Fused heterocyclic compounds and uses thereof

Abstract

Fused heterocylic compounds of the following Formula wherein R 1 , R 2 , R 5 , Z, J 1 and J 2 are described herein, and analogs thereof are provided which are useful in treating leukocyte activation-associated disorders.

1 . A compound of Formula (Ia) 
       
         
           
           
               
               
           
         
       
       their enantiomers, diastereomers, and pharmaceutically acceptable salts thereof, 
       wherein:
 W is S; 
 Y 1  is OT 10 ; 
 Y 2  is alkyl or haloalkyl; 
 J 1  is optionally substituted C 1  alkylene; 
 J 2  is optionally substituted C 2-3  alkylene; 
 T 10  is alkyl; 
 Z is selected from: 
 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 5  is selected from: 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         2 . A compound of  claim 1  selected from
 i. 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;
 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-methyl-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]pyrimidin-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-pyrido[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-tetrahydro-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-carboxylic 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-carboxylic acid ethyl ester; 
 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; 
 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; 
 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-tetrahydro-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-carboxylic acid ethyl ester 
 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; 
 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; 
 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-□ 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; 
 4-Methyl-2-[4-morpholin-4-yl-8-(1,1,3-trioxo-2,3-dihydro-1H-1□ 6 -benzo[d]isothiazol-5-ylmethyl)-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimidin-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-carboxylic 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-pyrido[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-pyrido[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-tetrahydro -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-methyl-thiazole-5-carboxylic acid ethyl ester; 
 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; 
 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; 
 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-carboxylic 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-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-pyridin-4-ylmethyl-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-pyridin-4-ylmethyl-5,6,7,8-tetrahydro-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-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-(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-carboxylic acid ethyl ester; 
 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; 
 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; 
 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; 
 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-pyrido[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-tetrahydro-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-tetrahydro-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-carboxylic acid ethyl ester; 
 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; 
 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)-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-2-sulfonylamino)-benzyl]-5,6,7,8-tetrahydro-pyrido[2,3-d]pyrimdin-2-ylamino}-4-methyl-thiazole-5-carboxylic acid ethyl ester; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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-tetrahydro-pyrido[2,3-d]pyrimidin-2-ylamino]-4-methyl-thiazole-5-carboxylic acid ethyl ester; 2-[8-[4-(1,1-Dioxo-1□ 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-carboxylic acid ethyl ester; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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; 
 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-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-carboxylic acid ethyl ester; 
 4-Methyl-2-[4-(3-oxo-piperazin-1-yl)-8-(2-sulfamoylamino-ethyl)-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-(2-sulfamoylamino-ethyl)-5,6,7,8-tetrahydro-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-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-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-tetrahydro-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-tetrahydro-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-tetrahydro-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-tetrahydro-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-pyrimido[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-tetrahydro-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-tetrahydro-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-tetrahydro-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-pyrimido[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-pyrimido[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-tetrahydro-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-tetrahydro-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-pyrimido[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-tetrahydro-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-tetrahydro-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-tetrahydro-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-carboxylic acid ethyl ester; 
 4-Methyl-2-[4-morpholin-4-yl-9-(3,4,5-trimethoxy-benzyl)-5,6,7,8-tetrahydro-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-tetrahydro-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-carboxylic acid ethyl ester; 
 2-[4-(2,6-Dimethyl-morpholin-4-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; 
 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; 
 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