U.S. patent application number 13/150675 was filed with the patent office on 2011-09-22 for fused heterocyclic compounds and uses thereof.
This patent application is currently assigned to Bristol-Myers Squibb Company. Invention is credited to Joseph Barbosa, Junqing Guo, William J. Pitts.
Application Number | 20110230468 13/150675 |
Document ID | / |
Family ID | 32312781 |
Filed Date | 2011-09-22 |
United States Patent
Application |
20110230468 |
Kind Code |
A1 |
Barbosa; Joseph ; et
al. |
September 22, 2011 |
FUSED HETEROCYCLIC COMPOUNDS AND USES THEREOF
Abstract
Fused heterocylic compounds of the following Formula
##STR00001## wherein R.sup.1, R.sup.2, R.sup.5, Z, J.sup.1 and
J.sup.2 are described herein, and analogs thereof are provided
which are useful in treating leukocyte activation-associated
disorders.
Inventors: |
Barbosa; Joseph;
(Lambertville, NJ) ; Pitts; William J.; (Newtown,
PA) ; Guo; Junqing; (Princeton, NJ) |
Assignee: |
Bristol-Myers Squibb
Company
|
Family ID: |
32312781 |
Appl. No.: |
13/150675 |
Filed: |
June 1, 2011 |
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Application
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Patent Number |
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12050227 |
Mar 18, 2008 |
7981881 |
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13150675 |
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10702295 |
Nov 6, 2003 |
7384937 |
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Current U.S.
Class: |
514/212.08 ;
514/215; 514/230.5; 514/234.2; 514/252.16; 514/264.11; 514/265.1;
540/524; 540/575; 540/578; 544/105; 544/117; 544/279; 544/280;
544/73 |
Current CPC
Class: |
A61P 9/10 20180101; A61P
19/00 20180101; C07D 487/04 20130101; C07D 471/04 20130101; A61P
37/02 20180101; A61P 1/00 20180101 |
Class at
Publication: |
514/212.08 ;
544/280; 514/265.1; 514/252.16; 544/117; 514/234.2; 540/524;
544/279; 514/264.11; 544/105; 514/230.5; 544/73; 540/578; 514/215;
540/575 |
International
Class: |
A61K 31/519 20060101
A61K031/519; C07D 487/04 20060101 C07D487/04; A61K 31/5377 20060101
A61K031/5377; A61K 31/55 20060101 A61K031/55; C07D 471/04 20060101
C07D471/04; C07D 498/04 20060101 C07D498/04; A61K 31/5383 20060101
A61K031/5383; A61P 37/02 20060101 A61P037/02 |
Claims
1. A compound of Formula (Ia) ##STR00524## their enantiomers,
diastereomers, and pharmaceutically acceptable salts thereof,
wherein: W is S; Y.sup.1 is OT.sup.10; Y.sup.2 is alkyl or
haloalkyl; J.sup.1 is optionally substituted C.sub.1 alkylene;
J.sup.2 is optionally substituted C.sub.2-3 alkylene; T.sup.10 is
alkyl; Z is selected from: ##STR00525## ##STR00526## ##STR00527##
R.sup.5 is selected from: ##STR00528## ##STR00529## ##STR00530##
##STR00531##
2. A compound of claim 1 selected from i.
2-[8-(4-Methanesulfonyl-benzyl)-4-piperazin-1-yl-5,6,7,8-tetrahydro-pyrid-
o[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester;
2-[8-(4-Methanesulfonyl-benzyl)-4-(1-tert-butoxycarbonyl-piperazin-
-4-yl)-5,6,7,8-tetrahydro
-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; 2-[4-Dimethylamino-8-(4-methane
sulfonyl-benzyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-m-
ethyl-thiazole-5-carboxylic acid ethyl ester;
2-(8-Benzyl-4-piperazin-1-yl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2--
ylamino)-4-methyl-thiazole-5-carboxylic acid ethyl ester;
2-[8-(4-Fluoro-benzyl)-4-piperazin-1-yl-5,6,7,8-tetrahydro-pyrido[2,3-d]p-
yrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester;
4-Methyl-2-(4-piperazin-1-yl-8-pyridin-3-ylmethyl-5,6,7,8-tetrahydro-pyri-
do[2,3-d]pyrimidin-2-ylamino)-thiazole-5-carboxylic acid ethyl
ester;
4-Methyl-2-[4-piperazin-1-yl-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrahyd-
ro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(3,4,5-trimethoxy-benzyl)-5,6,7,-
8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxy-
lic acid ethyl ester
4-Methyl-2-[4-(4-methyl-piperazin-5-trimethoxy-benzyl)-5,6,7,8-tetrahydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl
ester;
2-[4-(1-carboxyethyl-piperazin-4-yl)-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli-
c acid ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetra-
hydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(3-carboxyethyl-piperidin-1-yl)-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli-
c acid ethyl ester;
4-Methyl-2-[8-(3,4,5-trimethoxy-benzyl)-4-(3,4,5-trimethoxy-benzylamino)--
5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-{4-(3-oxo-piperazin-1-yl)-8-[4-(1H-tetrazol-5-yl)-benzyl]-5,6,-
7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxylic
acid ethyl ester;
2-{4-(4-Hydroxy-piperidin-1-yl)-8-[4-(1H-tetrazol-5-yl)-benzyl]-5,6,7,8-t-
etrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-[Ethyl-(2-methoxy-ethyl)-amino]-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli-
c acid ethyl ester
4-Methyl-2-[4-morpholin-4-yl-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrahyd-
ro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester;
2-[4-(4-Hydroxymethyl-piperidin-1-yl)-8-(3,4,5-trimethoxy-benzyl)--
5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-c-
arboxylic acid ethyl ester;
4-Methyl-2-[4-(3-oxo-piperazin-1-yl)-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester;
2-[4-Chloro-8-(1,1,3-trioxo-2,3-dihydro-1H-.quadrature..sup.6-benzo[d]iso-
thiazol-5-ylmethyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-
-methyl-thiazole-5-carboxylic acid ethyl ester;
4-Methyl-2-[4-morpholin-4-yl-8-(1,1,3-trioxo-2,3-dihydro-1H-1.quadrature.-
.sup.6-benzo[d]isothiazol-5-ylmethyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyri-
midin-2-ylamino]-thiazole-5-carboxylic acid ethyl ester;
4-Methyl-2-{8-[3-(morpholine-4-carbonyl)-4-sulfamoyl-benzyl]-4-morpholin--
4-yl-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carbo-
xylic acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-[4-morpholin-4-yl-8-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-py-
rido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl
ester;
4-Methyl-2-[8-(4-sulfamoyl-benzyl)-4-(3,4,5-trimethoxy-benzylamino)-5,6,7-
,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-[4-methylamino-8-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-pyrid-
o[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl
ester;
4-Methyl-2-[4-(3-oxo-piperazin-1-yl)-8-(4-sulfamoyl-benzyl)-5,6,7,8-tetra-
hydro -pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester;
2-{4-Chloro-8-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-benzyl]-
-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5--
carboxylic acid ethyl ester;
2-{-4-(4-Hydroxy-piperidin-1-yl)-8-[4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-
-3-yl)-benzyl]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-meth-
yl-thiazole-5-carboxylic acid ethyl ester;
2-[8-(4-Ethanesulfonylamino-benzyl)-4-(3-oxo-piperazin-1-yl)-5,6,7,8-tetr-
ahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(4-ethanesulfonylamino-benzyl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli-
c acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(4-methanesulfonylaminocarbonyl-benzyl)-
-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5--
carboxylic acid ethyl ester;
2-[8-(4-Methanesulfonylaminocarbonyl-benzyl)-4-(3-oxo-piperazin-1-yl)-5,6-
,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carb-
oxylic acid ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(4-methanesulfonylaminocarbonyl-benzyl)-
-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5--
carboxylic acid ethyl ester;
2-[4-(4-Hydroxymethyl-piperidin-1-yl)-8-(4-methanesulfonylaminocarbonyl-b-
enzyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiaz-
ole-5-carboxylic acid ethyl ester;
4-Methyl-2-(4-morpholin-4-yl-8-pyridin-4-ylmethyl-5,6,7,8-tetrahydro-pyri-
do[2,3-d]pyrimidin-2-ylamino)-thiazole-5-carboxylic acid ethyl
ester;
4-Methyl-2-[4-(3-oxo-piperazin-1-yl)-8-pyridin-4-ylmethyl-5,6,7,8-tetrahy-
dro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-pyridin-4-ylmethyl-5,6,7,8-tetra-
hydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-{4-morpholin-4-yl-8-[4-(propane-1-sulfonylamino)-benzyl]-5,6,7-
,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxylic
acid ethyl ester;
2-{4-(4-Hydroxy-piperidin-1-yl)-8-[4-(propane-1-sulfonylamino)-benzyl]-5,-
6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-car-
boxylic acid ethyl ester;
4-Methyl-2-{4-(3-oxo-piperazin-1-yl)-8-[4-(propane-1-sulfonylamino)-benzy-
l]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxy-
lic acid ethyl ester;
2-{4-(4-Hydroxymethyl-piperidin-1-yl)-8-[4-(propane-1-sulfonylamino)-benz-
yl]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-
-5-carboxylic acid ethyl ester;
2-{4-(2-Acetylamino-ethylamino)-8-[4-(propane-1-sulfonylamino)-benzyl]-5,-
6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-car-
boxylic acid ethyl ester;
2-[8-(4-Carbamoyl-benzyl)-4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido[2,3--
d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester;
2-[8-(4-Carbamoyl-benzyl)-4-(3-oxo-piperazin-1-yl)-5,6,7,8-tetrahydro-pyr-
ido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(4-carbamoyl-benzyl)-5,6,7,8-tet-
rahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[8-(4-Carbamoyl-benzyl)-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tetrahydro-
-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-[8-(4-methylsulfamoyl-benzyl)-4-morpholin-4-yl-5,6,7,8-tetrahy-
dro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester;
4-Methyl-2-{4-morpholin-4-yl-8-[4-(propane-2-sulfonylamino)-benzyl-
]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxyl-
ic acid ethyl ester;
2-{4-(4-Hydroxymethyl-piperidin-1-yl)-8-[4-(propane-2-sulfonylamino)-benz-
yl]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-
-5-carboxylic acid ethyl ester;
2-{4-(2-Acetylamino-ethylamino)-8-[4-(propane-2-sulfonylamino)-benzyl]-5,-
6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-4-methyl
-thiazole-5-carboxylic acid ethyl ester;
4-Methyl-2-{4-(3-oxo-piperazin-1-yl)-8-[4-(propane-2-sulfonylamino)-benzy-
l]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxy-
lic acid ethyl ester;
2-{4-(4-Hydroxy-piperidin-1-yl)-8-[4-(propane-2-sulfonylamino)-benzyl]-5,-
6,7,8-tetrahydro-pyrido[2,3-d]pyrimdin-2-ylamino}-4-methyl-thiazole-5-carb-
oxylic acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(4-isobutylcarbamoyl-benzyl)-5,6,7,8-te-
trahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(4-isobutylcarbamoyl-benzyl)-5,6,7,8-te-
trahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-Isobutylamino-8-(4-isobutylcarbamoyl-benzyl)-5,6,7,8-tetrahydro-pyri-
do[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester;
2-[8-(4-Isobutylcarbamoyl-benzyl)-4-morpholin-4-yl-5,6,7,8-tetrahy-
dro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[8-(4-Ethanesulfonylamino-benzyl)-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli-
c acid ethyl ester;
2-[8-(4-Ethanesulfonylamino-benzyl)-4-morpholin-4-yl-5,6,7,8-tetrahydro-p-
yrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[8-(4-Ethanesulfonylamino-benzyl)-4-isobutylamino-5,6,7,8-tetrah-
ydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl
-thiazole-5-carboxylic acid ethyl ester;
2-[8-(4-Ethanesulfonylamino-benzyl)-4-(3,4,5-trimethoxy-benzylamino)-5,6,-
7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carbo-
xylic acid ethyl ester;
2-(4-Isobutylamino-8-pyridin-4-ylmethyl-5,6,7,8-tetrahydro-pyrido[2,3-d]p-
yrimidin-2-ylamino)-4-methyl-thiazole-5-carboxylic acid ethyl
ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(6-trifluoromethyl-pyridin-3-ylmethyl)--
5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-c-
arboxylic acid ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(6-trifluoromethyl-pyridin-3-ylmethyl)--
5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-c-
arboxylic acid ethyl ester;
2-[8-{4-[Ethyl-(2-hydroxy-ethyl)-carbamoyl]-benzyl}-4-(3-hydroxy-pyrrolid-
in-1-yl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thi-
azole-5-carboxylic acid ethyl ester;
2-[8-{4-[Ethyl-(2-hydroxy-ethyl)-carbamoyl]-benzyl}-4-(3,4,5-trimethoxy-b-
enzylamino)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl--
thiazole-5-carboxylic acid ethyl ester;
2-(4-(2-Acetylamino-ethylamino)-8-{4-[ethyl-(2-hydroxy-ethyl)-carbamoyl]--
benzyl}-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino)-4-methyl-thia-
zole-5-carboxylic acid ethyl ester;
2-(8-{4-[Ethyl-(2-hydroxy-ethyl)-carbamoyl]-benzyl}-4-isobutylamino-5,6,7-
,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino)-4-methyl-thiazole-5-carbox-
ylic acid ethyl ester;
2-(4-[Ethyl-(2-hydroxy-ethyl)-amino]-8-{4-[ethyl-(2-hydroxy-ethyl)-carbam-
oyl]-benzyl}-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino)-4-methyl-
-thiazole-5-carboxylic acid ethyl ester;
2-(8-{4-[Ethyl-(2-hydroxy-ethyl)-carbamoyl]-benzyl}-4-morpholin-4-yl-5,6,-
7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino)-4-methyl-thiazole-5-carbo-
xylic acid ethyl ester;
2-[8-{4-[Ethyl-(2-hydroxy-ethyl)-carbamoyl]-benzyl}-4-(3-oxo-piperazin-1--
yl)-5,6,7,8-tetrahydro
-pyrido[2,3-d]pyrimin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(4-methylsulfamoyl-benzyl)-5,6,7,8-tetr-
ahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[8-[4-(1,1-Dioxo-1.quadrature..sup.6-thiomorpholine-4-carbonyl)-benzyl]-
-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2--
ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester;
4-Methyl-2-[8-(4-methylsulfamoyl-benzyl)-4-(3-oxo-piperazin-1-yl)-5,6,7,8-
-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(1-Hydroxymethyl-2-methyl-propylamino)-8-(4-methylsulfamoyl-benzyl)--
5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methy-thiazole-5-ca-
rboxylic acid ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(4-methylsulfamoyl-benzyl)-5,6,7,8-tetr-
ahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(2-Hydroxy-ethylamino)-8-(4-methylsulfamoyl-benzyl)-5,6,7,8-tetrahyd-
ro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-[Ethyl-(2-hydroxy-ethyl)-amino]-8-(4-methylsulfamoyl-benzyl)-5,6,7,8-
-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyl-
ic acid ethyl ester;
2-[4-(4-Carbamoyl-piperidin-1-yl)-8-(4-methylsulfamoyl-benzyl)-5,6,7,8-te-
trahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(3-Dimethylamino-propylamino)-8-(4-methylsulfamoyl-benzyl)-5,6,7,8-t-
etrahydro
-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli- c
acid ethyl ester;
2-[4-(3-Hydroxy-pyrrolidin-1-yl)-8-(4-methylsulfamoyl-benzyl)-5,6,7,8-tet-
rahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-(4-morpholin-4-yl-8-(2-sulfamoylamino-ethyl)-5,6,7,8-tetrahydr-
o-pyrido[2,3-d]pyrimidin-2-ylamino)-thiazole-5-carboxylic acid
ethyl ester;
2-[4-(2-Acetylamino-ethylamino)-8-(2-sulfamoylamino-ethyl)-5,6,7,8-
-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyl-
ic acid ethyl ester;
4-Methyl-2-[4-(3-oxo-piperazin-1-yl)-8-(2-sulfamoylamino-ethyl)-5,6,7,8-t-
etrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(2-sulfamoylamino-ethyl)-5,6,7,8-tetrah-
ydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; ii. the enantiomers, diastereomers, and
pharmaceutically acceptable salts of each of (i).
3. A compound of claim 1 selected from i.
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetra-
hydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-
-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[9-(2-Diisopropylamino-ethyl)-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tetr-
ahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl este;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(5-methyl-furan-2-ylmethyl)-5,6,7,8-tet-
rahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[9-[2-(4-Chloro-phenyl)-ethyl]-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tet-
rahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-{4-(4-Hydroxy-piperidin-1-yl)-9-[2-(4-methoxy-phenyl)-ethyl]-5,6,7,8-te-
trahydro-pyrimido[4,5-b]azepin-2-ylamino}-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-indan-1-yl-5,6,7,8-tetrahydro-pyrimido[-
4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(4-nitro-benzyl)-5,6,7,8-tetrahydro-pyr-
imido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester;
2-[9-Cyclohexylmethyl-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tetrahy-
dro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-phenethyl-5,6,7,8-tetrahydro-pyrimido[4-
,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(4-methanesulfonyl-benzyl)-5,6,7,8-tetr-
ahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(tetrahydro-furan-2-yl-methyl)-5,6,7,8--
tetrahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[9-(4-Hydroxy-cyclohexyl)-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tetrahyd-
ro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[9-Furan-2-yl-methyl-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tetrahydro-py-
rimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester;
2-[9-Cyclohexyl-4-(4-hydroxy-piperidin-1-yl)-5,6,7,8-tetrahydro-py-
rimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(2-methoxy-ethyl)-5,6,7,8-tetrah-
ydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-thiophen-2-yl-methyl-5,6,7,8-tetrahydro-
-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(3-morpholin-4-yl-propyl)-5,6,7,8-tetra-
hydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-[4-morpholin-4-yl-9-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-py-
rimido[4,5-b]azepin-2-ylamino]-thiazole-5-carboxylic acid ethyl
ester;
4-Methyl-2-[9-(4-sulfamoyl-benzyl)-4-thiomorpholin-4-yl-5,6,7,8-tetrahydr-
o-pyrimido[4,5-b]azepin-2-ylamino]-thiazole-5-carboxylic acid ethyl
ester;
2-[4-(3-Hydroxymethyl-piperidin-1-yl)-9-(4-sulfamoyl-benzyl)-5,6,7,8-tetr-
ahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; 2-[4-(2,6-Dim
ethyl-morpholin-4-yl)-9-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-pyrimido[-
4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester;
2-[4-(4-Acetyl-[1,4]diazepan-1-yl)-9-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahy-
dro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-[9-(4-sulfamoyl-benzyl)-4-(3,4,5-trimethoxy-benzylamino)-5,6,7-
,8-tetrahydro-pyrimido[4,5-b]azepin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-[4-(3-oxo-piperazin-1-yl)-9-(4-sulfamoyl
-benzyl)-5,6,7,8-tetrahydro-pyrimido[4,5-b]azepin-2-ylamino]-thiazole-5-c-
arboxylic acid ethyl ester;
4-Methyl-2-[4-morpholin-4-yl-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrahyd-
ro-pyrimido[4,5b]azepin-2-ylamino]-thiazole-5-carboxyl c acid ethyl
ester;
4-Methyl-2-[4-thiomorpholin-4-yl-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetr-
ahydro-pyrimido[4,5-b]azepin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester;
2-[4-(3-Hydroxymethyl-piperidin-1-yl)-9-(3,4,5-trimethoxy-benzyl)--
5,6,7,8-tetrahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-ca-
rboxylic acid ethyl ester;
2-[4-(2,6-Dimethyl-morpholin-4-yl)-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-te-
trahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
2-[4-(4-Acetyl-[1,4]diazepan-1-yl)-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-te-
trahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester;
4-Methyl-2-[9-(3,4,5-trimethoxy-benzyl)-4-(3,4,5-trimethoxy-benzylamino)--
5,6,7,8-tetrahydro-pyrimido[4,5-b]azepin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester; and
4-Methyl-2-[4-(3-oxo-piperazin-1-yl)-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8
tetrahydro-pyrimido[4,5-]azepin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester; or ii. the enantiomers, diastereomers, and
pharmaceutically acceptable salts of each of (i).
4. A pharmaceutical composition comprising at least one compound of
claim 1 and a pharmaceutically-acceptable carrier or diluent
Description
[0001] This application is a divisional of U.S. Ser. No.
12/050,227, filed Mar. 18, 2008, which is a divisional of U.S. Ser.
No. 10/702,295, filed Nov. 6, 2003, now U.S. Pat. No. 7,384,937
issued on Jun. 10, 2008, which claims priority from U.S.
provisional application Ser. No. 60/424,250 filed Nov. 6, 2002, the
entirety of which are incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates to fused heterocylic
compounds, pharmaceutical compositions containing these compounds,
and the use of these compounds in the treatment of leukocyte
activation-associated disorders.
BACKGROUND OF THE INVENTION
[0003] The immune system plays an important role in host defense.
In the treatment of leukocyte activation-associated disorders is
often desirable to attenuate the immune response. Such disorders
include the immune response incurred by transplantation or diseases
improved by decreased T-cell activation and proliferation. It is
accepted that agents that inhibit T-cell proliferation may be
useful in the treatment of the aforementioned disorders.
[0004] A number of agents demonstrate clinical or therapeutic
utility by attenuating or modulating the immune system. Such agents
include Cyclosporin A ("CsA"), azathioprine, tacrolimus, sirolimus
and mycophenolate mofetil. However, these agents often demonstrate
a relatively high incidence (25 to >50%) of multiple unique
liabilities during clinical or therapeutic use. For example, CsA
therapy is associated with nephrotoxicity, azathioprine therapy is
associated with leukopenia, and tacrolimus therapy is associated
with undesirable effects on the central nervous system. Also,
sirolimus therapy is associated with hypertension, hyperlipidemia
and hypercholesterolemia, and mycophenolate mofetil therapy is
associated with diarrhea.
[0005] The overproduction of cytokines, such as TNF-.alpha., is
also implicated in a wide variety of leukocyte
activation-associated disorders, including rheumatoid arthritis
(RA), psoriasis, multiple sclerosis, inflammatory bowel disease,
endotoxin shock, osteoporosis, Alzheimer's disease and congestive
heart failure, among others. See e.g., Henry et al., Drugs Fut.,
24:1345-1354 (1999); Salituro et al., Curr. Med. Chem., 6:807-823
(1999). There is convincing evidence in human patients that
cytokine protein antagonists can provide treatment for these
disorders. See e.g., Rankin et al., Br. J. Rheumatol., 34:334-342
(1995) (monoclonal antibody to TNF-.alpha.--Enbrel.RTM.); and
Moreland et al., Ann. Intern. Med., 130:478-486 (1999) (soluble
TNF-.alpha. receptor-Fc fusion protein--etanercept). Accordingly,
it is accepted that agents demonstrating TNF-.alpha. inhibitory
activity are useful for the treatment of leukocyte
activation-associated disorders.
[0006] As none of the current treatments provide complete relief of
symptoms and are to often associated with various liabilities, new
agents and improved methods for treating leukocyte
activation-associated disorders are needed.
SUMMARY OF THE INVENTION
[0007] The present invention provides novel fused heterocyclic
compounds of the following Formula (I), their enantiomers,
diastereomers, and pharmaceutically acceptable salts, prodrugs and
solvates thereof, for use in treating leukocyte
activation-associated disorders:
##STR00002##
wherein: [0008] R.sup.1 is hydrogen or alkyl; [0009] R.sup.2 is
[0010] (a) heteroaryl or heterocyclo, either of which may be
optionally independently substituted with one to three groups
selected from T.sup.1, T.sup.2 and/or T.sup.3; [0011] (b) aryl
substituted with one to three groups selected from T.sup.1, T.sup.2
and/or T.sup.3 provided that at least one of T.sup.1, T.sup.2
and/or T.sup.3 is other than H; or [0012] (c) aryl fused to a
heteroaryl or heterocyclo ring forming a fused ring system bound to
N* through the aryl wherein the fused ring system may be optionally
independently substituted with one to three groups selected from
T.sup.1, T.sup.2 and/or T.sup.3; [0013] provided that R.sup.2 is
not
[0013] ##STR00003## [0014] Z is --NR.sup.3R.sup.4,
--NR.sup.3SO.sub.2R.sup.6, OR.sup.4, SR.sup.4, haloalkyl or
halogen; [0015] J.sup.1 is O, S, S(O), S(O).sub.2 or optionally
substituted C.sub.1-3 alkylene; [0016] J.sup.2 is carbonyl or
optionally substituted C.sub.1-3 alkylene, provided that J.sup.1
and J.sup.2 taken together do not form an alkylene chain of greater
than 4 carbon atoms; [0017] R.sup.3 and R.sup.4 are independently
H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo or
(heterocyclo)alkyl, any of which may be optionally independently
substituted where valance allows with one to three groups T.sup.4,
T.sup.5 and/or T.sup.6, [0018] or R.sup.3 and R.sup.4 may be taken
together with the nitrogen atom to which they are attached to form
a heterocyclo or heteroaryl ring, either of which is optionally
independently substituted where valance allows with one to three
groups independently selected from T.sup.4, T.sup.5 and/or T.sup.6;
[0019] R.sup.5 is [0020] (i) H, cyano, alkyl, alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, any of which
may be independently substituted where valance allows with one to
three groups T.sup.7, T.sup.8 and/or T.sup.9; or [0021] (ii)
--C(O).sub.tR.sup.7, --C(O)--C(O)--C(O)OR.sup.7 or
--SO.sub.2R.sup.8; [0022] R.sup.6 is alkyl, alkenyl, aryl,
(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl,
(cycloalkyl)alkyl, heterocylo, or (heterocyclo)alkyl, any of which
may be optionally independently substituted where valance allows
with one to three groups T.sup.4, T.sup.5 and/or T.sup.6; [0023]
R.sup.7 is [0024] (i) H, alkyl, alkenyl, heterocyclo,
(heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl,
heteroaryl, aryl or (aryl)alkyl, any of which may be optionally
independently substituted where valance allows with one to three
groups T.sup.7, T.sup.8 and/or T.sup.9; or [0025] (ii)
--NR.sup.9R.sup.10 or) (NR.sup.9R.sup.10)alkyl; [0026] R.sup.8 is
[0027] (i) alkyl, alkenyl, heterocyclo, (heterocyclo)alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, heteroaryl, aryl or
(aryl)alkyl, any of which may be optionally independently
substituted where valance allows with one to three groups T.sup.7,
T.sup.8 and/or T.sup.9; or [0028] (ii) --NR.sup.9R.sup.10 or)
(NR.sup.9R.sup.10)alkyl; [0029] R.sup.9 and R.sup.10 are
independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocylo or
(heterocyclo)alkyl, any of which may be optionally independently
substituted where valance allows with one to three groups T.sup.7,
T.sup.8 and/or T.sup.9; [0030] T.sup.1-T.sup.9 are each
independently [0031] (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl,
alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,
(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, any of which
may be optionally independently substituted by one or more groups
selected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocyo)alkyl, heteroaryl,
(heteroaryl)alkyl, --OT.sup.10, --SH, --ST.sup.10, --C(O).sub.tH,
--C(O).sub.tT.sup.10, --O--C(O)T.sup.10,
T.sup.17C(O).sub.tN(T.sup.11)T.sup.10, --SO.sub.3H,
--S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.11)T.sup.10,
-T.sup.12--C(O)T.sup.10, -T.sup.12-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.11)-T.sup.13-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.16)-T.sup.15-T.sup.10 and
-T.sup.12-N(T.sup.16)-T.sup.13-H; or [0032] (ii) halo, cyano,
nitro, OH, oxo, --SH, amino, --OT.sup.10, --ST.sup.10,
--C(O).sub.tH, --C(O).sub.tT.sup.10, --O--C(O)T.sup.10,
T.sup.17C(O).sub.tN(T.sup.11)T.sup.10, --SO.sub.3H,
--S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.11)T.sup.10,
T.sup.12-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.11)-T.sup.13NT.sup.14T.sup.15,
T.sup.12-N(T.sup.16)-T.sup.15-T.sup.10 or
T.sup.12N(T.sup.16)-T.sup.13-H; [0033] t is 1 or 2; [0034] T.sup.10
is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl; [0035] T.sup.12 and T.sup.13 are each
independently a single bond, -T.sup.17-S(O).sub.t-T.sup.18-,
-T.sup.17-C(O)-T.sup.18-, -T.sup.17-C(S)-T.sup.18-,
-T.sup.17-O-T.sup.18-, -T.sup.17-S-T.sup.18-,
-T.sup.17-O--C(O)-T.sup.18-, -T.sup.17-C(O).sub.tT.sup.18-,
-T.sup.17--C(.dbd.NT.sup.19)-T.sup.18- or
-T.sup.17-C(O)--C(O)-T.sup.18-; [0036] T.sup.11, T.sup.14, T.sup.5,
T.sup.16 and T.sup.19 are each independently [0037] (i) hydrogen,
alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl, any of which may be optionally independently
substituted where valence permits by one or more groups selected
from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, --SH, --ST.sup.22,
--C(O).sub.tH, --C(O).sub.tT.sup.22, --O--C(O)T.sup.22 and
--S(O).sub.tT.sup.22; or [0038] (ii) halo, cyano, nitro, OH, oxo,
--SH, amino, --OT.sup.22, --ST.sup.22, --C(O).sub.tH,
--C(O).sub.tT.sup.22, --O--C(O)T.sup.22, --SO.sub.3H or
--S(O).sub.tT.sup.22; or [0039] (iii) T.sup.14 and T.sup.15 may
together be alkylene or alkenylene, completing a 3- to 8-membered
saturated or unsaturated ring together with the atoms to which they
are attached, which ring is substituted with one or more groups
listed in the description of T.sup.20; or [0040] (iv) T.sup.14 or
T.sup.15, together with T.sup.11, may be alkylene or alkenylene
completing a 3- to 8-membered saturated or unsaturated ring
together with the nitrogen atoms to which they are attached, which
ring is substituted with one or more groups listed in the
description of T.sup.20; or [0041] (v) T.sup.14 and T.sup.15 or
T.sup.11 and T.sup.16 together with the nitrogen atom to which they
are attached may combine to form a group --N.dbd.CT.sup.20T.sup.21;
[0042] T.sup.17 and T.sup.18 are each independently a single bond,
alkylene, alkenylene or alkynylene; [0043] T.sup.20 and T.sup.21
are each [0044] (i) independently hydrogen, alkyl, (hydroxy)alkyl,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
cycloalkenyl; (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, any of which
may be optionally independently substituted where valence permits
by one or more groups selected from alkyl, (hydroxy)alkyl, halo,
cyano, nitro, OH, oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocyo)alkyl, heteroaryl,
(heteroaryl)alkyl, --SH, --ST.sup.22, --C(O).sub.tH,
--C(O).sub.tT.sup.22, --O--C(O)T.sup.22 and --S(O).sub.tT.sup.22;
or [0045] (ii) halo, cyano, nitro, OH, oxo, --SH, amino,
--OT.sup.22, --ST.sup.22, --C(O).sub.tH, --C(O).sub.tT.sup.22,
--O--C(O)T.sup.22, --SO.sub.3H, --S(O).sub.tT.sup.22,
S(O).sub.tN(T.sup.11)T.sup.22; [0046] T.sup.22 is alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl.
[0047] The following are definitions of the terms as used
throughout this specification and claims. The initial definition
provided for a group or term herein applies to that group or term
throughout the present specification, individually or as part of
another group, unless otherwise indicated.
[0048] The terms "alk" or "alkyl" refer to straight or branched
chain hydrocarbon groups having 1 to 12 carbon atoms, preferably 1
to 8 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl,
n-butyl, i-butyl, t-butyl, pentyl, hexyl, heptyl, octyl, etc. Lower
alkyl groups, that is, alkyl groups of 1 to 6 carbon atoms, are
generally most preferred.
[0049] The term "substituted alkyl" refers to alkyl groups
substituted with one or more groups listed in the definition of
T.sup.1-T.sup.9, preferably selected from halo, cyano, O--R.sub.11,
S--R.sub.11, NR.sub.12R.sub.13, nitro, cycloalkyl, substituted
cycloalkyl, oxo, aryl, substituted aryl, heterocyclo, heteroaryl,
CO.sub.2R.sub.11, S(O)R.sub.11, SO.sub.2R.sub.11, SO.sub.3R.sub.11,
SO.sub.2NR.sub.12R.sub.13, C(O)NR.sub.12R.sub.13, C(O)alkyl and
C(O)H.
[0050] The term "alkylene" refers to a straight chain bridge of 1
to 4 carbon atoms connected by single bonds (e.g.,
--(CH.sub.2).sub.x-- wherein x is 1 to 5), which may be substituted
with one or more groups listed in the definition of
T.sup.1-T.sup.9.
[0051] The term "alkenyl" refers to straight or branched chain
hydrocarbon groups having 2 to 12 carbon atoms, preferably 2 to 4
carbon atoms, and at least one double carbon to carbon bond (either
cis or trans), such as ethenyl.
[0052] The term "substituted alkenyl" refers to an alkenyl group as
defined above substituted with one or more groups listed in the
definition of T.sup.1-T.sup.9, preferably selected from halo,
cyano, O--R.sub.11, S--R.sub.11, NR.sub.12R.sub.13, nitro,
cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl,
heterocyclo, heteroaryl, CO.sub.2R.sub.11, S(O)R.sub.11,
SO.sub.2R.sub.11, SO.sub.3R.sub.11, SO.sub.2NR.sub.12R.sub.13,
C(O)NR.sub.12R.sub.13, C(O)alkyl and C(O)H.
[0053] The term "alkynyl" refers to straight or branched chain
hydrocarbon group having 2 to 12 carbon atoms and one, two or three
triple bonds, preferably 2 to 6 carbon atoms and one triple
bond.
[0054] The term "substituted alkynyl" refers to an alkynyl group as
defined above substituted with one or more groups listed in the
definition of T.sup.1-T.sup.9, preferably selected from halo,
cyano, O--R.sub.11, S--R.sub.11, NR.sub.12R.sub.13, nitro,
cycloalkyl, substituted cycloalkyl, oxo, aryl, substituted aryl,
heterocyclo, heteroaryl, CO.sub.2R.sub.11, S(O)R.sub.11,
SO.sub.2R.sub.11, SO.sub.3R.sub.11, SO.sub.2NR.sub.12R.sub.13,
C(O)NR.sub.12R.sub.13, C(O).sub.talkyl and C(O)H.
[0055] The term "carbonyl" refers to C.dbd.O, which may also be
designated as C(O).
[0056] The group --C(O).sub.tX refers to C(O)X where t is 1 and the
structure
##STR00004##
where t is 2.
[0057] The term "halo" refers to chloro, bromo, fluoro and
iodo.
[0058] The term "cycloalkyl" refers to saturated and partially
unsaturated (containing 1 or 2 double bonds) cyclic hydrocarbon
groups containing 1 to 3 rings, including monocyclicalkyl,
bicyclicalkyl and tricyclicalkyl, containing a total of 3 to 20
carbons forming the rings, preferably 3 to 7 carbons, forming the
ring and which may be fused to 1 or 2 aromatic or heterocyclo
rings, which include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl,
cyclohexenyl,
##STR00005##
and the like.
[0059] The term "substituted cycloalkyl" refers to such cycloalkyl
group as defined above substituted with one or more groups listed
in the definition of T.sup.1-T.sup.9 preferably selected from
halogen, nitro, alkyl, substituted alkyl, alkenyl, cyano,
cycloalkyl, substituted cycloalkyl, aryl, substituted aryl,
heterocyclo, heteroaryl, oxo, OR.sub.11, CO.sub.2R.sub.11,
C(O)NR.sub.12R.sub.13, OC(O)R.sub.11, OC(O)OR.sub.11,
OC(O)NR.sub.12R.sub.13, OCH.sub.2CO.sub.2R.sub.11, C(O)R.sub.11,
NR.sub.12R.sub.13, NR.sub.14C(O)R.sub.11, NR.sub.14C(O)OR.sub.11,
NR.sub.14C(O)C(O)OR.sub.11, NR.sub.14C(O)C(O)NR.sub.12R.sub.13,
NR.sub.14C(O)C(O)alkyl, NR.sub.14C(NCN)OR.sub.11,
NR.sub.14C(O)NR.sub.12R.sub.13, NR.sub.14C(NCN)NR.sub.12R.sub.13,
NR.sub.14C(NR.sub.15NR.sub.12R.sub.13,
NR.sub.14SO.sub.2NR.sub.12R.sub.13, NR.sub.14SO.sub.2R.sub.11,
SR.sub.11, S(O)R.sub.11, SO.sub.2R.sub.11, SO.sub.3R.sub.11,
SO.sub.2NR.sub.12R.sub.13, NHOR.sub.11, NR.sub.14NR.sub.12R.sub.13,
N(COR.sub.11)OR.sub.14, N(CO.sub.2R.sub.11)OR.sub.14,
C(O)NR.sub.14(CR.sub.16R.sub.11).sub.rR.sub.11,
CO(CR.sub.16R.sub.17).sub.pO(CR.sub.12R.sub.13).sub.qCO.sub.2R.sub.11,
CO(CR.sub.16R.sub.17)OR.sub.11,
CO(CR.sub.16R.sub.17).sub.pC(CR.sub.18R.sub.13).sub.qR.sub.11,
CO(CR.sub.16R.sub.17).sub.rNR.sub.12R.sub.13,
OC(O)O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
OC(O)N(CR.sub.16R.sub.17).sub.rR.sub.11,
O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rOR.sub.11,
NR.sub.14C(.dbd.NC)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14CO(CR.sub.16R.sub.17).sub.rNR.sub.12R.sub.13,
NR.sub.14CR.sub.16R.sub.17).sub.mOR.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.rCO.sub.2R.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.13).sub.qR.sub.-
11,
CONR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.13).sub.qR-
.sub.11,
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.nCO(CR.sub.18R.sub.19).s-
ub.qR.sub.11 and
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.mOR.sub.11.
[0060] The terms "ar" or "aryl" refer to aromatic homocyclic (i.e.,
hydrocarbon) mono-, bi- or tricyclic ring-containing groups
preferably having 6 to 12 members such as phenyl, naphthyl and
biphenyl, as well as such rings fused to a cycloalkyl,
cycloalkenyl, heterocyclo, or heteroaryl ring. Examples
include:
##STR00006##
and the like.
[0061] The term "substituted aryl" refers to such aryl groups as
defined above substituted with one or more groups listed in the
definition of T.sup.1-T.sup.9, preferably selected from halogen,
nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl,
substituted cycloalkyl, aryl, substituted aryl, heterocyclo,
heteroaryl, oxo, CO.sub.2R.sub.11, C(O)NR.sub.12R.sub.13,
OC(O)R.sub.11, OC(O)OR.sub.11, OC(O)NR.sub.12R.sub.13,
OCH.sub.2CO.sub.2R.sub.11, C(O)R.sub.11, NR.sub.12R.sub.13,
NR.sub.14C(O)R.sub.11, NR.sub.14C(O)OR.sub.11,
Nit.sub.14C(O)C(O)OR.sub.11, NR.sub.14C(O)C(O)NR.sub.12R.sub.13,
NR.sub.14C(O)C(O)alkyl, NR.sub.14C(NCN)OR.sub.11,
NR.sub.14C(O)NR.sub.12R.sub.13, NR.sub.14C(NCN)NR.sub.12R.sub.13,
NR.sub.14C(NR.sub.15)NR.sub.12R.sub.13,
NR.sub.14SO.sub.2NR.sub.12R.sub.13, NR.sub.14SO.sub.2R.sub.11,
SR.sub.11, S(O)R.sub.11, SO.sub.2R.sub.11, SO.sub.3R.sub.11,
SO.sub.2NR.sub.12R.sub.13, NHOR.sub.11, NR.sub.14NR.sub.12R.sub.13,
N(COR.sub.11)OR.sub.14, N(CO.sub.2R.sub.11)OR.sub.14,
C(O)NR.sub.14(CR.sub.16R.sub.17).sub.rR.sub.11,
CO(CR.sub.16R.sub.17).sub.pO(CR.sub.12R.sub.13).sub.qCO.sub.2R.sub.11,
CO(CR.sub.16R.sub.17).sub.rOR.sub.11,
CO(CR.sub.16R.sub.17).sub.pO(CR.sub.18R.sub.19).sub.qR.sub.11,
CO(CR.sub.16R.sub.17).sub.rNR.sub.12R.sub.13,
OC(O)O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
OC(O)N(CR.sub.16R.sub.17).sub.rR.sub.11,
O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rOR.sub.11,
NR.sub.14C(.dbd.NC)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14CO(CR.sub.16R.sub.17).sub.rNR.sub.12R.sub.13,
NR.sub.14(CR.sub.16R.sub.17).sub.mOR.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.rCO.sub.2R.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.13).sub.qR.sub.-
11,
CONR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.19).sub.qR-
.sub.11,
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.nCO(CR.sub.18R.sub.19).s-
ub.qR.sub.11 and
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.mOR.sub.11 as well as
pentafluorophenyl.
[0062] The terms "heterocycle", "heterocyclic", "heterocyclic
group" or "heterocyclo" refer to fully saturated or partially
unsaturated cyclic groups (for example, 3 to 13 member monocyclic,
7 to 17 member bicyclic, or 10 to 20 member tricyclic ring systems,
preferably containing a total of 3 to 10 ring atoms) which have at
least one heteroatom in at least one carbon atom-containing ring.
Each ring of the heterocyclic group containing a heteroatom may
have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen
atoms and/or sulfur atoms, where the nitrogen and sulfur
heteroatoms may optionally be oxidized and the nitrogen heteroatoms
may optionally be quaternized. The heterocyclic group may be
attached at any heteroatom or carbon atom of the ring or ring
system. The rings of multi-ring heterocycles may be either fused,
bridged and/or joined through one or more spiro unions. Exemplary
heterocyclic groups include
##STR00007##
and the like.
[0063] The terms "substituted heterocycle" or "substituted
heterocyclo" and the like refer to such heterocyclo groups as
defined above substituted with one or more groups listed in the
definition of T.sup.1-T.sup.9, preferably selected from halogen,
nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl,
substituted cycloalkyl, aryl, substituted aryl, heterocyclo,
heteroaryl, oxo, OR.sub.11, CO.sub.2R.sub.11,
C(O)NR.sub.12R.sub.13, OC(O)R.sub.11, OC(O)OR.sub.11,
OC(O)NR.sub.12R.sub.13, OCH.sub.2CO.sub.2R.sub.11, C(O)R.sub.11,
NR.sub.12R.sub.13, NR.sub.14C(O)R.sub.11, NR.sub.14C(O)OR.sub.11,
NR.sub.14C(O)C(O)OR.sub.11, NR.sub.14C(O)C(O)NR.sub.12R.sub.13,
NR.sub.14C(O)C(O)alkyl, NR.sub.14C(NCN)OR.sub.11,
NR.sub.14C(O)NR.sub.12R.sub.13, NR.sub.14C(NCN)NR.sub.12R.sub.13,
NR.sub.14C(NR.sub.15)NR.sub.12R.sub.13,
NR.sub.14SO.sub.2NR.sub.12R.sub.13, NR.sub.14SO.sub.2R.sub.11,
SR.sub.11, S(O)R.sub.11, SO.sub.2R.sub.11, SO.sub.3R.sub.11,
SO.sub.2NR.sub.12R.sub.13, NHOR.sub.11, NR.sub.14NR.sub.12R.sub.13,
N(COR.sub.11)OR.sub.14, N(CO.sub.2R.sub.11)OR.sub.14,
C(O)NR.sub.14(CR.sub.16R.sub.17).sub.rR.sub.11,
CO(CR.sub.16R.sub.17).sub.pO(CR.sub.18R.sub.13).sub.qCO.sub.2R.sub.11,
CO(CR.sub.16R.sub.17).sub.rOR.sub.11,
CO(CR.sub.16R.sub.17).sub.pO(CR.sub.18R.sub.19)
CO(CR.sub.16R.sub.17).sub.pNR.sub.12R.sub.13,
OC(O)O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
OC(O)N(CR.sub.16R.sub.17).sub.rR.sub.11,
O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rOR.sub.11,
NR.sub.14C(.dbd.NC)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14CO(CR.sub.16R.sub.17).sub.rNR.sub.12R.sub.13,
NR.sub.14(CR.sub.16R.sub.17).sub.mOR.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.rCO.sub.2R.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.13).sub.qR.sub.-
11,
CONR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.19).sub.qR-
.sub.11,
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.nCO(CR.sub.18R.sub.19).s-
ub.qR.sub.11 and
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.mOR.sub.11.
[0064] The term "heteroaryl" as used herein alone or as part of
another group refers to a 5-6- or 7-membered aromatic rings
containing from 1 to 4 nitrogen atoms and/or 1 or 2 oxygen or
sulfur atoms provided that the ring contains at least 1 carbon atom
and no more than 4 heteroatoms. The heteroaryl ring is linked
through an available carbon or nitrogen atom. Also included within
the definition of heteroaryl are such rings fused to a cycloalkyl,
aryl, cycloheteroalkyl, or another heteroaryl ring. One, two, or
three available carbon or nitrogen atoms in the heteroaryl ring can
be optionally substituted with substituents listed in the
definition of T.sup.1-T.sup.9. Also an available nitrogen or sulfur
atom in the heteroaryl ring can be oxidized. Examples of heteroaryl
rings include
##STR00008## ##STR00009##
and the like.
[0065] The term "substituted heteroaryl" refers to such heteroaryl
groups as defined above substituted on any available atom with one
or more groups listed in the definition of T.sup.1-T.sup.9,
"preferably selected from" refers to such heterocyclo groups as
defined above substituted with one or more groups listed in the
definition of T.sup.1-T.sup.9, preferably selected from halogen,
nitro, alkyl, substituted alkyl, alkenyl, cyano, cycloalkyl,
substituted cycloalkyl, aryl, substituted aryl, heterocyclo,
heteroaryl, oxo, OR.sub.11, CO.sub.2R.sub.11,
C(O)NR.sub.12R.sub.13, OC(O)R.sub.11, OC(O)OR.sub.11,
OC(O)NR.sub.12R.sub.13, OCH.sub.2CO.sub.2R.sub.11, C(O)R.sub.11,
NR.sub.12R.sub.13, NR.sub.14C(O)R.sub.11, NR.sub.14C(O)OR.sub.11,
NR.sub.14C(O)C(O)OR.sub.11, NR.sub.14C(O)C(O)NR.sub.12R.sub.13,
NR.sub.14C(O)C(O)alkyl, NR.sub.14C(NCN)OR.sub.11,
NR.sub.14C(O)NR.sub.22R.sub.13, NR.sub.14C(NCN)NR.sub.12R.sub.13,
NR.sub.14C(NR.sub.15)NR.sub.12R.sub.13,
NR.sub.14SO.sub.2NR.sub.12R.sub.13, NR.sub.14SO.sub.2R.sub.11,
SR.sub.11, S(O)R.sub.11, SO.sub.2R.sub.11, SO.sub.3R.sub.11,
SO.sub.2NR.sub.12R.sub.13, NHOR.sub.11, NR.sub.14NR.sub.12R.sub.13,
N(COR.sub.11)OR.sub.14, N(CO.sub.2R.sub.11)OR.sub.14,
C(O)NR.sub.14(CR.sub.16R.sub.17).sub.rR.sub.11,
CO(CR.sub.16R.sub.17).sub.pO(CR.sub.12R.sub.13).sub.qCO.sub.2R.sub.11,
CO(CR.sub.16R.sub.17).sub.rOR.sub.11,
CO(CR.sub.16R.sub.17).sub.pO(CR.sub.18R.sub.19).sub.qR.sub.11,
CO(CR.sub.16R.sub.17).sub.rNR.sub.12R.sub.13,
OC(O)O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
OC(O)N(CR.sub.16R.sub.17).sub.rR.sub.11,
O(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14C(O)(CR.sub.16R.sub.17).sub.rOR.sub.11,
NR.sub.14C(.dbd.NC)(CR.sub.16R.sub.17).sub.rR.sub.11,
NR.sub.14CO(CR.sub.16R.sub.17).sub.rNR.sub.12R.sub.13,
NR.sub.14(CR.sub.16R.sub.17).sub.mOR.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.rCO.sub.2R.sub.11,
NR.sub.14(CR.sub.16R.sub.17).sub.mNR.sub.12R.sub.13,
NR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.19).sub.qR.sub.-
11,
CONR.sub.14(CR.sub.16R.sub.17).sub.nSO.sub.2(CR.sub.18R.sub.19).sub.qR-
.sub.11,
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.nCO(CR.sub.18R.sub.19).s-
ub.qR.sub.11 and
SO.sub.2NR.sub.14(CR.sub.16R.sub.17).sub.mOR.sub.11.
[0066] The variables employed in the preceeding definitions are
herein defined as follows:
[0067] R.sub.11, R.sub.14, and R.sub.15 are independently selected
from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, alkynyl, cycloalkyl, substituted cycloalkyl, C(O)alkyl,
C(O)substituted alkyl, C(O)cycloalkyl, C(O) substituted cycloalkyl,
C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl,
C(O)heterocyclo, C(O)heteroaryl, aryl, substituted aryl,
heterocyclo and heteroaryl.
[0068] R.sub.12 and R.sub.13 are independently selected from the
group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl,
substituted cycloalkyl, alkenyl, alkynyl, C(O)alkyl,
C(O)substituted alkyl, C(O)cycloalkyl, C(O)substituted cycloalkyl,
C(O)aryl, C(O)substituted aryl, C(O)Oalkyl, C(O)Osubstituted alkyl,
C(O)heterocyclo, C(O)heteroaryl, S(O).sub.2alkyl,
S(O).sub.2substituted alkyl, S(O).sub.2cycloalkyl,
S(O).sub.2substituted cycloalkyl, S(O).sub.2aryl,
S(O).sub.2substituted aryl, S(O).sub.2heterocyclo,
S(O).sub.2heteroaryl, aryl, substituted aryl, heterocyclo and
heteroaryl, or R.sub.12 and R.sub.13 taken together with the
nitrogen atom to which they are attached complete a heterocyclo or
heteroaryl ring.
[0069] R.sub.16 and R.sub.18 are independently selected from
hydrogen and alkyl or 1 to 4 carbons.
[0070] R.sub.17 and R.sub.19 are independently selected from
hydrogen, alkyl of 1 to 4 carbons, and substituted alkyl or 1 to 4
carbons.
[0071] n is zero or an integer from 1 to 4.
[0072] m is an integer from 2 to 6.
[0073] p is an integer from 1 to 3.
[0074] q is zero or an integer from 1 to 3.
[0075] r is zero or an integer from 1 to 6.
[0076] The variables employed within the definition of
T.sup.1-T.sup.9 are defined herein as follows:
[0077] T.sup.1-T.sup.9 are each independently [0078] (i) alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl, any of which may be optionally independently
substituted by one or more groups selected from alkyl,
(hydroxy)alkyl, halo, cyano, nitro, OH, oxo, (alkoxy)alkyl,
alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, aryl, (aryl)alkyl,
heterocyclo, (heterocyo)alkyl, heteroaryl or (heteroaryl)alkyl,
--OT.sup.10, --SH, --ST.sup.10, --C(O).sub.tH,
--C(O).sub.tT.sup.10, --O--C(O)T.sup.10,
T.sup.17C(O).sub.tN(T.sup.11)T.sup.10, --SO.sub.3H,
--S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.11)T.sup.10,
-T.sup.12-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.11)-T.sup.13-NT.sup.14T.sup.15,
T.sup.12-N(T.sup.16) T.sup.15-T.sup.10 and
-T.sup.12-N(T.sup.16)-T.sup.13-H; or [0079] (ii) halo, cyano,
nitro, OH, oxo, --SH, amino, --OT.sup.10, --ST.sup.10,
--C(O).sub.tH, --C(O).sub.tT.sup.10, --O--C(O)T.sup.10,
T.sup.17C(O).sub.tN(T.sup.11)T.sup.10, --SO.sub.3H,
--S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.11)T.sup.10,
T.sup.12-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.11)-T.sup.13-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.16)-T.sup.15-T.sup.10 or
-T.sup.12-N(T.sup.16)-T.sup.13-H;
[0080] The variable t is 1 or 2.
[0081] T.sup.10 is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl,
alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,
(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl.
[0082] T.sup.12 and T.sup.13 are each independently a single bond,
-T.sup.17-S(O).sub.t-T.sup.18-, -T.sup.17-C(O)-T.sup.18-,
-T.sup.17-C(S)-T.sup.18-, -T.sup.17-O-T.sup.18-,
-T.sup.17-S-T.sup.18-, -T.sup.17-O--C(O)-T.sup.18-,
-T.sup.17-C(O).sub.tT.sup.18-, T.sup.17-C(.dbd.NT.sup.19)-T.sup.18-
or -T.sup.17-C(O)--C(O)-T.sup.18-.
[0083] T.sup.11, T.sup.14, T.sup.15, T.sup.16 and T.sup.19 are each
independently [0084] (i) hydrogen, alkyl, (hydroxy)alkyl,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl, any of which
may be optionally independently substituted where valence permits
by one or more groups selected from alkyl, (hydroxy)alkyl, halo,
cyano, nitro, OH, oxo, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocyo)alkyl, heteroaryl,
(heteroaryl)alkyl, --SH, --ST.sup.22, --C(O).sub.tT.sup.22,
--C(O).sub.tT.sup.22, --O--C(O)T.sup.22 and --S(O).sub.tT.sup.22;
or [0085] (ii) halo, cyano, nitro, OH, oxo, --SH, amino,
--OT.sup.22, --ST.sup.22, --C(O).sub.tH, --C(O).sub.tT.sup.22,
--O--C(O)T.sup.22, --SO.sub.3H, --S(O).sub.tT.sup.22 and
S(O).sub.tN(T.sup.11)T.sup.22; or [0086] (iii) T.sup.14 and
T.sup.15 may together be alkylene or alkenylene, completing a 3- to
8-membered saturated or unsaturated ring together with the atoms to
which they are attached, which ring is substituted with one or more
groups listed in the description of T.sup.20; or [0087] (iv)
T.sup.14 or T.sup.15, together with T.sup.11, may be alkylene or
alkenylene completing a 3- to 8-membered saturated or unsaturated
ring together with the nitrogen atoms to which they are attached,
which ring is substituted with one or more groups listed in the
description of T.sup.20; or [0088] (v) T.sup.14 and T.sup.15 or
T.sup.11 and T.sup.16 together with the nitrogen atom to which they
are attached may combine to form a group
--N.dbd.CT.sup.20T.sup.21.
[0089] T.sup.17 and T.sup.18 are each independently a single bond,
alkylene, alkenylene or alkynylene.
[0090] T.sup.20 and T.sup.21 are each [0091] (i) independently
hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or
(heteroaryl)alkyl, any of which may be optionally independently
substituted where valence permits by one or more groups selected
from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, --SH, --ST.sup.22,
--C(O).sub.tH, --C(O).sub.tT.sup.22, --O--C(O)T.sup.22 and
--S(O).sub.tT.sup.22; or [0092] (ii) halo, cyano, nitro, OH, oxo,
--SH, amino, --OT.sup.22, --ST.sup.22, --C(O).sub.tH,
--C(O).sub.tT.sup.22, --O--C(O)T.sup.22, --SO.sub.3H,
--S(O).sub.tT.sup.22, S(O)N(T.sup.11)T.sup.22; or
[0093] T.sup.22 is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl,
alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,
(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyclo)alkyl, heteroaryl or (heteroaryl)alkyl.
[0094] The term "optionally substituted" is intended to be
synonymous with "unsubstituted or substituted". For example, an
optionally substituted heterocycle is equivalent to an
unsubstituted or substituted heterocycle.
[0095] "T-cell mediated diseases" refers to any disorder or disease
state in which modulation of the activity of T-cells is implicated
in a process which results in either a pathophysiological state or
a process where the normal function of T-cells is intended to be
suppressed for therapeutic benefit. Examples of T-cell mediated
disorders include transplant rejection, graph verses host disease,
and autoimmune disorders, such as rheumatoid arthritis, multiple
sclerosis, juvenile diabetes, asthma, and inflammatory bowel
disease, T-cell mediated hypersensitivity diseases, ischemic or
reperfusion injury, and T-cell proliferative disorders. T-cell
mediated diseases are included in the definition of "leukocyte
activation-associated disorders" which is defined infra.
[0096] The compounds of Formula (I) in accordance with the present
invention are employed, typically in the form of a pharmaceutical
composition including a pharmaceutically acceptable carrier for the
treatment of T-cell mediated disease. The compounds employed for
this purpose are typically administered in an amount from about
0.01 to 100 mg/kg/day.
[0097] The pharmaceutical compositions comprising at least one
compound of Formula (I) may be formulated, for example, by
employing conventional solid or liquid vehicles or diluents, as
well as pharmaceutical additives of a type appropriate to the mode
of desired administration (for example, excipients, binders,
preservatives, stabilizers, flavors, etc.) according to techniques
such as those well known in the art of pharmaceutical
formulation.
[0098] The compounds of Formula (I) may be administered by any
suitable means, for example, orally, such as in the form of
tablets, capsules, granules or powders; sublingually; buccally;
parenterally, such as by subcutaneous, intravenous, intramuscular,
or intrasternal injection or infusion techniques (e.g., as sterile
injectable aqueous or non-aqueous solutions or suspensions);
nasally such as by inhalation spray; topically, such as in the form
of a cream or ointment; or rectally such as in the form of
suppositories; in dosage unit formulations containing non-toxic,
pharmaceutically acceptable vehicles or diluents. The present
compounds may, for example, be administered in a form suitable for
immediate release or extended release. Immediate release or
extended release may be achieved by the use of suitable
pharmaceutical compositions comprising the present compounds, or,
particularly in the case of extended release, by the use of devices
such as subcutaneous implants or osmotic pumps. The present
compounds may also be administered in the form of liposomes.
[0099] Exemplary compositions for oral administration include
suspensions which may contain, for example, microcrystalline
cellulose for imparting bulk, alginic acid or sodium alginate as a
suspending agent, methylcellulose as a viscosity enhancer, and
sweeteners or flavoring agents such as those known in the art; and
immediate release tablets which may contain, for example,
microcrystalline cellulose, dicalcium phosphate, starch, magnesium
stearate and/or lactose and/or other excipients, binders,
extenders, disintegrants, diluents and lubricants such as those
known in the art. The present compounds may also be delivered
through the oral cavity by sublingual and/or buccal administration.
Molded tablets, compressed tablets or freeze-dried tablets are
exemplary forms which may be used. Exemplary compositions include
those formulating the present compound(s) with fast dissolving
diluents such as mannitol, lactose, sucrose and/or cyclodextrins.
Also included in such formulations may be high molecular weight
excipients such as celluloses (avicel) or polyethylene glycols
(PEG). Such formulations may also include an excipient to aid
mucosal adhesion such as hydroxy propyl cellulose (HPC), hydroxy
propyl methyl cellulose (HPMC), sodium carboxy methyl cellulose
(SCMC), maleic anhydride copolymer (e.g., Gantrez), and agents to
control release such as polyacrylic copolymer (e.g., Carbopol 934).
Lubricants, glidants, flavors, coloring agents and stabilizers may
also be added for ease of fabrication and use.
[0100] Exemplary compositions for nasal aerosol or inhalation
administration include solutions in saline which may contain, for
example, benzyl alcohol or other suitable preservatives, absorption
promoters to enhance bioavailability, and/or other solubilizing or
dispersing agents such as those known in the art.
[0101] Exemplary compositions for parenteral administration include
injectable solutions or suspensions which may contain, for example,
suitable non-toxic, parenterally acceptable diluents or solvents,
such as mannitol, 1,3-butanediol, water, Ringer's solution, an
isotonic sodium chloride solution, or other suitable dispersing or
wetting and suspending agents, including synthetic mono- or
diglycerides, and fatty acids, including oleic acid.
[0102] Exemplary compositions for rectal administration include
suppositories which may contain, for example, a suitable
non-irritating excipient, such as cocoa butter, synthetic glyceride
esters or polyethylene glycols, which are solid at ordinary
temperatures, but liquefy and/or dissolve in the rectal cavity to
release the drug.
[0103] Exemplary compositions for topical administration include a
topical carrier such as Plastibase (mineral oil gelled with
polyethylene).
[0104] The effective amount of a compound employed in the present
invention may be determined by one of ordinary skill in the art,
and includes exemplary dosage amounts for an adult human of from
about 0.01 to 100 mg/kg of body weight of active compound per day,
which may be administered in a single dose or in the form of
individual divided doses, such as from 1 to 4 times per day. It
will be understood that the specific dose level and frequency of
dosage for any particular subject may be varied and will depend
upon a variety of factors including the activity of the specific
compound employed, the metabolic stability and length of action of
that compound, the species, age, body weight, general health, sex
and diet of the subject, the mode and time of administration, rate
of excretion, drug combination, and severity of the particular
condition. Preferred subjects for treatment include animals, most
preferably mammalian species such as humans, and domestic animals
such as dogs, cats and the like, subject to inflammatory,
immunological, or respiratory cell-associated disorders.
[0105] Compounds of Formula (I) include salts, prodrugs and
solvates. The term "salt(s)", as employed herein, denotes acidic
and/or basic salts formed with inorganic and/or organic acids and
bases. Zwitterions (internal or inner salts) are included within
the term "salt(s)" as used herein (and may be formed, for example,
where the R substituents comprise an acid moiety such as a carboxyl
group). Also included herein are quaternary ammonium salts such as
alkylammonium salts. Pharmaceutically acceptable (i.e., non-toxic,
physiologically acceptable) salts are preferred, although other
salts are useful, for example, in isolation or purification steps
which may be employed during preparation. Salts of the compounds of
the Formula (I) may be formed, for example, by reacting a compound
I with an amount of acid or base, such as an equivalent amount, in
a medium such as one in which the salt precipitates or in an
aqueous medium followed by lyophilization.
[0106] Exemplary acid addition salts include acetates (such as
those formed with acetic acid or trihaloacetic acid, for example,
trifluoroacetic acid), adipates, alginates, ascorbates, aspartates,
benzoates, benzenesulfonates, bisulfates, borates, butyrates,
citrates, camphorates, camphorsulfonates, cyclopentanepropionates,
digluconates, dodecylsulfates, ethanesulfonates, fumarates,
glucoheptanoates, glycerophosphates, hemisulfates, heptanoates,
hexanoates, hydrochlorides, hydrobromides, hydroiodides,
2-hydroxyethanesulfonates, lactates, maleates, methanesulfonates,
2-naphthalenesulfonates, nicotinates, nitrates, oxalates,
pectinates, persulfates, 3-phenylpropionates, phosphates, picrates,
pivalates, propionates, salicylates, succinates, sulfates (such as
those formed with sulfuric acid), sulfonates (such as those
mentioned herein), tartrates, thiocyanates, toluenesulfonates,
undecanoates, and the like.
[0107] Exemplary basic salts (formed, for example, where the R
substituents comprise an acidic moiety such as a carboxyl group)
include ammonium salts, alkali metal salts such as sodium, lithium,
and potassium salts, alkaline earth metal salts such as calcium and
magnesium salts, salts with organic bases (for example, organic
amines) such as benzathines, dicyclohexylamines, hydrabamines,
N-methyl-D-glucamines, N-methyl-D-glucamides, t-butyl amines, and
salts with amino acids such as arginine, lysine and the like. The
basic nitrogen-containing groups may be quaternized with agents
such as lower alkyl halides (e.g. methyl, ethyl, propyl, and butyl
chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl,
diethyl, dibutyl, and diamyl sulfates), long chain halides (e.g.
decyl, lauryl, myristyl and stearyl chlorides, bromides and
iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and
others.
[0108] Prodrugs and solvates of the compounds of the invention are
also contemplated herein. The term "prodrug", as employed herein,
denotes a compound which, upon administration to a subject,
undergoes chemical conversion by metabolic or chemical processes to
yield a compound of Formula (I), or a salt and/or solvate thereof.
Solvates of compounds of Formula (I) are preferably hydrates.
[0109] Various forms of prodrugs are well known in the art. For
examples of such prodrug derivatives, see: [0110] a) Design of
Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in
Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.
(Acamedic Press, 1985); [0111] b) A Textbook of Drug Design and
Development, edited by Krosgaard-Larsen and H. Bundgaard, Chapter
5, "Design and Application of Prodrugs," by H. Bundgaard, pp.
113-191 (1991); and [0112] c) H. Bundgaard, Advanced Drug Delivery
Reviews, 8, 1-38 (1992), each of which is incorporated herein by
reference.
[0113] Solvates (e.g., hydrates) of the compounds of Formula (I)
are also with the scope of the present invention. Methods of
solvation are generally known in the art.
[0114] All stereoisomers of the present compounds, such as those
which may exist due to asymmetric carbons on the R substituents of
the compound of Formula (I), including enantiomeric and
diastereomeric forms, are within the scope of this invention.
Individual stereoisomers of the compounds of the invention may, for
example, be substantially free of other isomers, or may be admixed,
for example, as racemates or with all other, or other selected,
stereoisomers. The chiral centers of the present invention can have
an S or R configuration as defined by the IUPAC 1974
Recommendations.
Preferred Compounds
[0115] Preferred compounds within the scope of the present
invention include compounds of Formula (I) (above), their
enantiomers, diastereomers, and pharmaceutically acceptable salts,
prodrugs and solvates thereof, in which the subsituents R.sup.1,
R.sub.2, Z, J.sup.1, J.sup.2 and R.sup.5 are selected from the
following: [0116] R.sup.1 is hydrogen or alkyl; [0117] R.sup.2 is
[0118] (a) heteroaryl (preferably thiazolyl or oxazolyl) optionally
independently substituted with one to three groups selected from
T.sup.1, T.sup.2 and/or T.sup.3 (preferably T.sup.1, T.sup.2,
and/or T.sup.3 are alkyl, haloalkyl, cyano, halogen, heteroaryl,
--C(O).sub.tT.sup.10, OT.sup.10, --S(O).sub.tN(T.sup.11)T.sup.10 or
-T.sup.17NT.sup.11T.sup.10); or [0119] (b) aryl (preferably phenyl)
substituted with one to three groups (preferably at least one group
at the para position) selected from T.sup.1, T.sup.2 and/or T.sup.3
provided that at least one of T.sup.1, T.sup.2 and/or T.sup.3 is
other than H (T.sup.1 is preferably cyano, cyano,
C(O).sub.tT.sup.10, S(O).sub.tN(T.sup.11)T.sup.10 or heteroaryl
[heteroaryl is preferably imidazolyl, oxazolyl or thiazolyl, any of
which is optionally further substituted with one to two groups
preferably selected from cyano, C(O).sub.tT.sup.10,
S(O).sub.tN(T.sup.11)T.sup.10 and haloalkyl]); or [0120] (c) aryl
fused to a heteroaryl or heterocyclo ring forming a fused ring
system bound to N* through the aryl wherein the fused ring system
(preferably tetrahydro indole bound through the aryl ring, quinolyl
bound through the aryl ring [especially quinol-6-yl], quinazolinyl
bound through the aryl ring [especially quinazolin-7-yl],
cinnolinyl bound through the aryl ring [especially cinnolin-6-yl],
isoqinolinyl bound through the aryl ring [especially
isoquinol-6-yl], or phthalazinyl bound through the aryl ring
[especially phthalazin-6-yl]). may be optionally independently
substituted with one to three groups selected from T.sup.1, T.sup.2
and/or T.sup.3 (T.sup.1, T.sup.2, and/or T.sup.3 are preferably
selected from halogen, OH, OT.sup.10, alkyl, haloalkyl --CO.sub.tH,
--CO.sub.tT.sup.10 and --C(O)NT.sup.11T.sup.10); [0121] Z is
--NR.sup.3R.sup.4, --NR.sup.3SO.sub.2R.sup.6, OR.sup.4, SR.sup.4,
haloalkyl or halogen (preferably --NR.sup.3R.sup.4 or halogen, even
more preferably --NR.sup.3R.sup.4); [0122] J.sup.1 is O, S, S(O),
S(O).sub.2 or optionally substituted C.sub.1-3 alkylene (preferably
O, S or optionally substituted C.sub.1 alkylene); [0123] J.sup.2 is
carbonyl or optionally substituted C.sub.1-3 alkylene, provided
that J.sup.1 and J.sup.2 taken together do not form an alkylene
chain of greater than 4 carbon atoms; [0124] R.sup.3 and R.sup.4
are independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocyclo or
(heterocyclo)alkyl, any of which may be optionally independently
substituted where valance allows with one to three groups T.sup.4,
T.sup.5 and/or T.sup.6 (T.sup.4, T.sup.5 and/or T.sup.6 are
preferably selected from alkyl, hydroxyalkyl, halo, cyano, OH, oxo,
cycloalkyl, cycloalkenyl, heterocyclo, heteroaryl,
--C(O).sub.tT.sup.10, --C(O).sub.tH, --NHC(O)T.sup.10,
C(O)N(T.sup.11)(T.sup.10), OT.sup.10, ST.sup.10, S(O).sub.3H,
S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.10)(T.sup.11),
T.sup.17N(T.sup.14)(T.sup.15) and
T.sup.12N(T.sup.16)-T.sup.15-T.sup.10); [0125] or R.sup.3 and
R.sup.4 may be taken together with the nitrogen atom to which they
are attached to form a heterocyclo or heteroaryl ring (preferably
piperidyl, piperazinyl, morpholinyl, diazapanyl, 4
dioxa-8-azaspiro[4,5]decan-8-yl or pyrrolyl), either of which is
optionally independently substituted where valance allows with one
to three groups independently selected from T.sup.4, T.sup.5 and/or
T.sup.6 [preferably T.sup.4, T.sup.5 and/or T.sup.6 is selected
from alkyl, hydroxyalkyl, halo, cyano, OH, oxo, cycloalkyl,
cycloalkenyl, optionally substituted heterocyclo, optionally
substituted heteroaryl, --C(O).sub.tT.sup.10, --C(O).sub.tH,
--NHC(O)T.sup.10, C(O)N(T.sup.11)(T.sup.10), OT.sup.10, ST.sup.10,
S(O).sub.3H, S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.14)(T.sup.15),
T.sup.12N(T.sup.14)(T.sup.15) and
T.sup.12N(T.sup.16)-T.sup.15-T.sup.10]; [0126] R.sup.5 is [0127]
(i) H, cyano, alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, aryl, (aryl)alkyl, heterocyclo, (heterocyclo
[preferably piperizolyl, morpholinyl, and indanyl],)alkyl,
heteroaryl or (heteroaryl [preferably pyridyl, furanyl, thienyl,
benzoisothiazolyl, and thiazolyl])alkyl, any of which may be
independently substituted where valance allows with one to three
groups T.sup.7, T.sup.8 and/or T.sup.9 [T.sup.7, T.sup.8 and/or
T.sup.9 preferably selected from cyano, oxo, hydroxy, alkyl, halo,
haloalkyl, --OT.sup.10, --C(O).sub.tN(T.sup.11)(T.sup.10,
--C(O).sub.tNH S(O).sub.t(T.sup.11), --S(O)J.sup.10,
--S(O).sub.tN(T.sup.14)(T.sup.15), T.sup.12N(T.sup.14)(T.sup.15),
--C(O).sub.tT.sup.11, heterocyclo and heteroaryl, any of which may
be optionally substituted by one to three groups independently
preferably selected from cyano, oxo, hydroxy, alkyl, halo,
haloalkyl, and --OT.sup.10]; or [0128] (ii) --C(O).sub.tR.sup.7,
--C(O)--C(O)--C(O)OR.sup.7 or --SO.sub.2R.sup.8;
[0129] Preferred compounds of the present invention include
compounds of Formula (Ia)
##STR00010##
their enantiomers, diastereomers, and pharmaceutically acceptable
salts, prodrugs and solvates thereof, in which: [0130] W is O or S;
[0131] Y.sup.1 is --NHT.sup.15 or OT.sup.10; [0132] Y.sup.2 is
alkyl, or haloalkyl; [0133] Z is --NR.sup.3R.sup.4 or halogen;
[0134] J.sup.1 is O or optionally substituted C.sub.1-3 alkylene;
[0135] J.sup.2 is carbonyl or optionally substituted C.sub.1-3
alkylene, provided that J.sup.1 and J.sup.2 taken together do not
form an alkylene chain of greater than 4 carbon atoms; [0136]
R.sup.3 and R.sup.4 are independently H, alkyl, alkenyl, aryl,
(aryl)alkyl, heteroaryl, (heteroaryl)alkyl, cycloalkyl,
(cycloalkyl)alkyl, heterocyclo or (heterocyclo)alkyl, any of which
may be optionally independently substituted where valance allows
with one to three groups T.sup.4, T.sup.5 and/or T.sup.6; [0137] or
R.sup.3 and R.sup.4 may be taken together with the nitrogen atom to
which they are attached to form a heterocyclo or heteroaryl ring,
either of which is optionally independently substituted where
valance allows with one to three groups independently selected from
T.sup.4, T.sup.5 and/or T.sup.6; [0138] R.sup.5 is [0139] (i) H,
cyano, alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl, any of which may be independently substituted
where valance allows with one to three groups T.sup.7, T.sup.8
and/or T.sup.9; or [0140] (ii) --C(O).sub.tR.sup.7,
--C(O)--C(O)--C(O)OR.sup.7 or --SO.sub.2R.sup.8; [0141] R.sup.6 is
alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl, (heteroaryl)alkyl,
cycloalkyl, (cycloalkyl)alkyl, heterocylo, or (heterocyclo)alkyl,
any of which may be optionally independently substituted where
valance allows with one to three groups T.sup.4, T.sup.5 and/or
T.sup.6; [0142] R.sup.7 is [0143] (i) H, alkyl, alkenyl,
heterocyclo, (heterocyclo)alkyl, (hydroxy)alkyl, (alkoxy)alkyl,
(aryloxy)alkyl, heteroaryl, aryl or (aryl)alkyl, any of which may
be optionally independently substituted where valance allows with
one to three groups T.sup.7, T.sup.8 and/or T.sup.9; or [0144] (ii)
--NR.sup.9R.sup.10 or (NR.sup.9R.sup.10)alkyl; [0145] R.sup.8 is
[0146] (i) alkyl, alkenyl, heterocyclo, (heterocyclo)alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, (aryloxy)alkyl, heteroaryl, aryl or
(aryl)alkyl, any of which may be optionally independently
substituted where valance allows with one to three groups T.sup.7,
T.sup.8 and/or T.sup.9; or [0147] (ii) --NR.sup.9R.sup.10 or
(NR.sup.9R.sup.10)alkyl; [0148] R.sup.9 and R.sup.10 are
independently H, alkyl, alkenyl, aryl, (aryl)alkyl, heteroaryl,
(heteroaryl)alkyl, cycloalkyl, (cycloalkyl)alkyl, heterocylo or
(heterocyclo)alkyl, any of which may be optionally independently
substituted where valance allows with one to three groups T.sup.7,
T.sup.8 and/or T.sup.9; [0149] T.sup.1-T.sup.9 are each
independently [0150] (i) alkyl, (hydroxy)alkyl, (alkoxy)alkyl,
alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl,
(cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocylco)alkyl, heteroaryl or (heteroaryl)alkyl, any of which
may be optionally independently substituted by one or more groups
selected from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocyo)alkyl, heteroaryl or
(heteroaryl)alkyl, --OT.sup.10, --SH, --ST.sup.10, --C(O).sub.tH,
--C(O).sub.tT.sup.10, --O--C(O)T.sup.10,
T.sup.17C(O).sub.tN(T.sup.11)T.sup.10, --SO.sub.3H,
--S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.11)T.sup.10,
T.sup.12-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.11)-T.sup.13-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.16)-T.sup.15-T.sup.10 and
-T.sup.12-N(T.sup.16)-T.sup.13-H; or [0151] (ii) halo, cyano,
nitro, OH, oxo, --SH, amino, --OT.sup.10, --ST.sup.10,
--C(O).sub.tH, --C(O).sub.tT.sup.10, --O--C(O)T.sup.10,
T.sup.17C(O).sub.tN(T.sup.11)T.sup.10, --SO.sub.3H,
--S(O).sub.tT.sup.10, S(O).sub.tN(T.sup.11)T.sup.10,
-T.sup.12-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.11)-T.sup.13-NT.sup.14T.sup.15,
-T.sup.12-N(T.sup.16)-T.sup.15-T.sup.10 or
-T.sup.12-N(T.sup.16)-T.sup.13-H; [0152] t is 1 or 2; [0153]
T.sup.10 is alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl; [0154] T.sup.12 and T.sup.13 are each
independently a single bond, -T.sup.17-S(O).sub.t-T.sup.18-,
-T.sup.17-C(O)-T.sup.18-, -T.sup.17-C(S)-T.sup.18-,
-T.sup.17-O--C(O)-T.sup.18-, -T.sup.17-S-T.sup.18-,
-T.sup.17-O--C(O)-T.sup.18-, -T.sup.17-C(O).sub.tT.sup.18-,
-T.sup.17-C(.dbd.NT.sup.19)-T.sup.18- or
-T.sup.17-C(O)--C(O)-T.sup.18-; [0155] T.sup.11, T.sup.14,
T.sup.15, T.sup.16 and T.sup.19 are each independently [0156] (i)
hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl, any of which may be optionally independently
substituted where valence permits by one or more groups selected
from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, --SH, --ST.sup.22,
--C(O).sub.tH, --C(O).sub.tT.sup.22, --O--C(O)T.sup.22 and
--S(O).sub.tT.sup.22; or [0157] (ii) halo, cyano, nitro, OH, oxo,
--SH, amino, --OT.sup.22, --ST.sup.22, --C(O).sub.tH,
C(O).sub.tT.sup.22, --O--C(O)T.sup.22, --SO.sub.3H,
--S(O).sub.tT.sup.22 or S(O).sub.tN(T.sup.11)T.sup.22; [0158] (iii)
T.sup.14 and T.sup.15 may together be alkylene or alkenylene,
completing a 3- to 8-membered saturated or unsaturated ring
together with the atoms to which they are attached, which ring is
substituted with one or more groups listed in the description of
T.sup.20; or [0159] (iv) T.sup.14 or T.sup.15, together with
T.sup.11, may be alkylene or alkenylene completing a 3- to
8-membered saturated or unsaturated ring together with the nitrogen
atoms to which they are attached, which ring is substituted with
one or more groups listed in the description of T.sup.20; or [0160]
(v) T.sup.14 and T.sup.15 or T.sup.11 and T.sup.16 together with
the nitrogen atom to which they are attached may combine to form a
group --N--CT.sup.20T.sup.21; [0161] T.sup.17 and T.sup.18 are each
independently a single bond, alkylene, alkenylene or alkynylene;
[0162] T.sup.20 and T.sup.21 are each [0163] (i) independently
hydrogen, alkyl, (hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl,
cycloalkyl, (cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl,
aryl, (aryl)alkyl, heterocyclo, (heterocylco)alkyl, heteroaryl or
(heteroaryl)alkyl, any of which may be optionally independently
substituted where valence permits by one or more groups selected
from alkyl, (hydroxy)alkyl, halo, cyano, nitro, OH, oxo,
(alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl, (cycloalkyl)alkyl,
cycloalkenyl, (cycloalkenyl)alkyl, aryl, (aryl)alkyl, heterocyclo,
(heterocyo)alkyl, heteroaryl, (heteroaryl)alkyl, SH, --ST.sup.22,
--C(O).sub.tH, --C(O).sub.tT.sup.22, --O--C(O)T.sup.22 and
--S(O)T.sup.22; or [0164] (ii) halo, cyano, nitro, OH, oxo, --SH,
amino, --OT.sup.22, --ST.sup.22, --C(O).sub.tH, --C(O)T.sup.22,
--O--C(O)T.sup.22, --SO.sub.3H, --S(O).sub.tT.sup.22 or
S(O.sub.t)N(T.sup.11)T.sup.22; and [0165] T.sup.22 is alkyl,
(hydroxy)alkyl, (alkoxy)alkyl, alkenyl, alkynyl, cycloalkyl,
(cycloalkyl)alkyl, cycloalkenyl, (cycloalkenyl)alkyl, aryl,
(aryl)alkyl, heterocyclo, (heterocyclo)alkyl, heteroaryl or
(heteroaryl)alkyl.
[0166] More preferred compounds are compounds within the scope
Formula (Ia), their enantiomers, diastereomers, and
pharmaceutically acceptable salts, prodrugs and solvates thereof,
in which Z is selected from
##STR00011## ##STR00012## ##STR00013##
[0167] Also more preferred compounds include compounds within the
scope of Formula (Ia), their enantiomers, diastereomers, and
pharmaceutically acceptable salts, prodrugs and solvates thereof,
in which R.sup.5 is selected from:
##STR00014## ##STR00015## ##STR00016## ##STR00017##
[0168] Preferred compounds within the scope of the present
invention include compounds having Formula (II)
##STR00018##
their enantiomers, diastereomers, and pharmaceutically acceptable
salts, prodrugs and solvates thereof, in which: Q is O, S or
optionally substituted C.sub.1 alkylene (more preferably Q is
--CH.sub.2-- or O); and X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are
[0169] (i) independently chosen from hydrogen, T.sup.10, OT.sup.10
and NT.sup.14T.sup.15; and/or [0170] (ii) either X.sup.1 and
X.sup.2 or X.sup.3 and X.sup.4 may be taken together to be a
carbonyl group.
[0171] Preferred compounds within the scope of the present
invention include compounds having Formula (III)
##STR00019##
their enantiomers, diastereomers, and pharmaceutically acceptable
salts, prodrugs and solvates thereof, in which:
X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are
[0172] (i) independently chosen from hydrogen, T.sup.10, OT.sup.10
or NT.sup.14T.sup.15; and/or [0173] (ii) either X.sup.1 and X.sup.2
or X.sup.3 and X.sup.4 may be taken together to be a carbonyl
group.
[0174] More preferred compounds are compounds within the scope of
Formula (III) (above), their enantiomers, diastereomers, and
pharmaceutically acceptable salts, prodrugs and solvates thereof,
in which X.sup.1, X.sup.2, X.sup.3 and X.sup.4 are independently
chosen from hydrogen, T.sup.10, OT.sup.10 or NT.sup.14T.sup.15.
[0175] More preferred compounds also include compounds within the
scope of Formula (III), their enantiomers, diastereomers, and
pharmaceutically acceptable salts, prodrugs and solvates thereof,
in which:
X.sup.1, X.sup.2 are independently chosen from hydrogen, T.sup.10,
OT.sup.10 or NT.sup.14T.sup.15; and X.sup.3 and X.sup.4 are taken
together to be a carbonyl group.
[0176] Preferred compounds within the scope of the present
invention include compounds having Formula (IV)
##STR00020##
their enantiomers, diastereomers, and pharmaceutically acceptable
salts, prodrugs and to solvates thereof, wherein: Q is O, S or
optionally substituted C.sub.1 alkylene (more preferably Q is
--CH.sub.2-- or O), and X.sup.1, X.sup.2, X.sup.3, and X.sup.6 are
[0177] (i) independently chosen from hydrogen, T.sup.10, OT.sup.10
or NT.sup.14T.sup.15; and/or [0178] (ii) any one of X.sup.1 and
X.sup.2 or X.sup.3 and X.sup.4 or X.sup.5 and X.sup.6 may be taken
together to be a carbonyl group.
[0179] More preferred compounds of the present invention include
compounds of Formulas (I), (II), (III), or (IV), their enantiomers,
diastereomers, and pharmaceutically acceptable salts, prodrugs and
solvates thereof, in which R.sup.2 is chosen from:
##STR00021##
W is O or S;
Y.sup.1 is --NHT.sup.15 or OT.sup.10;
[0180] Y.sup.2 and Y.sup.3 are independently hydrogen, halo,
OT.sup.10, alkyl or haloalkyl; [0181] Y.sup.4 is optionally
substituted heteroaryl, cyano, C(O).sub.tT.sup.10 or
S(O).sub.tNT.sup.14T.sup.15; and [0182] Y.sup.5 is alkyl,
haloalkyl, NHT.sup.15 or OT.sup.10.
[0183] Even more preferred compounds of the present invention
include compounds of Formulas (I), (Ia), (II), (III), or (IV),
their enantiomers, diastereomers, and pharmaceutically acceptable
salts, prodrugs and solvates thereof, wherein R.sup.2 is
##STR00022##
[0184] W is O or S (preferably S);
[0185] Y.sup.1 is --NHT.sup.15 or OT.sup.10 (preferably OT.sup.10)
and
[0186] Y.sup.2 is alkyl, or haloalkyl (preferably alkyl).
[0187] More preferred compounds of the present invention include
compounds of Formulas (I), (Ia) (II), (III), or (IV), their
enantiomers, diastereomers, and pharmaceutically acceptable salts,
prodrugs and solvates thereof, wherein
R.sup.1 is H;
[0188] J.sup.1 is O, S or optionally substituted C.sub.1 alkylene;
J.sup.2 is C(O), or optionally substituted C.sub.1-3 alkylene; Z is
--NR.sup.3R.sup.4 or halo; R.sup.3 is H or alkyl;
[0189] Even more preferred compounds of the present invention
include compounds of Formula (I), (Ia), (II), (III), or (IV)
include: [0190] i.
2-[7-(4-Methanesulfonyl-benzyl)-4-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3--
d]pyrimidin2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester; [0191]
2-[7-(4-Methanesulfanyl-benzyl)-4-methylamino-5,6-dihydro-pyrrolo[-
2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0192]
2-[7-(3,4-Dimethoxy-benzyl)-4-(3-oxo-piperazin-1-yl)-5,6-dihydro-pyrrolo[-
2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0193]
2-[4-(2-Cyclohex-1-enyl-ethylamino)-7-pyridin-3-ylmethyl-5,6-dihydro
-pyrrolo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; [0194]
2-[4-(Butoxycarbonylmethyl-amino)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrol-
o[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0195]
2-(4-Cyclopentylamino-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrolo[2,3-d]pyri-
midin-2-ylamino)-4-methyl-thiazole-5-carboxylic acid ethyl ester;
[0196]
4-Methyl-2-{4-[(5-methyl-furan-2-ylmethyl)-amino]-7-pyridin-3-ylmethyl-5,-
6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxylic
acid ethyl ester; [0197]
4-Methyl-2-{4-[3-(2-methyl-piperidin-1-yl)-propylamino]-7-pyridin-3-ylmet-
hyl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxylic
acid ethyl ester; [0198]
4-Methyl-2-[4-(2-oxo-azepan-3-ylamino)-7-pyridin-3-ylmethyl-5,6-dihydro-p-
yrrolo[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl
ester; [0199]
4-Methyl-2-{7-pyridin-3-ylmethyl-4-[(thiophen-2-ylmethyl)-amino]-5-
,6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxylic
acid ethyl ester; [0200]
2-[4-(3-Imidazol-1-yl-propylamino)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrro-
lo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0201]
4-Methyl-2-[4-(1-carboxyethyl-piperidin-4-ylamino)-7-pyridin-3-ylmethyl-5-
,6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester; [0202]
2-[4-(6-Dimethylamino-hexylamino)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrol-
o[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0203]
4-Methyl-2-[4-(2-pyridin-4-yl-ethylamino)-7-pyridin-3-ylmethyl-5,6-dihydr-
o-pyrrolo[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester;
[0204]
2-[4-(4-Hydroxy-butylamino)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrol-
o[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0205]
2-{4-[(1-Ethyl-pyrrolidin-2-ylmethyl)-amino]-7-pyridin-3-ylmethyl-5,6-dih-
ydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-carboxylic
acid ethyl ester; [0206]
2-[4-(2-Acetylamino-ethylamino)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrolo[-
2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0207]
4-Methyl-2-{4-[2-(1-methyl-pyrrolidin-2-yl)-ethylamino]-7-pyridin-3-ylmet-
hyl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxylic
acid ethyl ester; [0208]
2-[4-(1-Hydroxymethyl-butylamino)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrol-
o[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0209]
4-Methyl-2-[4-(3-morpholin-4-yl-propylamino)-7-pyridin-3-ylmethyl-5,6-dih-
ydro-pyrrolo[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester; [0210]
2-{4-[2-(1H-Imidazol-4-yl)-ethylamino]-7-pyridin-3-ylmethyl-5,6-dihydro-p-
yrrolo[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-carboxylic
acid ethyl ester; [0211]
2-[4-{(S)-2-Carbamoyl-pyrrolidin-1-yl}-7-pyridin-3-ylmethyl-5,6-dihydro-p-
yrrolo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; [0212]
2-[4-(3-Hydroxy-pyrrolidin-1-yl)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrolo-
[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0213]
4-Methyl-2-(4-morpholin-4-yl-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino)-thiazole-5-carboxylic acid ethyl ester;
[0214]
4-Methyl-2-{4-[methyl-(1-methyl-piperidin-4-yl)-amino]-7-pyridin-3-ylmeth-
yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-thiazole-5-carboxylic
acid ethyl ester; [0215]
2-[4-(3-Diethylcarbamoyl-piperidin-1-yl)-7-pyridin-3-ylmethyl-5,6-dihydro-
-pyrrolo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; [0216]
2-{4-[4-(2-Hydroxy-ethyl)-piperidin-1-yl]-7-pyridin-3-ylmethyl-5,6-dihydr-
o-pyrrolo[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-carboxylic
acid ethyl ester; [0217]
4-Methyl-2-{4-[4-(2-oxo-2-pyrrolidin-1-yl-ethyl)-piperazin-1-yl]-7-pyridi-
n-3-ylmethyl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-thiazole-5-car-
boxylic acid ethyl ester; [0218]
2-{4-[4-(Furan-2-carbonyl)-piperazin-1-yl]-7-pyridin-3-ylmethyl-5,6-dihyd-
ro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-carboxylic
acid ethyl ester, [0219]
2-[4-(4-Hydroxy-piperidin-1-yl)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrolo[-
2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0220]
2-[4-(3-Acetylamino-pyrrolidin-1-yl)-7-pyridin-3-ylmethyl-5,6-dihydro-pyr-
rolo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester; [0221]
2-{4-[Ethyl-(1-ethyl-pyrrolidin-3-yl)-amino]-7-pyridin-3-ylmethyl-5,6-dih-
ydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-4-methyl-thiazole-5-carboxylic
acid ethyl ester; [0222]
4-Methyl-2-[4-(4-carboxyethyl-piperidin-1-yl)-7-pyridin-3-ylmethyl-5,6-di-
hydro-pyrrolo[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester; [0223]
2-[4-(4-Acetyl-piperazin-1-yl)-7-pyridin-3-ylmethyl-5,6-dihydro-pyrrolo[2-
,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester; [0224]
4-Methyl-2-{4-[3-(2-oxo-pyrrolidin-1-yl)-propylamino]-7-[4-(1H-tet-
razol-5-yl)-benzyl]-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino}-thiazol-
e-5-carboxylic acid ethyl ester; [0225]
4-Methyl-2-(4-morpholin-4-yl-6-oxo-7-pyridin-4-ylmethyl-5,6-dihydro-pyrro-
lo[2,3-d]pyrimidin-2-ylamino)-thiazole-5-carboxylic acid ethyl
ester; [0226]
4-Methyl-2-[4-morpholin-4-yl-8-(4-sulfamoyl-benzyl)-5,6,7,8-tetrah-
ydro-pyrido[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester; [0227]
4-Methyl-2-[4-methylamino-8-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-pyrid-
o[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid ethyl
ester; [0228] 2-[8-(4-Ethanesulfonylamino-benzyl)-4-(3
oxo-piperazin-1-yl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]--
4-methyl-thiazole-5-carboxylic acid ethyl ester; [0229]
2-[4-(2-Acetylamino-ethylamino)-8-(4-ethanesulfonylamino-benzyl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli-
c acid ethyl ester; [0230]
2-[8-(4-Methanesulfonylaminocarbonyl-benzyl)-4-(3-oxo-piperazin-1-yl)-5,6-
,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carb-
oxylic acid ethyl ester; [0231]
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahydro-
-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; or [0232]
2-[4-(4-Acetyl-[1,4]diazepan-1-yl)-9-(4-sulfamoyl-benzyl)-5,6,7,8-tetrahy-
dro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester; or [0233] ii. the enantiomers, diastereorners,
and pharmaceutically acceptable salts, prodrugs and solvates of
each of (i).
Methods of Preparation
[0234] Compounds having the structure of Formula (I) may be
prepared by reference to the methods illustrated in the following
Schemes A through D. In particular, Schemes A1, A2, A3 and A4
depict various methods by which compounds of Formula (I) may be
prepared. Scheme B illustrates the preparation of key intermediate
2-substituted malonates. Scheme C depicts a method by which amides
of Formula (I) may be prepared from esters of Formula (I). Finally,
schemes D1 and D2 outline the preparation of the intermediate
guanidines.
[0235] One of skill in the art understands that any compound of
Formula (I) may be produced by the above Schemes by the suitable
selection of appropriate substitution. Solvents, temperatures,
pressures, and other reaction conditions may readily be selected by
one of ordinary skill in the art. All documents cited are
incorporated herein by reference in their entirety. Starting
materials are commercially available or readily prepared by one of
ordinary skill in the art. Constituents of compounds are as defined
herein or elsewhere in the specification.
[0236] Compounds within the scope of the present invention may be
prepared by several methods. Compounds of formula II, III, or IV
where Q is not a heteroatom is prepared as shown in Scheme A1.
Guanidine A1.1 is heated in the presence of a base such as sodium
ethoxide with an appropriate 2-substituted malonate A1.2 to produce
intermediate A1.3 which upon reaction with phosphorous oxychloride
at elevated temperature provides intermediate A1.4. Cleavage of the
olefin by a two step protocol involving dihydroxylation with osmium
tetraoxide in the presence of a co-oxidant such as
N-methylmorpholine N-oxide to give intermediate A1.5 followed by
reaction with either sodium periodate or lead(IV) acetate to
provide intermediate A1.6. Reductive amination of A1.6 using sodium
triacetoxyborohydride and acetic acid in THF with amine A1.7
results in spontaneous ring closure giving intermediate A1.8.
Reaction with reagent A1.9, (an alcohol, a thiol or a sulfonamide)
in the presence of a suitable base provides A 1.10 which is a
compound described by Formula II, III, or IV.
##STR00023##
[0237] In the case of compounds of Formula II, III, or IV where Q
is a heteroatom (Scheme A2), guanidine A1.1 is heated in the
presence of a base such as sodium ethoxide with an appropriate
2-substituted malonate A2.1 to produce intermediate A2.2. Reaction
of A2.2 with phosphorous oxychloride in the presence of a base at
elevated temperature provides intermediate A2.3. Heating with amine
A1.7 in the presence of a base such as triethylamine or Hunigs base
in a solvent such as N-methyl pyrrolidone followed by hydrolysis
with aqueous acid provides intermediate A2.4. A2.4 is then reduced
with sodium cyanoborohydride in acetic acid to A2.5. Reaction with
reagent A1.9, (an amine, alcohol, thiol or sulfonamide) in the
presence of a suitable base provides compound A2.6 which is a
compound of Formula II, III, or IV.
##STR00024##
[0238] For the preparation of lactams of Formula II, III, or IV
where Q is not a heteroatom (Scheme A3), guanidine A1.1 is heated
in the presence of a base such as sodium ethoxide with an
appropriate 2-substituted malonate A3.1 to produce intermediate
A3.2. Reaction of A3.2 with phosphorous oxychloride at elevated
temperature provides intermediate A3.3 which is then heated with
amine A1.7 in the presence of a base such as triethylamine or
Hunigs base in a solvent such as N-methyl pyrrolidone. Reagent A1.9
(an amine, alcohol, thiol or sulfonamide) is then added directly to
the "same pot" and heated to provide compound A3.3 which is
described by Formula II, III, or IV.
##STR00025##
[0239] Alternatively, lactams of Formula II or IV where Q is a
heteroatom (Scheme A4), can be prepared directly from intermediate
A2.4 by reaction with an oxidant such as pyridinium dichromate (see
Takano, et al., J. Chem. Soc., 2, 156-158 (1986)), manganese
dioxide (see Nakatsuka et al., Tetrahedron Lett., 28, 3671-3674
(1987)) or Jones reagent (see Morales-Rios, et al., Tetrahedron,
52, 5339-5348 (1996)) to provide intermediate A4.1. Reaction with
reagent A1.9, (an amine, alcohol, thiol or sulfonamide) in the
presence of a suitable base provides compound A4.2.
##STR00026##
[0240] 2-Substituted malonates, AL2, A2.1, and A3.1, are either
commercially available, or readily prepared by one of the methods
outlined in Scheme B (entries 1-3) As depicted in Scheme B (entry
1), malonate esters, B1, can be alkylated at the 2-position with
alkyl halides using bases such as sodium hydride or sodium alkoxide
in solvents (including DMF or THF) to afford intermediates, B3. See
e.g., Molander, et al., J. Am. Chem. Soc., 118, 4059-4071 (1996).
As shown in Scheme B, (entry 2), 2-halo-malonate esters, B4,
undergo displacement with nucleophiles including thiolates
generated from the respective thiols by deprotonation with bases
such as sodium ethoxide. See e.g., Aveta, et al., Gazz. Chim.
Ital., 116, 649-652 (1996). It is well documented in the literature
that sulfides such as intermediate B6 can be selectively oxidized
either to the sulfoxide, B7, or sulfone, B8, with oxidants
(including m-chloroperoxybenzoic acid) by careful regulation of
experimental conditions such as temperature. See e.g., Fuj isawa,
et al., Tetrahedron Lett., 25, 5083-5086 (1984); and Sutton, et
al., Org. Lett., 2, 319-322 (2000). Additionally, as depicted in
Scheme B (entry 3), 2-substituted malonates, B10, can be prepared
by the reaction of diazomalonates with alcohols at elevated
temperatures in solvents such as benzene, chloroform or toluene in
the presence of transition metal catalysts, such as Rh(OAc).sub.2
dimer. See e.g., Connell, et al., Tetrahedron, 49, 5445-5460
(1993).
##STR00027##
[0241] Scheme C outlines the conversion of esters of Formula (I) to
amides of Formula (I). Hydrolysis of the ester C1.1 under basic
conditions (using e.g., sodium hydroxide) affords acid C2.
Alternatively, one may use a protecting group (such as a tert-butyl
or benzyl group as depicted in compounds C12 and C2.3,
respectively) which will readily allow removal (for instance, by
treatment with trifluoroacetic acid or reaction with hydrogen in
the presence of a suitable catalyst such as palladum on carbon
under elevated pressure) to produce acid C2. See e.g., Greene,
Theodora W., et al., Protective Groups in Organic Synthesis,
3.sup.rd ed. Coupling of acid C2 via standard amide bond coupling
techniques (EDCI/HOAt) with the appropriate amine, C3, gives the
desired amid; C4.
##STR00028##
[0242] The appropriately substituted guanidines referred to in
scheme A are either commercially available or readily prepared by a
number of methods known to one skilled in the art of organic
chemistry. As depicted in scheme D1, amines D1.1 may be reacted
with a number of reagents, such as the commercially available
2-3,5-dimethylpyrazole-1-carboxamidine nitrate, D1.2, to provide
the desired guanidine, D1.3.
##STR00029##
[0243] In some instances it is more convenient to prepare the
intermediate guanidines as illustrated in Scheme D2. An
alpha-haloketone, D2.1, is reacted with 2-imino-4-thiobiuret, D2.2,
to provide guanidine salt D2.3, which is liberated by treatment
with a basic resin, or sodium hydroxide, sodium methoxide, or an
amine base to provide intermediate D2.4. Then, D2.4 can be further
elaborated as described in Scheme A to provide compounds of Formula
(I).
##STR00030##
Utility
[0244] The compounds of Formula (I), are useful in the treatment
(including prevention, partial alleviation or cure) of leukocyte
activation-associated disorders. These disorders include (but are
not limited to) transplant rejection (such as organ transplant,
acute transplant, xenotransplant or heterograft or homograft such
as is employed in burn treatment); protection from ischemic or
reperfusion injury such as ischemic or reperfusion injury incurred
during organ transplantation, myocardial infarction, stroke or
other causes; transplantation tolerance induction; arthritis (such
as rheumatoid arthritis, psoriatic arthritis or osteoarthritis);
multiple sclerosis; respiratory and pulmonary diseases including
but not limited to asthma, exercise induced asthma, chronic
obstructive pulmonary disease (COPD), emphysema, bronchitis, and
acute respiratory distress syndrome (ARDS); inflammatory bowel
disease, including ulcerative colitis and Crohn's disease; lupus
(systemic lupus erythematosis); graft vs. host disease;
T-cell-mediated hypersensitivity diseases, including contact
hypersensitivity, delayed-type hypersensitivity, and
gluten-sensitive enteropathy (Celiac disease); psoriasis; contact
dermatitis (including that due to poison ivy); Hashimoto's
thyroiditis; Sjogren's syndrome; Autoimmune Hyperthyroidism, such
as Graves' Disease; Addison's disease (autoimmune disease of the
adrenal glands); Autoimmune polyglandular disease (also known as
autoimmune polyglandular syndrome); autoimmune alopecia; pernicious
anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre
syndrome; other autoimmune diseases; glomerulonephritis; serum
sickness; uticaria; allergic diseases such as respiratory allergies
(e.g., asthma, hayfever, allergic rhinitis) or skin allergies;
scleracierma; mycosis fungoides; acute inflammatory and respiratory
responses (such as acute respiratory distress syndrome and
ishchemia/reperfusion injury); dermatomyositis; alopecia greata;
chronic actinic dermatitis; eczema; Behcet's disease; Pustulosis
palmoplanteris; Pyoderma gangrenum; Sezary's syndrome; atopic
dermatitis; systemic schlerosis; and morphea.
[0245] The term "leukocyte activation-associated disorder" or
"leukocyte activation-mediated disorder" as used herein includes
each of the above referenced diseases or disorders. The compounds
of the present invention are useful for treating the aforementioned
exemplary disorders irrespective of their etiology.
[0246] The present invention thus provides methods for the
treatment of leukocyte activation-associated disorders (discussed
above) comprising the step of administering to a subject in need
thereof of at least one compounds of Formula (I). Other therapeutic
agents such as those described below may be employed with the
compounds of the present invention. In the methods of the present
invention, such other therapeutic agent(s) may be administered
prior to, simultaneously with or following the administration of
the compound(s) of the present invention.
[0247] The methods of treating diseases which would benefit from
administering compounds of Formula (I) alone or in combination with
each other and/or other suitable therapeutic agents useful in
treating such conditions. These agents include, without limitation:
immunosuppressants such as cyclosporins (e.g., cyclosporin A),
anti-IL-1 agents, such as Anakinra.RTM., the IL-1 receptor
antagonist, CTLA4-Ig, antibodies such as anti-ICAM-3, anti-IL-2
receptor (Anti-Tac.RTM.), anti-CD45RB, anti-CD2, anti-CD3,
anti-CD4, anti-CD80, anti-CD86, monoclonal antibody OKT3, agents
blocking the interaction between CD40 and CD154, such as antibodies
specific for CD40 and/or CD154 (i.e., CD40L), fusion proteins
constructed from CD40 and CD154 (CD40Ig and CD8-CD154), interferon
beta, interferon gamma, methotrexate, FK506 (tacrolimus,
Prograf.RTM.), rapamycin (sirolimus or Rapamune.RTM.)mycophenolate
mofetil, leflunomide (Arava.RTM.), azathioprine and
cyclophosphamide, inhibitors, such as nuclear translocation
inhibitors, of NF-kappa B function, such as deoxyspergualin (DSG),
non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen,
cyclooxygenase-2 (COX-2) inhibitors such as celecoxib
(Celebrex.RTM.) and rofecoxib (Vioxx.RTM.), or derivatives thereof,
steroids such as prednisone or dexamethasone, gold compounds
TNF-.alpha., inhibitors such as tenidap, anti-TNF antibodies or
soluble TNF receptor such as etanercept (Enbrel.RTM.), inhibitors
of p-38 kinase such as BIRB-796, RO-3201195, VX-850, and VX-750,
beta-2 agonists such as albuterol, levalbuterol (Xopenex.RTM.), and
salmeterol (Serevent.RTM.), inhibitors of leukotriene synthesis
such as montelukast (Singulair.RTM.) and zariflukast
(Accolate.RTM.), and anticholinergic agents such as ipratropium
bromide (Atrovent.RTM.), PDE4 inhibitors such as Arofyline,
Cilomilast, Roflumilast, C-11294A, CDC-801, BAY-19-8004,
Cipamfylline, SCH351591, YM-976, PD-189659, Mesiopram,
Pumafentrine, CDC-998, IC-485, and KW-4490, and PDE7 inhibitors
such as IC242. See Lee, et al., Cell Signalling, 14, 277-284,
(2002). Other compounds which may be used in combination with
compounds of Formula (I) to treat diseases are disclosed in the
following patent documents: WO 0068230, WO 0129049, WO 0132618, WO
0134601, WO 0136425, WO 0174786, WO 0198274, WO 0228847; U.S. Prov.
Appl. Ser. Nos. 60/287,964, and 60/355,141; as well as
anti-cytokines such as anti-IL-1 mAb or IL-1 receptor agonist;
anti-IL-4 or IL-4 receptor fusion proteins; and PTK inhibitors such
as those disclosed in U.S. Pat. Nos. 5,990,109, 6,235,740 and
6,239,133, U.S. Appl. Ser. Nos. 60/065,042 and. 09/173,413, filed
Nov. 10, 1997 and Oct. 15, 1998, respectively. All of the foregoing
patents and patent applications are incorporated herein by
reference in their entirety.
[0248] See also the following documents and references cited
therein: Hollenbaugh, D., et al., J. Immunol. Methods, 188(1), 1-7
(1995); Hollenbaugh, D., et al., EMBO J., 11(12), 4313-4321 (1992);
and Moreland, L. W., et al., New England J. of Medicine, 337(3),
141-147 (1997).
[0249] The above other therapeutic agents, when employed in
combination with the compounds of the present invention, may be
used, for example, in those amounts indicated in the Physicians'
Desk Reference (PDR) or as otherwise determined by one of ordinary
skill in the art.
[0250] Use of the compounds having Formula (I) of the present
invention in treating leukocyte activation-associated disorders is
exemplified by, but is not limited to, treating a range of
disorders such as: transplant (such as organ transplant, acute
transplant, xenotransplant or heterograft or homograft (such as is
employed in burn treatment)) rejection; protection from ischemic or
reperfusion injury such as ischemic or reperfusion injury incurred
during organ transplantation, myocardial infarction, stroke or
other causes; transplantation tolerance induction; arthritis (such
as rheumatoid arthritis, psoriatic arthritis or osteoarthritis);
multiple sclerosis; respiratory and pulmonary diseases including
but not limited to asthma, exercise induced asthma, chronic
obstructive pulmonary disease (COPD), emphysema, bronchitis, and
acute respiratory distress syndrome (ARDS); inflammatory bowel
disease, including ulcerative colitis and Crohn's disease; lupus
(systemic lupus erythematosis); graft vs. host disease; T-cell
mediated hypersensitivity diseases, including contact
hypersensitivity, delayed-type hypersensitivity, and
gluten-sensitive enteropathy (Celiac disease); psoriasis; contact
dermatitis (including that due to poison ivy); Hashimoto's
thyroiditis; Sjogren's syndrome; Autoimmune Hyperthyroidism, such
as Graves' Disease; Addison's disease (autoimmune disease of the
adrenal glands); Autoimmune polyglandular disease (also known as
autoimmune polyglandular syndrome); autoimmune alopecia; pernicious
anemia; vitiligo; autoimmune hypopituatarism; Guillain-Barre
syndrome; other autoimmune diseases; glomerulonephritis; serum
sickness; uticaria; allergic diseases such as respiratory allergies
(asthma, hayfever, allergic rhinitis) or skin allergies;
seleracierma; mycosis fungoides; acute inflammatory and respiratory
responses (such as acute respiratory distress syndrome and
ishchemialreperfusion injury); dermatomyositis; alopecia greata;
chronic actinic dermatitis; eczema; Behcet's disease; Pustulosis
palmoplanteris; Pyodeima gangrenum; Sezary's syndrome; atopic
dermatitis; systemic schlerosis; and morphea.
[0251] The combined activity of the present compounds towards
T-cells may be of value in the treatment of any of the
aforementioned disorders.
[0252] In a particular embodiment, the compounds of the present
invention are useful for the treatment of the aforementioned
exemplary disorders irrespective of their etiology, for example, in
the treatment of transplant rejection, rheumatoid arthritis,
multiple sclerosis, chronic obstructive pulmonary disease,
inflammatory bowel disease, lupus, graft v. host disease, T-cell
mediated hypersensitivity disease, psoriasis, Hashimoto's
thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis,
allergic disease such as allergic rhinitis, asthma, ischemic or
reperfusion injury, respiratory diseases such as asthma, COPD and
bronchitis or atopic dermatitis.
T-Cell Proliferation Assay
[0253] Peripheral blood mononuclear cells (PBMC) were isolated from
whole blood by density gradient centrifugation over Lymphoprep,
1.077. Cells were plated into 96 well U-bottom plates at
2.5.times.10.sub.5 cells/well in 10% FBS RPMI 1640 (Life
Technologies/Gibco-BRL) containing 10 ug/ml anti-CD3 (G19-4,
Bristol-Myers Squibb P.R.I., Princeton, N.J.) and 1 ug/ml anti-CD28
(9.3, Bristol-Myers Squibb P.R.I.) in the presence and absence of
inhibitors. DMSO (used as a solvent for inhibitors) was added to
the medium at 0.1% final concentration. The total volume per well
was 200 .mu.L. Cells were incubated at 37 C 5% CO2 for 3 days, at
which time of .sup.3H-thymidine was added to each well. Six hours
following the addition of .sup.3H-thmidine, the plates were
harvested onto filter plates, 30 ul EcoLite scintillant (ICN, Costa
Mesa, Calif.) was added per well, and plates read on a Top
Count-NXT scintillation counter.
TNF.alpha. Secretion Assay
[0254] The ability of compounds to inhibit the production and
secretion of TNF.alpha. from leukocytes was performed using either
PBMC (obtained as described above) or the THP-1 cell line as a
source of monocytes. Compounds were diluted in RPMI 1640
supplemented with 10% FBS and DMSO at a final concentration of
0.2%. Cells (2.times.10.sup.5/well in U-bottom 96 well plates) were
pre-incubated with compounds for 30 min at 37 C prior to addition
of lipopolysaccharide (LPS) at a final concentration of 6.25 ng/ml
in a total volume of 200 .mu.L. After 4 h at 37.degree. C., 50
.mu.L of supernatant was carefully aspirated for detection of
soluble TNF.alpha.. Soluble TNF.alpha. was detected by ELISA
developed by R&D Systems (Minneapolis, Minn.) according to the
manufacturer's instructions.
EXAMPLES
[0255] The following examples illustrate preferred embodiments of
the present invention and do not limit the scope of the present
invention which is defined in the claims. Abbreviations employed in
the Examples are defined below. Compounds of the Examples are
identified by the example and step in which they are prepared
(e.g., "AU" denotes the title compound of step 1 of Example A1), or
by the example only where the compound is the title compound of the
example (for example, "A2" denotes the title compound of Example
A2).
Abbreviations
[0256] Ac Acetyl [0257] AcOH Acetic acid [0258] aq. Aqueous [0259]
CDT Carbonyldiimidazole [0260] Bn Benzyl [0261] Bu Butyl [0262] Boc
tert-butoxycarbonyl [0263] DMAP Dimethylaminopyridine [0264] DMA
N,N-Dimethylacetamide [0265] DMF dimethylformamide [0266] DMSO
Dimethylsulfoxide [0267] EDC
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride [0268]
EtOAc Ethyl acetate [0269] Et Ethyl [0270] EtOH Ethanol [0271] H
Hydrogen [0272] h Hours [0273] i iso [0274] HPLC High pressure
liquid chromatography [0275] HOAc Acetic acid [0276] Lawesson's
Reagent
[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2-4-disufide
[0277] LC liquid chromatography [0278] Me Methyl [0279] MeOH
Methanol [0280] min. Minutes [0281] M.sup.+ (M+H).sup.+ [0282]
M.sup.+1 (M+H).sup.+ [0283] MS Mass spectrometry [0284] n normal
[0285] Pd/C Palladium on carbon [0286] Ph Phenyl [0287] Pr Propyl
[0288] Ret Time Retention time [0289] rt or RT Room temperature
[0290] sat. Saturated [0291] S-Tol-BINAP
(S)-(+2,2'-Bis(di-p-tolylphosphino)-1,1'-binapthyl [0292] t tert
[0293] TFA Trifluoroacetic acid [0294] THF Tetrahydrofuran [0295]
YMC YMC Inc, Wilmington, N.C. 28403
Example A1
2-[4-(4-Hydroxy-piperidin-1-yl)-7-pyridin-2-ylmethyl-5,6-dihydro-pyrrolo[2-
,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester
##STR00031##
[0296] A1.1:
2-[(Aminoiminomethyl)anaino]-4-methyl-5-thiazolecarboxylic acid
ethyl ester
##STR00032##
[0298] A solution of 2-imino-4-thiobiuret (20.0 g, 0.17 mol),
2-chloroaeetoacetate (28 g, 0.17 mol) in ethanol (500 mL) was
heated to 100.degree. C. for 4 hours. The reaction mixture was
concentrated to half volume and poured into 1 liter of 1N NaOH. The
white solid which precipitated out was collected by filtration and
dried under vacuum to yield A1.1 (30.5 g, 79%). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 4.22 (2H, q, J=7 Hz), 2.50 (3H, merge with
DMSO), 1.26 (3H, t, J=7 Hz). HPLC: 97.7%, ret. time=1.619 min.,
LC/MS (M+H).sup.+=229.
A1.2:
2-(5-Allyl-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-4-methy-
l-thiazole-5-carboxylic acid ethyl ester
##STR00033##
[0300] To a solution of NaOEt in EtOH [prepared by dissolving Na
(88 mg, 3.83 mmol, 2.5 eq) in 15 mL of absolute ethanol] was added
A1.1 (350 mg, 1.53 mmol, 1 eq) and the mixture was stirred at rt
for 20 min. Diethyl allylmalonate (0.30 mL, 1.53 mmol, 1 eq) was
added dropwise, the reaction mixture was heated at reflux for 22 h
and then cooled and poured onto a mixture of ice and 10% aq
H.sub.2SO.sub.4. The solid was collected by filtration, washed with
water and dried to afford A1.2 (346 mg, 67% yield) as a tan solid.
LC/MS: 337.58 [M+H].sup.+; HPLC: 93% at 3.49 min (Phenomenex Luna 5
.mu.m C18 column 4.6.times.50 mm, 10-90% aqueous methanol over 4
min containing 0.2% phosphoric acid, 4 mL/min, monitoring at 220
nm).
A1.3:
2-(5-Allyl-4,6-dichloro-pyrimidin-2-ylamino)-4-methyl-thiazole-5-car-
boxylic acid ethyl ester
##STR00034##
[0302] A mixture of A1.2 (346 mg, 1.03 mmol, 1 eq) and POCl.sub.3
(5 mL) was heated in a 100.degree. C. oil bath for 19 h. The
reaction mixture was poured onto ice, neutralized with 2 N NaOH,
and extracted with ethyl acetate. The organic phase was washed with
sat. NaHCO.sub.3, water and brine, dried over MgSO.sub.4 and
concentrated to afford A1.3 (285 mg, 74% yield) as a yellow solid.
LC/MS: 337.58 [M+H].sup.+; HPLC: >95% at 2.10 min (Xterra 5
.mu.m C18 column 4.6.times.30 mm, 10-90% aqueous methanol over 2
min containing 0.2% phosphoric acid, 5 mL/min, monitoring at 254
nm). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta. 5.90 (m, 1H),
5.10 (m, 2H), 4.27 (q, J=7.1 Hz, 2H), 3.53 (m, 2 H), 2.55 (s, 3H),
1.29 (t, J=7.1 Hz, 3H).
A1.4:
2-[4,6-Dichloro-5-(2-oxo-ethyl)-pyrimidin-2-ylamino]-4-methyl-thiazo-
le-5-carboxylic acid ethyl ester
##STR00035##
[0304] A solution of A1.3 (109 mg, 0.292 mmol, 1 eq) and NMO
monohydrate (79 mg, 0.584 mmol, 2 eq) in THF/H.sub.2O (6:1, 6.4 mL)
was cooled to 0.degree. C. and a 4 wt % aq solution of OsO.sub.4
(0.18 mL, 0.029 mmol, 0.1 eq) was added. The reaction mixture was
warmed to rt, stirred for 41 h and then quenched with a solution of
80 mg of NaHSO.sub.3 in 5 mL H.sub.2O and extracted twice with
ethyl acetate. The organic phase was washed with water and brine,
dried over Na.sub.2SO.sub.4 and concentrated.
[0305] The crude product in THF/ethanol/water (4:1:2, 5 mL) was
cooled to 0.degree. C., NaIO.sub.4 (125 mg, 0.584 mmol, 2 eq) was
added portionwise and the reaction mixture was stirred at 0.degree.
C. for 3 h and then warmed to rt and stirred overnight. The mixture
was poured into water and extracted with ethyl acetate. The organic
layer was washed with brine, dried over Na.sub.2SO.sub.4 and
concentrated. The crude product was passed through a silica gel
plug eluted first with dichloromethane (discarded) and then with
ethyl acetate. The ethyl acetate fractions were concentrated to
afford ALA (85 mg, 78% yield) as a white solid. HPLC: >95% at
3.58 min (Phenomenex Luna 5 .mu.m C18 column 4.6.times.50 mm,
10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid,
4 mL/min, monitoring at 254 nm). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 9.72 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 4.11
(m, 2H), 2.56 (s, 3H), 1.29 (t, J=7.1 Hz, 3H).
A1.5:
6-dihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino)-4-methyl-thiazole-5-car-
boxylic acid ethyl ester
##STR00036##
[0307] A mixture of A1.4 (34 mg, 0.0911 mmol, 1 eq) in THF (1 mL)
was treated with 2-picolylamine (10.3 mg, 0.0957 mmol, 1.05 eq),
Na(OAc).sub.3BH (29 mg, 0.137 mmol, 1.5 eq) and acetic acid (5.2
.mu.L, 0.0911 mmol, 1 eq). The reaction mixture was stirred at rt
for 10 min, 3 drops of Et.sub.3N were added and stirring continued
for 1 h. The mixture was poured into sat. NaHCO.sub.3, extracted
twice with ethyl acetate and the combined organic layers were
washed with brine, dried over Na.sub.2SO.sub.4 and concentrated.
Column chromatography (SiO.sub.2, eluted with ethyl acetate) gave
A1.5 (25 mg, 64% yield) as an off-white solid. LC/MS: 431.46
[M+H].sup.+; HPLC: >95% at 3.20 min (Phenomenex Luna 5 .mu.m C18
column 4.6.times.50 mm, 10-90% aqueous methanol over 4 min
containing 0.2% phosphoric acid, 4 mL/min, monitoring at 254 nm).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 9.53 (brs, 1H), 8.58 (d,
J=4.9 Hz, 1H), 7.67 (ddd, J=1.7, 7.7 , 7.7 Hz, 1H), 7.37 (d, J=7.7
Hz, 1H), 7.22 (m, 1H), 4.79 (s, 2H), 4.28 (q, J=7.1 Hz, 2H), 3.77
(t, J=8.4 Hz, 2H), 3.03 (J=8.2 Hz, 2H), 2.65 (s, 3H), 1.30 (t,
J=7.1 Hz, 3H).
A1.6:
2-[4-(4-Hydroxy-piperidin-1-yl)-7-pyridin-2-ylmethyl-5,6-dihdro-pyrr-
olo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylie acid
ethyl ester
[0308] A mixture of A1.5 (15 mg, 0.0348 mmol, 1 eq),
4-hydroxypiperidine (7 mg, 0.0696 mmol, 2 eq), Hunig's base (18
.mu.L, 0.1044 mmol, 3 eq) and n-butanol (0.5 mL) was heated in a
sealed tube at 150.degree. C. until the reaction was complete by
HPLC analysis. The reaction mixture was cooled to rt and
concentrated in vacuo. Column chromatography (SiO.sub.2, 5%
methanol/ethyl acetate) provided A1 (10.4 mg, 60% yield) as an oil.
LC/MS: 496.57 [M+H].sup.+; HPLC: 95% at 1.22 min (Xterra 5 .mu.m
C18 column 4.6.times.30 mm, 10-90% aqueous methanol over 2 min
containing 0.2% phosphoric acid, 5 mL/min, monitoring at 254 nm).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 8.70 (brs, 1H), 8.55 (d,
J=4.7 Hz, 1H), 7.63 (ddd, J=1.7, 7.7, 7.7 Hz, 1H), 7.33 (d, J=7.8
Hz, 1H), 7.18 (m, 1H), 4.69 (s, 2H), 4.26 (q, J=7.1 Hz, 2H),
4.15-4.20 (m, 2H), 3.94 (m, 1H), 3.53 (t, J=8.4 Hz, 2H), 3.28 (m,
2H), 3.09 (J=8.4 Hz, 2H), 2.60 (s, 3H), 1.96 (m, 2H), 1.58 (m, 2H),
1.31 (t, J=7.1 Hz, 3H).
Example A2-A72
##STR00037##
[0310] Examples A2 to A72 were prepared from intermediate A1.4 in a
similar manner to that used for Example A1 utilizing the
appropriate amine replacements.
TABLE-US-00001 TABLE A HPLC Reten- tion MS Ex. Z R.sup.5 Name (min)
Reported A2 ##STR00038## ##STR00039## 2-[7-(4-
Methanesulfonyl-benzyl)- 4-piperazin-1-yl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.19.sup.a 558.44 A3 ##STR00040## ##STR00041##
4-Methyl-2-[4-piperazin- 1-yl-7-(3,4,5-trimethoxy-
benzyl)-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino]-thiazole-5- carboxylic acid ethyl ester 1.35.sup.a
570.24 A4 ##STR00042## ##STR00043## 4-Methyl-2-[4-(4-methyl-
piperazin-1-yl)-7-(3,4,5- trimethoxy-benzyl)-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]- thiazole-5-carboxylic
acid ethyl ester 1.34.sup.a 584.56 A5 ##STR00044## ##STR00045##
4-Methyl-2-[4-(3-oxo- piperazin-1-yl)-7-pyridin- 2-ylmethyl-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2- ylamino]-thiazole-5- carboxylic
acid ethyl ester 1.18.sup.a 495.51 A6 ##STR00046## ##STR00047##
2-[7-(4-Methanesulfonyl- benzyl)-4-(3-oxo- piperazin-1-yl)-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5-
carboxylic acid ethyl ester 2.93.sup.b 572.31 A7 ##STR00048##
##STR00049## 2-[7-(4-Methanesulfonyl- benzyl)-4-morpholin-4-yl-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 3.02.sup.b 559.32
A8 ##STR00050## ##STR00051## 2-[7-(4-Methanesulfonyl-
benzyl)-4-(4-methyl- piperazin-1-yl)-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 2.41.sup.b 572.47 A9 ##STR00052## ##STR00053##
2-[4-(3-Hydroxymethyl- piperidin-1-yl)-7-(4-
methanesulfonyl-benzyl)- 5,6-dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 2.83.sup.b 587.32 A10 ##STR00054## ##STR00055##
2-[4-(3-Carbamoyl- piperazin-1-yl)-7-(4- methanesulfonyl-benzyl)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.35.sup.b 601.32
A11 ##STR00056## ##STR00057## 2-[4-(4-Hydroxymethyl-
piperidin-1-yl)-7-(4- methanesulfonyl-benzyl)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.73.sup.b 587.30
A12 ##STR00058## ##STR00059## 2-[4-(4-Dimethylamino-
piperidin-1-yl)-7-(4- methanesulfonyl-benzyl)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.17.sup.b 600.37
A13 ##STR00060## ##STR00061## 2-[4-(4-Hydroxy-3-
hydroxymethyl-piperidin- 1-yl)-7-(4- methanesulfonyl-benzyl)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.57.sup.b 603.37
A14 ##STR00062## ##STR00063## 2-[4-Dimethylamino-7-(4-
methanesulfonyl-benzyl)- 5,6-dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 2.78.sup.b 517.30 A15 ##STR00064## ##STR00065##
2-[7-(4-Methanesulfonyl- benzyl)-4-methylamino-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.64.sup.b 503.44
A16 ##STR00066## ##STR00067## 4-Methyl-2-[4-(3-oxo-
piperazin-1-yl)-7-(4- sulfamoyl-benzyl)-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- thiazole-5-carboxylic acid ethyl ester
2.78.sup.b 573.20 A17 ##STR00068## ##STR00069##
4-Methyl-2-[4-(3-oxo- piperazin-1-yl)-7-pyridin-
3-ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino]-thiazole-5- carboxylic acid ethyl ester 2.29.sup.b
495.25 A18 ##STR00070## ##STR00071## 2-[7-(3,4-Dimethoxy-
benzyl)-4-(3-oxo- piperazin-1-yl)-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 3.24.sup.b 554.51 A19 ##STR00072## Et 2-[7-Ethyl-4-(3-oxo-
piperazin-1-yl)-5,6- dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.86.sup.b 432.26
A20 ##STR00073## Et 2-[7-Ethyl-4-(4- sulfamoyl-benzylamino)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.77.sup.b 518.21
A21 ##STR00074## ##STR00075## 2-[7-(4-Cyano-benzyl)-4-
(3-oxo-piperazin-1-yl)5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 3.31.sup.b 519.20 A22 ##STR00076## ##STR00077##
2-[7-(2-Dimethylamino- ethyl)-4-(3-oxo-piperazin-
1-yl)-5,6-dihydro- pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 2.21.sup.b 475.28 A23
##STR00078## ##STR00079## 2-[7-Carboxymethyl-4-(3-
oxo-piperazin-1-yl)-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 2.65.sup.b 462.22 A24 ##STR00080## ##STR00081##
2-[7-(2-Dimethylamino- ethyl)-4-(3,4,5- trimethoxy-benzylamino)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 2.52.sup.b 572.32
A25 ##STR00082## ##STR00083## 4-Methyl-2-{4-(3-oxo-
piperazin-1-yl)-7-[4-(1H- tetrazol-5-yl)-benzyl]-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino}- thiazole-5-carboxylic
acid ethyl ester 3.07.sup.b 562.23 A26 ##STR00084## ##STR00085##
2-[4-(2-Cyclohex-1-enyl- ethylamino)-7-pyridin-3-
ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.69.sup.c 520.25 A27
##STR00086## ##STR00087## 2-{4-[(2,3-Dihydro- benzo[1,4]dioxin-2-
ylmethyl)-amino]-7- pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.61.sup.c 560.24 A28 ##STR00088## ##STR00089## 2-[4-
(Butoxycarbonylmethyl- amino)-7-pyridin-3- ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.49.sup.c 526.27 A29 ##STR00090## ##STR00091##
2-(4-Cyclopentylamino-7- pyridin-3-ylmethyl-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino)- 4-methyl-thiazole-5-
carboxylic acid ethyl ester 1.46.sup.c 480.26 A30 ##STR00092##
##STR00093## 4-Methyl-2-{4-[(5- methyl-furan-2-ylmethyl)-
amino]-7-pyridin-3- ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino}-thiazole-5- carboxylic acid ethyl ester 1.47.sup.c
506.25 A31 ##STR00094## ##STR00095## 4-Methyl-2-{4-[3-(2-
methyl-piperidin-1-yl)- propylamino]-7-pyridin-
3-ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino}-thiazole-5- carboxylic acid ethyl ester 1.17.sup.c
551.31 A32 ##STR00096## ##STR00097## 4-Methyl-2-[4-(2-oxo-
azepan-3-ylamino)-7- pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- thiazole-5-carboxylic acid ethyl ester
1.38.sup.c 523.27 A33 ##STR00098## ##STR00099##
4-Methyl-2-{7-pyridin-3- ylmethyl-4-[(thiophen-2-
ylmethyl)-amino]-5,6- dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino}-
thiazole-5-carboxylic acid ethyl ester 1.46.sup.c 508.19 34
##STR00100## ##STR00101## 2-[4-(3-Imidazol-1-yl-
propylamino)-7-pyridin- 3-ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.08.sup.c 520.25 A35 ##STR00102## ##STR00103##
4-Methyl-2-[4-(1- carboxyethyl-piperidin-4- ylamino)-7-pyridin-3-
ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino]-thiazole-5- carboxylic acid ethyl ester 1.53.sup.c
567.29 A36 ##STR00104## ##STR00105## 2-[4-(6-Dimethylamino-
hexylamino)-7-pyridin-3- ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.19.sup.c 539.33 A37 ##STR00106## ##STR00107##
4-Methyl-2-[4-(2-pyridin- 4-yl-ethylamino)-7-
pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- thiazole-5-carboxylic acid ethyl ester
1.10.sup.c 517.24 A38 ##STR00108## ##STR00109## 2-[4-(4-Hydroxy-
butylamino)-7-pyridin-3- ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.22.sup.c 484.25 A39 ##STR00110## ##STR00111##
2-{4-[(1-Ethyl-pyrrolidin- 2-ylmethyl)-amino]-7-
pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.20.sup.c 523.24 A40 ##STR00112## ##STR00113##
2-[4-(2-Acetylamino- ethylamino)-7-pyridin-3- ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.19.sup.c 497.24 A41 ##STR00114## ##STR00115##
4-Methyl-2-{4-[2-(1- methyl-pyrrolidin-2-yl)-
ethylamino]-7-pyridin-3- ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino}-thiazole-5- carboxylic acid
ethyl ester 1.13.sup.c 523.30 A42 ##STR00116## ##STR00117##
2-[4-(1-Hydroxymethyl- butylamino)-7-pyridin-3-
ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.40.sup.c 498.27 A43
##STR00118## ##STR00119## 4-Methyl-2-[4-(3- morpholin-4-yl-
propylamino)-7-pyridin- 3-ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-thiazole-5- carboxylic acid
ethyl ester 1.10.sup.c 539.30 A44 ##STR00120## ##STR00121##
2-{4-[2-(1H-Imidazol-4- yl)-ethylamino]-7-pyridin-
3-ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.11.sup.c 506.26 A45 ##STR00122## ##STR00123##
2-[4-{(S)-2-Carbamoyl- pyrrolidin-1-yl}-7- pyridin-3-ylmethyl-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5-
carboxylic acid ethyl ester 1.19.sup.c 509.22 A46 ##STR00124##
##STR00125## 2-[4-(3-Hydroxy- pyrrolidin-1-yl)-7-
pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.16.sup.c 482.25 A47 ##STR00126## ##STR00127##
4-Methyl-2-(4-morpholin- 4-yl-7-pyridin-3- ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino)-thiazole-5- carboxylic acid
ethyl ester 1.32.sup.c 482.23 A48 ##STR00128## ##STR00129##
4-Methyl-2-{4-[methyl- (1-methyl-piperidin-4-yl)-
amino]-7-pyridin-3- ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino}-thiazole-5- carboxylic acid ethyl ester 1.14.sup.c
523.31 A49 ##STR00130## ##STR00131## 2-[4-(3- Diethylcarbamoyl-
piperidin-1-yl)-7-pyridin- 3-ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.63.sup.c 577.27 A50 ##STR00132## ##STR00133##
2-{4-[4-(2-Hydroxy- ethyl)-piperidin-1-yl]-7-
pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.35.sup.c 524.26 A51 ##STR00134## ##STR00135##
4-Methyl-2-{4-[4-(2-oxo- 2-pyrrolidin-1-yl-ethyl)-
piperazin-1-yl]-7-pyridin- 3-ylmethyl-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino}-thiazole-5- carboxylic acid
ethyl ester 1.18.sup.c 592.30 A52 ##STR00136## ##STR00137##
2-{4-[4-(Furan-2- carbonyl)-piperazin-1-yl]-
7-pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.48.sup.c 575.25 A53 ##STR00138## ##STR00139##
2-[4-(4-Hydroxy- piperidin-1-yl)-7-pyridin- 3-ylmethyl-5,6-dihyro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino]-4-methyl- thiazole-5-carboxylic
acid
ethyl ester 1.23.sup.c 496.26 A54 ##STR00140## ##STR00141##
2-[4-(3-Acetylamino- pyrrolidin-1-yl)-7- pyridin-3-ylmethyl-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5-
carboxylic acid ethyl ester 1.17.sup.c 523.28 A55 ##STR00142##
##STR00143## 2-{4-[Ethyl-(1-ethyl- pyrrolidin-3-yl)-amino]-7-
pyridin-3-ylmethyl-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.09.sup.c 537.31 A56 ##STR00144## ##STR00145##
2-[4-(4-Carbamoyl- piperidin-1-yl)-7-pyridin-
3-ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.18.sup.c 523.25 A57 ##STR00146## ##STR00147## 4-Methyl-2-[4-(4-
carboxyethyl-piperidin-1- yl)-7-pyridin-3-ylmethyl-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
thiazole-5-carboxylic acid ethyl ester 1.54.sup.c 552.28 A58
##STR00148## ##STR00149## 2-[4-(4-Acetyl-piperazin-
1-yl)-7-pyridin-3- ylmethyl-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.28.sup.c 523.27 A59 ##STR00150## ##STR00151##
2-[7-(2-Benzyloxy-ethyl)- 4-(3-oxo-piperazin-1-yl)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 3.39.sup.b 538.22
A60 ##STR00152## ##STR00153## 2-[7-(2-Hydroxy-ethyl)-4-
(3-oxo-piperazin-1-yl)- 5,6-dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 2.44.sup.b 448.06 A61 ##STR00154## ##STR00155##
2-{4-(4-Hydroxy- piperidin-1-yl)-7-[4-(1H-
tetrazol-5-yl)-benzyl]-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.50.sup.c 563.27 A62 ##STR00156## ##STR00157##
4-Methyl-2-{4-[3-(2-oxo- pyrrolidin-1-yl)- propylamino]-7-[4-(1H-
tetrazol-5-yl)-benzyl]-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- thiazole-5-carboxylic acid ethyl ester
1.54.sup.c 604.33 A63 ##STR00158## ##STR00159## 4-Methyl-2-{4-
morpholin-4-yl-7-[4-(1H- tetrazol-5-yl)-benzyl]-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino}- thiazole-5-carboxylic
acid ethyl ester 1.48.sup.c 549.32 A64 ##STR00160## ##STR00161##
2-[7-(4-tert- Butoxycarbonyl-benzyl)- 4-(3-oxo-piperazin-1-yl)-
5,6-dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino]-
4-methyl-thiazole-5- carboxylic acid ethyl ester 3.95.sup.b 594.07
A65 ##STR00162## ##STR00163## 2-[7-(4-Carboxy-benzyl)-
4-(3-oxo-piperazin-1-yl)- 5,6-dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 3.18.sup.b 538.21 A66 ##STR00164## ##STR00165##
4-Methyl-2-{4- [(tetrahydro-furan-2- ylmethyl)-amino]-7-[4-
(1H-tetrazol-5-yl)- benzyl]-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino}-thiazole-5- carboxylic acid ethyl ester 1.64.sup.c
563.20 A67 ##STR00166## ##STR00167## 2-{4-Cyclopentylamino-
7-[4-(1H-tetrazol-5-yl)- benzyl]-5,6-dihydro-
pyrrolo[2,3-d]pyrimidin- 2-ylamino}-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.76.sup.c 547.15 A68 ##STR00168## ##STR00169##
2-{4-(4-Hydroxy- butylamino)-7-[4-(1H- tetrazol-5-yl)-benzyl]-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5-
carboxylic acid ethyl ester 1.56.sup.c 551.62 A69 ##STR00170##
##STR00171## 4-Methyl-2-[7-[4-(1H- tetrazol-5-yl)-benzyl]-4-
(2-thiophen-2-yl- ethylamino)-5,6-dihydro- pyrrolo[2,3-d]pyrimidin-
2-ylamino]-thiazole-5- carboxylic acid ethyl ester 1.76.sup.c
589.15 A70 ##STR00172## ##STR00173## 4-Methyl-2-{4-(3-methyl-
butylamino)-7-[4-(1H- tetrazol-5-yl)-benzyl]-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino}- thiazole-5-carboxylic
acid ethyl ester 1.76.sup.c 549.23 A71 ##STR00174## ##STR00175##
2-{4-(2-Ethoxy- ethylamino)-7-[4-(1H- tetrazol-5-yl)-benzyl]-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5-
carboxylic acid ethyl ester 1.64.sup.c 551.19 A72 ##STR00176##
##STR00177## 2-{4-(3-Hydroxymethyl- piperidin-1-yl)-7-[4-(1H-
tetrazol-5-yl)-benzyl]-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2-ylamino}- 4-methyl-thiazole-5- carboxylic acid ethyl
ester 1.59.sup.c 577.22 HPLC conditions used to determine retention
times: : .sup.aXterra 5 .mu.m C18 column 4.6 .times. 30 mm, 10-90%
aqueous methanol over 2 min containing 0.2% H.sub.3PO.sub.4, 5
mL/min, monitoring at 220 nm or 254 nm. .sup.bYMC CombiScreen 5
.mu.m C18 column 4.6 .times. 50 mm, 10-90% aqueous methanol over 4
min containing 0.1% TFA, 4 mL/min, monitoring at 220 nm or 254 nm.
.sup.cPhenomenex 5 .mu.m C18 column 4.6 .times. 30 mm, 10-90%
aqueous methanol over 2 min containing 0.2% H.sub.3PO.sub.4, 5
mL/min, monitoring at 220 nm or 254 nm
Example BI
4-Methyl-2-[4-morpholin-4-yl-6-oxo-7-(3,4,5-trimethoxy-benzyl)-5,6-dihydro-
-pyrrolo[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic acid
ethyl ester
##STR00178##
[0311] B1.1: 2-Ethoxycarbonyl-succinic acid diethyl ester
##STR00179##
[0313] To a suspension of NaH (1.58 g, 62.5 mmol) in THF (100 mL)
was added diethylmalonate (10 g, 62.5 mmol), followed by ethyl
bromoacetate (8.18 g, 48 mmol) under nitrogen. The reaction mixture
was stirred at room temperature for 4 hours and then poured into
saturated ammonium chloride solution (200 ml). It was extracted
with three potions of ethyl acetate (100 ml). The combined organic
phases were washed with brine (100 ml), dried over sodium sulfate
and the solvent was removed to yield B1.1 (13.94 g, 91%).
.sup.1H-NMR (CDCl.sub.3) .delta.: 4.13-4.28 (6H, m), 3.84 (1H, t,
J=7 Hz), 2.94 (2H, d, J=7 Hz), 1.24-1.33 (9H, m).
B1.2:
2-(5-Ethoxycarbonylmethyl-4,6-dihydroxy-pyrimidin-2-ylamino)-4-methy-
l-thiazole-5-carboxylic acid ethyl ester
##STR00180##
[0315] Sodium (0.766 g, 33.3 mmol) was added to ethanol (50 ml) and
stirred at room temperature until the sodium was completely
dissolved. To the reaction mixture was added A1.1 (2.53 g, 11.1
mmol) and B1.1 (3.0 g, 12.2 mmol) which was heated to 100.degree.
C. for 7 hrs and then it was cooled to RT. The solid was collected
as the desired product B1.2 (3.234 g, 76%). HPLC: 85%, ret.
time=3.457 min., LC/MS (M+H).sup.+=383.03.
B1.3:
2-(4,6-Dichloro-5-ethoxycarbonylmethyl-pyrimidin-2-ylamino)-4-methyl-
-thiazole-5-carboxylic acid ethyl ester
##STR00181##
[0317] A solution of B1.2 (1.07 g, 0.28 mmol) in POCl.sub.3 (3 ml)
was heated to 100.degree. C. for 4 hours and then it was cooled to
RT and poured into 50 ml of ice-water. It was neutralized with
NaOH/water (1/1) to approximately pH 7. The solid was collected by
filtration and then it was added to 10 ml of methanol and stirred
about 10 minutes. The solid was collected to yield the desired
product B1.3 (590 mg, 50%). HPLC: 82%, ret. time=3.903 min., LC/MS
(M+H).sup.+=418.96.
B1.4:
4-Methyl-2-[4-morpholin-4-yl-6-oxo-7-(3,4,5-trimethoxy-benzyl)-5,6-d-
ihydro-pyrrolo[2,3-d]pyrimidin-2-ylamino]-thiazole-5-carboxylic
acid ethyl ester
[0318] A solution of B1.3 (50 mg, 0.12 mmol),
3,4,5-trimethoxybenzylamine (24 mg, 0.12 mmol), and
diisopropylethylamine (17 mg, 0.13 mmol) in N-methyl-2-pyrrolidine
(0.5 ml) was heated to 100.degree. C. for 25 minutes under
microwave irradiation. Morpholine (22.5 mg, 0.258 mmol) was then
added and the reaction mixture was heated to 180.degree. C. for 15
minutes under microwave irradiation. Methanol (2 ml) was added and
the mixture was stirred at room temperature for 30 minutes. The
solid was collected to afford B1 (19 mg, 27%). .sup.1H-NMR (DMSO)
.delta.: 11.65 (1H, s), 6.66 (2H, s), 4.65 (2H, s), 4.09 (2H, q,
JJ=7 Hz), 3.73 (2H, s), 3.55-3.65 (14H, m), 3.50 (3H, s), 2.42 (3H,
s), 1.12 (3H, t, J=7 Hz). HPLC: 96%, ret. time=3.810 min., LC/MS
(M+H).sup.+=585.49.
Example B2-B32
##STR00182##
[0320] Examples 82 to B32 were prepared in a similar manner to that
used for Example B1 utilizing the appropriate amine
replacements.
TABLE-US-00002 TABLE B1 HPLC Retention.sup.a MS Ex. Z R.sup.5 Name
(min) Reported B2 ##STR00183## ##STR00184## 4-Methyl-2-[6-oxo-4-
(3-oxo-piperazin-1-yl)- 7-(4-sulfamoyl- benzyl)-5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino]-thiazole-5- carboxylic acid
ethyl ester 3.01 586.98 B3 ##STR00185## ##STR00186## 2-[7-(4-
Methanesulfonyl- benzyl)-6-oxo-4-(3- oxo-piperazin-1-yl)-
5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.10 586.20 B4 ##STR00187##
##STR00188## 2-[4-(4-Hydroxy- piperidin-1-yl)-6-oxo-
7-(3,4,5-trimethoxy- benzyl)-5,6-dihydro- pyrrolo[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 3.72 599.41 B5 ##STR00189## ##STR00190## 4-Methyl-2-[6-oxo-4-
(3-oxo-piperazin-1-yl)- 7-(3,4,5-trimethoxy- benzyl)-5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino]-thiazole-5- carboxylic acid
ethyl ester 3.52 598.38 B6 ##STR00191## ##STR00192## 4-Methyl-2-[4-
morpholin-4-yl-6-oxo- 7-(4-sulfamoyl- benzyl)-5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino]-thiazole-5- carboxylic acid
ethyl ester 3.32 574.38 B7 ##STR00193## ##STR00194##
2-[4-(4-Hydroxy- piperidin-1-yl)-6-oxo- 7-(4-sulfamoyl-
benzyl)-5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.21 588.36 B8 ##STR00195##
##STR00196## 4-Methyl-2-[4-(4- methyl-3-oxo- piperazin-1-yl)-6-oxo-
7-(4-sulfamoyl- benzyl)-5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 3.15 601.35 B9
##STR00197## ##STR00198## 4-Methyl-2-[6-oxo-4-
(3-oxo-piperazin-1-yl)- 7-(4-[1,2,4]triazol-4-yl-
benzyl)-5,6-dihydro- pyrrolo [2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 3.11 575.40 B10
##STR00199## ##STR00200## 2-[7-(4-Imidazol-1-yl-
benzyl)-6-oxo-4-(3- oxo-piperazin-1-yl)- 5,6-dihydro- pyrrolo[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 2.66 574.41 B11 ##STR00201## ##STR00202##
4-Methyl-2-{6-oxo-4- (3-oxo-piperazin-1-yl)-
7-[2-(1H-tetrazol-5-yl)- benzyl]-5,6-dihydro- pyrrolo[2,3-
d]pyrimidin-2- ylamino}-thiazole-5- carboxylic acid ethyl ester
3.16 576.40 B12 ##STR00203## ##STR00204## 2-{4-(4-Hydroxy-
piperidin-1-yl)-6-oxo- 7-[2-(1H-tetrazol-5-yl)-
benzyl]-5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino}-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.39 577.45 B13 ##STR00205##
##STR00206## 4-Methyl-2-{6-oxo-4- (3-oxo-piperazin-1-yl)-
7-[3-(1H-tetrazol-5-yl)- benzyl]-5,6-dihydro- pyrrolo[2,3-
d]pyrimidin-2- ylamino}-thiazole-5- carboxylic acid ethyl ester
3.34 576.43 B14 ##STR00207## ##STR00208## 4-Methyl-2-[6-oxo-4-
(3-oxo-piperazin-1-yl)- 7-pyridin-3-ylmethyl- 5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino]-thiazole-5- carboxylic acid
ethyl ester 2.47 509.43 B15 ##STR00209## ##STR00210##
2-{4-(4-Hydroxy- piperidin-1-yl)-6-oxo- 7-[3-(1H-tetrazol-5-yl)-
benzyl]-5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino}-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.53 577.41 B16 ##STR00211##
##STR00212## 4-Methyl-2-[6-oxo-4- (3-oxo-piperazin-1-yl)-
7-pyridin-2-ylmethyl- 5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 2.83 509.43 B17
##STR00213## ##STR00214## 2-[4-(4-Hydroxy- piperidin-1-yl)-6-oxo-
7-pyridin-3-ylmethyl- 5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester 2.76
510.26 B18 ##STR00215## ##STR00216## 2-[4-(4-Hydroxy-
piperidin-1-yl)-6-oxo- 7-pyridin-2-ylmethyl- 5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.01 510.24 B19 ##STR00217##
##STR00218## 4-Methyl-2-[6-oxo-4- (3-oxo-piperazin-1-yl)-
7-pyridin-4-ylmethyl- 5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 2.34 509.37 B20
##STR00219## ##STR00220## 4-Methyl-2-(4- morpholin-4-yl-6-oxo-
7-pyridin-4-ylmethyl- 5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino)-thiazole-5- carboxylic acid ethyl ester 2.69 496.38 B21
##STR00221## ##STR00222## 2-[4-(4-Hydroxy- piperidin-1-yl)-6-oxo-
7-pyridin-4-ylmethyl- 5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester 2.63
510.27 B22 ##STR00223## ##STR00224## 4-Methyl-2-{6-oxo-4-
(3-oxo-piperazin-1-yl)- 7-[4-(1H-tetrazol-5-yl)-
benzyl]-5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino}-thiazole-5- carboxylic acid ethyl ester 3.30 576.16 B23
##STR00225## ##STR00226## 2-{4-(4-Hydroxy- piperidin-1-yl)-6-oxo-
7-[4-(1H-tetrazol-5-yl)- benzyl]-5,6-dihydro- pyrrolo[2,3-
d]pyrimidin-2- ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl
ester 3.47 577.19 B24 ##STR00227## ##STR00228## 4-Methyl-2-{4-
morpholin-4-yl-6-oxo- 7-[4-(1H-tetrazol-5-yl)- benzyl]-5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino}-thiazole-5- carboxylic acid
ethyl ester 3.62 563.26 B25 ##STR00229## ##STR00230##
2-[7-(4-Cyano-benzyl)- 4-(4-hydroxy- piperidin-1-yl)-6-oxo-
5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.55 534.13 B26 ##STR00231##
##STR00232## 2-[4-(4-Hydroxy- piperidin-1-yl)-7-(4-
methyl-benzyl)-6-oxo- 5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester 3.95
523.15 B27 ##STR00233## ##STR00234## 2-[7-Benzyl-4-(4-
hydroxy-piperidin-1- yl)-6-oxo-5,6-dihydro- pyrrolo[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 3.78 509.14 B28 ##STR00235## ##STR00236##
2-[7-(3-Fluoro-benzyl)- 4-(4-hydroxy- piperidin-1-yl)-6-oxo-
5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.82 527.17 B29 ##STR00237##
##STR00238## 2-[4-(4-Hydroxy- piperidin-1-yl)-7-(3-
methoxy-benzyl)-6- oxo-5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester 3.80
539.17 B30 ##STR00239## ##STR00240## 2-[7-(3,4-Dimethoxy-
benzyl)-4-(4-hydroxy- piperidin-1-yl)-6-oxo- 5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.61 569.16 B31 ##STR00241##
##STR00242## 2-[4-(4-Hydroxy- piperidin-1-yl)-7-(4-
methoxy-benzyl)-6- oxo-5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester 3.76
539.17 B32 ##STR00243## ##STR00244## 2-[7-(4-Bromo-benzyl)-4-(4-
hydroxy-piperidin-1-yl)- 6-oxo-5,6- dihydro-pyrrolo[2,3-d]
pyrimidin-2- ylamino]-4-methyl-thiazole-5- carboxylic acid ethyl
ester 4.10 587.02 HPLC conditions used to determine retention
times: .sup.aYMC CombiScreen 5 .mu.m C18 column 4.6 .times. 50 mm,
10-90% aqueous methanol over 4 min containing 0.1% TFA, 4 mL/min,
monitoring at 220 nm or 254 nm
Example B33
2-[4-(4-Hydroxy-piperidin-1-yl)-6-oxo-7-(4-thiophen-3-yl-benzyl)-5,6-dihyd-
ro-pyrrolo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
##STR00245##
[0322] A degassed solution of 3-thiopheneboronic acid (4.4 mg,
0.034 mmol) in 0.4 M sodium carbonate solution (0.5 ml) was added
dropwise to the degassed suspension of B32 (20 mg, 0.034 mmol) and
tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol)
acetonitrile (0.5 ml) at 90.degree. C. under nitrogen. The reaction
mixture was heated at 90.degree. C. for 30 minutes. The hot
suspension was filtered to remove the catalyst and the filtrate was
concentrated to afford the crude product which was purified by
preparative TLC (silica, 2:1 EtOAc:hexanes) to yield B33 (6.2 mg,
31%). .sup.1H-NMR (DMSO) .delta.: 11.68 (1H, s), 7.82-7.86 (1H, m),
7.61-7.69 (3H, M), 7.51-7.54 (1H, m), 7.43 (2H, d, 8 Hz), 4.86 (2H,
s), 4.22 (2H, q, JJ=7 Hz), 4.08-4.18 (2H, m), 3.84 (2H, s),
3.74-3.81 (1H, m), 3.33-3.35 (2H, m, merge with water), 2.51 (3H,
s, merge with DMSO), 1.78-1.87 (2H, m), 1.36-1.48 (2H, m), 1.27
(3H, t, 7 Hz). HPLC:>95%, ret. time=4.120 min., LC/MS
(M+H).sup.+=591.11.
Example B34-B36
##STR00246##
[0324] Examples B34 and B35 were prepared in a similar manner to
that used for Example B33 utilizing the appropriate
heteroarylboronic acid replacement. Example B36 was isolated as a
side product during the preparation of Example B35.
TABLE-US-00003 TABLE B2 HPLC Retention.sup.a MS Ex. R.sup.5 Name
(min) Reported B34 ##STR00247## 2-[7-[4-(3,5-Dimethyl-
isoxazol-4-yl)-benzyl]- 4-(4-hydroxy- piperidin-1-yl)-6-oxo-
5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.81 604.14 B35 ##STR00248##
2-[7-[4-(1-tert- Butoxycarbonyl-1H- pyrrol-2-yl)-benzyl]-4-
(4-hydroxy-piperidin- 1-yl)-6-oxo-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 4.25 674.14 B36 ##STR00249## 2-{4-(4-Hydroxy-
piperidin-1-yl)-6-oxo- 7-[4-(1H-pyrrol-2-yl)- benzyl]-5,6-dihydro-
pyrrolo[2,3- d]pyrimidin-2- ylamino}-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.80 574.16 HPLC conditions
used to determine retention times: .sup.aYMC CombiScreen 5 .mu.m
C18 column 4.6 .times. 50 mm, 10-90% aqueous methanol over 4 min
containing 0.1% TFA, 4 mL/min, monitoring at 220 nm or 254 nm
Example B37
2-[7-(4-Carboxy-benzyl)-6-oxo-4-(3-oxo-piperazin-1-yl)-5,6-dihydro-pyrrolo-
[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester
##STR00250##
[0326] A solution of B1.3 (223 mg, 053 mmol),
t-butyl(4-aminomethyl)benzoate (110 mg, 0.53 mmol), and
diisopropylethylamine (108 uL, 0.56 mmol) in N-methyl-2-pyrrolidine
(2 ml) was heated to 100.degree. C. for 20 minutes under microwave
irradiation. Piperazin-2-one (113 mg, 1.12 mmol) was then added.
The reaction mixture was heated to 180.degree. C. for 10 minutes
under microwave irradiation, 10 ml of methanol was added and the
mixture stirred for 5 minutes. The solid which was collected was
dissolved in dichloromethane (0.5 ml) and TEA (0.5 ml) at
0-5.degree. C. The reaction mixture was warmed to RT, stirred for
30 minutes and concentrated. Methanol (2 ml) was added and the
mixture stirred for 10 minutes. The solid was collected to afford
B37 (97.3 mg, 73%). .sup.1H-NMR (DMSO) .delta.: 11.84 (1H, s), 8.28
(1H, s), 7.99 (2H, d, 8 Hz), 7.57 (2H, d, J=8 Hz), 5.04 (2H, s),
4.42 (2H, s), 4.32 (2H, q, J=7 Hz), 4.07 (2H, s), 3.96-4.02 (2H,
m), 3.55-3.75 (2H, m), 2.61 (3H, s, merge with DMSO), 1.38 (3H, t,
J=7 Hz). HPLC:89%, ret. time=3.31 min., LC/MS
(M+H).sup.+=552.05.
Example B38
2-[7-(4-Dimethylcarbamoyl-benzyl)-6-oxo-4-(3-oxo-piperazin-1-yl)-5,6-dihyd-
ro-pyrrolo[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
##STR00251##
[0328] A solution of B37 (15 mg, 0.027 mmol) dimethylamine
hydrochloride (2.66 mg, 0.0326 mmol) and diisopropylethylamine
(11.5 mg, 0.114 mmol) in DMF (1 ml) was treated with
bis(oxo-3-oxazolidinyl) phosphinic chloride (21 mg, 0.081 mmol) and
the reaction mixture was stirred at RT for 1 h. The reaction
mixture was purified by preparative HPLC to afford B38 (7.3 mg,
47%). .sup.1H-NMR (CDCl.sub.3) .delta.: 7.41 (2H, d, 8 Hz), 7.18
(2H, d, J=8 Hz), 6.47 (1H, s), 4.16-4.25 (4H, m), 3.83-3.90 (2H,
m), 3.56 (2H, s), 3.35-3.41 (2H, m), 2.92 (3H, s), 2.78 (3H, s),
2.52 (3H, s), 1.22 (3H, t, J=7 Hz). HPLC: >90%, ret. time=3.160
min., LC/MS (M+H).sup.+=579.15.
Example B39-B43
##STR00252##
[0330] Examples B39 to 843 were prepared in a similar manner to
that used for Example B38 utilizing the appropriate amine
replacement.
TABLE-US-00004 TABLE B3 HPLC Retention.sup.a MS Ex. R.sup.5 Name
(min) Reported B39 ##STR00253## 2-[7-[4-(4-Hydroxy-
piperidine-1-carbonyl)- benzyl]-6-oxo-4-(3- oxo-piperazin-1-yl)-
5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.12 635.12 B40 ##STR00254##
4-Methyl-2-[7-[4- (morpholine-4- carbonyl)-benzyl]-6- oxo-4-(3-oxo-
piperazin-1-yl)-5,6- dihydro-pyrrolo[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 3.15 621.12 B41
##STR00255## 2-[7-(4- Isobutylcarbamoyl- benzyl)-6-oxo-4-(3-
oxo-piperazin-1-yl)- 5,6-dihydro- pyrrolo[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester 3.45
607.19 B42 ##STR00256## 2-[7-[4-(3-Hydroxy- pyrrolidine-1-
carbonyl)-benzyl]-6- oxo-4-(3-oxo- piperazin-1-yl)-5,6-
dihydro-pyrrolo[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.05 621.13 B43 ##STR00257##
2-[7-{4-[(2-Hydroxy- ethyl)-methyl- carbamoyl]-benzyl}-6-
oxo-4-(3-oxo- piperazin-1-yl)-5,6- dihydro-pyrrolo[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 3.07 609.19 HPLC conditions used to determine retention
times: .sup.aYMC CombiScreen 5 .mu.m C18 column 4.6 .times. 50 mm,
10-90% aqueous methanol over 4 min containing 0.1% TFA, 4 mL/min,
monitoring at 220 nm or 254 nm
Example C1
2-[8-(4-Methanesulfonyl-benzyl)-4-(1-tert-butoxycarbonyl-piperazin-4-yl)-5-
,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-ca-
rboxylic acid ethyl ester
##STR00258##
[0331] C1
C1.1:
4-(2-Chloro-pyrido[2,3-d]pyrimidin-4-yl)-piperazine-1-carboxylic
acid tert-butyl ester
##STR00259##
[0333] A mixture of 2,4-dichloro-pyrido[2,3-d]pyrimidine (150 mg,
0.75 mmol, 1 eq) [prepared from 2-aminonicotinic acid by the
methods of Robins et al. (J. Am. Chem. Soc. 1955, 77, 1045.) and
Oakes et al. (J. Chem. Soc. 1956, 1045.)], N-t-butoxycarbonyl
piperazine (147 mg, 0.787 mmol, 1.05 eq) and Hunig's base (0.39 mL,
2.25 mmol, 3 eq) in ethanol (2.5 mL) was stirred at rt for 17 hr.
The white solid was collected by filtration, washed with water and
cold ethanol, and dried to afford C1.1 (105 mg, 40% yield). LC/MS:
350.41 [M+H].sup.+; HPLC: >95% at 1.44 min (Xterra 5 .mu.m C18
column 4.6.times.30 mm, 10-90% aqueous methanol over 2 min
containing 0.2% phosphoric acid, 5 mL/min, monitoring at 254
nm).
C1.2:
C4-(2-Chloro-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-4-yl)-piperaz-
ine-1-carboxylic acid tert-butyl ester
##STR00260##
[0335] A mixture of C1.1 (41 mg, 0.117 mmol, 1 eq), PtO.sub.2 (2.7
mg, 0.0117 mmol, 0.1 eq) and ethanol (1 mL) was stirred under a
H.sub.2 atmosphere (1 atm) for 4.5 h. The mixture was filtered
through celite and the filtrate was concentrated to afford C1.2 (41
mg, quant.) as a white solid. LC/MS: 354.42 [M+H].sup.+; HPLC: 96%
at 3.43 min (Phenomenex Luna 5 .mu.m C18 column 4.6.times.50 mm,
10-90% aqueous methanol over 4 min containing 0.2% phosphoric acid,
4 mL/min, monitoring at 254 nm). .sup.1H NMR (400 MHz, CD.sub.3OD):
.delta. 3.41 (m, 4H), 3.24 (m, 2H), 3.16 (m, 4H), 2.46 (m, 2H),
1.70 (m, 2H), 1.37 (s, 9H).
C1.3:
2-[8-(4-Methanesulfonyl-benzyl)-4-(1-tert-butoxycarbonyl-piperazin-4-
-yl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazol-
e-5-carboxylic acid ethyl ester
[0336] A solution of C1.2 (40 mg, 0.113 mmol, 1 eq) in DMF (1 mL)
at 0.degree. C. was treated with NaH (60% in mineral oil, 5 mg,
0.124 mmol, 1.1 eq). After stirring at 0.degree. C. for 10 min,
4-methylsulfonylbenzyl chloride (25 mg, 0.124 mmol, 1.1 eq) was
added, the reaction mixture was warmed to rt, stirred for 1.5 h and
then poured onto ice. The solid was collected by filtration, washed
with water and dried to afford (42 mg, 71% yield) a light yellow
solid. HPLC: >95% at 1.81 min (Xterra 5 .mu.m C18 column
4.6.times.30 mm, 10-90% aqueous methanol over 2 min containing 0.2%
phosphoric acid, 5 mL/min, monitoring at 254 nm).
[0337] To a mixture of this product (40 mg, 0.0766 mmol, 1 eq) and
ethyl 2-amino-4-methylthiazole-5-carboxylate (28.5 mg, 0.153 mmol,
2 eq) in N,N-dimethylacetamide (0.8 mL) in a 2-dram vial was added
tris(dibenzylideneacetone)dipalladium(0) (7 mg, 0.0077 mmol, 0.1
eq), 2-(di-t-butylphosphino)biphenyl (6.9 mg, 0.023 mmol, 0.3 eq)
and potassium phosphate (33 mg, 0.153 mmol, 2 eq). The vial was
purged with N.sub.2, sealed and heated in a 105.degree. C. oil bath
for 2.5 h. The reaction mixture was cooled to rt, filtered and
concentrated in vacuo. Column chromatography (SiO.sub.2, 60% ethyl
acetate/heptane.fwdarw.ethyl acetate) gave C1 (35 mg, 68% yield) as
a yellow solid. LC/MS: 672.44 [M+H].sup.+; HPLC: 96% at 1.87 min
(Xterra 5 .mu.m C18 column 4.6.times.30 mm, 10-90% aqueous methanol
over 2 min containing 0.2% phosphoric acid, 5 mL/min, monitoring at
254 nm). .sup.1H NMR (500 MHz, DMSO-d.sub.6): .delta. 11.26 (br s,
1H), 7.87 (d, J=8.2 Hz, 2H), 7.57 (d, J=8.2 Hz, 2H), 4.99 (s, 2H),
4.15 (q, J=6.6 Hz, 2H), 3.45 (m, 4H), 3.36 (m, 2H), 3.24 (m, 4H),
3.17 (s, 3H), 2.54 (m, 2H), 2.47 (s, 3H), 1.79 (m, 2H), 1.42 (s,
9H), 1.21 (m, 3H).
Example C2
2-[8-(4-Methanesulfonyl-benzyl)-4-piperazin-1-yl-5,6,7,8-tetrahydro-pyrido-
[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester
##STR00261##
[0339] A solution of C1 (17.6 mg, 0.026 mmol, 1 eq) in
dichloromethane (1.5 mL) was cooled to 0.degree. C. and
trifluoroacetic acid (0.2 mL) was added dropwise. The reaction
mixture was stirred at 0.degree. C. for 4.5 h and then ether (ca. 2
mL) was added. The precipitated beige solid was collected by
filtration and dried to afford C2 (7.5 mg, 42% yield) as the
trifluoroacetic acid salt. LC/MS: 572.44 [M+H].sup.+; HPLC: >95%
at 1.24 min (Xterra 5 .mu.m C18 column 4.6.times.30 mm, 10-90%
aqueous methanol over 2 min containing 0.2% phosphoric acid, 5
mL/min, monitoring at 254 nm).
Example C3-C7
##STR00262##
[0341] Example C3 was prepared in a similar manner to that used for
Example C2 utilizing dimethylamine in place of N-t-butoxycarbonyl
piperazine in step C1.1. Examples C4 to C7 were prepared in a
similar manner to that used for Example C2 utilizing the
appropriate replacement for 4-methylsulfonylbenzyl chloride in step
C1.3.
TABLE-US-00005 TABLE C1 HPLC Retention MS Ex. Z R.sup.5 Name
(min).sup.a Reported C3 ##STR00263## ##STR00264##
2-[4-Dimethylamino-8- (4-methanesulfonyl- benzyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.37 531.55 C4 ##STR00265##
##STR00266## 2-(8-Benzyl-4- piperazin-1-yl-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino)-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.55 494.35 C5 ##STR00267##
##STR00268## 2-[8-(4-Fluoro-benzyl)- 4-piperazin-1-yl-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.57 512.27 C6 ##STR00269##
##STR00270## 4-Methyl-2-[4- piperazin-1-yl-8- pyridin-3-ylmethyl-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino)-thiazole-5-
carboxylic acid ethyl ester 0.95 495.37 C7 ##STR00271##
##STR00272## 4-Methyl-2-(4- piperazin-1-yl-8-(3,4,5-
trimethoxy-benzyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 1.40 584.05 HPLC
conditions used to determine retention times: .sup.aXterra 5 .mu.m
C18 column 4.6 .times. 30 mm, 10-90% aqueous methanol over 2 min
containing 0.2% H.sub.3PO.sub.4, 5 mL/min, monitoring at 220 nm or
254 nm.
Example C8
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrah-
ydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
##STR00273##
[0342] C8.1: 2-But-3-enyl-malonic acid diethyl ester
##STR00274##
[0344] A mixture of sodium hydride (60% in mineral oil, 435 mg,
10.87 mmol, 1.1 eq) in DMF (20 mL) was treated dropwise with
diethyl malonate (1.5 mL, 9.88 mmol, 1.0 eq). The reaction mixture
was then cooled to 0.degree. C. and 4-bromo-1-butene (1.0 mL, 9.88
mmol, 1 eq) was added dropwise. The reaction mixture was warmed to
rt, stirred for 3 days and then partitioned between ether and
water. The layers were separated, the aqueous layer was extracted
with ether (2.times.50 mL) and the combined organic phases were
washed with water (2.times.) and brine, dried over MgSO.sub.4 and
concentrated. Column chromatography (SiO.sub.2, 5% ether/heptane)
gave C8.1 (1.51 g, 71% yield) as a colorless oil. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 5.77 (m, 1H), 5.00 (m, 2H), 4.13 (q,
J=7.1 Hz, 4H), 3.43 (t, J=7.4 Hz, 1H), 2.02 (m, 2H), 1.84 (m, 2H),
1.17 (t, J=7.1 Hz, 6H).
C8.2:
2-(5-But-3-enyl-4,6-dioxo-1,4,5,6-tetrahydro-pyrimidin-2-ylamino)-4--
methyl-thiazole-5-carboxylic acid ethyl ester
##STR00275##
[0346] To a solution of NaOEt in EtOH [prepared by dissolving Na
(101 mg, 4.38 mmol, 2.5 eq) in 12 mL of absolute ethanol] was added
A1.1 (400 mg, 1.75 mmol, 1 eq) and the mixture was stirred at rt
for 10 min. A solution of C8.1 (376 mg, 1.75 mmol, 1 eq) in ethanol
(5 mL) was added dropwise, the reaction mixture was heated at
reflux for 20.5 h and then cooled and poured onto a mixture of ice
and 10% aq H.sub.2SO.sub.4. The solid was collected by filtration,
washed with water and dried to afford C8.2 (430 mg, 70% yield) as a
white solid. LC/MS: 351.57 [M+H].sup.+; HPLC: >95% at 1.74 min
(Xterra 5 .mu.m C18 column 4.6.times.30 mm, 10-90% aqueous methanol
over 2 min containing 0.2% phosphoric acid, 5 mL/min, monitoring at
254 nm).
C83:
2-(5-But-3-enyl-4,6-dichloro-pyrimidin-2-ylamino)-4-methyl-thiazole-5-
-carboxylic acid ethyl ester
##STR00276##
[0348] A mixture of C8.2 (430 mg, 1.23 mmol, 1 eq) and POCl.sub.3
(4 mL) was heated in a 100.degree. C. oil bath for 28 h. The
reaction mixture was poured onto ice, neutralized with 2 N NaOH,
and extracted with ethyl acetate. The organic phase was washed with
sat. NaHCO.sub.3 and brine, dried over MgSO.sub.4 and concentrated
to afford C8.3 (383 mg, 80% yield) as a beige solid. LC/MS: 387.22
[M+H].sup.+; HPLC: >95% at 2.15 min (Xterra 5 .mu.m C18 column
4.6.times.30 mm, 10-90% aqueous methanol over 2 min containing 0.2%
phosphoric acid, 5 mL/min, monitoring at 254 nm). .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 12.65 (br s, 1H), 5.90 (m, 1H), 5.03
(m, 2H), 4.27 (q, J=7.1 Hz, 2 H), 2.85 (m, 2H), 2.54 (s, 3H), 2.31
(m, 2H), 1.29 (t, J=7.1 Hz, 3H).
C8.4:
2-[4,6-Dichloro-5-(3,4-dihydroxy-butyl)-pyrimidin-2-ylamino]-4-methy-
l-thiazole-5-carboxylic acid ethyl ester
##STR00277##
[0350] To a mixture of C8.3 (383 mg, 0.988 mmol, 1 eq) and NMO
monohydrate (267 mg, 1.976 mmol, 2 eq) in THF/water (9:1, 10 mL) at
0.degree. C. was added a solution of OsO.sub.4 in water (4 wt %,
0.61 mL, 0.0988 mmol, 0.1 eq). The reaction mixture was warmed to
rt, stirred for 16.5 h and then quenched with a solution of 300 mg
of NaHSO.sub.3 in 20 mL of water. The off-white solid was collected
by filtration, washed with water and ether, and dried to afford
C8.4 (280 mg, 67% yield). LC/MS: 421.42 [M+H].sup.+; HPLC: 96% at
1.66 min (Xterra 5 .mu.m C18 column 4.6.times.30 mm, 10-90% aqueous
methanol over 2 min containing 0.2% phosphoric acid, 5 mL/min,
monitoring at 254 nm).
C8.5:
2-[4,6-Dichloro-5-(3-oxo-propyl)-pyrimidin-2-ylamino]-4-methyl-thiaz-
ole-5-carboxylic acid ethyl ester
##STR00278##
[0352] A mixture of C8.4 (30 mg, 0.0712 mmol, 1 eq) in THF/methanol
(1:1, 1 mL) at 0.degree. C. was treated with Pb(OAc).sub.4 (35 mg,
0.0783 mmol, 1.1 eq). After 3 h at 0.degree. C., the reaction
mixture was diluted with ethyl acetate, washed with water and
brine, dried over Na.sub.2SO.sub.4 and concentrated to afford C8.5
(28 mg, quantitative yield) as a white solid. HPLC: >95% at 1.80
min (Xterra 5 .mu.m C18 column 4.6.times.30 mm, 10-90% aqueous
methanol over 2 min containing 0.2% phosphoric acid, 5 mL/min,
monitoring at 254 nm). .sup.1H NMR (400 MHz, CDCl.sub.3): .delta.
9.88 (s, 1H), 4.36 (q, J=7.1 Hz, 2H), 3.17 (m, 2H), 2.78 (m, 2H),
2.73 (s, 3H), 1.40 (t, J=7.1 Hz, 3H).
C8.6:
2-[4-Chloro-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrahydro-pyrido[2,-
3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester
##STR00279##
[0354] To a solution of C8.5 (500 mg, 1.28 mmol) in THF (14 mL),
was added 3,4,5-trimethoxybenzylamine (0.230 mL, 1.35 mmol),
Na(OAc).sub.3BH (407 mg, 1.92 mmol) and AcOH (0.073 mL, 1.28 mmol).
The reaction was stirred at room temperature for 1 hr, and then
quenched with NaHCO.sub.3 and extracted with EtOAc. The organic
layer was washed with 1N HCl and brine, dried (Na.sub.2SO.sub.4),
filtered and concentrated in vacuo to yield 641 mg (94% yield) of
C8.6 as a dark tan solid. MS, (ES), m/e: 535 (MH+). 1H NMR
(DMSO-d.sub.6): 1.11 (t, 3H, J=7.0 Hz), 1.88 (m, 2H), 2.52 (s, 3H),
2.66 (t, 2H, J=6.0 Hz), 3.40 (t, 2H, J=5.0 Hz), 3.65 (s, 2H), 3.73
(s, 9H), 4.13 (q, 2H, J=7.0 Hz), 6.69 (s, 2H), 11.7 (s, 1H).
C8.7:
2-[4-(4-Hydroxy-piperidin-1-yl)-8-(3,4,5-trimethoxy-benzyl)-5,6,7,8--
tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxyli-
c acid ethyl ester
[0355] To a solution of C8.6 (500 mg, 0.940 mmol) in n-BuOH (2 mL),
was added 4-hydroxypiperidine (208 mg, 2.1 mmol), and Hunig's base
(738 mL, 4.1 mmol). The reaction mixture was heated at 200.degree.
C. under microwave irradiation for 30 min and then diluted with
MeOH and purified by preparative HPLC to afford CS. MS, (ES), m/e:
598.73 (MH+). HPLC: 1.59 min (Phenomenex 5 .mu.m C18 column
4.6.times.30 mm, 10-90% aqueous methanol over 2 min containing 0.2%
phosphoric acid, 5 mL/min, monitoring at 254 nm).
Example C9-C82
##STR00280##
[0357] Examples C9 to C82 were prepared in a similar manner to that
used for Example C8 utilizing the appropriate amine
replacements.
TABLE-US-00006 TABLE C2 HPLC Retention MS Ex. Z R.sup.5 Name (min)
Reported C9 ##STR00281## ##STR00282## 4-Methyl-2-[4-(4-
methyl-piperazin-1-yl)- 8-(3,4,5-trimethoxy- benzyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-thiazole-5-
carboxylic acid ethyl ester 1.38.sup.a 598.55 C10 ##STR00283##
##STR00284## 2-[4-(1-carboxyethyl- piperazin-4-yl)-8-
(3,4,5-trimethoxy- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.77.sup.b 655.78 C11 ##STR00285## ##STR00286##
2-[4-(2-Acetylamino- ethylamino)-8-(3,4,5- trimethoxy-benzyl)-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.63.sup.b 599.71 C12
##STR00287## ##STR00288## 2-[4-(3-carboxyethyl- piperidin-1-yl)-8-
(3,4,5-trimethoxy- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.85.sup.b 654.79 C13 ##STR00289## ##STR00290##
4-Methyl-2-[8-(3,4,5- trimethoxy-benzyl)-4- (3,4,5-trimethoxy-
benzylamino)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 1.67.sup.a 694.81
C14 ##STR00291## ##STR00292## 4-Methyl-2-{4-(3-oxo-
piperazin-1-yl)-8-[4- (1H-tetrazol-5-yl)- benzyl]-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino}-thiazole-5-
carboxylic acid ethyl ester 1.53.sup.b 577.23 C15 ##STR00293##
##STR00294## 2-{4-(4-Hydroxy- piperidin-1-yl)-8-[4-
(1H-tetrazol-5-yl)- benzyl]-5,6,7,8- tetrahydro-pyrido[2,3- d]
pyrimidin-2- ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.55.sup.b 576.22 C16 ##STR00295## ##STR00296##
2-[4-[Ethyl-(2- methoxy-ethyl)- amino]-8-(3,4,5-
trimethoxy-benzyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.53.sup.b 600.74 C17 ##STR00297## ##STR00298## 4-Methyl-2-[4-
morpholin-4-yl-8- (3,4,5-trimethoxy- benzyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-thiazole-5-
carboxylic acid ethyl ester 1.68.sup.b 584.70 C18 ##STR00299##
##STR00300## 2-[4-(4- Hydroxymethyl- piperidin-1-yl)-8-
(3,4,5-trimethoxy- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3- d]
pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.63.sup.b 612.75 C19 ##STR00301## ##STR00302##
4-Methyl-2-[4-(3-oxo- piperazin-1-yl)-8- (3,4,5-trimethoxy-
benzyl)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 1.62.sup.b 597.70
C20 Cl ##STR00303## 2-[4-Chloro-8-(1,1,3- trioxo-2,3-dihydro-1H-
1.lamda..sup.6-benzo[d]isothiazol- 5-ylmethyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.67.sup.c 550.14 C21
##STR00304## ##STR00305## 4-Methyl-2-[4- morpholin-4-yl-8-
(1,1,3-trioxo-2,3- dihydro-1H-1.lamda..sup.6- benzo[d]isothiazol-5-
ylmethyl)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]thiazole-5- carboxylic acid ethyl ester 1.43.sup.b 600.27
C22 ##STR00306## ##STR00307## 4-Methyl-2-{8-[3- (morpholine-4-
carbonyl)-4-sulfamoyl- benzyl]-4-morpholin-4-
yl-5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino}-thiazole-5- carboxylic acid ethyl ester 1.43.sup.b 687.32
C23 ##STR00308## ##STR00309## 2-[4-(4-Hydroxy-
piperidin-1-yl)-8-(4- sulfamoyl-benzyl)- 5,6,7,8-tetrahydro-
pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.22.sup.c 588.28 C24 ##STR00310## ##STR00311##
2-[4-(2-Acetylamino- ethylamino)-8-(4- sulfamoyl-benzyl)-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.24.sup.c 589.25 C25
##STR00312## ##STR00313## 4-Methyl-2-[4- morpholin-4-yl-8-(4-
sulfamoyl-benzyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 1.46.sup.b 574.20
C26 ##STR00314## ##STR00315## 4-Methyl-2-[8-(4-
sulfamoyl-benzyl)-4- (3,4,5-trimethoxy- benzylamino)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-thiazole-5-
carboxylic acid ethyl ester 1.58.sup.b 684.22 C27 ##STR00316##
##STR00317## 4-Methyl-2-[4- methylamino-8-(4- sulfamoyl-benzyl)-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]-thiazole-5-
carboxylic acid ethyl ester 1.44.sup.b 518.19 C28 ##STR00318##
##STR00319## 4-Methyl-2-[4-(3-oxo- piperazin-1-yl)-8-(4-
sulfamoyl-benzyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 1.45.sup.b 587.15
C29 Cl ##STR00320## 2-{4-Chloro-8-[4-(5- oxo-4,5-dihydro-
[1,2,4]oxadiazol-3-yl)- benzyl]-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.76.sup.b 528.94 C30 ##STR00321## ##STR00322##
2-{4-(4-Hydroxy- piperidin-1-yl)-8-[4-(5- oxo-4,5-dihydro-
[1,2,4]oxadiazol-3-yl)- benzyl]-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.61.sup.b 593.49 C31 ##STR00323## ##STR00324## 2-[8-(4-
Ethanesulfonylamino- benzyl)-4-(3-oxo- piperazin-1-yl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.59.sup.b 614.75 C32
##STR00325## ##STR00326## 2-[4-(2-Acetylamino- ethylamino)-8-(4-
ethanesulfonylamino- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.59.sup.b 616.77 C33 ##STR00327## ##STR00328##
2-[4-(4-Hydroxy- piperidin-1-yl)-8-(4- methanesulfonylamino
carbonyl-benzyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.42.sup.c 629.76 C34 ##STR00329## ##STR00330## 2-[8-(4-
Methanesulfonylamino carbonyl-benzyl)-4-(3- oxo-piperazin-1-yl)-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.50.sup.b 628.73 C35
##STR00331## ##STR00332## 2-[4-(2-Acetylamino- ethylamino)-8-(4-
methanesulfonylamino carbonyl-benzyl)- 5,6,7,8-tetrahydro-
pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.54.sup.b 630.75 C36 ##STR00333## ##STR00334##
2-[4-(4- Hydroxymethyl- piperidin-1-yl)-8-(4- methanesulfonylamino
carbonyl-benzyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.55.sup.b 643.79 C37 ##STR00335## ##STR00336## 4-Methyl-2-(4-
morpholin-4-yl-8- pyridin-4-ylmethyl- 5,6,7,8-tetrahydro-
pyrido[2,3- d]pyrimidin-2- ylamino)-thiazole-5- carboxylic acid
ethyl ester 1.37.sup.b 495.61 C38 ##STR00337## ##STR00338##
4-Methyl-2-[4-(3-oxo- piperazin-1-yl)-8- pyridin-4-ylmethyl-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]-thiazole-5-
carboxylic acid ethyl ester 1.32.sup.b 508.61 C39 ##STR00339##
##STR00340## 2-[4-(2-Acetylamino- ethylamino)-8-pyridin-
4-ylmethyl-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.25.sup.b 510.62 C40 ##STR00341## ##STR00342## 4-Methyl-2-{4-
morpholin-4-yl-8-[4- (propane-1- sulfonylamino)- benzyl]-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino}-thiazole-5-
carboxylic acid ethyl ester 1.68.sup.b 615.78 C41 ##STR00343##
##STR00344## 2-{4-(4-Hydroxy- piperidin-1-yl)-8-[4- (propane-1-
sulfonylamino)- benzyl]-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.64.sup.b 629.81 C42 ##STR00345## ##STR00346##
4-Methyl-2-{4-(3-oxo- piperazin-1-yl)-8-[4- (propane-1-
sulfonylamino)- benzyl]-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino}-thiazole-5- carboxylic acid ethyl ester
1.66.sup.b 628.78 C43 ##STR00347## ##STR00348## 2-{4-(4-
Hydroxymethyl- piperidin-1-yl)-8-[4- (propane-1- sulfonylamino)-
benzyl]-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.68.sup.b 643.83 C44 ##STR00349## ##STR00350##
2-{4-(2-Acetylamino- ethylamino)-8-[4- (propane-1- sulfonylamino)-
benzyl]-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.66.sup.b 630.79 C45 ##STR00351## ##STR00352## 2-[8-(4-Carbamoyl-
benzyl)-4-morpholin-4- yl-5,6,7,8-tetrahydro- pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.51.sup.b 537.65 C46 ##STR00353## ##STR00354##
2-[8-(4-Carbamoyl- benzyl)-4-(3-oxo- piperazin-1-yl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.49.sup.b 550.64 C47
##STR00355## ##STR00356## 2-[4-(2-Acetylamino- ethylamino)-8-(4-
carbamoyl-benzyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.52.sup.b 552.66 C48 ##STR00357## ##STR00358## 2-[8-(4-Carbamoyl-
benzyl)-4-(4-hydroxy- piperidin-1-yl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.57.sup.b 551.67 C49
##STR00359## ##STR00360## 4-Methyl-2-[8-(4- methylsulfamoyl-
benzyl)-4-morpholin-4- yl-5,6,7,8-tetrahydro- pyrido[2,3-
d]pyrimidin-2- ylamino]-thiazole-5- carboxylic acid ethyl ester
1.55.sup.b 587.72 C50 ##STR00361## ##STR00362## 4-Methyl-2-{4-
morpholin-4-yl-8-[4- (propane-2- sulfonylamino)- benzyl]-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino}-thiazole-5-
carboxylic acid ethyl ester 1.67.sup.b 615.78 C51 ##STR00363##
##STR00364## 2-{4-(4- Hydroxymethyl- piperidin-1-yl)-8-[4-
(propane-2- sulfonylamino)- benzyl]-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.66.sup.b 643.83 C52 ##STR00365## ##STR00366##
2-{4-(2-Acetylamino- ethylamino)-8-[4- (propane-2- sulfonylamino)-
benzyl]-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino}-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.64.sup.b 630.79 C53 ##STR00367## ##STR00368##
4-Methyl-2-{4-(3-oxo- piperazin-1-yl)-8-[4- (propane-2-
sulfonylamino)- benzyl]-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino}-thiazole-5- carboxylic acid ethyl ester
1.63.sup.b 628.78 C54 ##STR00369## ##STR00370## 2-{4-(4-Hydroxy-
piperidin-1-yl)-8-[4- (propane-2- sulfonylamino)- benzyl]-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino}-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.66.sup.b 629.81 C55
##STR00371## ##STR00372## 2-[4-(4-Hydroxy- piperidin-1-yl)-8-(4-
isobutylcarbamoyl- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.68.sup.d 607.78 C56 ##STR00373## ##STR00374##
2-[4-(2-Acetylamino- ethylamino)-8-(4- isobutylcarbamoyl-
benzyl)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.73.sup.b 608.77 C57 ##STR00375## ##STR00376##
2-[4-Isobutylamino-8- (4-isobutylcarbamoyl- benzyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.88.sup.b 579.77 C58
##STR00377## ##STR00378## 2-[8-(4- Isobutylcarbamoyl-
benzyl)-4-morpholin-4- yl-5,6,7,8-tetrahydro- pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.74.sup.b 593.75 C59 ##STR00379## ##STR00380## 2-[8-(4-
Ethanesulfonylamino-
benzyl)-4-(4-hydroxy- piperidin-1-yl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.61.sup.b 615.78 C60
##STR00381## ##STR00382## 2-[8-(4- Ethanesulfonylamino-
benzyl)-4-morpholin-4- yl-5,6,7,8-tetrahydro- pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.63.sup.b 601.75 C61 ##STR00383## ##STR00384## 2-[8-(4-
Ethanesulfonylamino- benzyl)-4- isobutylamino-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.81.sup.b 587.77 C62
##STR00385## ##STR00386## 2-[8-(4- Ethanesulfonylamino-
benzyl)-4-(3,4,5- trimethoxy- benzylamino)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.72.sup.b 711.87 C63
##STR00387## ##STR00388## 2-(4-Isobutylamino-8- pyridin-4-ylmethyl-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino)-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.50.sup.b 481.62 C64
##STR00389## ##STR00390## 2-[4-(4-Hydroxy- piperidin-1-yl)-8-(6-
trifluoromethyl- pyridin-3-ylmethyl)- 5,6,7,8-tetrahydro-
pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.76.sup.b 578.71 C65 ##STR00391## ##STR00392##
2-[4-(2-Acetylamino- ethylamino)-8-(6- trifluoromethyl-
pyridin-3-ylmethyl)- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.68.sup.b 579.15 C66 ##STR00393## ##STR00394## 2-[8-{4-[Ethyl-(2-
hydroxy-ethyl)- carbamoyl]-benzyl}-4- (3-hydroxy-pyrrolidin-
1-yl)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.47.sup.b 609.75 C67 ##STR00395## ##STR00396## 2-[8-{4-[Ethyl-(2-
hydroxy-ethyl)- carbamoyl]-benzyl}-4- (3,4,5-trimethoxy-
benzylamino)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.58.sup.c 719.87 C68 ##STR00397## ##STR00398##
2-(4-(2-Acetylamino- ethylamino)-8-{4- [ethyl-(2-hydroxy-
ethyl)-carbamoyl]- benzyl}-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino)-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.48.sup.c 624.77 C69 ##STR00399## ##STR00400##
2-(8-{4-[Ethyl-(2- hydroxy-ethyl)- carbamoyl]-benzyl}-4-
isobutylamino-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino)-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.62.sup.b 595.77 C70 ##STR00401## ##STR00402## 2-(4-[Ethyl-(2-
hydroxy-ethyl)-amino]- 8-{4-[ethyl-(2- hydroxy-ethyl)-
carbamoyl]-benzyl}- 5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2-
ylamino)-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.58.sup.b 611.77 C71 ##STR00403## ##STR00404## 2-(8-{4-[Ethyl-(2-
hydroxy-ethyl)- carbamoyl]-benzyl}-4- morpholin-4-yl-
5,6,7,8-tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino)-4-methyl-
thiazole-5-carboxylic acid ethyl ester l.58.sup.b 609.75 C72
##STR00405## ##STR00406## 2-[8-{4-[Ethyl-(2- hydroxy-ethyl)-
carbamoyl]-benzyl}-4- (3-oxo-piperazin-1-yl)- 5,6,7,8-tetrahydro-
pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.57.sup.b 622.75 C73 ##STR00407## ##STR00408##
2-[4-(4-Hydroxy- piperidin-1-yl)-8-(4- methylsulfamoyl-
benzyl)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.51.sup.b 601.75 C74 ##STR00409## ##STR00410## 2-[8-[4-(1,1-Dioxo-
1.lamda..sup.6-thiomorpholine-4- carbonyl)-benzyl]-4-(4-
hydroxy-piperidin-1- yl)-5,6,7,8-tetrahydro- pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.49.sup.b 669.83 C75 ##STR00411## ##STR00412##
4-Methyl-2-[8-(4- methylsulfamoyl- benzyl)-4-(3-oxo-
piperazin-1-yl)-5,6,7,8- tetrahydro-pyrido[2,3- d] pyrimidin-2-
ylamino]-thiazole-5- carboxylic acid ethyl ester 1.54.sup.b 600.72
C76 ##STR00413## ##STR00414## 2-[4-(1- Hydroxymethyl-2-
methyl-propylamino)- 8-(4-methylsulfamoyl- benzyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.68.sup.b 603.77 C77
##STR00415## ##STR00416## 2-[4-(2-Acetylamino- ethylamino)-8-(4-
methylsulfamoyl- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.55.sup.b 602.74 C78 ##STR00417## ##STR00418##
2-[4-(2-Hydroxy- ethylamino)-8-(4- methylsulfamoyl-
benzyl)-5,6,7,8- tetrahydro-pyrido[2,3- d]pyrimidin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.51.sup.b 561.69 C79 ##STR00419## ##STR00420## 2-[4-[Ethyl-(2-
hydroxy-ethyl)-amino]- 8-(4-methylsulfamoyl- benzyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.53.sup.b 589.74 C80
##STR00421## ##STR00422## 2-[4-(4-Carbamoyl- piperidin-1-yl)-8-(4-
methylsulfamoyl- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.47.sup.d 628.78 C81 ##STR00423## ##STR00424## 2-[4-(3-
Dimethylamino- propylamino)-8-(4- methylsulfamoyl- benzyl)-5,6,7,8-
tetrahydro-pyrido[2,3- d]pyrimidin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.42.sup.b 602.78 C82
##STR00425## ##STR00426## 2-[4-(3-Hydroxy- pyrrolidin-1-yl)-8-(4-
methylsulfamoyl- benzyl)-5,6,7,8- tetrahydro-pyrido[2,3-
d]pyrimidin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl
ester 1.48.sup.b 587.72 HPLC conditions used to determine retention
times: .sup.aXterra 5 .mu.m C18 column 4.6 .times. 30 mm, 10-90%
aqueous methanol over 2 min containing 0.2% H.sub.3PO.sub.4, 5
mL/min, monitoring at 220 nm or 254 nm. .sup.bPhenomenex 5 .mu.m
C18 column 4.6 .times. 30 mm, 10-90% aqueous methanol over 2 min
containing 0.2% H.sub.3PO.sub.4, 5 mL/min, monitoring at 220 nm or
254 nm. .sup.cYMC CombiScreen 5 .mu.m C18 column 4.6 .times. 50 mm,
10-90% aqueous methanol over 4 min containing 0.1% TFA, 4 mL/min,
monitoring at 220 nm or 254 nm. .sup.dPhenomenex 5 .mu.m C18 column
4.6 .times. 30 mm, 10-90% aqueous methanol over 2 min containing
0.1% TFA, 5 mL/min, monitoring at 220 nm or 254 nm
Example C83
4-Methyl-2-(4-morpholin-4-yl-8-(2-sulfamoylamino
-ethyl)-5,6,7,8-tetrahydro
pyrido[2,3-d]pyrimidin-2-ylamino)-thiazole-5-carboxylie acid ethyl
ester
##STR00427##
[0358] C83.1:
2-[8-(2-tert-Butoxycarbonylamino-ethyl)-4-chloro-5,6,7,8-tetrahydro-pyrid-
o[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid
ethyl ester
##STR00428##
[0360] Intermediate C83.1 was prepared in an analogous manner to
C8.6 with the exception that 3,4,5-trimethoxybenzylamine was
replaced by t-butyl N-(2-aminoethyl)carbamate. HPLC: >95%
(Phenomenex 5 .mu.m C18 column 4.6.times.30 mm, 10-90% aqueous
methanol over 2 min containing 0.1% TFA, 5 mL/min, monitoring at
254 nm) ret. time=1.43 min., LC/MS (M+H)=498.16.
C83.2: 2-[8-(2-amino-ethyl)-4-chloro-5,6,7,8-tetrahydro-pyrido
ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester
##STR00429##
[0362] Trifluoroacetic acid (20% solution in dichloromethane, 10
mL) was added in one portion to C83.1 (250 mg, 0.42 mmol) at room
temperature under a nitrogen atmosphere. After stirring overnight,
toluene (1 mL) was added and the solution was concentrated in
vacuo. Two subsequent additions of toluene (2.times.5 mL) followed
by concentration in vacuo left the crude trifluoroacetie acid salt
of C83.2 as a yellow residue (210 mg, 98%), which was used
immediately without characterisation.
C83.3: 2-[8-(2-t-Butoxycarbonyl sulfamoylamino-ethyl)
4-chloro-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-th-
iazole-5-carboxylic acid ethyl ester
##STR00430##
[0364] Chlorosulfonyl isocyanate (0.076 mL, 0.87 mmol) was
dissolved in dry dichloromethane (5 mL) and cooled in an ice-bath,
and tert-butyl alcohol (0.064 g, 0.87 mmol) added dropwise. This
solution was allowed to stir for 1 hr and was then added to a
mixture of the TFA salt of C83.2 (0.39 g, 0.79 mmol) and
triethylamine (0.24 mL, 1.7 mmol) in THF (10 mL) under a nitrogen
atmosphere. After stirring at room temperature overnight, the
reaction mixture was quenched by the addition of water (10 mL). The
aqueous phase was extracted with ethyl acetate (3.times.15 mL), and
the combined organics were then dried (MgSO.sub.4) and evaporated
in vacuo. The crude product was purified by column chromatography
using 1:1 hexane:ethyl acetate as eluent to give C83.3 (0.26 g,
56%) as a white solid. .sup.1H-NMR (DMSO-d.sub.6) .delta.: 4.23
(2H, q, J=8 Hz), 3.78-3.69 (2H, m), 3.50-3.36 (4H, m), 2.64-2.58
(2H, m), 2.56 (3H, s), 1.56-1.43 (2H, m), 1.39 (9H, s), 1.35 (3H,
t, J=8 Hz). HPLC: 95%, ret. time=1.627 min., LC/MS
(M+H).sup.+=577.17.
C83.4:
2-[4-Chloro-8-(2-sulfamoylamino-ethyl)-5,6,7,8-tetrahydro-pyrido[2,-
3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester
##STR00431##
[0366] Trifluoroacetic acid (20% solution in dichloromethane, 10
mL) was added in one portion to C83.3 (100 mg, 0.17 mmol) at room
temperature under a nitrogen atmosphere. After stirring overnight,
toluene (1 mL) was added and the solution was concentrated in
vacuo. Two subsequent additions of toluene (2.times.5 mL) followed
by concentration in vacuo left the crude trifluoroacetic acid salt
of C83.4 as a white residue (98 mg, 100%). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 4.23 (2H, q, J=8 Hz), 3.90-3.84 (2H, m),
3.50-3.46 (2H, m), 3.44-3.40 (2H, m), 2.64-2.58 (2H, m), 2.56 (3H,
s), 1.56-1.43 (2H, m), 1.35 (3H, t, J=8 Hz). HPLC: 95%, ret.
time=1.432 min., LC/MS (M+H).sup.+=476.14.
C83.5:
4-Methyl-2-(4-morpholin-4-yl-8-(2-sulfamoylamino-ethyl)-5,6,7,8-tet-
rahydro-pyrido[2,3-d]pyrimidin-2-ylamino)-thiazole-5-carboxylic
acid ethyl ester
[0367] Example C83 was prepared in an analogous manner to Example
C8 from intermediate C83.4 and morpholine. HPLC: ret. time=1.63
min. (Phenomenex 5 .mu.m C18 column 4.6.times.30 mm, 10-90% aqueous
methanol over 2 min containing 0.2% H.sub.3PO.sub.4, 5 mL/min,
monitoring at 220 nm or 254 nm), LC/MS (M+H).sup.+=527.72.
Example C84-C86
##STR00432##
[0369] Examples C84 to C86 were prepared in a similar manner to
that used for Example C83 utilizing the appropriate amine
replacement for morpholine in step C83.5.
TABLE-US-00007 TABLE C3 HPLC Retention MS Ex. Z Name (min).sup.a
Reported C84 ##STR00433## 2-[4-(2- Acetylamino- ethyl- amino)-8-(2-
sulfa- moylamino- ethyl)- 5,6,7,8- tetrahydro- pyrido[2,3-
d]pyrimidin-2- ylamino]-4-me thyl-thiazole-5- carboxylic acid ethyl
ester 1.57 542.71 C85 ##STR00434## 4-Methyl-2- [4-(3-oxo-
piperazin-1- yl)-8-(2- sulfa- moylamino- ethyl)- 5,6,7,8-
tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]- thiazole-5-
carboxylic acid ethyl ester 1.58 540.73 C86 ##STR00435## 2-[4-(4-
Hydroxy- piperidin-1- yl)-8-(2- sulfa- moylamino- ethyl)- 5,6,7,8-
tetrahydro- pyrido[2,3- d]pyrimidin-2- ylamino]-4- methyl-
thiazole-5- carboxylic acid ethyl ester 1.56 541.74
.sup.aPhenomenex 5 .mu.m C18 column 4.6 .times. 30 mm, 10-90%
aqueous methanol over 2 min containing 0.2% H.sub.3PO.sub.4, 5
mL/min, monitoring at 220 nm or 254 nm
Example D1
2-[8-(4-Methanesulfonyl-benzyl)-4-(3-oxo-piperazin-1-yl)-6,7-dihydro-pyrim-
ido[5,4-b][1,4]oxazin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
##STR00436##
[0370] D1.1: 2-Diazo-malonic acid diethyl ester
##STR00437##
[0372] A solution of diethylmalonate (13.9 g, 87 mmol) in
acetonitrile (150 ml) at 0-5.degree. C. was added triethylamine
(10.5 g, 104 mmol), followed by tosyl azide (20.5 g, 104 mmol) in
acetonitrile (100 ml). The reaction mixture was warmed up to room
temperature and stirred for 16 hours which was concentrated to
afford a crude product. It was diluted with diethyl ether (100 ml)
and stirred for 10 minutes. The white solid was removed with
filtration. The organic phase was washed with 1 N NaOH solution (50
ml), water (50 ml), brine (50 ml), and dried over sodium sulfate.
The solution was filtered through florisil and concentrated in
vacuo. The crude product mixture was purified by silica gel column
chromatography with hexanes:EtOAc (100:15) to yield D1.1 (16.38 g,
100%). .sup.1H-NMR (CDCl.sub.3) .delta.: 4.35 (4H, q, J=7 Hz), 1.37
(3H, t, J=7 Hz). HPLC: 92.6%, ret. time=2.220 min., LC/MS
(M+H).sup.+=187.
D1.2: 2-(2,2-Diethoxy-ethoxy)-malonic acid diethyl ester
##STR00438##
[0374] A solution of D1.1 (16.3 g, 87.5 mmol), glycoldehyde diethyl
acetal (10.2 g, 76.2 mmol) and rhodium(II) acetate dimer (0.674 g,
1.52 mmol) in toluene (250 ml) was heated to 65.degree. C. for 2
hours and then it was cooled to room temperature. The catalyst was
removed by filtration. The filtrate was concentrated to yield a
crude product which was purified by silica gel column
chromatography with hexanes:
[0375] EtOAc (7:3) to yield D1.2 (14.86 g, 67%). .sup.1H-NMR
(CDCl.sub.3) .delta.: 4.79 (1H, s), 4.77 (1H, t, J=5 Hz), 4.30-4.40
(4H, m), 3.75-3.84 (4H, m), 3.61-3.69 (2H, m), 1.38 (6H, t, J=7
Hz), 1.30 (6H, t, J=7 Hz).
D1.3:
2-[5-(2,2-Diethoxy-ethoxy)-4,6-dihydroxy-pyrimidin-2-ylamino]-4-meth-
yl-thiazole-5-carboxylic acid ethyl ester
##STR00439##
[0377] Sodium (2.23 g, 97 mmol) in ethanol (170 ml) was stirred at
room temperature until the sodium dissolved. The reaction mixture
was treated with A1.1 (7.37 g, 32.3 mmol), followed by D1.2 (11.8
g, 40.4 mmol) and then heated at 100.degree. C. for 3 hours. The
reaction mixture was cooled to RT and the solid was collected by
filtration to afforded D1.3 (14.8 g, 100%). LC/MS
(M+H).sup.+=429.31.
D1.4:
2-[4,6-Dichloro-5-(2,2-diethoxy-ethoxy)-pyrimidin-2-ylamino]-4-methy-
l-thiazole-5-carboxylic acid ethyl ester
##STR00440##
[0379] To a solution of diisopropylethylamine (5.46 g, 42 mmol) in
POCl.sub.3 (12 ml) at 0-5.degree. was added D1.3 (6 g, 14 mmol) in
portions. The reaction mixture was warmed up to room temperature
and then it was heated to 100.degree. C. for 90 minutes. The
reaction mixture was distilled to remove POCl.sub.3 to yield a dark
crude product which was added to ice water (100 ml) and neutralized
with 1 N NaOH to pH 7. The solid was collected to afford D1.4 (4.97
g, 76%). HPLC: 90%, ret. time=4.230 min., LC/MS
(M+H).sup.+=465.07.
D1.5:
2-[4-Chloro-7-hydroxy-8-(4-methanesulfonyl-benzyl)-6,7-dihydro-pyrim-
ido[5,4-b][1,4]oxazin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
##STR00441##
[0381] A solution of D1.4 (90 mg, 0.194 mmol),
4-methylsulfonylbenzylamine.cndot.HCl (45.3 mg, 0.194 mmol) and
diisopropylethylamine (56.2 mg, 0.388 mmol) in
N-methyl-2-pyrrolidinone (0.5 ml) was heated to 120.degree. C. for
15 minutes under microwave irradiation and then it was cooled down
to RT. The reaction mixture was treated with 1N HCl solution (0.225
ml, 0.25 mmol), heated to 120.degree. C. for 15 minutes under
microwave irradiation and then it was neutralized with saturated
NaHCO.sub.3 solution and diluted with water (5 ml). The solid was
collected by filtration to yield D1.5 (89 mg, 85%). .sup.1H-NMR
(DMSO-d.sub.6) .delta.: 11.74 (1H, s), 7.79 (2H, d, J=8 Hz), 7.58
(2H, d, J=8 Hz), 6.73 (1H, d, J=7 Hz), 5.27 (1H, d, J=16 Hz), 5.02
(1H, d, J=7H, z), 4.82 (1H, d, J=16 Hz), 4.05-4.22 (4H, m), 3.11
(3H, s), 2.40 (3H, s), 1.12 (3H, t, J=7 Hz). HPLC: 87.4%, ret.
time=3.120 min., LC/MS (M+H).sup.+=540.02.
D1.6:
2-[4-Chloro-8-(4-methanesulfonyl-benzyl)-6,7-dihydro-pyrimido[5,4-b]-
[1,4]oxazin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester
##STR00442##
[0383] A solution of D1.5 (88 mg, 0.163 mmol) and sodium
cyanoborohydride (105 mg, 1.59 mmol) in acetic acid (5 ml) was
stirred at RT for three days. The reaction mixture was concentrated
to yield a crude product which was treated with water (5 ml) and
stirred for 5 minutes. The solid was collected by filtration to
afford D1.6 (79.5 mg, 93%). .sup.1H-NMR (DMSO-d.sub.6) .delta.:
11.71 (1H, s), 7.83 (2H, d, J=8 Hz), 7.56 (2H, d, J=8 Hz), 7.28
(2H, s), 5.03 (1H, s), 4.19-4.25 (2H, m), 4.07 (2H, q, J=7 Hz),
3.52-3.58 (2H, m), 3.12 (3H, s), 2.40 (3H, s), 1.08 (3H, t, J=7
Hz). HPLC: 80%, ret. time=3.367 min., LC/MS (M+H).sup.+=524.01.
D1.7:
2-[8-(4-Methanesulfonyl-benzyl)-4-(3-oxo-piperazin-1-yl)-6,7-dihydro-
-pyrimido[5,4-b][1,4]oxazin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
[0384] A solution of D1.6 (20 mg, 0.0381 mmol), piperazin-2-one (16
mg, 0.159 mmol) and diisopropylethylamine (20.4 mg, 0.159 mmol) in
N-methyl-2-pyrrolidinone (0.5 ml) was heated to 220.degree. C. for
20 minutes under microwave irradiation and then it was cooled down
to RT. The reaction mixture was purified by preparative HPLC to
yield D1 (13 mg, 58%). .sup.1H-NMR (DMSO-d.sub.6) .delta.: 11.14
(1H, s), 7.85 (1H, s), 7.73 (2H, d, J=8 Hz), 7.44 (2H, d, J=8 Hz),
4.84 (2H, s), 3.94-4.04 (6H, m), 3.64-3.70 (2H, m), 3.33-3.37 (2H,
m), 3.11-3.17 (2H, m), 3.03 (3H, s), 2.31 (3H, s), 1.02 (3H, t, J=7
Hz). HPLC: >97%, ret. time=3.117 min., LC/MS
(M+H).sup.+=588.07.
Example D2 to D7
[0385] Examples D2 to D7 were prepared in a similar manner to that
used for Example D1 utilizing the appropriate amine
replacements.
##STR00443##
TABLE-US-00008 TABLE D HPLC MS Retention Reported Ex Z R.sup.5 Name
(min).sup.a (M + H).sup.+ D2 ##STR00444## ##STR00445##
4-Methyl-2-[4-morpholin- 4-yl-8-(3,4,5-trimethoxy-
benzyl)-6,7-dihydro- pyrimido[5,4- b][1,4]oxazin-2-ylamino]-
thiazole-5-carboxylic acid ethyl ester 3.65 587.16 D3 ##STR00446##
##STR00447## 4-Methyl-2-[4-morpholin- 4-yl-8-(4-sulfamoyl-
benzyl)-6,7-dihydro- pyrimido[5,4- b][1,4]oxazin-2-ylamino]-
thiazole-5-carboxylic acid ethyl ester 3.68 576.09 D4 ##STR00448##
##STR00449## 2-[4-(4-Hydroxy- piperidin-1-yl)-8-(4-
sulfamoyl-benzyl)-6,7- dihydro-pyrimido[5,4-
b][1,4]oxazin-2-ylamino]- 4-methyl-thiazole-5- carboxylic acid
ethyl ester 2.95 590.08 D5 ##STR00450## ##STR00451##
4-Methyl-2-[4-(3-oxo- piperazin-1-yl)-8-(4- sulfamoyl-benzyl)-6,7-
dihydro-pyrimido[5,4- b][1,4]oxazin-2-ylamino]-
thiazole-5-carboxylic acid ethyl ester 3.01 589.08 D6 ##STR00452##
##STR00453## 2-[8-(4-Methanesulfonyl- benzyl)-4-morpholin-4-yl-
6,7-dihydro-pyrimido[5,4- b][1,4] oxazin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 3.39 575.09 D7 ##STR00454##
##STR00455## 2-[4-(4-Hydroxy- piperidin-1-yl)-8-(4-
methanesulfonyl-benzyl)- 6,7-dihydro-pyrimido[5,4- b][1,4]
oxazin-2- ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
3.08 589.10 .sup.aYMC CombiScreen 5 .mu.m C18 column 4.6 .times. 50
mm, 10-90% aqueous methanol over 4 min containing 0.1% TFA, 4
mL/min, monitoring at 220 nm or 254 nm
Example E1
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrah-
ydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
##STR00456##
[0386] E1.1: 2-Pent-4-enyl-malonic acid diethyl ester
##STR00457##
[0388] A mixture of sodium hydride (60% in mineral oil, 2.4 g, 60.5
mmol, 1.1 eq) and diethyl malonate (8.34 mL, 55 mmol, 1 eq) in DMF
(200 mL) was cooled to 0.degree. C. and 5-bromo-1-pentene (6.5 mL,
55 mmol, 1 eq) was added dropwise. The reaction mixture was warmed
to rt, stirred for 14 hours and then partitioned between ether and
water. The layers were separated, the aqueous layer was extracted
with ether (2.times.250 mL) and the combined organic phases were
washed with water (2.times.) and brine, dried over MgSO.sub.4 and
concentrated to give E1.1 as a colorless oil (12.7 g, 100% yield).
.sup.1H NMR (400 MHz, CDCl.sub.3): .delta. 5.71 (m, 1H), 4.92 (m,
2H), 4.12 (q, J=7.1 Hz, 4H), 3.25 (t, J=7.58 Hz, 1H), 2.01 (m, 2H),
1.83 (m, 2H), 1.36 (m, 2H), 1.20 (t, J=7.1 Hz, 6H).
E1.2:
2-(4,6-Dichloro-5-pent-4-enyl-pyrimidin-2-ylamino)-4-methyl-thiazole-
-5-carboxylic acid ethyl ester
##STR00458##
[0390] To a solution of NaOEt in EtOH [prepared by dissolving Na
(1.61 g, 70 mmol, 3.5 eq) in 150 mL of absolute ethanol] was added
dropwi se E1.1 (5.0 g, 22 mmol, 1.1 eq) and the mixture was stirred
at rt for 1 h. A1.1 (4.54 g, 20 mmol, 1 eq) was added, the reaction
mixture was heated at reflux for 16 h and then cooled, concentrated
to 1/3 of the original volume, diluted with water (200 mL) and
acidified with acetic acid. After stirring for 1 h, the solid was
collected by filtration, washed with water and dried to afford a
light pink solid. The resulting solid was suspended in phosphorous
oxychloride (25 mL) and stirred at 95.degree. C. for 2 hours. The
reaction mixture was poured onto ice, neutralized with NaOH
(pellets) and the solid was collected by filtration and vacuum
dried to afford E1.2 as a light brown solid (5.83 g, 66% yield).
LC/MS: 401 [M+H].sup.+.
E1.3:
2-[4,6-Dichloro-5-(4-oxo-butyl)-pyrimidin-2-ylamino]-4-methyl-thiazo-
le-5-carboxylic acid ethyl ester
##STR00459##
[0392] To a mixture of E1.2 (2.0 g, 4.98 mmol, 1 eq) and NMO (1.16
g, 9.97 mmol, 2 eq) in THF/water (3:2, 60 mL) at 0.degree. C. was
added a solution of OsO.sub.4 in 2-methyl-2-propanol (2.5 wt %, 2.0
mL, 0.19 mmol, 0.04 eq). The reaction mixture was warmed to rt,
stirred for 168 h and then quenched with a solution of 500 mg of
NaHSO.sub.3 in 30 mL of water, extracted with AcOEt and dried with
MgSO.sub.4. The resulting brown solid was disolved in THF:MeOH
(1:1, 60 mL), cooled to 0.degree. C. and treated with Pb(0Ac).sub.4
(1.87 g, 4.21 mmol, 1.1 eq). The resulting mixture was warmed to
23.degree. C. and stirred 18 h, then diluted with ethyl acetate,
washed with water and brine, dried over MgSO.sub.4 and
concentrated. The residue was purified by flash chromatography
(hexane/ethyl acetate 30% to 50%) to yield E1.3 as a white solid
(422 mg, 10% yield). .sup.1H NMR (400 MHz, DMSO-d.sub.6): .delta.
9.50 (s, 1H), 4.07 (q, J=7.1 Hz, 2H), 2.58 (m, 2H), 2.39 (m, 2H),
2.35 (s, 3H), 1.61 (m, 2H), 1.09 (t, J=7.1 Hz, 3H). LC/MS: 403
[M+H].sup.+.
E1.4:
2-[4-Chloro-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrahydro-pyrimido[-
4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl
ester
##STR00460##
[0394] To a solution of E1.3 (27 mg, 0.067 mmol, 1.0 eq) and acetic
acid (4 .mu.L, 0.067 mmol, 1.0 eq) in THF (3 mL), was added
3,4,5-trimethoxybenzylamine (14 mg, 0.070 mmol, 1.05 eq) and the
mixture was stirred for 15 min. Then Na(OAc).sub.3BH (21 mg, 0.1
mmol, 1.5 eq) was added and the reaction was stirred at room
temperature. After 45 min, it was quenched with NaHCO.sub.3 and
extracted with EtOAc, dried MgSO.sub.4 and concentrated in vacuo to
yield E1.4 (37 mg, 100% yield) as a white solid. .sup.1H NMR (400
MHz, DMSO-d.sub.6): .delta. 11.7 (s, 1H), 6.62 (s, 2H), 4.81 (br s,
2H), 4.04 (q, 2H, J=7.1 Hz), 3.65 (s, 6H), 3.56 (s, 3H), 3.46 (m,
2H), 2.79 (m, 2H), 2.42 (s, 3H), 1.78 (m, 2H), 1.67 (m, 2H), 1.06
(t, 3H, J=7.1 Hz). LC/MS: 548 [M+H].sup.+.
E1.5:
2-[4-(4-Hydroxy-piperidin-1-yl)-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8--
tetrahydro-pyrimido[4,5-b]azepin-2-ylamino]-4-methyl-thiazole-5-carboxylic
acid ethyl ester
[0395] To a solution of E1.4 (30 mg, 0.055 mmol, 1.0 eq) in NMP
(1.5 mL), was added 4-hydroxypiperidine (6.6 mg, 0.066 mmol, 1.2
eq), and triethylamine (10 .mu.L). The reaction mixture was stirred
at 100.degree. C. for 7 h and then acidified with acetic acid,
purified by Prep HPLC (acetonitrile/water/5 mM ammonium acetate,
column Primesphere C18 21.times.100 mm) and freeze dried to give E1
as a white solid (18 mg, 55% yield). .sup.1H NMR (400 MHz,
DMSO-d.sub.6): .delta. 11.17 (s, 1H), 6.67 (s, 2H), 4.68 (br s,
2H), 4.66 (d, 1H, J=4.3 Hz) 4.07 (q, 2H, J=7.0 Hz), 3.66 (s, 6H),
3.61 (m, 3H), 3.56 (s, 3H), 3.37 (m, 1H), 2.95 (m, 2H), 2.48 (m,
2H), 2.42 (s, 3H), 1.75 (m, 2H), 1.65 (m, 4H), 1.42 (m, 2H), 1.12
(t, 3H, J=7.0 Hz), HPLC: 100%, ret. time=2.017 min.
(Acetonitrile/water/5 mM ammonium acetate, column Primesphere C18
4.6.times.30 mm), LC/MS: 613 [M+H].sup.+.
Example E2-E32
##STR00461##
[0397] Examples E2 to E32 were prepared in a similar manner to that
used for Example E1 utilizing the appropriate amine
replacements.
TABLE-US-00009 TABLE E HPLC MS Retention Reported Ex. Z R.sup.5
Name (min) (M + H).sup.+ E2 ##STR00462## ##STR00463##
2-[4-(4-Hydroxy- piperidin-1-yl)-9-(4- sulfamoyl-benzyl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.68.sup.a 602 E3
##STR00464## ##STR00465## 2-[9-(2- Diisopropylamino-ethyl)-
4-(4-hydroxy-piperidin-1- yl)-5,6,7,8-tetrahydro-
pyrimido[4,5-b]azepin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.71.sup.a 560 E4 ##STR00466## ##STR00467##
2-[4-(4-Hydroxy- piperidin-1-yl)-9-(5- methyl-furan-2-ylmethyl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-5-carboxylic
acid ethyl ester 1.95.sup.a 527 E5 ##STR00468## ##STR00469##
2-[9-[2-(4-Chloro- phenyl)-ethyl]-4-(4- hydroxy-piperidin-1-yl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino}-4-methyl-
thiazole-5-carboxylic acid ethyl ester 2.12.sup.a 571 E6
##STR00470## ##STR00471## 2-{4-(4-Hydroxy- piperidin-1-yl)-9-[2-(4-
methoxy-phenyl)-ethyl]- 5,6,7,8-tetrahydro-
pyrimido[4,5-b]azepin-2- ylamino}-4-methyl thiazole-5-carboxylic
acid ethyl ester 2.00.sup.a 567 E7 ##STR00472## ##STR00473##
2-[4-(4-Hydroxy- piperidin-1-yl)-9-indan-1- yl-5,6,7,8-tetrahydro-
pyrimido[4,5-b]azepin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 2.07.sup.a 549 E8 ##STR00474## ##STR00475##
2-[4-(4-Hydroxy- piperidin-1-yl)-9-(4-nitro- benzyl)-5,6,7,8-
tetrahydro-pyrimido[4,5- b]azepin-2-ylamino]-4- methyl-thiazole-5-
carboxylic acid ethyl ester 1.92.sup.a 568 E9 ##STR00476##
##STR00477## 2-[9-Cyclohexylmethyl-4- (4-hydroxy-piperidin-1-
yl)-5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 2.16.sup.a 529 E10
##STR00478## ##STR00479## 2-[4-(4-Hydroxy- piperidin-1-yl)-9-
phenethyl-5,6,7,8- tetrahydro-pyrimido[4,5- b]azepin-2-ylamino]-4-
methyl-thiazole-5- carboxylic acid ethyl ester 1.80.sup.b 537 E11
##STR00480## ##STR00481## 2-[4-(4-Hydroxy- piperidin-1-yl)-9-(4-
methanesulfonyl-benzyl)- 5,6,7,8-tetrahydro-
pyrimido[4,5-b]azepin-2- ylamino]-4-methyl- thaizole-5-carboxylic
acid ethyl ester 1.74.sup.a 601 E12 ##STR00482## ##STR00483##
2-[4-(4-Hydroxy- piperidin-1-yl)-9- (tetrahydro-furan-2-yl-
methyl)-5,6,7,8- tetrahydro-pyrimido[4,5- b]azepin-2-ylamino]-4-
methyl-thiazole-5- carboxylic acid ethyl ester 1.81.sup.a 517 E13
##STR00484## ##STR00485## 2-[9-(4-Hydroxy-
cyclohexyl)-4-(4-hydroxy- piperidin-1-yl)-5,6,7,8-
tetrahydro-pyrimido[4,5- b]azepin-2-ylamino]-4- methyl-thiazole-5-
carboxylic acid ethyl ester 1.61.sup.a 531 E14 ##STR00486##
##STR00487## 2-[9-Furan-2-yl-methyl-4- (4-hydroxy-piperidin-1-
yl)-5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid 1.88.sup.a 513 E15 ##STR00488##
##STR00489## 2-[9-Cyclohexyl-4-(4- hydroxy-piperidin-1-yl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 2.10.sup.a 515 E16
##STR00490## ##STR00491## 2-[4-(4-Hydroxy- piperidin-1-yl)-9-(2-
methoxy-ethyl)-5,6,7,8- tetrahydro-pyrimido[4,5-
b]azepin-2-ylamino]-4- methyl-thiazole-5- carboxylic acid ethyl
ester 1.75.sup.a 491 E17 ##STR00492## ##STR00493## 2-[4-(4-Hydroxy-
piperidin-1-yl)-9- thiophen-2-yl-methyl 5,6,7,8-tetrahydro-
pyrimido[4,5-b]azepin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.67.sup.b 529 E18 ##STR00494## ##STR00495##
2-[4-(4-Hydroxy- piperidin-1-yl)-9-(3- morpholin-4-yl-propyl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.22.sup.b 560 E19
##STR00496## ##STR00497## 4-Methyl-2-[4-morpholin-
4-yl-9-(4-sulfamoyl- benzyl)-5,6,7,8- tetrahydro-pyrimido[4,5-
b]azepin-2-ylamino]- thiazole-5-carboxylic acid ethyl ester
1.55.sup.b 588 E20 ##STR00498## ##STR00499## 4-Methyl-2-[9-(4-
sulfamoyl-benzyl)-4- thiomorpholin-4-yl- 5,6,7,8-tetrahydro-
pyrimido[4,5-b]azepin-2- ylamino]-thiazole-5- carboxylic acid ethyl
ester 1.72.sup.b 604 E21 ##STR00500## ##STR00501##
2-[4-(3-Hydroxymethyl- piperidin-1-yl)-9-(4- sulfamoyl-benzyl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.52.sup.b 616 E22
##STR00502## ##STR00503## 2-[4-(2,6-Dimethyl- morpholin-4-yl)-9-(4-
sulfamoyl-benzyl)- 5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.74.sup.b 616 E23 ##STR00504## ##STR00505## 2-[4-(4-Acetyl-
[1,4]diazepan-1-yl)-9-(4- sulfamoyl-benzyl)- 5,6,7,8-tetrahydro-
pyramido[4,5-b]azepin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.69.sup.b 643 E24 ##STR00506## ##STR00507##
4-Methyl-2-[9-(4- sulfamoyl-benzyl)-4- (3,4,5-trimethoxy-
benzylamino)-5,6,7,8- tetrahydro-pyramido[4,5- b]azepin-2-ylamino]-
thiazole-5-carboxylic acid ethyl ester 1.66.sup.b 698 E25
##STR00508## ##STR00509## 4-Methyl-2-[4-(3-oxo-
piperazin-1-yl)-9-(4- sulfamoyl-benzyl)- 5,6,7,8-tetrahydro-
pyrimido[4,5-b] azepin-2- ylamino]-thiazole-5- carboxylic acid
ethyl ester 1.43.sup.b 601 E26 ##STR00510## ##STR00511##
4-Methyl-2-[4-morpholin- 4-yl-9-(3,4,5-trimethoxy- benzyl)-5,6,7,8-
tetrahydro-pyrimido[4,5- b]azepin-2-ylamino]- thiazole-5-carboxylic
acid ethyl ester 1.74.sup.b 599 E27 ##STR00512## ##STR00513##
4-Methyl-2-[4- thiomorpholin-4-yl-9- (3,4,5-trimethoxy-benzyl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-thiazole-5-
carboxylic acid ethyl ester 1.92.sup.b 615 E28 ##STR00514##
##STR00515## 2-[4-(3-Hydroxymethyl- piperidin-1-yl)-9-(3,4,5-
trimethoxy-benzyl)- 5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2-
ylamino]-4-methyl- thiazole-5-carboxylic acid ethyl ester
1.71.sup.b 627 E29 ##STR00516## ##STR00517## 2-[4-(2-6-Dimethyl-
morpholin-4-yl)-9-(3,4,5- trimethoxy-benzyl)- 5,6,7,8-tetrahydro-
pyrimido[4,5b]azepin-2- ylamino]-4-methyl- thiazole-5-carboxylic
acid ethyl ester 1.95.sup.b 627 E30 ##STR00518## ##STR00519##
2-[4-(4-Acetyl- [1,4]diazepan-1-yl)-9- (3,4,5-trimethoxy-benzyl)-
5,6,7,8-tetrahydro- pyrimido[4,5-b]azepin-2- ylamino]-4-methyl-
thiazole-5-carboxylic acid ethyl ester 1.89.sup.b 654 E31
##STR00520## ##STR00521## 4-Methyl-2-[9-(3,4,5-
trimethoxy-benzyl)-4- (3,4,5-trimethoxy- benzylamino)-5,6,7,8-
tetrahydro-pyrimido[4,5- b]azepin-2-ylamino]- thiazole-5-carboxylic
acid ethyl ester 1.84.sup.b 709 E32 ##STR00522## ##STR00523##
4-Methyl-2-[4-(3-oxo- piperazin-1-yl)-9- (3,4,5-trimethoxy-
benzyl)-5,6,7,8- tetrahydro-pyrimido[4,5- b]azepin-2-ylamino]-
thiazole-5-carboxylic acid ethyl ester 1.59.sup.b 612 HPLC
conditions used to determine retention times: .sup.a2 min gradient
0-100% B in A; (A; 0.05% ammonium acetate in 90/10
water/acetonitrile; B; 0.05% ammonium acetate in 90/10
water/acetonitrile; B; 0.05% ammonium acetate in 10/90
water/acetonitrile) using a Primesphere C-18 4.6 .times. 30 mm
column at 254 nm. .sup.b2 min gradient 0-100% B in A; (A; 0.05% TFA
in 90/10 water/acetonitrile; B; 0.05% TFA in 10/90
water/acetonitrile) using a Primesphere C-18 4.6 .times. 30 mm
column at 254 nm
* * * * *