Process for Preparing Pyrido[2,3-d]pyrimidin-7-one and 3,4-Dihydropyrimido[4,5-d]pyrimidin-2(1H)-one Derivatives

Abstract

The present invention is directed to a novel method of preparing of 2,4,8-trisubstituted pyrido[2,3-d]pyrimidin-7-one pharmacophores of Formula (II) or (IIa) wherein G1 is CH 2 ; G2 is CH; Rx is chloro, bromo, iodo, or O—S(O) 2 CF 3 ; R g is a C 1-10 alkyl; m is 0, or an integer having a value of 1, or 2; R 3 is a C 1-10 alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkyl C 1-10 alkyl, aryl, arylC 1-10 alkyl, heteroaryl, heteroarylC 1-10 alkyl, heterocyclic or a heterocyclylC 1-10 alkyl moiety, and wherein each of these moieties may be optionally substituted. which comprises reacting a compound of the formula: wherein Ry is chloro, bromo, iodo, O—S(O) 2 CF 3 ; and Rg is a C 1-10 alkyl; with a olefin forming reagent in a suitable base to yield a compound of Formula (II), or (IIa) wherein m=0 and oxidizing the sulphur as necessary or desired.

1 . A compound of formula (II): 
     
       
         
         
             
             
         
       
     
     wherein
 G1 is CH 2 ; 
 G2 is CH; 
 Rx is chloro, bromo, iodo, or O—S(O) 2 CF 3 ; 
 Rg is a C 1-10  alkyl; 
 m is 0, or an integer having a value of 1, or 2; 
 R 3  is a C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl C 1-10  alkyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, heterocyclic or a heterocyclylC 1-10  alkyl moiety, and wherein each of these moieties may be optionally substituted. 
 
   
   
       2 . The compound according to  claim 1  which is Formula (II). 
   
   
       3 . The compound according to  claim 1  which is Formula (IIa). 
   
   
       4 . The compound according to  claim 1  wherein Rg is methyl. 
   
   
       5 . The compound according to  claim 4  wherein m is 0. 
   
   
       6 . The compound according to  claim 4  wherein m is 2. 
   
   
       7 . The compound according  claim 1  wherein Rx is chloro. 
   
   
       8 . The compound according  claim 1  wherein R 3  is an optionally substituted aryl. 
   
   
       9 . The compound according to  claim 8  wherein R 3  is optionally substituted independently, one or more times, independently at each occurrence by halogen, C 1-10  alkyl, hydroxy, C 1-10  alkoxy, cyano, nitro, amino, or halosubstituted C 1-10  alkyl. 
   
   
       10 . The compound according to  claim 9  wherein R 3  is a phenyl substituted one or more times independently by fluorine, chlorine, or methyl. 
   
   
       11 . The compound according to  claim 8  wherein R 3  is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl. 
   
   
       12 . The compound according to  claim 1  which is: 
     4-Chloro-8-(4-trifluoromethyl-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one; 
     4-Chloro-8-(4-trifluoromethyl-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one; 
     4-Chloro-8-(2,4-difluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one; 
     4-Chloro-8-(2,4-difluoro-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one; 
     4-Chloro-8-(2,6-difluoro-phenyl)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one; and 
     4-Chloro-8-(2,6-difluoro-phenyl)-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one. 
   
   
       13 . A compound of the formula: 
     
       
         
         
             
             
         
       
     
     wherein
 G1 is —CH 2 : 
 G2 is CH; 
 Rx is chloro, bromo, iodo, or O—S(O) 2 CF 3 ; 
 X is R 2 , OR 2″ , S(O) m R 2″ , (CH 2 ) n′ N(R 11 )S(O) m R 2′ , (CH 2 ) n′ N(R 11 )C(O)R 2′ , (CH 2 ) n NR 4 R 14 , or (CH 2 ) n′ N(R 2′ )(R 2″ ), or N(R 10′ )—R h —NH—C(═N—CN)NRqRq′; 
 X 1  is N(R 11 ), O, S(O) m , or CR 10 R 20 ; 
 R h  is selected from an optionally substituted C 1-10  alkyl, —CH 2 —C(O)—CH 2 —, —CH 2 CH 2 —O—CH 2 —CH 2 —, —CH 2 —C(O)N(R 10′ )CH 2 —CH 2 —, —CH 2 —N(R 10′ )C(O)CH 2 —, —CH 2 —CH(OR 10′ )—CH 2 , —CH 2 —C(O)O—CH 2 —CH 2 —, or —CH 2 —CH 2 —O—C(O)CH 2 —; 
 R q  and R q′  are independently selected at each occurrence from hydrogen, C 1-10  alkyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, C 5-7  cycloalkenyl, C 5-7  cycloalkenyl-C 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, heterocyclic, or a heterocyclylC 1-10  alkyl moiety, wherein all of the moieties, excluding hydrogen, are optionally substituted, or R q  and R q′  together with the nitrogen to which they are attached form a 5 to 7 membered optionally substituted ring, which ring may contain an additional heteroatom selected from oxygen, nitrogen or sulfur; 
 R 2  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylalkyl, aryl, arylC 1-10 -alkyl, heteroaryl, heteroarylC 1-10 -alkyl, heterocyclic, or a heterocyclylC 1-10 -alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or R 2  is the moiety (CR 10 R 20 ) q′ X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ), or C(A 1 )(A 2 )(A 3 ); 
 R 2′  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylalkyl, aryl, arylC 1-10 -alkyl, heteroaryl, heteroarylC 1-10  alkyl, heterocyclic, or a heterocyclylC 1-10  alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; 
 R 2″  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylalkyl, aryl, arylC 1-10 -alkyl, heteroaryl, heteroarylC 1-10 -alkyl, heterocyclic, or a heterocyclylC 1-10 -alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; or
 wherein R 2″  is the moiety (CR 10 R 20 ) t X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ); 
 
 A 1  is an optionally substituted C 1-10  alkyl, heterocyclic, heterocyclic C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, aryl, or aryl C 1-10  alkyl; 
 A 2  is an optionally substituted C 1-10  alkyl, heterocyclic, heterocyclic C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, aryl, or aryl C 1-10  alkyl; 
 A 3  is hydrogen or is an optionally substituted C 1-10  alkyl; 
 R 3  is a C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkyl C 1-10  alkyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, heterocyclic or a heterocyclylC 1-10  alkyl moiety, and wherein each of these moieties may be optionally substituted; 
 R 4  and R 14  are each independently selected from hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, aryl, aryl-C 1-14  alkyl, heterocyclic, heterocyclic C 1-4  alkyl, heteroaryl or a heteroaryl C 1-4  alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted; or the R 4  and R 14  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; 
 R 10  and R 20  are independently selected from hydrogen or C 1-4 alkyl; 
 R 10′  is independently selected at each occurrence from hydrogen or C 1-4 alkyl; 
 R 11  is independently selected from hydrogen or C 1-4 alkyl; 
 n′ is independently selected at each occurrence from 0 or an integer having a value of 1 to 10; 
 m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2; 
 q is 0 or an integer having a value of 1 to 10; 
 q′ is 0, or an integer having a value of 1 to 6; or 
 t is an integer having a value of 2 to 6. 
 
   
   
       14 . The compound according to  claim 13  which is Formula (III). 
   
   
       15 . The compound according to  claim 13  which is Formula (IIIa). 
   
   
       16 . The compound according to  claim 13  wherein Rx is chloro. 
   
   
       17 . The compound according to  claim 13  wherein R 3  is an optionally substituted aryl. 
   
   
       18 . The compound according to  claim 17  wherein R 3  is optionally substituted independently, one or more times, independently at each occurrence by halogen, C 1-10  alkyl, hydroxy, C 1-10  alkoxy, cyano, nitro, amino, or halosubstituted C 1-10  alkyl. 
   
   
       19 . The compound according to  claim 18  wherein R 3  is phenyl substituted one or more times independently by fluorine, chlorine or methyl. 
   
   
       20 . The compound according to  claim 13  wherein R 3  is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl. 
   
   
       21 . The compound according to  claim 13  wherein X is R 2 , and R 2  is (CR 10 R 20 ) q′ X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ), or C(A 1 )(A 2 )(A 3 ). 
   
   
       22 . The compound according to  claim 21  wherein at least one of A 1 , A 2  or A 3  is a C 1-10  alkyl substituted by (CR 10 R 20 ) n OR 6 ; and wherein
 n is 0, or an integer having a value of 1 to 10;   m is 0 or an integer having a value of 1 or 2;   R 6  is independently selected from hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10  alkyl, aryl, arylC 1-10  alkyl, heteroaryl or a heteroarylC 1-10  alkyl moiety, and wherein these moieties, excluding hydrogen may be optionally substituted independently at each occurrence, one or more times, by halogen; hydroxy; hydroxy substituted C 1-10 alkyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; S(O) m  alkyl; C(O); NR 4′ R 14′ ; C 1-10  alkyl; C 3-7 cycloalkyl; C 3-7 cycloalkyl C 1-10  alkyl; halosubstituted C 1-10  alkyl; an unsubstituted aryl or arylalkyl, or an aryl or arylalkyl substituted one or two times by halogen, hydroxy, hydroxy substituted alkyl, C 1-10  alkoxy, S(O) m alkyl, amino, mono & di-substituted C 1-4  alkyl amino, C 1-4  alkyl, or CF 3 ;   R 4′  and R 14′  are each independently selected at each occurrence from hydrogen or C 1-4  alkyl, or R 4′  and R 14′  can cyclize together with the nitrogen to which they are attached to form an optionally substituted 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ; and   R 9′  is independently selected at each occurrence from hydrogen, or C 1-4  alkyl.   
   
   
       23 . The compound according to  claim 21  wherein X 1  is N(R 10′ ), q is 0 or 1, q′ is 0, and R 6  is hydrogen. 
   
   
       24 . The compound according to  claim 13  wherein X is (CH 2 ) n′ NR 4 R 14 , or (CH 2 ) n′ N(R 2′ )(R 2″ ). 
   
   
       25 . The compound according to  claim 24  wherein X is (CH 2 ) n′ NR 4 R 14 , and R 4  and R 14  are independently selected from hydrogen, optionally substituted C 1-10  alkyl, optionally substituted aryl, optionally substituted aryl-C 1-4  alkyl, optionally substituted heterocyclic, optionally substituted heterocylic C 1-4  alkyl, optionally substituted heteroaryl or optionally substituted heteroaryl C 1-4  alkyl. 
   
   
       26 . The compound according to  claim 25  wherein the C 1-10  alkyl may be substituted one or more times, independently at each occurrence with NR 4′ R 14′ ; halogen, hydroxy, alkoxy, C(O)NR 4′ R 14′ ; or NR 4′ C(O) C 1-10 alkyl; and wherein
 R 4′  and R 14′  are independently selected at each occurrence from hydrogen or C 1-4  alkyl, or R 4′  and R 14′  together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members, which ring optionally contains an additional heteroatom selected from NR 9′ ; and   R 9′  is independently selected at each occurrence from hydrogen, or C 1-4  alkyl.   
   
   
       27 . The compound according to  claim 24  wherein X is (CH 2 ) n′ N(R 2′ )(R 2″ ), and R 2′  is an optionally substituted C 1-10  alkyl, cycloalkyl, heterocyclic, heterocyclyl C 1-10  alkyl, or heteroarylalkyl. 
   
   
       28 . The compound according to  claim 27  wherein the R 2 , moieties, excluding hydrogen, are optionally substituted 1 to 4 times, independently, at each occurrence, by C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 3-7 cycloalkylC 1-10 alkyl, C 5-7 cycloalkenyl, C 5-7  cycloalkenyl C 1-10  alkyl, halogen, —C(O), cyano, nitro, aryl, aryl C 1-10  alkyl, aryl, aryl C 1-10  alkyl, heterocyclic, heterocyclic C 1-10  alkyl, heteroaryl, heteroaryl C 1-10  alkyl, (CR 10 R 20 ) n OR 6 , (CR 10 R 20 ) n SH, (CR 10 R 20 ) n S(O) m R 7 , (CR 10 R 20 ) n N(R 10′ )S(O) 2 R 7 , (CR 10 R 20 ) n NR e R e′ , (CR 10 R 20 ) n NR e R e′ C 1-4 alkylNR e R e′ , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR e R e′ , (CR 10 R 20 ) n C(Z)R 6 , (CR 10 R 20 ) n OC(Z)R 6 , (CR 10 R 20 ) n C(Z)OR 6 , (CR 10 R 20 ) n C(Z)NR e R e′ , (CR 10 R 20 ) n N(R 10′ )C(Z)R 6 , (CR 10 R 20 ) n N(R 10′ )C(═N(R 10′ ))NR e R e′ , (CR 10 R 20 ) n C(═NOR 6 ) NR e R e′ , (CR 10 R 20 ) n OC(Z) NR e R e′ , (CR 10 R 20 ) n N(R 10′ )C(Z) NR e R e′ , or (CR 10 R 20 ) n N(R 10′ )C(Z)OR 7 ; and wherein
 R 6  is independently selected at each occurrence from hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl or heteroarylC 1-10  alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted;   R 7  is independently selected at each occurrence from C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6  alkyl, heteroaryl, or heteroarylC 1-6 alkyl moiety, and wherein each of these moieties may be optionally substituted;   R e  are R e′  are each independently selected at each occurrence from hydrogen, C 1-4  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, aryl, aryl-C 1-4  alkyl, heterocyclic, heterocyclic C 1-4  alkyl, heteroaryl or a heteroaryl C 1-4  alkyl moiety; or R e  and R e′  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; and
 wherein each of these moieties, excluding hydrogen, may be substituted 1 to 4 times, independently at each occurrence by halogen; hydroxy; hydroxy substituted C 1-10 alkyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; amino, mono & di-substituted C 1-4  alkyl amino, S(O) m R f ; C(O)R j ; C(O)O R j ; (CR 10 R 20 ) n N(R 10 )C(Z)OR 7 ; (CR 10 R 20 ) n N(R 10′ )C(Z)NR d R d′ ; C(O)NR 4′ R 14′ ; NR 4′ C(O)C 1-10 alkyl; NR 4′ C(O)aryl; cyano; nitro; C 1-10  alkyl; C 3-7 cycloalkyl; C 3-7 cycloalkyl C 1-10  alkyl; halosubstituted C 1-10  alkyl; aryl, aryl C 1-4  alkyl, heterocyclic, heterocyclicC 1-4  alkyl, heteroaryl, or heteroarylC 1-4 alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C 1-4  alkyl, hydroxy, hydroxy substituted C 1-4  alkyl, C 1-10  alkoxy, S(O) m alkyl, amino, mono & di-substituted C 1-4  alkyl amino, C 1-4  alkyl, or CF 3 ; 
   R d  and R d′  are each independently selected from hydrogen, C 1-4  alkyl, C 3-5  cycloalkyl, C 3-5  cycloalkylC 1-4 alkyl, or the R d  and R d′  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 5 to 6 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ; and
 wherein the R d  and R d′  moieties which are C 1-4  alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-4  alkyl, and the R 4  and R 14  cyclized ring are optionally substituted, 1 to 4 times, independently by halogen; halosubstituted C 1-4  alkyl; hydroxy; hydroxy substituted C 1-4 alkyl; C 1-4  alkoxy; halosubstituted C 1-4  alkoxy; S(O) m R f ; C(O)R j ; ; C(O)O R j ; C(O)NR 4′ R 14′ , NR 4′ C(O)C 1-4 alkyl; S(O) 2 NR 4′ R 14′ OC 1-4  alkyl; NR 4′ R 14′ S(O) 2 C 1-4  alkyl; or NR 4′ R 14′ ; 
   R f  is independently selected at each occurrence from C 1-10 alkyl, aryl, aryl C 1-10 alkyl, heteroaryl, heteroaryl C 1-10 alkyl, heterocyclic, or a heterocyclic C 1-10 alkyl moiety, and wherein these moieties may all be optionally substituted;   R f′  is independently selected at each occurrence from hydrogen, C 1-10 alkyl, aryl, aryl C 1-10 alkyl, heteroaryl, heteroaryl C 1-10 alkyl, heterocyclic, heterocyclic C 1-10 alkyl, or NR 4′ R 14′  and wherein these moieties may all be optionally substituted;   R 4′  and R 14′  are each independently selected at each occurrence from hydrogen or C 1-4  alkyl, or R 4′  and R 14′  can cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ;   R 9′  is independently selected at each occurrence from hydrogen, or C 1-4  alkyl;   R j  is independently selected at each occurrence from hydrogen, C 1-4 alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or a heterocyclic C 1-4 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; and   n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10.   
   
   
       29 . The compound according to  claim 28  wherein R 2′  is a heterocyclic or a heterocyclic alkyl substituted one or more times, independently by C 1-10  alkyl, aryl, arylalkyl, (CR 10 R 20 ) n NR e R e′ , or (CR 10 R 20 ) n N(R 10 )C(Z)OR 7 . 
   
   
       30 . The compound according to  claim 13  wherein the (CH 2 ) n′ N(R 2′ )(R 2″ ) moiety is 1-(phenylmethyl)-4-piperidinamine, 2-[4-(phenylmethyl)-1-piperazinyl]ethylamine, 2-(1-piperidinyl)ethylamine, 2-(1-methyl-2-pyrrolidinyl)ethylamine, 1-[(phenylmethyl)-3-pyrrolidinyl]amine, 3-[(1-pyrrolidinyl)propyl]amine, 3-[(hexahydro-1H-azepin-1-yl)propyl]amine, (1-methyl-4-piperidinyl)amine, 3-[(4-morpholinyl)propyl]amine, 3-[(2-oxo-1-pyrrolidinyl)propyl]amine, 2-[(4-morpholinyl)ethyl]amine, 2-[(1-pyrrolidinyl)ethyl]amine, or [(1-ethyl-2-pyrrolidinyl)methyl]amine. 
   
   
       31 . The compound according to  claim 13  wherein R 2′  is a C 1-10  alkyl substituted by (CR 10 R 20 ) n NR e R e′  or (CR 10 R 20 ) n NR e R e′ C 1-4 alkylNR e R e′ ; and wherein
 R e  are R e′  are each independently selected at each occurrence from hydrogen, C 1-4  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-14 alkyl, aryl, aryl-C 1-4  alkyl, heterocyclic, heterocyclic C 1-4  alkyl, heteroaryl or a heteroaryl C 1-4  alkyl moiety; or R e  and R e′  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; and
 wherein each of these moieties, excluding hydrogen, may be substituted 1 to 4 times, independently at each occurrence by halogen; hydroxy; hydroxy substituted C 1-10 alkyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; amino, mono & di-substituted C 1-4  alkyl amino, S(O) m R f′ ; C(O)R j ; C(O)OR j ; (CR 10 R 20 ) n N(R 10′ )C(Z)OR 7 ; (CR 10 R 20 ) n N(R 10′ )C(Z)NR d R d′ ; C(O)NR 4′ R 14′ ; NR 4′ C(O)C 1-10 alkyl; NR 4′ C(O)aryl; cyano; nitro; C 1-10  alkyl; C 3-7 cycloalkyl; C 3-7 cycloalkyl C 1-10  alkyl; halosubstituted C 1-10  alkyl; aryl, aryl C 1-4  alkyl, heterocyclic, heterocyclicC 1-4  alkyl, heteroaryl, or heteroarylC 1-4 alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C 1-4  alkyl, hydroxy, hydroxy substituted C 1-4  alkyl, C 1-10  alkoxy, S(O) m alkyl, amino, mono & di-substituted C 1-4  alkyl amino, C 1-4  alkyl, or CF 3 ; 
   R d  and R d′  are each independently selected from hydrogen, C 1-4  alkyl, C 3-5  cycloalkyl, C 3-5  cycloalkylC 1-4 alkyl, or the R d  and R d′  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 5 to 6 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ; and
 wherein the R d  and R d′  moieties which are C 1-4  alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-4  alkyl, and the R 4  and R 14  cyclized ring are optionally substituted, 1 to 4 times, independently by halogen; halosubstituted C 1-4  alkyl; hydroxy; hydroxy substituted C 1-4 alkyl; C 1-4  alkoxy; halosubstituted C 1-4  alkoxy; S(O) m Rf, C(O)R j ; C(O)O R j ; C(O)NR 4′ R 14′ NR 4′ C(O)C 1-4 alkyl; S(O) 2 NR 4′ R 14′ C 1-4  alkyl; NR 4′ R 14′ S(O) 2 C 1-4  alkyl; or N 4′ R 14′ ; 
   R f  is independently selected at each occurrence from C 1-10 alkyl, aryl, aryl C 1-10  alkyl, heteroaryl, heteroaryl C 1-10 alkyl, heterocyclic, or a heterocyclic C 1-10  alkyl moiety, and wherein these moieties may all be optionally substituted;   R f′  is independently selected at each occurrence from hydrogen, C 1-10 alkyl, aryl, aryl C 1-10 alkyl, heteroaryl, heteroaryl C 1-10 alkyl, heterocyclic, heterocyclic C 1-10 alkyl, or NR 4′ R 14′  and wherein these moieties may all be optionally substituted;   R 4′  and R 14′  are each independently selected at each occurrence from hydrogen or C 1-4  alkyl, or R 4′  and R 14′  can cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ;   R 9′  is independently selected at each occurrence from hydrogen, or C 1-4  alkyl;   Rj is independently selected at each occurrence from hydrogen, C 1-4 alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or a heterocyclic C 1-4 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; and   n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10.   
   
   
       32 . The compound according to  claim 31  wherein R e  and R e′  are independently selected from methyl, ethyl, isopropyl, n-butyl, or t-butyl. 
   
   
       33 . The compound according to  claim 13  wherein (CH 2 ) n′ N(R 2′ )(R 2″ ) is 3-(dimethylamino)propyl(methyl)amine, 3-(diethylamino)propylamine, propylamine, (2,2-dimethylpropyl)amine, (2-hydroxypropyl)amino, 2-(dimethylamino)ethylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(dimethylamino)propylamine, 2-(dimethylamino)ethyl(methyl)amine, 3-(diethylamino)propylamine, 2-(methylamino)ethylamine, [(1-methylethyl)amino]ethylamine, 3-(diethylamino)propylamine, 3-(dibutylamino)propylamine, 3-[(1-methylethyl)amino]propylamine, 3-(1,1-dimethylethyl)aminopropylamino, 3-(dimethylamino)-2,2-dimethylpropylamine, 4-(diethylamino)-1-methylbutylamine, or 3-[[3-(dimethylamino)propyl]-(methyl)amino]propyl(methyl)amine. 
   
   
       34 . The compound according to  claim 13  wherein R 3  is an aryl optionally substituted one or more times independently at each occurrence with halogen, nitro, C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7 cycloalkyl, C 3-7 cycloalkylC 1-10  alkyl, C 5-7 cycloalkenyl, C 5-7 cycloalkenylC 1-10  alkyl, (CR 10 R 20 ) n OR 6 , (CR 10 R 20 ) n SH, (CR 10 R 20 ) n S(O) m R 7 , (CR 10 R 20 ) n N(R 10′ )S(O) 2 R 7 , (CR 10 R 20 ) n NR 16 R 26 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR 16 R 26 , (CR 10 R 20 ) n C(Z)R 6 , (CR 10 R 20 ) n OC(Z)R 6 , (CR 10 R 20 ) n C(Z)OR 6 , (CR 10 R 20 ) n C(Z)NR 16 R 26 , (CR 10 R 20 ) n N(R 10′ )C(Z)R 6 , (CR 10 R 20 ) n N(R 10′ )C(═N(R 10′ ))NR 16 R 26 , (CR 10 R 20 ) n OC(Z) NR 16 R 26 , (CR 10 R 20 ) n N(R 10′ )C(Z) NR 16 R 26 , or (CR 10 R 20 ) n N(R 10′ )C(Z)OR 7 ; and wherein
 R 6  is independently selected from hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10 alkyl, aryl, arylC 1-10  alkyl, heteroaryl or a heteroarylC 1-10  alkyl moiety, and wherein these moieties, excluding hydrogen may be optionally substituted;   R 7  is C 1-6 alkyl, aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6  alkyl, heteroaryl, or heteroarylC 1-6 alkyl; and wherein each of these moieties may be optionally substituted;   R 10′  is independently selected at each occurrence from hydrogen or C 1-4  alkyl;   R 10  and R 20  are independently selected at each occurrence from hydrogen or C 1-4  alkyl;   R 16  and R 26  are each independently selected from hydrogen, or C 1-4  alkyl; or the R 16  and R 26  together with the nitrogen which they are attached form an unsubstituted or substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ;   R 9′  is independently selected at each occurrence from hydrogen, or C 1-4  alkyl;   n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10;   m is independently selected from 0 or an integer having a value of 1 or 2;   Z is independently at each occurrence selected from oxygen or sulfur.   
   
   
       35 . The compound according to  claim 33  wherein R 3  is an optionally substituted phenyl. 
   
   
       36 . The compound according to  claim 35  wherein the optional substituents on the phenyl ring are independently selected at each occurrence from halogen, C 1-10 alkyl, (CR 10 R 20 ) n OR 6 , cyano, nitro, (CR 10 R 20 ) n NR 16 R 26 , or halosubstituted C 1-10 alkyl. 
   
   
       37 . The compound according  claim 24  wherein the phenyl is substituted one or more times by halogen, hydroxy, alkoxy, amino or CF 3 . 
   
   
       38 . The compound according to  claim 36  wherein R 3  is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl. 
   
   
       39 . The compound according to  claim 13  which is: 
     2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(4-trifluoromethyl-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; 
     2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(2,4-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one; and 
     2-(Hydroxy-hydroxymethyl-ethylamino)-4-Chloro-8-(2,6-difluoro-phenyl)-8H-pyrido[2,3-d]pyrimidin-7-one. 
   
   
       40 . The compound according to  claim 13  which is: 
     4-Chloro-8-(2,6-difluorophenyl)-2-{[2-hydroxy-1-(hydroxymethyl)ethyl]-amino}pyrido[2,3-d]pyrimidin-7(8H)-one; 
     4-chloro-2-{[3-(diethylamino)propyl]amino}-8-(2,6-difluorophenyl)pyrido[2,3-d]pyrimidin-7(8H)-one; 
     4-chloro-8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)pyrido[2,3-d]pyrimidin-7(8H)-one. 
   
   
       41 . The compound according to  claim 2  wherein R 9  is methyl. 
   
   
       42 . The compound according to  claim 3  wherein R 9  is methyl. 
   
   
       43 . The compound according to  claim 41  wherein m is 0. 
   
   
       44 . The compound according to  claim 42  wherein m is 0. 
   
   
       45 . The compound according to  claim 41  wherein m is 2. 
   
   
       46 . The compound according to  claim 42  wherein m is 2. 
   
   
       47 . The compound according  claim 43  wherein Rx is chloro. 
   
   
       48 . The compound according  claim 44  wherein Rx is chloro. 
   
   
       49 . The compound according to  claim 47  wherein R 3  is phenyl or a phenyl substituted one or more times independently by fluorine, chlorine, or methyl. 
   
   
       50 . The compound according to  claim 49  wherein R 3  is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl. 
   
   
       51 . The compound according to  claim 48  wherein R 3  is phenyl or a phenyl substituted one or more times independently by fluorine, chlorine, or methyl. 
   
   
       52 . The compound according to  claim 51  wherein R 3  is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl. 
   
   
       53 . The compound according to  claim 14  wherein Rx is chloro. 
   
   
       54 . The compound according to  claim 15  wherein Rx is chloro. 
   
   
       55 . The compound according to  claim 54  wherein R 3  is an optionally substituted aryl. 
   
   
       56 . The compound according to  claim 55  wherein R 3  is optionally substituted independently, one or more times, independently at each occurrence by halogen, C 1-10  alkyl, hydroxy, C 1-10  alkoxy, cyano, nitro, amino, or halosubstituted C 1-10  alkyl. 
   
   
       57 . The compound according to  claim 54  wherein R 3  is phenyl, or phenyl substituted one or more times independently by fluorine, chlorine or methyl. 
   
   
       58 . The compound according to  claim 54  wherein R 3  is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl. 
   
   
       59 . The compound according to  claim 33  wherein Rx is chloro. 
   
   
       60 . The compound according to  claim 59  which is Formula (III). 
   
   
       61 . The compound according to  claim 59  wherein R 3  is a phenyl substituted one or more times independently by fluorine, chlorine or methyl. 
   
   
       62 . The compound according to  claim 61  wherein X is 2-(dimethylamino)ethylamino. 
   
   
       63 . The compound according to  claim 13  wherein X is R 2 . 
   
   
       64 . The compound according to  claim 63  wherein R 2  is an optionally substituted heterocyclic selected from the group consisting of tetrahydropyrrole, tetrahydropyran, tetrahydrofuran, tetrahydrothiophene, aziridinyl, pyrrolinyl, pyrrolidinyl, 2-oxo-1-pyrrolidinyl, 3-oxo-1-pyrrolidinyl, 1,3-benzodioxol-5-yl, imidazolinyl, imidazolidinyl, indolinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, piperazinyl, morpholino and thiomorpholino. 
   
   
       65 . The compound according to  claim 64  wherein R 2  is an optionally substituted one or mores times independently by an optionally substituted heterocyclic, heterocyclic alkyl, aryl, arylalkyl, alkyl, (CR 10 R 20 ) n NR e R e′ , or (CR 10 R 20 ) n N(R 10′ )C(Z)OR 7 ; and 
     wherein
 R e  are R e′  are each independently selected at each occurrence from hydrogen, C 1-4  alkyl, C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, aryl, aryl-C 1-14  alkyl, heterocyclic, heterocyclic C 1-4  alkyl, heteroaryl or a heteroaryl C 1-4  alkyl moiety; or R e  and R e′  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 4 to 7 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or nitrogen; and
 wherein each of these moieties, excluding hydrogen, may be substituted 1 to 4 times, independently at each occurrence by halogen; hydroxy; hydroxy substituted C 1-10 alkyl; C 1-10  alkoxy; halosubstituted C 1-10  alkoxy; amino, mono & di-substituted C 1-4  alkyl amino, S(O) m R f′ ; C(O)R j ; C(O)OR j ; (CR 10 R 20 ) n N(R 10′ )C(Z)OR 7 ; (CR 10 R 20 ) n N(R 10′ )C(Z)NR d R d′ ; C(O)NR 4′ R 14′ ; NR 4′ C(O) C 1-10 alkyl; NR 4′ C(O)aryl; cyano; nitro; C 1-10  alkyl; C 3-7 cycloalkyl; C 3-7 cycloalkyl C 1-10  alkyl; halosubstituted C 1-10  alkyl; aryl, aryl C 1-4  alkyl, heterocyclic, heterocyclicC 1-4  alkyl, heteroaryl, or heteroarylC 1-4 alkyl, and wherein these aryl, heterocyclic, and heteroaryl containing moieties may be optionally substituted one to two times independently at each occurrence by halogen, C 1-4  alkyl, hydroxy, hydroxy substituted C 1-4  alkyl, C 1-10  alkoxy, S(O) m alkyl, amino, mono & di-substituted C 1-4  alkyl amino, C 1-4  alkyl, or CF 3 ; 
 
 R d  and R d′  are each independently selected from hydrogen, C 1-4  alkyl, C 3-5  cycloalkyl, C 3-5  cycloalkylC 1-4 alkyl, or the R d  and R d′  together with the nitrogen which they are attached form an optionally substituted heterocyclic ring of 5 to 6 members, which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ; and
 wherein the R d  and R d′  moieties which are C 1-4  alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkylC 1-4  alkyl, and the R 4  and R 14  cyclized ring are optionally substituted, 1 to 4 times, independently by halogen; halosubstituted C 1-4  alkyl; hydroxy; hydroxy substituted C 1-4 alkyl; C 1-4  alkoxy; halosubstituted C 1-4  alkoxy; S(O) m R f , C(O)R j ; C(O)O R j ; C(O)NR 4′ R 14′ , NR 4′ C(O)C 1-4 alkyl; S(O) 2 NR 4′ R 14′ C 1-4  alkyl; NR 4′ R 14′ S(O) 2 C 1-4  alkyl; or NR 4′ R 14′ ; 
 
 R f  is independently selected at each occurrence from C 1-10 alkyl, aryl, aryl C 1-10 alkyl, heteroaryl, heteroaryl C 1-10 alkyl, heterocyclic, or a heterocyclic C 1-10 alkyl moiety, and wherein these moieties may all be optionally substituted; 
 R f′  is independently selected at each occurrence from hydrogen, C 1-10 alkyl, aryl, aryl C 1-10 alkyl, heteroaryl, heteroaryl C 1-10 alkyl, heterocyclic, heterocyclic C 1-10 alkyl, or NR 4′ R 14′  and wherein these moieties may all be optionally substituted; 
 R 4′  and R 14′  are each independently selected at each occurrence from hydrogen or C 1-4  alkyl, or R 4′  and R 14′  can cyclize together with the nitrogen to which they are attached to form a 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR 9′ ; 
 R 9′  is independently selected at each occurrence from hydrogen, or C 1-4  alkyl; 
 Rj is independently selected at each occurrence from hydrogen, C 1-4 alkyl, aryl, aryl C 1-4 alkyl, heteroaryl, heteroaryl C 1-4 alkyl, heterocyclic, or a heterocyclic C 1-4 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted; and 
 n is independently selected at each occurrence from 0 or an integer having a value of 1 to 10. 
 
   
   
       66 . The compound according to  claim 65  wherein the R 2  optionally substituted heterocyclic is selected from an optionally substituted morpholino, piperidine, or pyrrolidinyl. 
   
   
       67 . The compound according to  claim 64  wherein R 2  is an optionally substituted piperidinyl or piperazinyl ring. 
   
   
       68 . The compound according to  claim 63  wherein R 2  is a 4-amino-1-piperidinyl, 1,1-dimethylethyl)oxy]-carbonyl}amino)-1-piperidinyl, 4-methyl-1-piperazinyl, 4-ethyl-1-piperazinyl, 4-propyl-1-piperazinyl, 4-butyl-1-piperazinyl, 4-(methylamino)-1-piperidinyl, 1,1-dimethylethyl-4-piperidinyl}methylcarbamate, 4-phenyl-1-piperazinyl, 1,4′-bipiperidin-1′-yl, 4-(1-pyrrolidinyl)-1-piperidinyl, 4-methyl-1,4′-bipiperidin-1′-yl, 4-(4-morpholinyl)-1-piperidinyl, 4-(diphenylmethyl)-1-piperazinyl, or 4-methylhexahydro-1H-1,4-diazepin-1-yl. 
   
   
       69 . The compound according to  claim 68  wherein R 2  is 4-methyl-1,4′-bipiperidin-1′-yl, or (1-pyrrolidinyl)-1-piperidinyl.