Novel compounds

Abstract

Novel substituted 2,4,8-trisubstituted-8H-pyrido[2,3-d]pyrimidin-7-one compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

1 . A process for producing a compound according to Formula (Ia) 
       
         
           
           
               
               
           
         
         R 1  is an optionally substituted aryl ring; 
         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, which moieties are all optionally substituted, or R 2  is the moiety X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ), or C(A 1 )(A 2 )(A 3 ); 
         A 1  is an optionally substituted C 1-10  alkyl; 
         A 2  is an optionally substituted C 1-10  alkyl; 
         A 3  is hydrogen or is an optionally substituted C 1-10  alkyl; 
         R 3  is an optionally substituted aryl; 
         R 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4  alkyl, or 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 NR 9 ; 
         R 6  is 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 may be optionally substituted; 
         R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl; 
         R 10  and R 20  are independently selected from hydrogen or C 1-4 alkyl; 
         X is R 2 , OR 2 , S(O) m R 2 , (CH 2 ) n N(R 10 )S(O) m R 2 , (CH 2 ) n N(R 10 )C(O)R 2 , (CH 2 ) n NR 4 R 14 , or (CH 2 ) n N(R 2 ) 2 ; 
         X 1  is N(R 10 ), O, S(O) m , or CR 10 R 20 ; 
         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; 
         q is 0 or an integer having a value of 1 to 10; 
         Z is oxygen or sulfur; 
         or a pharmaceutically acceptable salt thereof; 
         which process comprises reacting a compound of the formula: 
       
       
         
           
           
               
               
           
         
         wherein 
         R′ 1  is a halogen, or an optionally substituted aryl; 
         R 3  is an optionally substituted aryl; 
         m is 0 or an integer having a value of 1 or 2; and 
         Rg is a C 1-4  alkyl; 
         with a mixture of an acetylating agent, and a base, and optionally with heating to yield a compound of Formula (Ia), wherein X is S(O)m-Rg and thereafter if necessary, converting a precursor of R′ 1 , wherein R′ 1  is halogen, to R 1  as optionally substituted aryl, and X as S(O)m-Rg to yield another group X as defined in Formula (Ia), or a pharmaceutically acceptable salt thereof. 
       
     
     
         2 . The process according to  claim 1  wherein the base is pyridine, diisopropyl ethylamine, or pyrrolidine. 
     
     
         3 . The process according to  claim 1  wherein the acetylating agent is acetic anhydride, acetyl chloride, or ketene. 
     
     
         4 . The process according to  claim 2  wherein the acetylating agent is acetic anhydride, acetyl chloride, or ketene. 
     
     
         5 . The process according to  claim 1  wherein in the compound of Formula (VIa) m is 0. 
     
     
         6 . The process according to  claim 1  wherein in the resulting compound of Formula (Ia) m to is 0. 
     
     
         7 . The process according to  claim 6  wherein the compound of Formula (Ia) when m is 0, is oxidized to a compound of Formula (Ia) wherein m is 2. 
     
     
         8 . The process according to  claim 7  wherein the oxidation uses meta chloroperoxybenozic acid, OsO4 and catalytic tertiary amine N-oxide derivatives, hydrogen peroxide and other peracids, oxygen, ozone, organic peroxides, potassium permanganate, zinc permanganate, potassium persulfate and sodium hypochlorite. 
     
     
         9 . The process according to  claim 7  wherein the sulfoxide of Formula (Ia) wherein m is 2 is displaced by a primary or secondary alkylamine. 
     
     
         10 . The process according to  claim 9  wherein the displacement is in a polar aprotic solvent. 
     
     
         11 . The process according to  claim 1  wherein in the compound of Formula (Ia):
 R 1  is an optionally substituted aryl ring; 
 R 2  is the moiety X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ); 
 A 1  is an optionally substituted C 1-10  alkyl; 
 A 2  is an optionally substituted C 1-10  alkyl; 
 A 3  is hydrogen or is an optionally substituted C 1-10  alkyl; and wherein A 1 , A 2 , and A 3 , excluding hydrogen, are optionally substituted 1 to 4 times by (CR 10 R 20 ) n OR 6 ; 
 R 3  is an optionally substituted aryl; 
 R 6  is hydrogen, or C 1-10  alkyl; 
 R 10  and R 20  are independently selected from hydrogen or C 1-4 alkyl; 
 X is R 2 ; 
 X 1  is N(R 10 ), O, S(O) m , or CR 10 R 20 ; 
 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; and 
 q is 0 or an integer having a value of 1 to 10. 
 
     
     
         12 . The process according to  claim 1  wherein X is (CH 2 ) n NR 4 R 14 , or (CH 2 ) n N(R 2 ) 2 . 
     
     
         13 . The process according to  claim 11  wherein R 3  is an optionally substituted phenyl. 
     
     
         14 . The process according to  claim 13  wherein R 3  is optionally substituted one or more times independently with 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, halogen, cyano, nitro, (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 NHS(O) 2 R 7 , (CR 10 R 20 ) n NR 4 R 14 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR 4 R 14 , (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 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)R 6 , (CR 10 R 20 ) n NR 10 C(═NR 10 )NR 4 R 14 , (CR 10 R 20 ) n OC(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 1 OC(Z)NR 4 R 14 , or (CR 10 R 20 ) n NR 10 C(Z)OR 7 ; and wherein R 7  is a 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 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4  alkyl, or 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 NR 9 ; 
 R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl; and 
 Z is oxygen or sulfur. 
 
     
     
         15 . The process according to  claim 14  wherein the R 3  optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         16 . The process according to  claim 11  wherein R 3  is a phenyl ring, substituted one or more times independently by halogen, C 1-4  alkyl, or halo-substituted-C 1-4  alkyl. 
     
     
         17 . The process according to  claim 16  wherein the phenyl ring is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         18 . The process according to  claim 11  wherein R 3  is phenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl. 
     
     
         19 . The process according to  claim 18  wherein R 3  is 2,6-difluorophenyl. 
     
     
         20 . The process according to  claim 1  wherein R 3  in Formula (VIa) is a 2,6-difluorophenyl. 
     
     
         21 . The process according to  claim 1  wherein the R′ 1  in Formula (VIa) is optionally substituted phenyl. 
     
     
         22 . The process according to  claim 21  wherein the R′ 1  in Formula (VIa) is a phenyl optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         23 . The process according to  claim 22  wherein the R′ 1  phenyl in Formula (VIa) is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         24 . The process according to  claim 1  wherein X is R 2  and R 2  is the moiety X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ). 
     
     
         25 . The process according to  claim 24  wherein X 1  is oxygen or N(R 10 ). 
     
     
         26 . The process according to  claim 25  wherein at least one of A 1 , A 2  or A 3  is substituted by (CR 10 R 20 ) n OR 6 . 
     
     
         27 . The process according to  claim 26  wherein q is 0, n is 0, and R 6  is hydrogen. 
     
     
         28 . The process according to  claim 11  wherein q is 0. 
     
     
         29 . The process according to  claim 28  wherein X 1  is N(R 10 ), and R 10  is hydrogen, and A 1  and A 2  are independently CH 2 OH. 
     
     
         30 . The process according to  claim 29  wherein A 3  is hydrogen. 
     
     
         31 . The process according to  claim 27  wherein X 1  is N(R 10 ), and R 10  is hydrogen. 
     
     
         32 . The process according to  claim 11  wherein the aryl ring of R 1  is optionally substituted one or more times, independently, by halogen, C 1-4  alkyl, halo-substituted-C 1-4  alkyl, cyano, nitro, (CR 10 R 20 ) v NR 4 R 14 , (CR 10 R 20 ) v C(Z)NR 4 R 14 , (CR 10 R 20 ) v C(Z)OR 8 , (CR 10 R 20 ) v COR a′ , (CR 10 R 20 ) v C(O)H, SR 5 , S(O)R 5 , S(O) 2 R 5 , (CR 10 R 20 ) v OR 8 , ZC(Z)R 11 , NR 10 C(Z)R 11 , or NR 10 S(O) 2 R 7 ; and wherein
 R 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4  alkyl, or 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 NR 9 ; 
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 4 R 14 , excluding the moieties SR 5  being SNR 4 R 14 , S(O) 2 R 5  being SO 2 H and S(O)R 5  being SOH; 
 R 7  is a 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 8  is hydrogen, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4  alkyl, heterocyclyl, heterocyclylC 1-4  alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7 , or (CR 10 R 20 ) t NR 4 R 14 ; and wherein the cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties may be optionally substituted; 
 R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl; 
 R 11  is C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4  alkyl, heterocyclyl, heterocyclylC 1-4  alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7  or (CR 10 R 20 ) v NR 4 R 14 ; and wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and heterocyclylalkyl moieties may be optionally substituted; 
 v is 0 or an integer having a value of 1 or 2; 
 t is an integer having a value of 1 to 3; 
 Z is oxygen or sulfur; 
 R a′  is C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-2  cycloalkyl, C 5-2  cycloalkenyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4  alkyl, heterocyclyl, heterocyclylC 1-4  alkyl, (CR 10 R 20 ) v OR 7 , (CR 10 R 20 ) v S(O) m R 7 , (CR 10 R 20 ) v NHS(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 , wherein the aryl, arylalkyl, heteroaryl, and heteroaryl alkyl may be optionally substituted. 
 
     
     
         33 . The process according to  claim 1  wherein R 1  is an optionally substituted phenyl. 
     
     
         34 . The process according to  claim 11  wherein R 1  is an optionally substituted phenyl. 
     
     
         35 . The process according to  claim 33  wherein the phenyl is optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         36 . The process according to  claim 34  wherein the phenyl is optionally substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         37 . The process according to  claim 36  wherein the R 1  phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         38 . The process according to  claim 36  wherein R 1  is 2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl. 
     
     
         39 . The process according to  claim 38  wherein R 1  is 2-methyl-4-fluorophenyl. 
     
     
         40 . The process according to  claim 1  wherein the compound of Formula (Ia) is 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof. 
     
     
         41 . A process of making a compound of the formula: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is an optionally substituted aryl ring; 
         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, which moieties are all optionally substituted, or R 2  is the moiety X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ), or C(A 1 )(A 2 )(A 3 ); 
         A 1  is an optionally substituted C 1-10  alkyl; 
         A 2  is an optionally substituted C 1-10  alkyl; 
         A 3  is hydrogen or is an optionally substituted C 1-10  alkyl; 
         R 3  is an optionally substituted aryl; 
         R 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4  alkyl, or 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 NR 9 ; 
         R 6  is 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 may be optionally substituted; 
         R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl; 
         R 10  and R 20  are independently selected from hydrogen or C 1-4 alkyl; 
         X is R 2 , OR 2 , S(O) m R 2 , (CH 2 ) n N(R 10 )S(O) m R 2 , (CH 2 ) n N(R 10 )C(O)R 2 , (CH 2 ) n NR 4 R 14 , or (CH 2 ) n N(R 2 ) 2 ; 
         X 1  is N(R 10 ), O, S(O) m , or CR 10 R 20 ; 
         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; 
         q is 0 or an integer having a value of 1 to 10; 
         Z is oxygen or sulfur; 
         or a pharmaceutically acceptable salt thereof; 
         which process comprises reacting a compound of the formula: 
       
       
         
           
           
               
               
           
         
         wherein 
         R 1  is an optionally substituted aryl; 
         R 3  is an optionally substituted aryl; and 
         R 12  is a C 1-10  alkyl, aryl, heteroaryl, or arylalkyl; 
         m is 0 or an integer having a value of 1 or 2; and 
         R 9  is a C 1-4  alkyl; 
         with heating in a suitable organic solvent, and optionally with a base; to yield a compound of Formula (Ia) wherein X is S(O)m-Rg and thereafter if necessary, converting X as S(O)m-Rg to another group X as defined in Formula (Ia), or a pharmaceutically acceptable salt thereof. 
       
     
     
         42 . The process according to  claim 41  wherein the organic solvent is an organic hydrocarbon, cresol, dioxane, DMF, pyridine, or xylene. 
     
     
         43 . The process according to  claim 42  wherein the base is diisopropyl ethylamine, pyridine, DBU, lithium bis(trimethylsilyl)amide, or LDA. 
     
     
         44 . The process according to  claim 41  wherein the base is diisopropyl ethylamine, pyridine, DBU, lithium bis(trimethylsilyl)amide, or LDA. 
     
     
         45 . The process according to  claim 41  wherein R 3  is an optionally substituted phenyl. 
     
     
         46 . The process according to  claim 41  wherein in the compound of Formula (Va) m is 0. 
     
     
         47 . The process according to  claim 41  wherein in the resulting compound of Formula (Ia) m is 0. 
     
     
         48 . The process according to  claim 47  wherein the compound of Formula (Ia) when m is 0, is oxidized to a compound of Formula (Ia) wherein m is 2. 
     
     
         49 . The process according to  claim 41  wherein in the compound of Formula (Ia):
 R 1  is an optionally substituted aryl ring; 
 R 2  is the moiety X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ); 
 A 1  is an optionally substituted C 1-10  alkyl; 
 A 2  is an optionally substituted C 1-10  alkyl; 
 A 3  is hydrogen or is an optionally substituted C 1-10  alkyl; and wherein A 1 , A 2 , and A 3 , excluding hydrogen, are optionally substituted 1 to 4 times by (CR 10 R 20 ) n OR 6 ; 
 R 3  is an optionally substituted aryl; 
 R 6  is hydrogen, or C 1-10  alkyl; 
 R 10  and R 20  are independently selected from hydrogen or C 1-4 alkyl; 
 X is R 2 ; 
 X 1  is N(R 10 ), O, S(O) m , or CR 10 R 20 ; 
 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; and 
 q is 0 or an integer having a value of 1 to 10. 
 
     
     
         50 . The process according to  claim 41  wherein X is (CH 2 ) n NR 4 R 14 , or (CH 2 ) n N(R 2 ) 2 . 
     
     
         51 . The process according to  claim 49  wherein R 3  is a phenyl ring optionally substituted one or more times independently with 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, halogen, cyano, nitro, (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 NHS(O) 2 R 7 , (CR 10 R 20 ) n NR 4 R 14 , (CR 10 R 20 ) n CN, (CR 10 R 20 ) n S(O) 2 NR 4 R 14 , (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 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)R 6 , (CR 10 R 20 ) n NR 10 C(═NR 10 )NR 4 R 14 , (CR 10 R 20 ) n OC(Z)NR 4 R 14 , (CR 10 R 20 ) n NR 10 C(Z)NR 4 R 14 , or (CR 10 R 20 ) n NR 10 C(Z)OR 7 ; and wherein R 7  is a 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 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4  alkyl, or 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 NR 9 ; 
 R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl; and 
 Z is oxygen or sulfur. 
 
     
     
         52 . The process according to  claim 51  wherein the R 3  optional substituent is independently selected from halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         53 . The process according to  claim 49  wherein R 3  is a phenyl ring, substituted one or more times independently by halogen, C 1-4  alkyl, or halo-substituted-C 1-4  alkyl. 
     
     
         54 . The process according to  claim 53  wherein the phenyl ring is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         55 . The process according to  claim 40  wherein R 3  is phenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2,6-difluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl. 
     
     
         56 . The process according to  claim 55  wherein R 3  is 2,6-difluorophenyl. 
     
     
         57 . The process according to  claim 49  wherein R 3  in Formula (Va) is a 2,6-difluorophenyl. 
     
     
         58 . The process according to  claim 49  wherein the R 1  in Formula (Va) is an optionally substituted phenyl. 
     
     
         59 . The process according to  claim 58  wherein the R 1  phenyl is substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         60 . The process according to  claim 59  wherein the R 1  phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         61 . The process according to  claim 49  wherein R 2  is the moiety X 1 (CR 10 R 20 ) q C(A 1 )(A 2 )(A 3 ). 
     
     
         62 . The process according to  claim 61  wherein X 1  is oxygen or N(R 10 ). 
     
     
         63 . The process according to  claim 62  wherein at least one of A 1 , A 2  or A 3  is substituted by (CR 10 R 20 ) n OR 6 . 
     
     
         64 . The process according to  claim 63  wherein q is 0, n is 0, and R 6  is hydrogen. 
     
     
         65 . The process according to  claim 49  wherein q is 0. 
     
     
         66 . The process according to  claim 65  wherein X 1  is N(R 10 ), and R 10  is hydrogen, and A 1  and A 2  are independently CH 2 OH. 
     
     
         67 . The process according to  claim 66  wherein A 3  is hydrogen. 
     
     
         68 . The process according to  claim 64  wherein X 1  is N(R 10 ), and R 10  is hydrogen. 
     
     
         69 . The process according to  claim 49  wherein R 1  is optionally substituted one or more times, independently, by halogen, C 1-4  alkyl, halo-substituted-C 1-4  alkyl, cyano, nitro, (CR 10 R 20 ) v NR 4 R 14 , (CR 10 R 20 ) v C(Z)NR 4 R 14 , (CR 10 R 20 ) v C(Z)OR 8 , (CR 10 R 20 ) v COR a′ , (CR 10 R 20 ) v C(O)H, SR 5 , S(O)R 5 , S(O) 2 R 5 , (CR 10 R 20 ) v OR 8 , ZC(Z)R 11 , NR 10 C(Z)R 11 , or NR 10 S(O) 2 R 7 ; and wherein
 R 4  and R 14  are each independently selected from hydrogen, optionally substituted C 1-4  alkyl, optionally substituted C 3-7  cycloalkyl, C 3-7  cycloalkylC 1-4 alkyl, optionally substituted aryl, or optionally substituted aryl-C 1-4  alkyl, or 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 NR 9 ; 
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 4 R 14 , excluding the moieties SR S  being SNR 4 R 14 , S(O) 2 R 5  being SO 2 H and S(O)R 5  being SOH; 
 R 7  is a 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 8  is hydrogen, C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4  alkyl, heterocyclyl, heterocyclylC 1-4  alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7 , or (CR 10 R 20 ) t NR 4 R 14 ; and wherein the cycloalkyl, cycloalkenyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclic and heterocyclic alkyl moieties may be optionally substituted; 
 R 9  is hydrogen, C(Z)R 6  or optionally substituted C 1-10  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl; 
 R 11  is C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4  alkyl, heterocyclyl, heterocyclylC 1-4  alkyl, (CR 10 R 20 ) t OR 7 , (CR 10 R 20 ) t S(O) m R 7 , (CR 10 R 20 ) t NHS(O) 2 R 7  or (CR 10 R 20 ) v NR 4 R 14 ; and wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl, heterocyclyl, and heterocyclylalkyl moieties may be optionally substituted; 
 v is 0 or an integer having a value of 1 or 2; 
 t is an integer having a value of 1 to 3; 
 Z is oxygen or sulfur; 
 R a′  is C 1-4  alkyl, halo-substituted C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4  alkyl, heterocyclyl, heterocyclylC 1-4  alkyl, (CR 10 R 20 ) v OR 7 , (CR 10 R 20 ) v S(O) m R 7 , (CR 10 R 20 ) v NHS(O) 2 R 7 , or (CR 10 R 20 ) v NR 4 R 14 , wherein the aryl, arylalkyl, heteroaryl, and heteroaryl alkyl may be optionally substituted. 
 
     
     
         70 . The process according to  claim 41  wherein R 1  is an optionally substituted phenyl. 
     
     
         71 . The process according to  claim 49  wherein R 1  is an optionally substituted phenyl. 
     
     
         72 . The process according to  claim 70  wherein the phenyl is substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         73 . The process according to  claim 71  wherein the phenyl is substituted one or more times independently by halogen, alkyl, hydroxy, alkoxy, amino, or halosubstituted alkyl. 
     
     
         74 . The process according to  claim 73  wherein the R 1  phenyl is substituted in the 2, 4, or 6-position, di-substituted in the 2,4-position, or tri-substituted in the 2,4,6-position. 
     
     
         75 . The process according to  claim 74  wherein R 1  is 2,4-difluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-methyl-4-fluorophenyl, or 2,4,6-trifluorophenyl. 
     
     
         76 . The process according to  claim 75  wherein R 1  is 2-methyl-4-fluorophenyl. 
     
     
         77 . The process according to  claim 41  wherein R 1  is 2-methyl-4-fluorophenyl. 
     
     
         78 . The process according to  claim 41  wherein the compound of Formula (Ia) is 8-(2,6-Difluoro-phenyl)-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one, or a pharmaceutically acceptable salt thereof.