Substituted bicyclic derivatives useful as anticancer agents

Abstract

The invention relates to compounds of the formula 1 and to pharmaceutically acceptable salts and solvates thereof, wherein A, X, R 1 , R 3 and R 4 are as defined herein. The invention also relates to methods of treating abnormal cell growth in mammals with administering the compounds of formula 1 and to pharmaceutical compositions for treating such disorders which contain the compounds of formula 1. The invention also relates to methods of preparing the compounds of formula 1.

1 . A compound of the formula I  
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or solvate thereof, wherein: 
 X is N or CH;  
 A represents a fused 5, 6 or 7-membered ring optionally containing 1 to 4 heteroatoms which may be the same or different and which are selected from —N(R 1 )—, O, and S(O) j , wherein j is an integer from 0 to 2, the fused ring containing a total of 1, 2 or 3 double bonds inclusive of the bond in the pyridine or pyrimidine ring to which it is fused wherein the R 1  group attached to the nitrogen is absent if a double bond includes the foregoing optional nitrogen moiety —N(R 1 )—, with the proviso that the fused ring does not form part of a purine and that the fused ring does not contain two adjacent O or S(O) j  atoms, and wherein the carbon atoms of the A moiety are optionally substituted with 1 to 3 R 5  groups;  
 each R 1  and R 2  is independently H or C 1 -C 6  alkyl;  
 R 3  is —(CR 1 R 2 ) m —R 8  wherein m is 0 or 1;  
 or R 1  and R 3  are taken together to form a group of the formula  
                     
 wherein said group is optionally substituted with 1 to 3 R 5  groups;  
 
         R 4  is —(CR 1 R 2 ) m —C≡C—(CR 1 R 2 ) t R 9 , —(CR 1 R 2 ) m —C═C—(CR 1 R 2 ) t —R 9 , —C═NOR 12 , or —X 1 —R 12  wherein m is an integer from 0 to 3, t is an integer from 0 to 5, and X 1  is a divalent group derived from azetidine, oxetane or a C 3 -C 4  carbocyclic group;  
         or R 4  is —(CR 1 R 2 ) m —C≡C—(CR 1 R 2 ) k R 13  or —(CR 1 R 2 ) m _C═C—(CR 1 R 2 ) k R 13  wherein k is an integer from 1 to 3 and m is an integer from 0 to 3;  
         or R 4  is —(CR 1 R 2 ) t R 9 , wherein t is an integer from 0 to 5 and the attachment point to R 9  is through a carbon atom of the R 9  group;  
         each R 5  is independently selected from halo, hydroxy, —NR 1 R 2 , C 1 -C 6  alkyl, trifluoromethyl, C 1 -C 6  alkoxy, trifluoromethoxy, —C(O)R 6 , —CO 2 R 6 , —NR 6 C(O)R 1 , —C(O)NR 6 R 7 , —SO 2 NR 6 R 7 , —NR 6 C(O)NR 7 R 1 , and —NR 6 C(O)OR 7 ;  
         each R 6  and R 7  is independently selected from H, C 1 -C 6  alkyl, —(CR 1 R 2 ) t (C 6 -C 10  aryl), and —(CR 1 R 2 ) t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, and the alkyl, aryl and heterocyclic moieties of the foregoing R 6  and R 7  groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, —NR 1 R 2 , trifluoromethyl, trifluoromethoxy, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, hydroxy, and C 1 -C 6  alkoxy;  
         R 8  is independently selected from —(CR 1 R 2 ) t (C 6 -C 10  aryl) and —(CR 1 R 2 ) t (4-10 membered heterocyclic), wherein t is an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic group are optionally substituted with an oxo (═O) moiety, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups;  
         R 9  is a non-aromatic mono-cyclic ring, a fused or bridged bicyclic ring, or a spirocyclic ring, wherein said ring contains from 3 to 12 carbon atoms in which from 0 to 3 carbon atoms are optionally replaced with a hetero moiety independently selected from N, O, S(O) j  wherein j is an integer from 0 to 2, and —NR 12 —, provided that two O atoms, two S(O) j  moieties, an O atom and a S(O) j  moiety, an N atom and an S atom, or an N atom and an O atom are not attached directly to each other within said ring, and wherein the carbon atoms of said ring are optionally substituted with 1 to 2 R 11  groups;  
         each R 10  is independently selected from halo, cyano, nitro, trifluoromethoxy, trifluoromethyl, azido, hydroxy, C 1 -C 6  alkoxy, C 1 -C 10  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —C(O)R 6 , —C(O)OR 6 , —OC(O)R 6 , —NR 6 C(O)R 7 , —NR 6 C(O)NR 1 R 7 , —NR 6 C(O)OR 7 , —C(O)NR 6 R 7 , —NR 5 R 7 , —NR 6 OR 7 , —SO 2 NR 6 R 7 , —S(O) j (C 1 -C 6  alkyl) wherein j is an integer from 0 to 2, —(CR 1 R 2 ) t (C 6 -C 10  aryl), —(CR 1 , R 2 ) t (4-10 membered heterocyclic), —(CR 1 R 2 ) q C(O)(CR 1 R 2 ) t (C 6 -C 10  aryl), —(CR 1 R 2 ) q C(O)(CR 1 R 2 ) t (4-10 membered heterocyclic), —(CR 1 R 2 ) t O(CR 1 R 2 ) q (C 6 -C 10  aryl), —(CR 1 R 2 ) t O(CR 1 R 2 ) q (4-10 membered heterocyclic), —(CR 1 R 2 ) q S(O) j (CR 1 R 2 ) t (C 6 -C 10 aryl), and —(CR 1 R 2 ) q S(O) j (CR 1 R 2 ) t (4-10 membered heterocyclic), wherein j is 0, 1 or 2, q and t are each independently an integer from 0 to 5, 1 or 2 ring carbon atoms of the heterocyclic moieties of the foregoing R 10  groups are optionally substituted with an oxo (═O) moiety, and the alkyl, alkenyl, alkynyl, aryl and heterocyclic moieties of the foregoing R 10  groups are optionally substituted with 1 to 3 substituents independently selected from halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, azido, —OR 6 , —C(O)R 6 , —C(O)OR 6 , —OC(O)R 6 , —NR 6 C(O)R 7 , —C(O)NR 6 R 7 , —NR 6 R 7 , —NR 6 OR 7 , C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, —(CR 1 R 2 ) t (C 6 -C 10  aryl), and —(CR 1 R 2 ) t  4-10 membered heterocyclic), wherein t is an integer from 0 to 5;  
         each R 11  is independently selected from —R 12 , —OR 1 , —NR 1 R 2 , —NR 6 C(O)R 7 , —NR 6 C(O)NR 7 R 1 , —NR 6 C(O)OR 7 , and —NR 6 SO 2 NR 7 R 1 , or R 11  replaces two hydrogen atoms on a carbon to form an oxo (C═O) group;  
         R 12  is R 6 , —C(O)R 6  or —SO 2 R 6 , —C(O)NR 6 R 7 , —SO 2 NR 6 R 7 , or —C 2 R 6 ;  
         R 13  is —NR 1 R 12  or —OR 12    
         and wherein any of the above-mentioned substituents comprising a CH 3  (methyl), CH 2  (methylene), or CH (methine) group which is not attached to a halogeno, SO or SO2 group or to a N, O or S atom optionally bears on said group a substituent selected from hydroxy, halo, C 1 -C 4  alkyl, C 1 -C 4  alkoxy and —NR 1 R 2 .  
       
     
     
         2 . A compound according to  claim 1  wherein the A moiety is selected from  
       
         
           
           
               
               
           
         
       
       wherein the above A moieties bear an R 4  group as a substituent and optionally bear 1 to 3 R 5  groups as substituents.  
     
     
         3 . A compound according to  claim 1  wherein the A moiety is selected from  
       
         
           
           
               
               
           
         
       
       wherein the above A moieties bear an R 4  group as a substituent and optionally bear 1 to 3 R 5  groups as substituents.  
     
     
         4 . A compound according to  claim 1  wherein the A moiety is selected from  
       
         
           
           
               
               
           
         
       
       wherein the above A moieties bear an R 4  group as a substituent and optionally bear 1 to 3 R 5  groups as substituents.  
     
     
         5 . A compound according to  claim 1  wherein the A moiety is selected from  
       
         
           
           
               
               
           
         
       
       wherein the above A moieties bear an R 4  group as a substituent and optionally bear 1 to 3 R 5  groups as substituents.  
     
     
         6 . A compound according to  claim 1  wherein the A moiety is  
       
         
           
           
               
               
           
         
         wherein the above A moiety bears an R 4  group as a substituent and optionally bears 1 to 3 R 5  groups as substituents.  
       
     
     
         7 . A compound according to  claim 5  wherein R 4  is —(CR 1 R 2 ) m —C≡C—(CR 1 R 2 ) t R 9  wherein m is an integer from 0 to 3 and t is an integer from 0 to 5.  
     
     
         8 . A compound according to  claim 6  wherein R 4  is —(CR 1 R 2 ) m —C≡C—(CR 1 R 2 ) t R 9  wherein m is an integer from 0 to 3 and t is an integer from 0 to 5.  
     
     
         9 . A compound according to  claim 5  wherein R 4  is —(CR 1 R 2 ) m —C═C—(CR 1 R 2 ) t —R 9  and m is an integer from 0 to 3 and t is an integer from 0 to 5.  
     
     
         10 . A compound according to  claim 6  wherein R 4  is —(CR 1 R 2 ) m —C═C—(CR 1 R 2 ) t —R 9  and m is an integer from 0 to 3 and t is an integer from 0 to 5.  
     
     
         11 . A compound according to  claim 5  wherein R 4  is —(CR 1 R 2 ) m —C═C—(CR 1 R 2 ) k R 13  or —(CR 1 R 2 ) m —C═C—(CR 1 R 2 ) k R 13  wherein m is an integer from 0 to 3 and k is an integer from 1 to 3; and q is an integer from 1 to 6.  
     
     
         12 . A compound according to  claim 6  wherein R 4  is —(CR 1 R 2 ) m —C≡C—(CR 1 R 2 ) k R 13  or —(CR 1 R 2 ) m —C═C—(CR 1 R 2 ) k R 13  wherein m is an integer from 0-3 and k is an integer from 1 to 3.  
     
     
         13 . A compound according to  claim 5  wherein R 4  is —C═NOR 2 , or —X 1 —R 12  wherein X 1  is a divalent group derived from azetidine, oxetane or a C 3 -C 4  carbocyclic group; or R 4  is —(CR 1 R 2 ) t R 9 , wherein the attachment point to R 9  is through a carbon atom of R 9 .  
     
     
         14 . A compound according to  claim 6  wherein R 4  is —C═NOR 12 , or —X—R 12  wherein X 1  is a divalent group derived from azetidine, oxetane or a C 3 -C 4  carbocyclic group; or R 4  is —(CR 1 R 2 ) t R 9 , wherein the attachment point to R 9  is through a carbon atom of R 9 .  
     
     
         15 . A compound according to  claim 7  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyl), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ) t (benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         16 . A compound according to  claim 8  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyl), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ) t (benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         17 . A compound according to  claim 9  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyl), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ) t (benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         18 . A compound according to  claim 10  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyl), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ) t (benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         19 . A compound according to  claim 11  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyl), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ) t (benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         20 . A compound according to  claim 12  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyl), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ),(benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         21 . A compound according to  claim 13  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyi), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ) t (benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         22 . A compound according to  claim 14  wherein R 8  is selected from —(CR 1 R 2 ) t (phenyl), —(CR 1 R 2 ) t (pyridyl), —(CR 1 R 2 ) t (pyrimidinyl), —(CR 1 R 2 ) t (indolyl), —(CR 1 R 2 ) t (indazolyl) and —(CR 1 R 2 ) t (benzimidazolyl), wherein t is an integer from 0 to 5, and each of the foregoing R 8  groups is optionally substituted with 1 to 5 R 10  groups.  
     
     
         23 . A compound according to  claim 16  wherein the m variable in the R 4  group is 0, t in the R 8  group is an integer between 0 and 2, and R 9  is a 4 to 10 membered heterocyclic group having 1 to 3 hetero moieties as indicated in  claim 1  wherein said R 9  is optionally substituted with 1 to 2 R 11  groups.  
     
     
         24 . A compound according to  claim 20  wherein R 4  is —(CR 1 R 2 ) m —C≡C—(CR 1 R 2 ) k R 13  wherein m is 0 and k is an integer from 1 or 2.  
     
     
         25 . A compound according to  claim 22  wherein R 4  is —(CR 1 R 2 ) t R 9 , wherein the attachment point to R 9  is through a carbon atom of R 9 ; t is an integer from 0 to 2, and R 9  is a 4-10 membered heterocyclic group having 1 to 3 hetero moieties as indicated in  claim 1  wherein said R 9  is optionally substituted with 1 to 2 R 11  groups.  
     
     
         26 . A compound according to  claim 1  selected from the group consisting of: 
 Acetic acid 3-[4-(1-benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-allyl ester;  
 (1-Benzenesulfonyl-1H-indol-5-yl)-{6-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl]-quinazolin-4-yl}-amine;  
 (1-Benzenesulfonyl-1H-indol-5-yl)-[6-(3-pyrrolidin-1-yl-prop-1-ynyl)-quinazolin-4-yl]-amine;  
 4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;  
 (1-Benzenesulfonyl-1H-indol-5-yl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;  
 [6-(4-Amino-tetrahydro-pyran-4-ylethynyl)-quinazolin-4-yl]-(1-benzenesulfonyl-1H-indol-5-yl)-amine;  
 1-Methyl-4-{4-[3-methyl-4-(pyrid in-2-ylmethoxy)-phenylamino]-quinazolin-6-ylethynyl}-piperidin-4-ol;  
 1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;  
 4-{4-[4-(1-Phenyl-ethoxy)-phenylamino]-quinazol in-6-ylethynyl}-tetrahydro-pyran-4-ol;  
 1-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-yl]-4,4-dimethyl-pent-1-yn-3-ol;  
 4,4-Dimethyl-1-{4-[4-(1-phenyl-ethoxy)-phenylamino]-quinazolin-6-yl}-pent-1-yn-3-ol;  
 3-{4-[1-(Propane-2-sulfonyl)-1H-indol-5-ylamino]-quinazolin-6-ylethynyl}-piperidin-3-ol;  
 1-Methyl-3-[4-(4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-pyrrolidin-2-yl-prop-2-yn-1-ol;  
 5-[4-(1-Benzyl-1H-indazol-5-ylamino)-quinazolin-6-ylethynyl]-4,4-dimethyl-oxazol idin-2-one;  
 4-Amino-1-[4-(3-chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-pent-1-yn-3-ol;  
 4-Amino-1-[4-(3-chloro4-phenoxy-phenylamino)-quinazolin-6-yl]-4-methyl-pent-1-yn-3-ol;  
 3-{2-[4-(3-Methyl4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;  
 and the pharmaceutically acceptable salts and solvates of the foregoing compounds.  
 
     
     
         27 . A compound according to  claim 1  selected from the group consisting of: 
 (+)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(R)-ylethynyl-quinazolin4-yl)-amine;  
 (−)-(3-Methyl-4-phenoxy-phenyl)-(6-piperidin-3(S)-ylethynyl-quinazolin-4-yl)-amine;  
 3-(S)-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylic acid methylamide;  
 3-(S)-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidine-1-carboxylic acid methylamide;  
 (3-Methyl-4-phenoxy-phenyl)-(6-pyrrolidin-3-ylethynyl-quinazolin-4-yl)-amine;  
 3-[4-(5-Methyl-6-phenoxy-pyridin-3-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 (−)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 (+)-3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-tetrahydro-pyran-4-ol;  
 {6-[1-(2-Methoxy-ethyl)-piperidin-3-ylethynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;  
 [4-(2-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;  
 [4-(3-Fluoro-phenoxy)-3-methyl-phenyl]-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;  
 (6-Azetid in-3-ylethynyl-quinazolin-4-yl)-(3-methyl-4-phenoxy-phenyl)-amine;  
 3-{4-[4-(2-Fluoro-phenoxy)-3-methyl-phenylamino]-qu inazolin-6-ylethynyl}-piperidin-3-ol;  
 3-{4-[4-(3-Fluoro-phenoxy)-3-methyl-phenyl amino]-qu inazol in-6-ylethynyl}-piperidin-3-ol;  
 4-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-4-ol;  
 (3-Chloro-4-phenoxy-phenyl)-(6-piperidin-3-ylethynyl-quinazolin-4-yl)-amine;  
 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-8-aza-bicyclo[3.2.1]octan-3-ol;  
 (3-Chloro-4-phenoxy-phenyl)-(6-piperidin-4-ylethynyl-quinazolin-4-yl)-amine;  
 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-pyrrolidin-3-ol;  
 3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-7-ylethynyl]-piperidin-3-ol;  
 and the pharmaceutically acceptable salts and solvates of the foregoing compounds.  
 
     
     
         28 . A compound according to  claim 1  selected from the group consisting of: 
 N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;  
 N-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;  
 (3-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-qu inazolin-6-yl]-prop-2-ynyl}-3-aza-bicyclo[3.1.0]hex-6-yl)-methanol;  
 4-{3-[4-(3-Methoxy-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-piperazine-1-carboxylic acid methylamide;  
 {6-[3-(1,1-Dioxo-1-thiomorpholin-4-yl)-prop-1-ynyl]-quinazolin-4-yl}-(3-methyl-4-phenoxy-phenyl)-amine;  
 1-{3-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazol in-6-yl]-prop-2-ynyl}-piperidin-4-ol;  
 N-{1-Methyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;  
 N-{3-[4-(3-Chloro-4-phenoxy-phenylamino)-quinazolin-6-yl]-1-methyl-prop-2-ynyl}-acetamide;  
 N-{1,1-Dimethyl-3-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-prop-2-ynyl}-acetamide;  
 4-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-qu inazolin-6-ylethynyl]-1-methyl-piperidin-4-ol;  
 3-[4-(1-Benzenesulfonyl-1H-indol-5-ylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 3-[4-(3-Bromo-4-phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 3-[4-(4-Benzenesulfonyl-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 3-[4-(4-Cyclohexyloxy-3-methyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 2-Methyl-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-2-ol;  
 2-Amino-4-[4-(3-methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-but-3-yn-1-ol;  
 3-[4-(3-Methyl-4-phenylsulfanyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 and the pharmaceutically acceptable salts and solvates of the foregoing compounds.  
 
     
     
         29 . A compound according to  claim 1  selected from the group consisting of: 
 3-[4-(3-Chloro-4-fluoro-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 3-[4-(3-Ethynyl-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 (3-Methyl-4-phenoxy-phenyl)-[6-(1-methyl-piperidin-3-ylethynyl)-quinazolin-4-yl]-amine;  
 (3-Methyl-4-phenoxy-phenyl)-[6-(2-piperidin-3-yl-ethyl)-quinazolin-4-yl]-amine;  
 3-{2-[4-(3-Methyl-4-phenoxy-phenylamino)-quinazolin-6-yl]-ethyl}-piperidin-3-ol;  
 3-[4-(4-Phenoxy-phenylamino)-quinazolin-6-ylethynyl]-piperidin-3-ol;  
 3-Oxo-5-(4-pyrrolidin-1-yl-butyl)-1,2,3,5-tetrahydro-benzo[4,5]imidazo[1,2-a]pyridine-4-carboxylic acid benzylamide;  
 and the pharmaceutically acceptable salts and solvates of the foregoing compounds.  
 
     
     
         30 . A method for the treatment of abnormal cell growth in a mammal comprising administering to said mammal an amount of a compound of  claim 1  that is effective in treating abnormal cell growth.  
     
     
         31  A method according to  claim 30  wherein said abnormal cell growth is cancer.  
     
     
         32 . A method according to  claim 31  wherein said cancer is selected from lung cancer, bone cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system (CNS), primary CNS lymphoma, spinal axis tumors, brain stem glioma, pituitary adenoma, or a combination of one or more of the foregoing cancers.  
     
     
         33 . A method for the treatment of abnormal cell growth in a mammal which comprises administering to said mammal an amount of a compound of  claim 1  that is effective in treating abnormal cell growth in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antibodies, cytotoxics, anti-hormones, and anti-androgens.  
     
     
         34 . A pharmaceutical composition for the treatment of abnormal cell growth in a mammal comprising an amount of a compound of  claim 1  that is effective in treating abnormal cell growth, and a pharmaceutically acceptable carrier.  
     
     
         35 . A method of preparing a compound of  claim 1  which comprises either (a) reacting a compound of the formula 11 or 2 with a compound of the formula 3 
       
         
           
           
               
               
           
         
       
       wherein Z is a leaving group and A, X, R 1 , R 4  and R 3  are as defined above, or (b) reacting a compound of the formula 7 with a compound of the formula 3 
       
         
           
           
               
               
           
         
       
       wherein X, R 1 , A, R 1  and R 3  are as defined above and Z 1  is an activating group, to provide an intermediate of the formula 5 
       
         
           
           
               
               
           
         
       
       wherein Z 1 , X, R 1 , A, and R 3  are as defined above and Z 1  is converted to an R 4  group which optionally may be converted to another R 4  group.