2.5H), 3.53 (d,
J=8.8 Hz, 0.5H), 3.37 (s, 3H), 3.01-3.16 (m, 1.5H), 2.81-3.00 (m,
1H), 2.61-2.79 (m, 1H), 2.46-2.61 (m, 2H), 1.39 (d, J=6.5 Hz,
1.5H), 1.29 (d, J=6.5 Hz, 1.5H), 0.95-1.14 (m, 4H)
[1576] LC-MS: m/z 450.2 (M+H).sup.+
Compound 381 (General Procedure 8)
(R)--N-(3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpipera-
zin-1-yl)pyridin-3-yloxy)methyl)phenyl)acrylamide
[1577] .sup.1H NMR (CHLOROFORM-d) .delta. 8.11 (br. s., 1H), 7.82
(br. s., 1H), 7.52 (d, J=8.3 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H),
7.13-7.23 (m, 2H), 6.45 (dd, J=16.8, 1.3 Hz, 1H), 6.31 (dd, J=16.8,
10.0 Hz, 1H), 5.76 (dd, J=10.2, 1.4 Hz, 1H), 4.99 (s, 2H), 4.86
(br. s., 0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.18 (br. s., 0.5H),
3.81-3.99 (m, 2H), 3.72 (t, J=6.0 Hz, 2.5H), 3.45-3.59 (m, 0.5H),
3.35 (s, 3H), 3.00-3.16 (m, 1.5H), 2.81-2.99 (m, 1H), 2.62-2.79 (m,
1H), 2.41-2.62 (m, 2H), 1.39 (d, J=6.8 Hz, 1.5H), 1.25-1.32 (m,
1.5H), 0.94-1.15 (m, 4H)
[1578] LC-MS: m/z 504.2 (M+H).sup.+
Compound 382 (General Procedure 8)
(R)-2-bromo-N-(3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methy-
lpiperazin-1-yl)pyridin-3-yloxy)methyl)phenyl)acetamide
[1579] .sup.1H NMR (CHLOROFORM-d) .delta. 8.52 (s, 1H), 7.73 (s,
1H), 7.48 (d, J=8.0 Hz, 1H), 7.38 (t, J=7.8 Hz, 1H), 7.12-7.26 (m,
2H), 5.02 (s, 2H), 4.87 (br. s., 0.5H), 4.50 (d, J=13.3 Hz, 0.5H),
4.19 (d, J=8.5 Hz, 0.5H), 4.03 (s, 2H), 3.81-3.99 (m, 2H),
3.64-3.81 (m, 2.5H), 3.45-3.61 (m, 0.5H), 3.36 (s, 3H), 3.02-3.18
(m, 1.5H), 2.82-3.02 (m, 1H), 2.62-2.80 (m, 1H), 2.42-2.62 (m, 2H),
1.39 (d, J=6.5 Hz, 1.5H), 1.22-1.33 (m, 1.5H), 0.95-1.14 (m,
4H)
[1580] LC-MS: m/z 570.1 (M+H).sup.+
Compound 388 (General Procedure 8)
6-cyclopropyl-2-((R)-4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-(1-(-
pyridin-4-yl)ethoxy)nicotinonitrile
[1581] .sup.1H NMR (CHLOROFORM-d) .delta. 8.57-8.70 (m, 2H), 7.33
(d, J=6.0 Hz, 2H), 6.96 (d, J=3.3 Hz, 1H), 5.17 (q, J=6.4 Hz, 1H),
4.86 (br. s., 0.5H), 4.49 (d, J=12.8 Hz, 0.5H), 4.17 (br. s.,
0.5H), 3.81-4.05 (m, 2H), 3.63-3.81 (m, 2.5H), 3.51 (d, J=15.3 Hz,
0.5H), 3.36 (s, 3H), 3.07 (t, J=12.9 Hz, 1.5H), 2.81-3.00 (m, 1H),
2.60-2.78 (m, 1H), 2.46-2.60 (m, 2H), 1.67 (d, J=6.5 Hz, 3H), 1.36
(d, J=5.0 Hz, 1.5H), 1.24-1.28 (m, 1.5H), 0.99-1.16 (m, 4H)
[1582] LC-MS: m/z 450.2 (M+H).sup.+
Compound 389 (General Procedure 8)
N-(4-(1-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)pyridin-3-yloxy)ethyl)phenyl)acrylamide
[1583] .sup.1H NMR (CHLOROFORM-d) .delta. 8.03 (br. s., 1H),
7.56-7.64 (m, 2H), 7.30 (d, J=8.3 Hz, 2H), 6.90-7.05 (m, 1H), 6.43
(dd, J=16.8, 1.3 Hz, 1H), 6.29 (dd, J=16.8, 10.0 Hz, 1H), 5.74 (dd,
J=10.0, 1.3 Hz, 1H), 5.05-5.19 (m, 1H), 4.85 (br. s., 0.5H), 4.48
(d, J=12.5 Hz, 0.5H), 4.16 (br. s., 0.5H), 3.65-3.95 (m, 5.5H),
3.50 (d, J=11.3 Hz, 0.5H), 3.34 (s, 3H), 2.97-3.14 (m, 1.5H),
2.77-2.95 (m, 1H), 2.61-2.77 (m, 1H), 2.47-2.61 (m, 2H), 1.65 (d,
J=6.3 Hz, 3H), 1.36 (d, J=6.5 Hz, 1.5H), 1.26 (d, J=5.0 Hz, 1.5H),
0.97-1.15 (m, 4H)
[1584] LC-MS: m/z 518.2 (M+H).sup.+
Compound 400 (General Procedure 8)
(R,E)-N-(3-((5-cyano-2-cyclopropyl-6-(4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)pyridin-3-yloxy)methyl)phenyl)but-2-enamide
[1585] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (br. s., 1H), 7.47
(d, J=8.0 Hz, 1H), 7.30-7.40 (m, 2H), 7.10-7.23 (m, 2H), 6.88-7.09
(m, 1H), 5.96 (dd, J=15.1, 1.5 Hz, 1H), 5.01 (s, 2H), 4.87 (br. s.,
0.5H), 4.50 (d, J=13.6 Hz, 0.5H), 4.18 (br. s., 0.5H), 3.82-4.00
(m, 2H), 3.64-3.80 (m, 2.5H), 3.46-3.62 (m, 0.5H), 3.36 (s, 3H),
3.01-3.16 (m, 1.5H), 2.83-3.01 (m, 1H), 2.62-2.77 (m, 1H),
2.44-2.61 (m, 2H), 1.93 (dd, J=6.9, 1.6 Hz, 3H), 1.39 (d, J=6.5 Hz,
1.5H), 1.29 (d, J=7.0 Hz, 1.5H), 0.95-1.13 (m, 4H)
[1586] LC-MS: m/z 518.2 (M+H).sup.+
Compound 407 (General Procedure 8)
N-(3-(1-(5-cyano-2-cyclopropyl-6-((R)-4-(3-methoxypropanoyl)-3-methylpiper-
azin-1-yl)pyridin-3-yloxy)ethyl)phenyl)acrylamide
[1587] .sup.1H NMR (CHLOROFORM-d) .delta. 7.75 (br. s., 1H), 7.63
(br. s., 1H), 7.46 (br. s., 1H), 7.34 (t, J=7.8 Hz, 1H), 7.13 (d,
J=7.5 Hz, 1H), 6.94-7.01 (m, 1H), 6.46 (dd, J=16.8, 1.3 Hz, 1H),
6.28 (dd, J=16.9, 10.2 Hz, 1H), 5.79 (dd, J=10.3, 1.0 Hz, 1H), 5.13
(q, J=6.1 Hz, 1H), 4.86 (br. s., 0.5H), 4.49 (d, J=13.3 Hz, 0.5H),
4.17 (br. s., 0.5H), 3.78-3.95 (m, 2H), 3.63-3.78 (m, 2.5H), 3.52
(d, J=14.6 Hz, 0.5H), 3.37 (s, 3H), 2.98-3.14 (m, 1.5H), 2.79-2.97
(m, 1H), 2.63-2.78 (m, 1H), 2.48-2.63 (m, 2H), 1.68 (d, J=6.3 Hz,
3H), 1.38 (d, J=6.3 Hz, 1.5H), 1.24-1.30 (m, 1.5H), 1.00-1.14 (m,
4H)
[1588] LC-MS: m/z 518.2 (M+H).sup.+
Compound 827 (General Procedure 6)
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-hexanoylpiperazin-1-yl)-4-methyl-2'-v-
inyl-3,4'-bipyridine-5-carbonitrile
[1589] .sup.1H NMR (CHLOROFORM-d) .delta. 8.69 (d, J=4.7 Hz, 1H),
7.23 (s, 1H), 7.07 (d, J=4.7 Hz, 1H), 6.87 (dd, J=17.6, 10.9 Hz,
1H), 6.19-6.36 (m, 1H), 5.47-5.63 (m, 1H), 4.34 (d, J=12.9 Hz, 1H),
4.26 (d, J=12.6 Hz, 1H), 4.10 (br. s., 0.65H), 3.64-3.91 (m,
1.35H), 2.88-3.38 (m, 2H), 2.37 (br. s., 2H), 2.21 (s, 3H),
1.61-1.73 (m, 2H), 1.51-1.61 (m, 1H), 1.44 (br. s., 1H), 1.35 (br.
s., 4H), 1.04-1.17 (m, 2H), 0.90-0.98 (m, 3H), 0.87 (dd, J=8.1, 3.1
Hz, 2H), 0.60 (br. s., 1H), 0.55 (br. s., 1H), 0.23-0.50 (m,
2H)
[1590] LC-MS: m/z 484.3 (M+H).sup.+
Compound 826 (General Procedure 6)
(R)-6-(4-(3-cyclobutylpropanoyl)-3-cyclopropylpiperazin-1-yl)-2-cyclopropy-
l-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1591] .sup.1H NMR (CHLOROFORM-d) .delta. 8.70 (d, J=5.0 Hz, 1H),
7.25 (s, 1H), 7.09 (d, J=4.7 Hz, 1H), 6.88 (dd, J=17.6, 10.9 Hz,
1H), 6.28 (d, J=17.6 Hz, 1H), 5.51-5.64 (m, 1H), 4.34 (d, J=12.9
Hz, 1H), 4.26 (d, J=12.0 Hz, 1H), 4.09 (br. s., 0.6H), 3.63-3.92
(m, 1.4H), 3.01-3.13 (m, 2H), 2.25-2.38 (m, 2H), 2.22 (s, 3H),
2.00-2.13 (m, 4H), 1.82-1.90 (m, 2H), 1.75 (q, J=7.4 Hz, 2H),
1.61-1.69 (m, 2H), 1.56 (td, J=8.3, 4.0 Hz, 1H), 1.12 (br. s., 2H),
0.80-0.94 (m, 2H), 0.61 (br. s., 1H), 0.55 (br. s., 1H), 0.44 (br.
s., 2H)
[1592] LC-MS: m/z 496.3 (M+H).sup.+
Compound 825 (General Procedure 6)
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-cyclopropylpropanoyl)piperazin-1-y-
l)-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1593] .sup.1H NMR (CHLOROFORM-d) .delta. 8.72 (d, J=5.0 Hz, 1H),
7.26 (s, 1H), 7.09 (d, J=4.7 Hz, 1H), 6.89 (dd, J=17.6, 10.9 Hz,
1H), 6.27 (d, J=17.6 Hz, 1H), 5.52-5.65 (m, 1H), 4.34 (d, J=12.6
Hz, 1H), 4.26 (d, J=12.6 Hz, 1H), 4.02-4.17 (m, 0.6H), 3.71-3.95
(m, 1.4H), 2.95-3.4 (m, 2H), 2.45-2.56 (m, 1H), 2.36 (t, J=7.5 Hz,
3H), 2.22 (s, 3H), 1.63-1.70 (m, 2H), 1.11 (br. s., 2H), 0.75-0.89
(m, 3H), 0.51-0.74 (m, 3H), 0.34-0.50 (m, 4H), 0.10 (d, J=4.1 Hz,
2H)
[1594] LC-MS: m/z 482.2 (M+H).sup.+
Compound 582 (General Procedure 7)
(R)-5-((5-cyano-2-cyclopropyl-6-(4-(3-hydroxypropanoyl)-3-methylpiperazin--
1-yl)pyridin-3-yl)amino)picolinonitrile
[1595] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.18-8.17 (d, 1H),
7.61 (s, 1H), 7.51-7.49 (d, 1H), 6.89-6.86 (dd, 1H), 6.38 (s, 1H),
4.87 (s, 0.5H), 4.53-4.50 (d, 0.5H); 4.27-4.16 (dd, 2H) 3.92 (s,
2H) 3.75-3.10 (m, 4H) 2.69-2.51 (m, 2H), 2.07-2.02 (m, 1H),
1.41-1.26 (m, 3H), 1.43-1.10 (m, 2H), 1.04-1.01 (m, 2H).
[1596] LC-MS: m/z 432.2 (M+H).sup.+
Compound 577 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((6--
vinylpyridin-3-yl)amino)nicotinonitrile
[1597] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.15-8.14 (d, 1H),
7.58 (s, 1H), 7.26-7.23 (d, 1H), 6.97-6.94 (dd, 1H), 6.79-6.72 (q,
1H), 6.03-5.98 (dd, 1H), 5.58 (s, 1H), 5.36-5.33 (dd, 1H), 4.88 (s,
0.5H), 4.54-4.51 (d, 0.5H); 4.20-4.09 (dd, 2H) 3.93 (s, 2H)
3.75-3.52 (m, 2H) 3.25-2.98 (m, 3H), 2.71-2.50 (m, 2H), 2.18-2.10
(m, 1H), 1.41-1.26 (m, 3H), 1.43-1.30 (m, 2H), 1.13-1.11 (m, 2H),
1.03-1.09 (m, 2H).
[1598] LC-MS: m/z 433.2 (M+H).sup.+
Compound 298 (General Procedure 6)
(R)-6-cyclopropyl-5-(4-fluorophenyl)-4-(methoxymethyl)-2-(4-(3-methoxyprop-
anoyl)-3-methylpiperazin-1-yl)nicotinonitrile
[1599] .sup.1H NMR (CHLOROFORM-d) .delta. t: 7.21-7.27 (m, 2H),
7.11-7.19 (m, 2H), 4.85-4.95 (s, 0.5H), 4.45-4.57 (m, 0.5H),
4.05-4.27 (m, 4H), 3.74 (t, J=6.4 Hz, 2.5H), 3.57-3.63 (m, 0.5H),
3.35-3.40 (m, 3H), 3.29 (s, 3H), 3.09-3.26 (m, 2H), 2.59 (br. s.,
1H), 1.60-1.70 (m, 1H), 1.38-1.44 (m, 1H), 1.30 (d, J=6.8 Hz, 2H),
1.25 (s, 1H), 1.04-1.10 (m, 2H), 0.81-0.88 (m, 2H).
[1600] LC-MS: m/z 487.2 (M+H).sup.+
Compound 823 (General Procedure 6)
2-Cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-4-ethyl-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1601] .sup.1H NMR (CHLOROFORM-d) .delta. 8.57-8.87 (m, 1H), 7.25
(s, 1H), 7.02-7.16 (m, 1H), 6.89 (dd, J=17.5, 10.7 Hz, 1H), 6.30
(d, J=17.3 Hz, 1H), 5.59 (d, J=10.9 Hz, 1H), 5.27 (t, J=6.6 Hz,
1H), 4.51-4.78 (m, 2H), 4.30-4.42 (m, 1H), 4.26 (d, J=11.4 Hz, 1H),
4.09 (d, J=9.1 Hz, 1H), 3.84-3.98 (m, 1H), 3.56-3.84 (m, 1H),
2.95-3.45 (m, 3H), 2.68-2.92 (m, 2H), 2.41-2.63 (m, 3H), 1.49-1.55
(m, 1H), 1.34 (d, J=8.2 Hz, 1H), 1.10 (t, J=7.6 Hz, 5H), 0.80-0.94
(m, 3H), 0.35-0.75 (m, 4H)
[1602] LC-MS: m/z 498.3 (M+H).sup.+
Compound 805 (General Procedure 6)
2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(tetrahydrofuran-2-yl)acetyl)pipe-
razin-1-yl)-4-methyl-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1603] .sup.1H NMR (CHLOROFORM-d) .delta. 8.69 (d, J=5.0 Hz, 1H),
7.23 (s, 1H), 7.07 (d, J=5.0 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz,
1H), 6.22-6.40 (m, 1H), 5.57 (dd, J=10.9, 0.9 Hz, 1H), 4.60-4.70
(m, 0.5H), 4.18-4.41 (m, 3H), 4.02-4.15 (m, 0.5H), 3.89 (d, J=7.3
Hz, 1.5H), 3.63-3.82 (m, 1.5H), 2.90-3.45 (m, 3H), 2.64-2.85 (m,
1H), 2.53 (dd, J=14.8, 6.0 Hz, 1H), 2.08-2.32 (m, 4H), 1.88-2.00
(m, 2H), 1.51-1.69 (m, 2H), 1.43 (d, J=13.8 Hz, 1H), 1.11 (s, 2H),
0.87 (dd, J=7.9, 2.9 Hz, 2H), 0.35-0.66 (m, 4H)
[1604] LC-MS: m/z 498.3 (M+H).sup.+
Compound 806 (General Procedure 6)
2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(5-oxotetrahydrofuran-2-yl)acetyl-
)piperazin-1-yl)-4-methyl-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1605] .sup.1H NMR (CHLOROFORM-d) .delta. 8.71 (d, J=4.7 Hz, 1H),
7.25 (s, 1H), 7.09 (d, J=4.7 Hz, 1H), 6.90 (dd, J=17.3, 10.9 Hz,
1H), 6.31 (d, J=17.3 Hz, 1H), 5.60 (d, J=11.2 Hz, 1H), 4.94-5.08
(m, 1H), 4.17-4.45 (m, 2H), 4.08 (s, 1H), 3.79 (s, 2H), 2.80-3.45
(m, 4H), 2.51-2.73 (m, 4H), 2.19-2.28 (m, 3H), 1.57 (td, J=8.1, 4.0
Hz, 1H), 1.12 (s, 3H), 0.88 (dd, J=7.9, 3.2 Hz, 3H), 0.25-0.74 (m,
4H)
[1606] LC-MS: m/z 512.3 (M+H).sup.+
Compound 808 (General Procedure 7)
2-(5-cyano-2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl-
)piperazin-1-yl)pyridin-3-ylamino)pyrimidine-4-carbonitrile
[1607] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.59 (d, J=4.7 Hz, 1H),
7.87-8.13 (m, 1H), 7.00-7.17 (m, 2H), 5.10-5.32 (m, 2H), 4.67-4.83
(m, 1H), 4.47-4.63 (m, 1H), 4.39 (d, J=11.7 Hz, 1H), 4.30 (d,
J=12.3 Hz, 1H), 4.08 (d, J=7.3 Hz, 1H), 3.92 (d, J=12.9 Hz, 1H),
3.64-3.84 (m, 1H), 3.18-3.45 (m, 1H), 2.93-3.18 (m, 3H), 2.54 (d,
J=6.7 Hz, 1H), 1.94-2.14 (m, 2H), 1.86 (br. s., 2H), 1.46 (d, J=8.2
Hz, 1H), 1.39 (br. s., 1H), 1.33 (br. s., 1H), 1.27 (s, 1H),
0.97-1.23 (m, 4H), 0.63 (br. s., 1H), 0.54 (br. s., 1H), 0.27-0.50
(m, 2H).
[1608] LC-MS: m/z 485.2 (M+H).sup.+
Compound 809 (General Procedure 7)
5-(4-cyanopyridin-2-ylamino)-6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)--
oxetan-2-yl)acetyl)piperazin-1-yl)nicotinonitrile
[1609] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.65 (d, J=5.3 Hz, 1H),
7.65 (s, 1H), 7.39 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd,
J=17.3, 10.9 Hz, 1H), 6.20-6.35 (m, 1H), 5.51-5.65 (m, 1H), 4.55
(d, J=12.9 Hz, 1H), 4.29-4.48 (m, 1H), 4.05-4.29 (m, 2H), 4.00 (br.
s., 1H), 3.80 (br. s., 1H), 3.62-3.77 (m, 1H), 3.54 (br. s., 2H),
3.22 (d, J=12.6 Hz, 2H), 3.09 (t, J=10.9 Hz, 1H), 2.40-2.54 (m,
3H), 2.01-2.17 (m, 4H), 1.15-1.45 (m, 11H), 0.94-1.10 (m, 3H),
0.74-0.94 (m, 2H), 0.65 (br. s., 2H), 0.47 (br. s., 3H).
[1610] LC-MS: m/z 484.2 (M+H).sup.+
Compound 803 (General Procedure 6)
2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(3-(oxetan-2-yl)propanoyl)piperazin--
1-yl)-4-methyl-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1611] .sup.1H NMR (CHLOROFORM-d) .delta. 8.69 (d, J=5.0 Hz, 1H),
7.23 (s, 1H), 7.07 (d, J=3.8 Hz, 1H), 6.87 (dd, J=17.3, 10.9 Hz,
1H), 6.29 (d, J=17.3 Hz, 1H), 5.45-5.62 (m, 1H), 4.88 (s, 1H),
4.64-4.74 (m, 1H), 4.54 (dt, J=8.8, 5.9 Hz, 1H), 4.33 (d, J=12.6
Hz, 1H), 4.18-4.29 (m, 1H), 4.03-4.15 (m, 1H), 3.60-3.90 (m, 1H),
3.09-3.39 (m, 2H), 2.94-3.09 (m, 1H), 2.66-2.78 (m, 1H), 2.25-2.60
(m, 3H), 2.21 (s, 3H), 2.01-2.14 (m, 2H), 1.51-1.68 (m, 1H), 1.43
(d, J=12.9 Hz, 1H), 1.00-1.16 (m, 2H), 0.87 (dd, J=7.9, 2.9 Hz,
2H), 0.25-0.65 (m, 4H)
[1612] LC-MS: m/z 498.3 (M+H).sup.+
Compound 802 (General Procedure 5)
2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(5-oxotetrahydrofuran-2-yl)acetyl-
)piperazin-1-yl)-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1613] .sup.1H NMR (CHLOROFORM-d) .delta. 8.67 (d, J=5.0 Hz, 1H),
7.60-7.71 (m, 1H), 7.40 (s, 1H), 7.21-7.27 (m, 1H), 6.89 (dd,
J=17.5, 10.7 Hz, 1H), 6.29 (d, J=17.3 Hz, 1H), 5.58 (d, J=10.9 Hz,
1H), 4.94-5.06 (m, 1H), 4.35-4.75 (m, 2.5H), 4.01-4.09 (m, 0.5H),
3.70-3.81 (m, 1.5H), 2.90-3.40 (m, 3.5H), 2.50-2.79 (m, 4H),
1.98-2.04 (m, 1H), 1.29-1.37 (m, 2H), 1.22 (dt, J=7.0, 3.5 Hz, 2H),
0.97-1.06 (m, 2H), 0.26-0.70 (m, 4H)
[1614] LC-MS: m/z 498.2 (M+H).sup.+
Compound 801 (General Procedure 5)
2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(2-(tetrahydrofuran-2-yl)acetyl)pipe-
razin-1-yl)-2'-vinyl-[3,4'-bipyridine]-5-carbonitrile
[1615] .sup.1H NMR (CHLOROFORM-d) .delta. 8.65 (d, J=5.0 Hz, 1H),
7.64 (s, 1H), 7.39 (s, 1H), 7.23 (d, J=4.7 Hz, 1H), 6.88 (dd,
J=17.6, 10.9 Hz, 1H), 6.28 (d, J=17.6 Hz, 1H), 5.56 (d, J=10.9 Hz,
1H), 4.50-4.62 (m, 1H), 4.43 (d, J=12.9 Hz, 1H), 4.21-4.35 (m, 1H),
4.05-4.11 (m, 1H), 3.80-3.92 (m, 1.5H), 3.62-3.80 (m, 1.5H),
3.07-3.41 (m, 3H), 2.45-2.97 (m, 2H), 2.15-2.20 (m, 1H), 1.98-2.05
(m, 2H), 1.92 (dt, J=14.2, 6.9 Hz, 2H), 1.62 (d, J=7.3 Hz, 1H),
1.16-1.24 (m, 2H), 1.00 (dd, J=7.5, 3.4 Hz, 2H), 0.34-0.71 (m,
4H)
[1616] LC-MS: m/z 484.3 (M+H).sup.+
Compound 824 (General Procedure 7)
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-5-((2-(hydroxymethyl)pyridin-4-yl)amino)nicotinonitrile
[1617] .sup.1H NMR (400 MHz, MeOD) .delta. 8.08 (d, J=6.5 Hz, 1H),
7.80 (d, J=2.2 Hz, 1H), 6.81 (d, J=2.0 Hz, 1H), 6.71 (dd, J=6.4,
2.3 Hz, 1H), 6.18-6.11 (m, 1H), 5.62 (dd, J=6.8, 5.5 Hz, 1H), 5.24
(s, 1H), 4.66 (d, J=7.0 Hz, 3H), 4.51 (d, J=13.1 Hz, 1H), 4.37 (s,
1H), 4.14-3.97 (m, 1H), 3.71 (dd, J=10.8, 4.4 Hz, 2H), 3.62 (s,
1H), 3.18-3.04 (m, 1H), 2.84 (s, 1H), 2.49 (d, J=6.5 Hz, 1H),
2.17-2.09 (m, 1H), 1.96 (s, 1H), 1.53-1.25 (m, 3H), 1.21-1.13 (m,
2H), 1.04 (dd, J=7.7, 3.4 Hz, 2H), 0.71-0.36 (m, 4H).
[1618] LC-MS: m/z 489.2 (M+H).sup.+
Compound 810 (General Procedure 5)
Sodium
(R)-3-(4-(5-cyano-2-cyclopropyl-2'-vinyl-[3,4'-bipyridin]-6-yl)-2-c-
yclopropylpiperazin-1-yl)-3-oxopropyl phosphate
[1619] .sup.1H NMR (400 MHz, D.sub.2O) .delta. 8.37 (d, J=5.0 Hz,
1H), 7.61 (s, 1H), 7.40 (s, 1H), 7.26 (s, 1H), 6.74 (dd, J=17.5,
11.3 Hz, 1H), 6.04 (d, J=17.8 Hz, 1H), 5.51 (d, J=11.2 Hz, 1H),
4.47 (s, 1H), 4.35 (s, 2H), 3.91 (d, J=6.7 Hz, 3H), 3.82 (s, 1H),
3.56 (q, J=7.1 Hz, 2H), 3.20 (s, 1H), 2.78 (s, 1H), 2.71-2.63 (m,
1H), 1.92 (s, 1H), 1.55 (s, 4H), 1.18 (s, 2H), 0.89 (s, 1H),
0.45-0.46 (m, 2H), 0.37-0.22 (m, 2H).
[1620] LC-MS: m/z 568.2 (M+H).sup.+
Compound 828 (General Procedure 7)
[1621] 1H NMR (CHLOROFORM-d) .delta. 8.07 (d, J=5.3 Hz, 1H), 7.81
(s, 1H), 7.02 (br. s., 1H), 6.71-6.84 (m, 1H), 6.55 (dd, J=17.6,
10.9 Hz, 1H), 6.38 (s, 1H), 5.86 (d, J=17.6 Hz, 1H), 5.42 (d,
J=11.2 Hz, 1H), 4.18-4.44 (m, 3H), 4.11 (q, J=7.0 Hz, 1H),
3.81-3.99 (m, 2H), 3.62-3.81 (m, 2H), 3.11 (d, J=12.9 Hz, 2H), 3.04
(m, 1H), 2.73 (d, J=6.5 Hz, 1H), 2.08-2.28 (m, 2H), 1.82-1.97 (m,
2H), 1.59 (dd, J=12.0, 7.9 Hz, 1H), 1.25 (t, J=7.0 Hz, 1H),
1.04-1.18 (m, 2H), 0.88-1.02 (m, 2H), 0.51-0.59 (m, 2H), 0.42-0.49
(m, 2H)
[1622] LC-MS: m/z 499.2 (M+H).sup.+
Compound 829 (General Procedure 7)
[1623] 1H NMR (CHLOROFORM-d) .delta. 7.56 (s, 1H), 7.14 (d, J=7.3
Hz, 1H), 6.11 (br, s, 1H), 5.79 (dd, J=7.3, 2.3 Hz, 1H), 5.58 (br.
s., 1H), 5.26 (t, J=6.6 Hz, 1H), 4.71 (td, J=7.9, 6.2 Hz, 1H), 4.56
(m, 1H), 4.43 (d, J=12.3 Hz, 1H), 4.32 (d, J=12.6 Hz, 1H), 4.06 (d,
J=9.1 Hz, 0.5H), 3.92 (d, J=12.3 Hz, 0.5H), 3.69-3.82 (m, 1H), 3.47
(s, 3H), 3.08-3.34 (m, 2H), 2.92-3.08 (m, 2.5H), 2.78-2.90 (m,
1.5H), 2.54 (d, J=7.3 Hz, 1H), 2.06-2.17 (m, 1H), 1.27 (s, 1H),
1.06-1.16 (m, 2H), 0.98-1.05 (m, 2H), 0.53-0.63 (m, 2H), 0.30-0.49
(m, 2H)
[1624] LC-MS: m/z 489.2 (M+H).sup.+
Compound 830 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-hexanoylpiperazin-1-yl)-5-(4-vinylpyr-
idin-2-ylamino)nicotinonitrile
[1625] .sup.1H NMR (CHLOROFORM-d) .delta. 8.02 (d, J=4.4 Hz, 1H),
7.72 (s, 1H), 6.82 (d, J=5.3 Hz, 1H), 6.56 (dd, J=17.3, 10.9 Hz,
1H), 6.34 (s, 1H), 5.90 (d, J=17.6 Hz, 1H), 5.49 (d, J=10.9 Hz,
1H), 4.40 (d, J=12.9 Hz, 1H), 4.29 (d, J=12.0 Hz, 1H), 4.11 (br.
s., 1H), 3.80 (br. s., 2H), 3.16 (br. s., 2H), 2.90-3.11 (m, 1H),
2.25-2.45 (m, 5H), 1.56-1.73 (m, 4H), 1.20-1.48 (m, 4H), 1.07-1.20
(m, 2H), 0.82-1.07 (m, 2H).
[1626] LC-MS: m/z 485.2 (M+H).sup.+
Compound 818 (General Procedure 5)
[1627] .sup.1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=4.7 Hz, 1H),
7.66 (s, 1H), 7.41 (s, 1H), 7.22-7.28 (m, 1H), 6.90 (dd, J=17.3,
10.9 Hz, 1H), 6.31 (d, J=17.3 Hz, 1H), 5.60 (d, J=10.9 Hz, 1H),
4.55 (d, J=12.9 Hz, 1H), 4.43 (dd, J=12.9, 2.1 Hz, 1H), 4.14 (m,
2H), 3.72 (m, 1H), 3.43-3.63 (m, 2H), 3.22 (d, J=11.4 Hz, 2H),
3.01-3.16 (m, 2H), 2.06-2.11 (m, 1H), 1.79-2.09 (m, 1H), 1.65 (br.
s., 1H), 1.40-1.53 (m, 1H), 1.17-1.25 (m, 2H), 0.96-1.08 (m, 2H),
0.66-0.75 (m, 2H), 0.39-0.61 (m, 2H)
[1628] LC-MS: m/z 483.7 (M+H).sup.+
Compound 821 (General Procedure 5)
[1629] 1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=5.3 Hz, 1H), 7.65
(s, 1H), 7.33-7.46 (m, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd,
J=17.5, 10.7 Hz, 1H), 6.24-6.39 (m, 1H), 5.57 (dd, J=10.9, 1.2 Hz,
1H), 5.01 (t, J=6.3 Hz, 1H), 4.56 (m, 1.5H), 4.44 (d, J=14.1 Hz,
1H), 3.79 (m, 1H), 3.22 (m, 1.5H), 2.70 (d, J=6.7 Hz, 1H),
2.49-2.65 (m, 3H), 1.90-2.14 (m, 4H), 1.35 (m, 1H), 1.21 (m, 3H),
0.92-1.08 (m, 2H), 0.48 (m, 4H)
[1630] LC-MS: m/z 498.7 (M+H).sup.+
Compound 822 (General Procedure 5)
[1631] .sup.1H NMR (CHLOROFORM-d) .delta. 8.64 (d, J=4.7 Hz, 1H),
7.53 (s, 1H), 7.38 (s, 1H), 7.22 (dd, J=5.0, 1.5 Hz, 1H), 6.87 (dd,
J=17.6, 10.9 Hz, 1H), 6.18-6.36 (m, 1H), 5.49-5.62 (m, 1H),
4.67-4.71 (m, 0.5H), 4.54 (d, J=12.6 Hz, 1H), 4.36-4.46 (m, 1H),
4.28 (quin, J=6.5 Hz, 1H), 4.11 (d, J=7.9 Hz, 0.5H), 3.81-4.00 (m,
1.5H), 3.63-3.79 (m, 1.5H), 3.08-3.20 (m, 1H), 2.64-2.85 (m, 2H),
2.46-2.60 (m, 1H), 2.08-2.24 (m, 1H), 1.97-2.08 (m, 1H), 1.82-1.97
(m, 2H), 1.52-1.70 (m, 1H), 1.26-1.30 (m, 2H), 1.12-1.24 (m, 2H),
0.92-1.05 (m, 2H), 0.49-0.73 (m, 2H), 0.45 (m, 2H)
[1632] LC-MS: m/z 484.7 (M+H).sup.+
Compound 811 (General Procedure 6)
[1633] .sup.1H NMR (CHLOROFORM-d) .delta. 7.23 (s, 1H), 7.07 (dd,
J=5.0, 1.2 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz, 1H), 6.29 (d, J=17.3
Hz, 1H), 5.57 (dd, J=10.9, 1.2 Hz, 1H), 4.32 (d, J=12.9 Hz, 1H),
4.23 (dd, J=12.6, 2.1 Hz, 1H), 4.14 (m, 1H), 3.99 (br. s., 1H),
3.72 (br. s., 1.5H), 3.42-3.57 (m, 2.5H), 3.10-3.25 (m, 2H),
2.98-3.10 (m, 3H), 2.10-2.38 (m, 4H), 1.51-1.62 (m, 1H), 1.45 (dq,
J=14.7, 7.3 Hz, 1H), 1.07-1.17 (m, 2H), 0.88 (dd, J=7.9, 3.2 Hz,
2H), 0.66 (br. s., 1H), 0.30-0.59 (m, 3H)
[1634] LC-MS: m/z 497.7 (M+H).sup.+
Compound 814 (General Procedure 5)
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(2-(2-oxopyrrolidin-1-yl)acetyl)piper-
azin-1-yl)-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1635] .sup.1H NMR (CHLOROFORM-d) .delta. 8.65 (d, J=5.3 Hz, 1H),
7.65 (s, 1H), 7.39 (s, 1H), 7.24 (dd, J=5.0, 1.5 Hz, 1H), 6.88 (dd,
J=17.3, 10.9 Hz, 1H), 6.20-6.35 (m, 1H), 5.51-5.65 (m, 1H), 4.55
(d, J=12.9 Hz, 1H), 4.29-4.48 (m, 1H), 4.05-4.29 (m, 2H), 4.00 (br.
s., 1H), 3.80 (br. s., 1H), 3.62-3.77 (m, 1H), 3.54 (br. s., 2H),
3.22 (d, J=12.6 Hz, 2H), 3.09 (t, J=10.9 Hz, 1H), 2.40-2.54 (m,
3H), 2.01-2.17 (m, 4H), 1.15-1.45 (m, 4H), 0.94-1.10 (m, 3H),
0.74-0.94 (m, 2H), 0.65 (br. s., 2H), 0.47 (br. s., 3H).
[1636] LC-MS: m/z 497.2 (M+H).sup.+
Compound 815 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(4-hydroxybutanoyl)piperazin-1-yl)-5--
((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1637] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10 (d, J=5.5 Hz,
1H), 7.84 (s, 1H), 6.86 (dd, J=5.5, 1.1 Hz, 1H), 6.80 (s, 1H), 6.59
(dd, J=17.6, 10.9 Hz, 1H), 6.44 (s, 1H), 5.93 (d, J=17.5 Hz, 1H),
5.51 (d, J=10.9 Hz, 1H), 4.75-4.61 (m, 0.5H), 4.37 (d, J=12.8 Hz,
1H), 4.27 (d, J=12.6 Hz, 1H), 4.10 (d, J=7.2 Hz, 0.5H), 3.85 (d,
J=10.0 Hz, 0.5H), 3.81-3.65 (m, 2.5H), 3.30 (dd, J=9.3, 5.7 Hz,
1H), 3.22-3.12 (m, 1H), 3.12-2.97 (m, 1H), 2.66-2.43 (m, 2H),
2.21-2.14 (m, 1H), 1.97 (dd, J=12.0, 6.2 Hz, 2H), 1.46 (dd, J=8.5,
6.8 Hz, 1H), 1.14 (dd, J=7.1, 4.0 Hz, 2H), 1.04 (ddd, J=9.5, 6.4,
3.0 Hz, 2H), 0.77-0.38 (m, 4H).
[1638] LC-MS: m/z 473.2 (M+H).sup.+
Compound 816 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(2-(2-oxopyrrolidin-1-yl)acetyl)piper-
azin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1639] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (d, J=5.6 Hz,
1H), 7.83 (s, 1H), 7.19 (s, 1H), 6.87 (dd, J=5.7, 1.3 Hz, 1H), 6.60
(dd, J=17.5, 10.9 Hz, 1H), 6.44 (s, 1H), 5.95 (d, J=17.5 Hz, 1H),
5.54 (d, J=10.9 Hz, 1H), 4.55 (s, 0.5H), 4.39 (d, J=12.9 Hz, 1H),
4.28 (dd, J=12.7, 2.1 Hz, 1H), 4.19 (s, 1H), 4.00 (s, 0.5H), 3.75
(dd, J=30.5, 3.9 Hz, 2H), 3.55 (s, 2H), 3.33 (s, 1H), 3.18 (d,
J=11.9 Hz, 1H), 3.05 (t, J=13.2 Hz, 1H), 2.47 (t, J=8.0 Hz, 2H),
2.21-2.16 (m, 1H), 2.12 (dt, J=15.4, 7.6 Hz, 2H), 1.28 (d, J=5.1
Hz, 1H), 1.19-1.10 (m, 2H), 1.05 (ddd, J=9.0, 6.6, 2.5 Hz, 2H),
0.78-0.41 (m, 4H).
[1640] LC-MS: m/z 513.6 (M+H).sup.+
Compound 817 (General Procedure 7)
(R)-2-(4-(2-cyclobutylacetyl)-3-cyclopropylpiperazin-1-yl)-6-cyclopropyl-5-
-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1641] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.07 (d, J=5.6 Hz,
1H), 7.80 (s, 1H), 6.87 (dd, J=5.7, 1.2 Hz, 1H), 6.59 (dd, J=17.6,
10.8 Hz, 1H), 6.43 (s, 1H), 5.95 (d, J=17.5 Hz, 1H), 5.54 (d,
J=10.8 Hz, 1H), 4.65 (d, J=11.7 Hz, 0.4H), 4.41 (d, J=12.6 Hz, 1H),
4.30 (d, J=12.3 Hz, 1H), 4.09 (d, J=5.2 Hz, 0.6H), 3.91-3.59 (m,
1.5H), 3.34-3.10 (m, 1.5H), 3.09-2.94 (m, 1H), 2.74 (dt, J=15.5,
7.8 Hz, 1H), 2.52 (s, 2H), 2.25-2.12 (m, 3H), 1.98-1.82 (m, 2H),
1.82-1.63 (m, 2H), 1.28 (s, 1H), 1.19-1.09 (m, 2H), 1.04 (dt,
J=6.9, 3.0 Hz, 2H), 0.78-0.34 (m, 4H).
[1642] LC-MS: m/z 483.6 (M+H).sup.+
Compound 812 (General Procedure 7)
6-cyclopropyl-2-((3R)-3-cyclopropyl-4-(3-(oxetan-2-yl)propanoyl)piperazin--
1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1643] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.13 (d, J=5.4 Hz,
1H), 7.85 (s, 1H), 6.83 (dd, J=5.4, 1.3 Hz, 1H), 6.59 (dd, J=17.6,
10.8 Hz, 1H), 6.41 (s, 1H), 6.39 (s, 1H), 5.90 (d, J=17.6 Hz, 1H),
5.47 (d, J=11.0 Hz, 1H), 4.89 (s, 1H), 4.70 (dd, J=14.1, 7.8 Hz,
1H), 4.55 (dd, J=14.7, 5.8 Hz, 1H), 4.36 (d, J=12.8 Hz, 1H), 4.25
(dd, J=12.5, 1.8 Hz, 1H), 4.09 (dd, J=7.2, 2.6 Hz, 1H), 3.78 (ddd,
J=23.5, 14.1, 6.1 Hz, 1.5H), 3.28 (s, 0.5H), 3.13 (d, J=12.4 Hz,
1H), 3.02 (dd, J=21.5, 9.8 Hz, 1H), 2.74 (ddd, J=14.2, 11.1, 8.0
Hz, 1H), 2.62-2.47 (m, 1H), 2.46-2.32 (m, 2H), 2.23-1.98 (m, 3H),
1.28 (d, J=4.8 Hz, 1H), 1.19-1.09 (m, 2H), 1.02 (ddd, J=9.4, 6.4,
3.0 Hz, 2H), 0.75-0.35 (m, 4H).
[1644] LC-MS: m/z 499.6 (M+H).sup.+
Compound 813 (General Procedure 7)
6-cyclopropyl-2-((3R)-3-cyclopropyl-4-(2-(tetrahydrofuran-2-yl)acetyl)pipe-
razin-1-yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1645] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.12 (d, J=5.4 Hz,
1H), 7.84 (s, 1H), 6.84 (dd, J=5.4, 1.2 Hz, 1H), 6.59 (dd, J=17.5,
10.8 Hz, 1H), 6.46 (s, 1H), 6.41 (s, 1H), 5.91 (d, J=17.6 Hz, 1H),
5.47 (d, J=10.9 Hz, 1H), 4.69 (d, J=13.9 Hz, 0.5H), 4.46-4.33 (m,
1H), 4.28 (dd, J=15.4, 9.1 Hz, 2H), 4.11 (d, J=5.3 Hz, 0.5H),
3.98-3.83 (m, 1.5H), 3.75 (dt, J=22.2, 11.1 Hz, 1.5H), 3.40-3.09
(m, 2H), 3.09-2.93 (m, 1H), 2.83-2.47 (m, 2H), 2.47-2.29 (m, 0.5H),
2.26-2.12 (m, 2H), 2.11-1.99 (m, 0.5H), 1.93 (dt, J=13.7, 7.0 Hz,
2H), 1.28 (d, J=5.3 Hz, 1H), 1.19-1.09 (m, 2H), 1.02 (ddd, J=9.8,
6.6, 2.9 Hz, 2H), 0.77-0.32 (m, 4H).
[1646] LC-MS: m/z 499.3 (M+H).sup.+COMPOUND 807 (General Procedure
7)
(R)-6-cyclopropyl-2-(3-isopropyl-4-(3-methoxypropanoyl)piperazin-1-yl)-4-m-
ethyl-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile
[1647] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.19 (d, J=6.1 Hz,
1H), 6.69 (dd, J=17.4, 10.9 Hz, 1H), 6.57 (s, 1H), 6.45 (s, 1H),
6.21 (d, J=17.6 Hz, 1H), 6.18-6.10 (m, 1H), 5.60 (d, J=11.1 Hz,
1H), 4.71 (d, J=13.2 Hz, 0.5H), 4.50-4.37 (m, 1.5H), 4.33-4.25 (m,
1H), 3.87 (d, J=13.1 Hz, 0.5H), 3.82-3.67 (m, 2H), 3.60 (d, J=10.2
Hz, 0.5H), 3.47 (dd, J=18.2, 7.7 Hz, 0.5H), 3.38 (d, J=4.2 Hz, 3H),
3.14 (ddd, J=13.3, 9.5, 5.2 Hz, 1.5H), 3.09-2.94 (m, 1H), 2.81-2.56
(m, 2H), 2.38 (s, 3H), 2.25 (dd, J=13.6, 6.4 Hz, 0.5H), 2.07 (ddd,
J=15.8, 11.1, 6.8 Hz, 1.5H), 1.15-1.09 (m, 1H), 1.04 (dd, J=6.5,
2.9 Hz, 4H), 0.97 (dd, J=7.5, 5.0 Hz, 2H), 0.93 (d, J=6.8 Hz,
1.5H), 0.86 (d, J=6.8 Hz, 1.5H).
[1648] LC-MS: m/z 489.6 (M+H).sup.+
Compound 799 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-isopropylpiperazin-1-yl)-4-m-
ethyl-5-((2-vinylpyridin-4-yl)amino)nicotinonitrile
[1649] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.23 (d, J=5.7 Hz,
1H), 6.70 (dd, J=17.4, 10.8 Hz, 1H), 6.50 (s, 1H), 6.33 (s, 1H),
6.16 (d, J=17.4 Hz, 1H), 5.74 (s, 1H), 5.48 (dd, J=10.8, 0.9 Hz,
1H), 4.69 (d, J=9.7 Hz, 0.5H), 4.41 (ddd, J=6.7, 6.1, 4.4 Hz,
1.5H), 4.27 (t, J=10.2 Hz, 1H), 4.00-3.86 (m, 2H), 3.76 (d, J=13.5
Hz, 0.5H), 3.60-3.52 (m, 1H), 3.50-3.44 (m, 1H), 3.17-3.05 (m, 2H),
3.01 (dd, J=11.6, 9.4 Hz, 0.5H), 2.61 (pd, J=11.7, 5.1 Hz, 2H),
2.38 (s, 3H), 2.33-2.22 (m, 0.5H), 2.11 (ddd, J=12.7, 9.3, 5.2 Hz,
1.5H), 1.11 (ddd, J=8.9, 6.6, 4.7 Hz, 1H), 1.05 (d, J=6.5 Hz, 4H),
0.97 (dt, J=7.8, 6.6 Hz, 2H), 0.93 (d, J=6.9 Hz, 1.5H), 0.86 (d,
J=6.8 Hz, 1.5H).
[1650] LC-MS: m/z 475.2 (M+H).sup.+
Compound 798 (General Procedure 7)
(R,E)-6-cyclopropyl-2-(3-cyclopropyl-4-(5-hydroxypent-2-enoyl)piperazin-1--
yl)-5-((4-vinylpyridin-2-yl)amino)nicotinonitrile
[1651] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.10 (d, J=5.3 Hz,
1H), 7.83 (s, 1H), 6.89-6.77 (m, 2H), 6.57 (dd, J=17.6, 10.8 Hz,
1H), 6.53-6.43 (m, 1H), 6.40 (s, 1H), 6.39-6.26 (m, 1H), 5.88 (d,
J=17.5 Hz, 1H), 5.44 (d, J=10.9 Hz, 1H), 4.74-4.43 (m, 0.3H), 4.35
(t, J=11.7 Hz, 1H), 4.26 (d, J=12.5 Hz, 1H), 4.11-3.87 (m, 0.8H),
3.78 (dd, J=11.6, 5.5 Hz, 2H), 3.75-3.68 (m, 1H), 3.53 (m, 0.5H),
3.45 (m, 0.5H), 3.42-3.28 (m, 0.5H), 3.24-3.11 (m, 1.5H), 3.03 (td,
J=12.6, 3.3 Hz, 1H), 2.49 (dd, J=12.5, 6.2 Hz, 2H), 2.22-2.15 (m,
1H), 1.45 (d, J=6.5 Hz, 1H), 1.17-1.08 (m, 2H), 1.00 (ddd, J=9.4,
6.5, 3.0 Hz, 2H), 0.73-0.32 (m, 4H).
[1652] LC-MS: m/z 485.6 (M+H).sup.+
Compound 581 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-((2--
vinylpyridin-4-yl)amino)nicotinonitrile
[1653] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.27 (d, J=5.7 Hz,
1H), 7.62 (s, 1H), 6.71 (dd, J=17.4, 10.8 Hz, 1H), 6.58 (d, J=2.0
Hz, 1H), 6.45 (dd, J=5.7, 2.2 Hz, 1H), 6.19 (d, J=17.2 Hz, 1H),
5.90 (s, 1H), 5.48 (d, J=11.2 Hz, 1H), 4.90 (s, 0.5H), 4.54 (d,
J=13.6 Hz, 0.5H), 4.23 (dd, J=31.3, 14.0 Hz, 2.5H), 3.94 (s, 2H),
3.74 (d, J=13.6 Hz, 0.5H), 3.57 (t, J=11.0 Hz, 0.5H), 3.29 (dd,
J=10.5, 6.5 Hz, 1H), 3.15 (dd, J=23.7, 11.6 Hz, 1H), 3.09-2.99 (m,
0.5H), 2.62 (m, J=34.8, 15.8 Hz, 2H), 2.12 (td, J=8.1, 4.1 Hz, 1H),
1.43 (d, J=6.4 Hz, 1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.13 (dd,
J=7.2, 4.2 Hz, 2H), 1.03 (ddd, J=10.0, 6.4, 3.3 Hz, 2H).
[1654] LC-MS: m/z 447.6 (M+H).sup.+
Compound 642 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-methoxypropanoyl)-3-methylpiperazin-1-yl)-5-((2--
vinylpyridin-4-yl)amino)nicotinonitrile
[1655] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.23 (d, J=5.9 Hz,
1H), 7.61 (s, 1H), 6.72 (dd, J=17.5, 10.9 Hz, 1H), 6.62 (s, 1H),
6.53 (d, J=4.4 Hz, 1H), 6.24 (d, J=17.4 Hz, 1H), 5.53 (d, J=10.9
Hz, 1H), 4.92 (s, 1H), 4.55 (d, J=16.6 Hz, 1H), 4.25 (t, J=11.9 Hz,
2H), 4.17 (d, J=13.8 Hz, 1H), 3.82 (d, J=8.4 Hz, 1H), 3.76 (t,
J=6.2 Hz, 2H), 3.58 (d, J=12.3 Hz, 1H), 3.39 (s, 3H), 3.30 (d,
J=13.0 Hz, 1H), 3.15 (t, J=11.7 Hz, 1H), 3.06 (d, J=12.2 Hz, 1H),
2.73 (ddd, J=22.9, 14.3, 6.7 Hz, 1H), 2.64-2.53 (m, 1H), 2.09 (td,
J=7.9, 4.1 Hz, 1H), 1.40 (d, J=5.7 Hz, 2H), 1.30 (d, J=7.1 Hz, 2H),
1.13 (dd, J=6.8, 4.1 Hz, 2H), 1.02 (dd, J=7.6, 3.3 Hz, 2H).
[1656] LC-MS: m/z 447.2 (M+H).sup.+
Compound 643 (General Procedure 7)
(R)-5-((2-chloropyridin-4-yl)-amino)-6-cyclopropyl-2-(4-(3-methoxypropanoy-
l)-3-methylpiperazin-1-yl)nicotinonitrile
[1657] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.06 (d, J=4.9 Hz,
1H), 7.59 (s, 1H), 6.53 (s, 1H), 6.50 (s, 1H), 6.00 (s, 1H), 4.91
(s, 1H), 4.55 (d, J=10.6 Hz, 1H), 4.29 (d, J=11.2 Hz, 2H), 4.20 (d,
J=12.9 Hz, 1H), 3.82 (d, J=13.8 Hz, 1H), 3.73 (dt, J=9.5, 5.8 Hz,
2H), 3.57 (t, J=11.0 Hz, 1H), 3.39 (s, 3H), 3.30 (d, J=12.0 Hz,
1H), 3.15 (t, J=11.8 Hz, 1H), 3.07 (d, J=12.0 Hz, 1H), 2.83-2.65
(m, 1H), 2.60 (dd, J=13.4, 7.5 Hz, 1H), 2.07 (ddd, J=12.6, 7.0, 4.8
Hz, 1H), 1.40 (d, J=6.4 Hz, 2H), 1.34-1.27 (m, 1H), 1.13 (s, 2H),
1.09-0.99 (m, 2H).
[1658] LC-MS: m/z 455.3 (M+H).sup.+
Compound 796 (General Procedure 6)
(R)-2-cyclopropyl-6-(3-cyclopropyl-4-(3-(furan-2-yl)propanoyl)piperazin-1--
yl)-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1659] .sup.1H NMR (CHLOROFORM-d) .delta. 8.69 (d, J=5.0 Hz, 1H),
7.31-7.38 (m, 1H), 7.23 (s, 1H), 7.07 (d, J=4.1 Hz, 1H), 6.88 (dd,
J=17.6, 10.9 Hz, 1H), 6.21-6.40 (m, 2H), 6.06 (d, J=2.9 Hz, 1H),
5.57 (d, J=11.4 Hz, 1H), 4.22 (d, J=12.6 Hz, 2H), 2.93-3.18 (m,
4H), 2.72 (br. s., 2H), 2.21 (s, 3H), 1.33-1.62 (m, 2H), 1.03-1.33
(m, 3H), 0.87 (dd, J=7.9, 3.2 Hz, 2H), 0.44 (br. s., 4H).
[1660] LC-MS: m/z 508.6 (M+H).sup.+
Compound 797 (General Procedure 6)
(R)-6-(4-(3-cyclopentylpropanoyl)-3-cyclopropylpiperazin-1-yl)-2-cycloprop-
yl-4-methyl-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1661] .sup.1H NMR (CHLOROFORM-d) .delta. 8.69 (d, J=4.7 Hz, 1H),
7.23 (s, 1H), 7.07 (d, J=4.4 Hz, 1H), 6.87 (dd, J=17.5, 10.7 Hz,
1H), 6.12-6.41 (m, 1H), 5.41-5.69 (m, 1H), 4.19-4.48 (m, 2H),
3.96-4.19 (m, 1H), 3.80 (br. s., 1H), 3.15 (br. s., 2H), 3.04 (br.
s., 1H), 2.28-2.49 (m, 2H), 2.21 (s, 3H), 1.86 (br. s., 1H), 1.80
(br. s., 3H), 1.47-1.72 (m, 8H), 1.11 (br. s., 4H), 0.73-1.00 (m,
3H), 0.60 (br. s., 1H), 0.55 (br. s., 1H), 0.23-0.50 (m, 2H).
[1662] LC-MS: m/z 510.7 (M+H).sup.+
Compound 804 (General Procedure 5)
(R)-di-tert-butyl
4-(4-(5-cyano-2-cyclopropyl-2'-vinyl-3,4'-bipyridin-6-yl)-2-cyclopropylpi-
perazin-1-yl)-4-oxobutyl phosphate
[1663] .sup.1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=5.0 Hz, 1H),
7.65 (s, 1H), 7.40 (s, 1H), 7.25 (dd, J=5.1, 1.6 Hz, 1H), 6.89 (dd,
J=17.6, 10.9 Hz, 1H), 6.30 (d, J=16.7 Hz, 1H), 5.58 (d, J=11.2 Hz,
1H), 4.56 (d, J=12.9 Hz, 1H), 4.35-4.49 (m, 1H), 3.99-4.20 (m, 3H),
3.71-3.84 (m, 1H), 2.99-3.22 (m, 2H), 2.53 (d, J=5.9 Hz, 1H),
2.00-2.07 (m, 3H), 1.66 (d, J=12.3 Hz, 3H), 1.52 (s, 18H),
1.18-1.25 (m, 2H), 0.98-1.06 (m, 2H), 0.62 (br. s., 1H), 0.56 (br.
s., 1H), 0.47 (d, J=5.0 Hz, 2H)
[1664] LC-MS: m/z 650.3 (M+H).sup.+
Compound 560 (General Procedure 7)
(R)-6-cyclopropyl-2-(3-cyclopropyl-4-(3,3,3-trifluoropropanoyl)piperazin-1-
-yl)-5-(quinolin-4-ylamino)nicotinonitrile
[1665] .sup.1H NMR (CHLOROFORM-d) .delta. 8.55 (d, J=5.5 Hz, 1H),
8.11 (d, J=8.3 Hz, 1H), 8.03 (d, J=8.3 Hz, 1H), 7.80 (t, J=7.3 Hz,
1H), 7.71 (s, 1H), 7.63 (t, J=7.7 Hz, 1H), 6.36 (d, J=5.5 Hz, 1H),
4.52 (d, J=13.3 Hz, 1H), 4.41 (d, J=13.8 Hz, 1H), 4.15 (br. s.,
1H), 3.69-3.86 (m, 2H), 3.12-3.35 (m, 4H), 2.01-2.13 (m, 1H),
1.33-1.35 (m, 1H), 1.12-1.21 (m, 2H), 0.95-1.07 (m, 2H), 0.45-0.73
(m, 4H)
[1666] LC-MS: m/z 521.2 (M+H).sup.+
Compound 617 (General Procedure 7)
(R)-6-cyclopropyl-2-(4-(3-hydroxypropanoyl)-3-methylpiperazin-1-yl)-5-(6-v-
inylpyrimidin-4-ylamino)nicotinonitrile
[1667] .sup.1H NMR (CHLOROFORM-d) .delta. 8.58-8.68 (m, 1H),
7.72-7.80 (m, 1H), 6.90-7.01 (m, 1H), 6.53-6.66 (m, 1H), 6.35-6.48
(m, 1H), 6.27 (s, 1H), 5.62 (dd, J=10.5, 1.3 Hz, 1H), 4.90 (br. s.,
0.5H), 4.54 (d, J=13.6 Hz, 0.5H), 4.11-4.34 (m, 2.5H), 3.93 (br.
s., 2H), 3.74 (d, J=13.6 Hz, 0.5H), 3.50-3.65 (m, 0.5H), 3.45 (br.
s., 0.5H), 3.23-3.32 (m, 1H), 3.10-3.20 (m, 0.5H), 2.98-3.09 (m,
0.5H), 2.48-2.76 (m, 2H), 2.08-2.16 (m, 1H), 1.42 (d, J=6.5 Hz,
1.5H), 1.32 (d, J=6.8 Hz, 1.5H), 1.10-1.20 (m, 2H), 0.97-1.09 (m,
2H)
[1668] LC-MS: m/z 434.3 (M+H).sup.+
Compound 700 (General Procedure 5)
(R)-5-(2-amino-6-vinylpyrimidin-4-yl)-2-(4-(cyclopropanecarbonyl)-3-cyclop-
ropylpiperazin-1-yl)-6-cyclopropylnicotinonitrile
[1669] .sup.1H NMR (CHLOROFORM-d) .delta. 7.97 (s, 1H), 6.89 (s,
1H), 6.66 (dd, J=17.3, 10.5 Hz, 1H), 6.52 (d, J=17.8 Hz, 1H), 5.74
(d, J=10.5 Hz, 1H), 5.41 (br. s., 2H), 4.66 (d, J=12.5 Hz, 1H),
4.52 (d, J=12.5 Hz, 1H), 3.16-4.28 (m, 5H), 2.33-2.49 (m, 1H), 1.72
(br. s., 2H), 1.21-1.26 (m, 2H), 0.98-1.15 (m, 4H), 0.82 (dd,
J=7.8, 2.3 Hz, 2H), 0.63 (br. s., 1H), 0.36-0.58 (m, 3H)
[1670] LC-MS: m/z 456.4 (M+H).sup.+
Compound 751 (General Procedure 7)
6-cyclopropyl-2-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-5-(2-vinylpyridin-4-ylamino)nicotinonitrile
[1671] .sup.1H NMR (CHLOROFORM-d) .delta. 8.24 (d, J=5.9 Hz, 1H),
7.62 (s, 1H), 6.70 (dd, J=17.3, 10.9 Hz, 1H), 6.61 (d, J=2.1 Hz,
1H), 6.49 (d, J=5.9 Hz, 1H), 6.19 (d, J=17.6 Hz, 1H), 6.04 (br. s.,
1H), 5.53 (d, J=10.9 Hz, 1H), 5.27 (quin, J=6.7 Hz, 1H), 4.69-4.79
(m, 1H), 4.42-4.58 (m, 2H), 4.35 (d, J=12.9 Hz, 1H), 4.09 (d, J=8.8
Hz, 1H), 3.95 (d, J=13.8 Hz, 1H), 3.67-3.82 (m, 1H), 2.75-3.34 (m,
5H), 2.55 (d, J=9.1 Hz, 1H), 2.08 (td, J=8.1, 4.0 Hz, 1H), 1.33
(br. s., 1H), 1.10-1.18 (m, 2H), 1.03 (dd, J=7.8, 3.4 Hz, 2H), 0.63
(br. s., 1H), 0.55 (br. s., 1H), 0.47 (d, J=5.9 Hz, 2H)
[1672] LC-MS: m/z 485.6 (M+H).sup.+
Compound 752 (General Procedure 5)
2-cyclopropyl-6-((R)-3-cyclopropyl-4-(2-((R)-oxetan-2-yl)acetyl)piperazin--
1-yl)-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1673] .sup.1H NMR (CHLOROFORM-d) .delta. 8.66 (d, J=5.0 Hz, 1H),
7.65 (s, 1H), 7.35-7.46 (m, 1H), 7.23 (dd, J=5.1, 1.6 Hz, 1H), 6.88
(dd, J=17.5, 10.7 Hz, 1H), 6.21-6.36 (m, 1H), 5.49-5.61 (m, 1H),
5.27 (quin, J=6.6 Hz, 1H), 4.72 (td, J=7.9, 6.2 Hz, 1H), 4.50-4.65
(m, 2H), 4.44 (d, J=12.9 Hz, 1H), 4.09 (d, J=8.2 Hz, 0.6H),
3.84-4.02 (m, 0.7H), 3.74 (t, J=12.0 Hz, 0.7H), 3.25 (br. s., 1H),
2.91-3.23 (m, 3.5H), 2.55-2.9 (m, 2.5H), 2.55 (d, J=8.8 Hz, 1H),
1.97-2.11 (m, 1H), 1.33 (br. s., 1H), 1.18-1.26 (m, 2H), 0.94-1.07
(m, 2H), 0.63 (br. s., 1H), 0.56 (br. s., 1H), 0.47 (br. s.,
2H)
[1674] LC-MS: m/z 470.2 (M+H).sup.+
Compound 800 (General Procedure 5)
2-cyclopropyl-6-((3R)-3-cyclopropyl-4-(3-(tetrahydrofuran-2-yl)propanoyl)p-
iperazin-1-yl)-2'-vinyl-3,4'-bipyridine-5-carbonitrile
[1675] .sup.1H NMR (CHLOROFORM-d) .delta.: 8.63 (d, J=5.3 Hz, 1H),
7.62 (s, 1H), 7.37 (s, 1H), 7.21 (dd, J=5.0, 1.5 Hz, 1H), 6.86 (dd,
J=17.5, 10.7 Hz, 1H), 6.26 (d, J=17.6 Hz, 1H), 5.54 (d, J=10.9 Hz,
1H), 4.53 (d, J=12.9 Hz, 1H), 4.41 (d, J=12.6 Hz, 1H), 4.00-4.22
(m, 1H), 3.85 (d, J=6.5 Hz, 3H), 3.62-3.77 (m, 2H), 3.08-3.29 (m,
3H), 2.31-2.60 (m, 2H), 1.83-2.11 (m, 5H), 1.68-1.83 (m, 1H),
1.46-1.58 (m, 1H), 1.20 (dt, J=7.3, 3.6 Hz, 2H), 0.93-1.07 (m, 2H),
0.49-0.76 (m, 2H), 0.43 (br. s., 2H)
[1676] LC-MS: m/z 498.7 (M+H).sup.+
[1677] Having thus described several aspects of several
embodiments, it is to be appreciated various alterations,
modifications, and improvements will readily occur to those skilled
in the art. Such alterations, modifications, and improvements are
intended to be part of this disclosure, and are intended to be
within the spirit and scope of the invention. Accordingly, the
foregoing description and drawings are by way of example only.
* * * * *