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

• US 20090048444A1
• Filed: 10/17/2008
• Published: 02/19/2009
• Est. Priority Date: 03/25/2005
• Status: Abandoned Application

• Current Assignee: Glaxo Group Limited (GSK plc)
• Original Assignee: Glaxo Group Limited (GSK plc)
• Inventors: Callahan, James F., Yan, Hongxing, Wan, Zehong, Boehm, Jeffrey C., Lin, Xichen
• Application Number:
  US12/253,327
• Publication Number:
  US 20090048444A1
• Time in Patent Office: Days
• US Class Current: 544/256
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 471/04 Ortho-condensed systems
• CPC Class Codes: C07D 487/04 Ortho-condensed systems

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 CH₂;
• G2 is CH;
• Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;
• R_g is a C_1-10 alkyl;
• m is 0, or an integer having a value of 1, or 2;
• R₃ 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)₂CF₃; 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.

Claims

1. A compound of formula (II):

wherein

G1 is CH₂;

G2 is CH;

Rx is chloro, bromo, iodo, or O—

S(O)₂CF₃;

Rg is a C_1-10 alkyl;

m is 0, or an integer having a value of 1, or 2;

R₃ 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 R₃ is an optionally substituted aryl.

9. The compound according to claim 8 wherein R₃ 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 R₃ is a phenyl substituted one or more times independently by fluorine, chlorine, or methyl.

11. The compound according to claim 8 wherein R₃ 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.

41. The compound according to claim 2 wherein R₉ is methyl.

42. The compound according to claim 3 wherein R₉ 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 R₃ is phenyl or a phenyl substituted one or more times independently by fluorine, chlorine, or methyl.

50. The compound according to claim 49 wherein R₃ 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 R₃ is phenyl or a phenyl substituted one or more times independently by fluorine, chlorine, or methyl.

52. The compound according to claim 51 wherein R₃ is phenyl, 4-trifluoromethyl-phenyl, 2-fluorophenyl, 2,6-difluoro-phenyl, 2,4-difluoro-phenyl, 2-chlorophenyl, 2-methylphenyl, or 2,6-dimethylphenyl.

13. A compound of the formula:

wherein

G1 is —

CH₂;

G2 is CH;

Rx is chloro, bromo, iodo, or O—

S(O)₂CF₃;

X is R₂, OR_2″

, S(O)_mR_2″

, (CH₂)_n′

N(R₁₁)S(O)_mR_2′

, (CH₂)_n′

N(R₁₁)C(O)R_2′

, (CH₂)_nNR₄R₁₄, or (CH₂)_n′

N(R_2′

)(R_2″

), or N(R_10′

)—

R_h—

NH—

C(═

N—

CN)NRqRq′

;

X₁ is N(R₁₁), O, S(O)_m, or CR₁₀R₂₀;

R_h is selected from an optionally substituted C_1-10 alkyl, —

CH₂—

C(O)—

CH₂—

, —

CH₂CH₂—

O—

CH₂—

CH₂—

, —

CH₂—

C(O)N(R_10′

)CH₂—

CH₂—

, —

CH₂—

N(R_10′

)C(O)CH₂—

, —

CH₂—

CH(OR_10′

)—

CH₂, —

CH₂—

C(O)O—

CH₂—

CH₂—

, or —

CH₂—

CH₂—

O—

C(O)CH₂—

;

R_q and R_q′

are independently selected at each occurrence from hydrogen, C_1-10 alkyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-10alkyl, C_5-7 cycloalkenyl, C_5-7 cycloalkenyl-C_1-10alkyl, 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;

R₂ 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 R₂ is the moiety (CR₁₀R₂₀)_q′

X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃);

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 (CR₁₀R₂₀)_tX₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃);

A₁ 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;

A₂ 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;

A₃ is hydrogen or is an optionally substituted C_1-10 alkyl;

R₃ 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;

R₄ and R₁₄ are each independently selected from hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-4alkyl, 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 R₄ and R₁₄ 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;

R₁₀ and R₂₀ are independently selected from hydrogen or C_1-4alkyl;

R_10′

is independently selected at each occurrence from hydrogen or C_1-4alkyl;

R₁₁ is independently selected from hydrogen or C_1-4alkyl;

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 R₃ is an optionally substituted aryl.

18. The compound according to claim 17 wherein R₃ 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 R₃ is phenyl substituted one or more times independently by fluorine, chlorine or methyl.

20. The compound according to claim 13 wherein R₃ 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 R₂, and R₂ is (CR₁₀R₂₀)_q′

X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), or C(A₁)(A₂)(A₃).

22. The compound according to claim 21 wherein at least one of A₁, A₂ or A₃ is a C_1-10 alkyl substituted by (CR₁₀R₂₀)_nOR₆;

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;

R₆ 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_1-10alkyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

S(O)_m alkyl;

C(O);

NR_4′

R_14′

;

C_1-10 alkyl;

C_3-7cycloalkyl;

C_3-7cycloalkyl 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)_malkyl, amino, mono &

di-substituted C_1-4 alkyl amino, C_1-4 alkyl, or CF₃;

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 X₁ is N(R_10′

), q is 0 or 1, q′

is 0, and R₆ is hydrogen.

24. The compound according to claim 13 wherein X is (CH₂)_n′

NR₄R₁₄, or (CH₂)_n′

N(R_2′

)(R_2″

).

25. The compound according to claim 24 wherein X is (CH₂)_n′

NR₄R₁₄, and R₄ and R₁₄ 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_1-10alkyl; 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 (CH₂)_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 R₂, 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_3-7cycloalkylC_1-10alkyl, C_5-7cycloalkenyl, 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, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR_eR_e′

, (CR₁₀R₂₀)_nNR_eR_e′

C_1-4alkylNR_eR_e′

, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR_eR_e′

, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR_eR_e′

, (CR₁₀R₂₀)_nC(═

NOR₆) NR_eR_e′

, (CR₁₀R₂₀)_nOC(Z) NR_eR_e′

, (CR₁₀R₂₀)_nN(R_10′

)C(Z) NR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R₆ is independently selected at each occurrence from hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or heteroarylC_1-10 alkyl, wherein each of these moieties, excluding hydrogen are optionally substituted;

R₇ is independently selected at each occurrence from C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl 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_1-4alkyl, 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_1-10alkyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

amino, mono &

di-substituted C_1-4 alkyl amino, S(O)_mR_f;

C(O)R_j;

C(O)O R_j;

(CR₁₀R₂₀)_nN(R₁₀)C(Z)OR₇;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_dR_d′

;

C(O)NR_4′

R_14′

;

NR_4′

C(O)C_1-10alkyl;

NR_4′

C(O)aryl;

cyano;

nitro;

C_1-10 alkyl;

C_3-7cycloalkyl;

C_3-7cycloalkyl C_1-10 alkyl;

halosubstituted C_1-10 alkyl;

aryl, aryl C_1-4 alkyl, heterocyclic, heterocyclicC_1-4 alkyl, heteroaryl, or heteroarylC_1-4alkyl, 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)_malkyl, amino, mono &

di-substituted C_1-4 alkyl amino, C_1-4 alkyl, or CF₃;

R_d and R_d′

are each independently selected from hydrogen, C_1-4 alkyl, C_3-5 cycloalkyl, C_3-5 cycloalkylC_1-4alkyl, 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_3-6cycloalkyl, C_3-6cycloalkylC_1-4 alkyl, and the R₄ and R₁₄ cyclized ring are optionally substituted, 1 to 4 times, independently by halogen;

halosubstituted C_1-4 alkyl;

hydroxy;

hydroxy substituted C_1-4alkyl;

C_1-4 alkoxy;

halosubstituted C_1-4 alkoxy;

S(O)_mR_f;

C(O)R_j;

;

C(O)O R_j;

C(O)NR_4′

R_14′

, NR_4′

C(O)C_1-4alkyl;

S(O)₂NR_4′

R_14′

OC_1-4 alkyl;

NR_4′

R_14′

S(O)₂C_1-4 alkyl;

or NR_4′

R_14′

;

R_f is independently selected at each occurrence from C_1-10alkyl, aryl, aryl C_1-10alkyl, heteroaryl, heteroaryl C_1-10alkyl, heterocyclic, or a heterocyclic C_1-10alkyl moiety, and wherein these moieties may all be optionally substituted;

R_f′

is independently selected at each occurrence from hydrogen, C_1-10alkyl, aryl, aryl C_1-10alkyl, heteroaryl, heteroaryl C_1-10alkyl, heterocyclic, heterocyclic C_1-10alkyl, 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_1-4alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl 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, (CR₁₀R₂₀)_nNR_eR_e′

, or (CR₁₀R₂₀)_nN(R₁₀)C(Z)OR₇.

30. The compound according to claim 13 wherein the (CH₂)_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 (CR₁₀R₂₀)_nNR_eR_e′

or (CR₁₀R₂₀)_nNR_eR_e′

C_1-4alkylNR_eR_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_1-14alkyl, 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_1-10alkyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

amino, mono &

di-substituted C_1-4 alkyl amino, S(O)_mR_f′

;

C(O)R_j;

C(O)OR_j;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_dR_d′

;

C(O)NR_4′

R_14′

;

NR_4′

C(O)C_1-10alkyl;

NR_4′

C(O)aryl;

cyano;

nitro;

C_1-10 alkyl;

C_3-7cycloalkyl;

C_3-7cycloalkyl C_1-10 alkyl;

halosubstituted C_1-10 alkyl;

aryl, aryl C_1-4 alkyl, heterocyclic, heterocyclicC_1-4 alkyl, heteroaryl, or heteroarylC_1-4alkyl, 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)_malkyl, amino, mono &

di-substituted C_1-4 alkyl amino, C_1-4 alkyl, or CF₃;

R_d and R_d′

are each independently selected from hydrogen, C_1-4 alkyl, C_3-5 cycloalkyl, C_3-5 cycloalkylC_1-4alkyl, 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_3-6cycloalkyl, C_3-6cycloalkylC_1-4 alkyl, and the R₄ and R₁₄ cyclized ring are optionally substituted, 1 to 4 times, independently by halogen;

halosubstituted C_1-4 alkyl;

hydroxy;

hydroxy substituted C_1-4alkyl;

C_1-4 alkoxy;

halosubstituted C_1-4 alkoxy;

S(O)_mRf, C(O)R_j;

C(O)O R_j;

C(O)NR_4′

R_14′

NR_4′

C(O)C_1-4alkyl;

S(O)₂NR_4′

R_14′

C_1-4 alkyl;

NR_4′

R_14′

S(O)₂C_1-4 alkyl;

or N_4′

R_14′

;

R_f is independently selected at each occurrence from C_1-10alkyl, aryl, aryl C_1-10 alkyl, heteroaryl, heteroaryl C_1-10alkyl, 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_1-10alkyl, aryl, aryl C_1-10alkyl, heteroaryl, heteroaryl C_1-10alkyl, heterocyclic, heterocyclic C_1-10alkyl, 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_1-4alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl 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 (CH₂)_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 R₃ 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_3-7cycloalkyl, C_3-7cycloalkylC_1-10 alkyl, C_5-7cycloalkenyl, C_5-7cycloalkenylC_1-10 alkyl, (CR₁₀R₂₀)_nOR₆, (CR₁₀R₂₀)_nSH, (CR₁₀R₂₀)_nS(O)_mR₇, (CR₁₀R₂₀)_nN(R_10′

)S(O)₂R₇, (CR₁₀R₂₀)_nNR₁₆R₂₆, (CR₁₀R₂₀)_nCN, (CR₁₀R₂₀)_nS(O)₂NR₁₆R₂₆, (CR₁₀R₂₀)_nC(Z)R₆, (CR₁₀R₂₀)_nOC(Z)R₆, (CR₁₀R₂₀)_nC(Z)OR₆, (CR₁₀R₂₀)_nC(Z)NR₁₆R₂₆, (CR₁₀R₂₀)_nN(R_10′

)C(Z)R₆, (CR₁₀R₂₀)_nN(R_10′

)C(═

N(R_10′

))NR₁₆R₂₆, (CR₁₀R₂₀)_nOC(Z) NR₁₆R₂₆, (CR₁₀R₂₀)_nN(R_10′

)C(Z) NR₁₆R₂₆, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; and

wherein

R₆ is independently selected from hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, heterocyclyl, heterocyclyl C_1-10alkyl, aryl, arylC_1-10 alkyl, heteroaryl or a heteroarylC_1-10 alkyl moiety, and wherein these moieties, excluding hydrogen may be optionally substituted;

R₇ is C_1-6alkyl, aryl, arylC_1-6alkyl, heterocyclic, heterocyclylC_1-6 alkyl, heteroaryl, or heteroarylC_1-6alkyl; 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;

R₁₀ and R₂₀ are independently selected at each occurrence from hydrogen or C_1-4 alkyl;

R₁₆ and R₂₆ are each independently selected from hydrogen, or C_1-4 alkyl;

or the R₁₆ and R₂₆ 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 R₃ 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_1-10alkyl, (CR₁₀R₂₀)_nOR₆, cyano, nitro, (CR₁₀R₂₀)_nNR₁₆R₂₆, or halosubstituted C_1-10alkyl.

37. The compound according claim 24 wherein the phenyl is substituted one or more times by halogen, hydroxy, alkoxy, amino or CF₃.

38. The compound according to claim 36 wherein R₃ 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.

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 R₃ is an optionally substituted aryl.

56. The compound according to claim 55 wherein R₃ 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 R₃ is phenyl, or phenyl substituted one or more times independently by fluorine, chlorine or methyl.

58. The compound according to claim 54 wherein R₃ 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 R₃ 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 R₂.

64. The compound according to claim 63 wherein R₂ 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 R₂ is an optionally substituted one or mores times independently by an optionally substituted heterocyclic, heterocyclic alkyl, aryl, arylalkyl, alkyl, (CR₁₀R₂₀)_nNR_eR_e′

, or (CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇; 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_1-4alkyl, 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_1-10alkyl;

C_1-10 alkoxy;

halosubstituted C_1-10 alkoxy;

amino, mono &

di-substituted C_1-4 alkyl amino, S(O)_mR_f′

;

C(O)R_j;

C(O)OR_j;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)OR₇;

(CR₁₀R₂₀)_nN(R_10′

)C(Z)NR_dR_d′

;

C(O)NR_4′

R_14′

;

NR_4′

C(O) C_1-10alkyl;

NR_4′

C(O)aryl;

cyano;

nitro;

C_1-10 alkyl;

C_3-7cycloalkyl;

C_3-7cycloalkyl C_1-10 alkyl;

halosubstituted C_1-10 alkyl;

aryl, aryl C_1-4 alkyl, heterocyclic, heterocyclicC_1-4 alkyl, heteroaryl, or heteroarylC_1-4alkyl, 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)_malkyl, amino, mono &

di-substituted C_1-4 alkyl amino, C_1-4 alkyl, or CF₃;

R_d and R_d′

are each independently selected from hydrogen, C_1-4 alkyl, C_3-5 cycloalkyl, C_3-5 cycloalkylC_1-4alkyl, 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_3-6cycloalkyl, C_3-6cycloalkylC_1-4 alkyl, and the R₄ and R₁₄ cyclized ring are optionally substituted, 1 to 4 times, independently by halogen;

halosubstituted C_1-4 alkyl;

hydroxy;

hydroxy substituted C_1-4alkyl;

C_1-4 alkoxy;

halosubstituted C_1-4 alkoxy;

S(O)_mR_f, C(O)R_j;

C(O)O R_j;

C(O)NR_4′

R_14′

, NR_4′

C(O)C_1-4alkyl;

S(O)₂NR_4′

R_14′

C_1-4 alkyl;

NR_4′

R_14′

S(O)₂C_1-4 alkyl;

or NR_4′

R_14′

;

R_f is independently selected at each occurrence from C_1-10alkyl, aryl, aryl C_1-10alkyl, heteroaryl, heteroaryl C_1-10alkyl, heterocyclic, or a heterocyclic C_1-10alkyl moiety, and wherein these moieties may all be optionally substituted;

R_f′

is independently selected at each occurrence from hydrogen, C_1-10alkyl, aryl, aryl C_1-10alkyl, heteroaryl, heteroaryl C_1-10alkyl, heterocyclic, heterocyclic C_1-10alkyl, 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_1-4alkyl, aryl, aryl C_1-4alkyl, heteroaryl, heteroaryl C_1-4alkyl, heterocyclic, or a heterocyclic C_1-4alkyl 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 R₂ optionally substituted heterocyclic is selected from an optionally substituted morpholino, piperidine, or pyrrolidinyl.

67. The compound according to claim 64 wherein R₂ is an optionally substituted piperidinyl or piperazinyl ring.

68. The compound according to claim 63 wherein R₂ 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 R₂ is 4-methyl-1,4′

-bipiperidin-1′

-yl, or (1-pyrrolidinyl)-1-piperidinyl.