Process for preparing pyrido[2,3-d]pyrimidin-7-one and 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one derivatives

• US 20060258687A1
• Filed: 03/24/2006
• Published: 11/16/2006
• Est. Priority Date: 03/25/2005
• Status: Active Grant

• Current Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Original Assignee: Glaxo Group Limited (Glaxosmithkline Holdings Ltd.)
• Inventors: Callahan, James F., Yan, Hongxing, Wan, Zehong, Boehm, Jeffrey C.
• Granted Patent: US 7,479,558 B2
• Time in Patent Office: Days
• US Class Current: 514/262.100
• 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 or NH: G2 is CH or nitrogen;
• Rx is chloro, bromo, iodo, or O—S(O)₂CF₃;
• R_g is a C_1-10alkyl; 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 the formula:

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 claims 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 1.

7. The compound according to claim 1 wherein Rx is chloro.

8. The compound according to 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-trifluoromethylphenyl, 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.

43. A process for making a compound of Formula (II) and (IIa) according to claim 1 wherein m=0, and G1 or G2 are CH, which comprises reacting a compound of the formula:

44. The process according to claim 43 wherein the olefin forming reagent is selected from Bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate, Bis(2,2,2-trifluoroethyl)-(ethoxycarbonylmethyl)phosphonate, Bis(2,2,2-trifluoroethyl)-(isopropoxycarbonylmethyl)phosphonate, (Diethoxy-phosphoryl)-acetic acid methyl ester, (Diisopropoxy-phosphoryl)-acetic acid methyl ester, (Diphenyloxy-phosphoryl)-acetic acid methyl ester, (Diethoxy-phosphoryl)-acetic acid ethyl ester, (Diisopropoxy-phosphoryl)-acetic acid ethyl ester, or (Diphenyloxy-phosphoryl)-acetic acid ethyl ester.

45. The process according to claim 44 wherein the base is selected from triethylamine, pyridine, diisopropyl ethyl amine, or pyrrolidone, or combinations thereof.

46. The process according to claims 43 wherein the process further comprises an organic solvent.

47. The process according to claim 46 wherein the solvent is chloroform, methylene chloride, acetonitrile, toluene, DMF, or n-methylpyrrolidine, or combinations thereof.

48. The process according to claim 43 wherein the olefin forming reagent is Bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate, and the base is triethylamine.

49. The process according to claim 43 wherein Rx is chloro.

50. The process according to claim 43 wherein Rg is methyl.

51. The process according to claim 43 which further comprises reacting the compound of formula (II) or (IIa) with an oxidizing agent to yield the corresponding sulfone or sulfoxide of formula (II), or (IIa) or a mixture thereof.

52. The process according to claim 51 wherein the oxidizing regent is 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodinate, potassium periodinate, Oxone, OsO4, catalytic tertiary amine N-oxide, a peracid, oxygen, ozone, an organic peroxide, an inorganic peroxide, potassium permanganate, zinc permanganate, potassium persulfate, or sodium hyperchlorite, or a combination of hydrogen peroxide and sodium tungstate, acetic acid or sodium hyperchlorite.

53. A process for making a compound of Formula (II), or (IIa) according to claim 1 wherein m=0, and G1 or G2 are CH, which comprises reacting a compound of the formula:

54. The process according to claim 53 wherein the aceylating agent is acetic anhydride or acetyl chloride.

55. The process according to claim 53 wherein the solvent is chloroform, tetrahydrofuran, methylene chloride, acetonitrile, toluene, DMF, n-methylpyrrolidine, or dioxane, or a combination or mixture thereof.

56. The process according to claim 53 wherein Rx is chloro.

57. The process according to claim 53 which further comprises reacting the compound of Formula (II) with an oxidizing agent to yield the corresponding sulfone or sulfoxide of Formula (II), or a mixture thereof.

58. The process according to claim 57 wherein the oxidizing regent is 3-chloroperoxybenzoic acid, hydrogen peroxide, sodium periodinate, potassium periodinate, Oxone, OsO4, catalytic tertiary amine N-oxide, a peracid, oxygen, ozone, peroxide, an organic peroxide, potassium permanganate, zinc permanganate, potassium persulfate, or sodium hyperchlorite.

59. A process for making a compound Formula (III), or (IIIa) according to claim 7, which process comprises reacting a compound of Formula (II) or (IIa) according to claim 1 with the compound X—

Y, wherein X is as defined for compounds of Formula (III), and Y is NH₂, NH(R₁₀), OH, or SH in an anhydrous organic solvent to yield a compound of Formula (III), provided that

a) X is R₂ and 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;

or

b) X is (CH₂)_n′

N(R_10′

)S(O)_mR_2′

, (CH₂)_n′

N(R_10′

)C(O)R_2′

, (CH₂)_n′

NR₄R₁₄, (CH₂)_n′

N(R_2′

)(R_2″

), and n′

is greater than 2.

60. The process according to claim 59 wherein the solvent methylene chloride, chloroform, acetonitrile, benzene, THF, hexane, ethyl ether, tert-butyl methyl ether, DMSO, DMF, toluene, DMF, acetone, n-methyl-pyrrolidine, or dioxane, or a combination or mixture thereof.

61. The process according to claim 59 which further comprises a base.

62. The process according to claim 61 wherein the base is triethyl amine, diisopropyl ethyl amine, NaH, n-Buli, tert-BuLi, tert-BuOK, Li₂CO₃, Cs₂CO₃ or pyridine.

63. A process for making a compound Formula (III), or (IIIa) according to claim 7, which comprises reacting a compound of Formula (II) or (IIa) according to claim 1 with the compound X—

Y, wherein X is as defined for compounds of Formula (III), and

Y is hydrogen, a metal, a boronic acid derivative, or a trialkyl tin derivative, in an anhydrous organic solvent which does not contain a nucleophile to yield a compound of Formula (III) or (IIIa);

provided that

when Y is hydrogen then

a) X═

OR_2′

, or X is S(O)_mR_2′

(and m=0);

or

b) X is (CH₂)_n′

N(R_10′

)S(O)_mR_2′

, (CH₂)_n′

N(R_10′

)C(O)R_2′

, (CH₂)_n′

NR₄R₄, or (CH₂)_n′

N(R_2′

)(R_2″

) and n′

=0;

or

c) X═

R₂ and R₂═

(CR₁₀R₂₀)_q′

X₁(CR₁₀R₂₀)_qC(A₁)(A₂)(A₃), q′

=0, and

X₁ is N(R_10′

), O, S(O)_m and m=0.

d) when X is N(R_10′

)—

R_h—

NH—

C(═

N—

CN)NRqRq′

; and

when Y is a metal, such as Li, Mg, or any other appropriate metal or metal complexes;

then

a) X is R₂, and R₂ is C_1-10 alkyl, C_3-7 cycloalkyl, C₃-₇ cycloalkylC_1-10 alkyl, aryl, arylC_1-10 alkyl, heteroaryl, heteroaryl C_1-10 alkyl, heterocyclic, or a heterocyclylC_1-10 alkyl moiety; and

when Y is a boronic acid, (B(OH)₂) or boronic ester derivatives

a) X═

R₂, and R₂=aryl, or heteroaryl; and

when Y is a trialkyl tin derivative, such as (C_1-4 alkyl)₃Sn, then

a) X═

R₂, and R₂=aryl, or heteroaryl.

64. The process according to claim 63 wherein the anhydrous organic solvent is selected from CH₂Cl₂, chloroform, CH₃CN, benzene, THF, hexane, ethyl ether, tert-butyl methyl ether, DMSO, DMF and toluene.

65. The process according to claim 63 which further comprises a base.

66. The process according to claim 65 wherein the base is triethyl amine, diisopropyl ethyl amine, NaH, n-Buli, tert-BuLi, tert-BuOK, Li₂CO₃, Cs₂CO₃ or pyridine.

67. A process to make a compound of Formula (I) and (Ia) as defined herein which comprises reacting a compound of Formula (III), or (IIIa) according to claim 7 with a coupling agent selected from an arylboronic acid, a heteroarylboronic acid or their corresponding boronic acid esters, with a palladium catalyst, in a solvent, to yield a compound of Formula (I) or (Ia).

68. The process according to claim 67 wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium (0), PdCl₂, Pd(OAc)₂, (CH₃CN)₂PdCl₂, Pd(dppf)₂, or [1,1′

-bis(diphenylphosphino)-ferrocene]-dichloropalladium(II).

69. The process according to claim 68 wherein the palladium catalyst is tetrakis(triphenylphosphine)palladium (0).

70. The process according to claim 67 wherein the solvent is dioxane, THF, DMF, DMSO, NMP, acetone, water, or a combination or a mixture thereof.

71. The process according to claim 70 wherein the solvent is THF and H₂O, or dioxane and H₂O.

72. The process according to claim 67 which further comprises a base.

73. The process according to claim 72 wherein the base is NaHCO₃, KHCO₃, Na₂CO₃, K₂CO₃, KOAc or a combination or mixture thereof.

74. The process according to claim 72 wherein the base is K₂CO₃ or KOAc or a combination or mixture thereof.

75. The process according to claim 67 wherein the arylboronic acid is R₁B(OH)₂, R₁B(O—

C_1-4 alkyl)₂, or

76. The process according to claim 75 wherein the phenyl ring is substituted by one or more times independently at each occurrence by halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, cyano, nitro, (CR₁₀R₂₀)_v′

NR_dR_d′

, (CR₁₀R₂₀)_v′

C(O)R₁₂, SR₅, S(O)R₅, S(O)₂R₅, or (CR₁₀R₂₀)_v′

OR₁₃, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, (CR₁₀R₂₀)_vC(Z)OR₈, (CR₁₀R₂₀)_vCOR_a′

, (CR₁₀R₂₀)_vC(O)H, ZC(Z)R₁₁, N(R_10′

)C(Z)R₁₁, N(R_10′

)S(O)₂R₇, C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b, C(Z)O(CR₁₀R₂₀)_vR_b, N(R_10′

)C(Z)(CR₁₀R₂₀)_vR_b;

N(R_10′

)C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b;

or N(R_10′

)OC(Z)(CR₁₀R₂₀)_vR_b; and

wherein

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, (CR₁₀R₂₀)_vOR₇, (CR₁₀R₂₀)_vS(O)_mR₇, (CR₁₀R₂₀)_v N(R_10′

)S(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄; and

wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;

R_b is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-10 alkyl, aryl, arylC_1-10alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic, or a heterocyclylC_1-10 alkyl moiety, which moieties excluding hydrogen, may all be optionally substituted;

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;

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;

R₈ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-4 alkyl, C_5-7 cycloalkenyl, C_5-7cycloalkenyl C_1-4 alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, or a heterocyclylC_1-4 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted independently at each occurrence;

R_9′

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

m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;

v is independently selected at each occurrence from 0, or an integer having a value of 1 to 2.

v′

is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;

R₄ and R₁₄ are each independently selected at each occurrence from hydrogen, C_1-10 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 heteroaryl C_1-4 alkyl;

or the R₄ and R₁₄ 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 nitrogen; and

wherein all of these moieties, excluding hydrogen, are 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 an optionally substituted 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR_9′

;

R₅ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl or NR_4′

R_14′

, excluding the moieties SR₅ being SNR_4′

R_14′

, S(O)₂R₅ being SO₂H and S(O)R₅ being SOH;

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

R_10′

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

R₁₁ is independently selected at each occurrence from hydrogen, or C_1-4 alkyl;

R₁₂ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-4 alkyl, C_5-7 cycloalkenyl, C_5-7cycloalkenyl C_1-4 alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, or heterocyclylC_1-4 alkyl, and wherein these moieties, excluding hydrogen, may be optionally substituted; and

R₁₃ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-4 alkyl, C_5-7 cycloalkenyl, C_5-7cycloalkenyl C_1-4 alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, or a heterocyclylC_1-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted.

77. The process according to claim 76 wherein the phenyl ring is substituted one or more times independently at each occurrence by halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_v′

OR₁₃, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b, and (CR₁₀R₂₀)_vC(Z)OR₈.

78. The process according to claim 77 wherein R₈ is hydrogen, or C_1-4 alkyl, R₁₃ is hydrogen, or C_1-4 alkyl, such as methyl;

Rb is suitably hydrogen, C_1-4 alkyl, aryl, or heteroaryl.

79. The proves according to claim 78 wherein the phenyl ring is substituted by 2-methoxy, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 2-fluoro, 3- fluoro, 4-fluoro, 4-difluoro, 2,4,6-trifluoro, 3,4-difluoro, 3,5-difluoro, 2-methyl-4-fluoro, 2-methyl-4-chloro, 2-methylsulfanyl, 3-methylsulfanyl, 4-methylsulfanyl, 2-phenyl, 3-phenyl, 4-phenyl, 2-methyl, 3-methyl, 4-methyl, 3-fluoro-4-phenyl, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2-methylsulfonyl, 3-methylsulfonyl, 4-methylsulfonyl, 3-N-cyclopropylamide, 2-methyl-3-fluoro-5-N-cyclopropylamide, 2-C(O)OH, 3-C(O)OH, 4-C(O)OH, 2-methyl-5-C(O)OH, 2-methyl-3-C(O)OH, 2-methyl-4-C(O)OH, 2-methyl-3-F-5-C(O)OH, 4-F-phenyl1-amide, 2-ethyl-5-C(O)OH, 2-ethyl-3-C(O)OH, 2-ethyl-4-C(O)OH, 2-methyl-5-dimethylamide, 2-methyl-4-dimethylamide, 5-dimethylamide, and 4-dimethylamide.

80. The process according to claim 77 wherein the phenyl is di-substituted independently at each occurrence by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

81. The process according to claim 75 wherein the aryl is phenyl, 2-methyl-4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, or 2-methyl-3-fluorophenyl, 2-methyl-4-fluorophenyl, and 2-methyl-4-chlorophenyl.

82. The process according to claim 75 wherein the phenyl is substituted in the 4- or 5-position by C(Z)N(R_10′

)(CR₁₀R₂₀)_v R_b, Z is oxygen, and R_b is an optionally substituted C_1-10alkyl, or an optionally substituted heteroaryl.

83. The process according to claim 82 wherein the phenyl ring is also substituted one or more times independently at each occurrence by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

84. The process according to claim 81 wherein the aryl is 4-methyl-N-1,3-thiazol-2-ylbenzamide, N-(4-fluorophenyl)-4-methylbenzamide, 4-methyl-N-isopropylbenzamide or 4-methyl-N-propylbenzamide.

85. A process for making compounds of Formula (I) and (Ia) as defined herein, which comprises reacting a compound of Formula (III) or (IIIa), according to claim 7 with an R₁—

ZnBr, R₁—

ZnCl, R₁—

Zn—

R1, (R₁)₂—

CuLi, R₁—

Sn(CH₃)₃, R₁—

Sn(CH₂CH₂CH₂CH₃)₃, or other R₁-organometallic reagents with an organic solvent, to yield a compound of Formula (I) or (Ia).

86. The process according to claim 85 wherein the solvent is dioxane, THF, methylene chloride, chloroform, benzene, hexane, ethyl ether, tert-butyl methyl ether or a combination or a mixture thereof.

87. The process according to claim 85 which further comprises a catalyst.

88. The process according to claim 87 wherein the catalyst is tetrakis(triphenylphosphine)palladium (0), PdCl₂, Pd(OAc)₂, (CH₃CN)₂PdCl₂, or Pd(dppf)₂.

89. The process according to claim 85 wherein the R₁-moiety in the organometallic reagent is a phenyl ring substituted by one or more times independently at each occurrence by halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, cyano, nitro, (CR₁₀R₂₀)_v′

NR_dR_d′

, (CR₁₀R₂₀)_v′

C(O)R₁₂, SR₅, S(O)R₅, S(O)₂R₅, or (CR₁₀R₂₀)_v′

OR₁₃, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, (CR₁₀R₂₀)_vC(Z)OR₈, (CR₁₀R₂₀)_vCOR_a′

, (CR₁₀R₂₀)_vC(O)H, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_vOR₈, ZC(Z)R₁₁, N(R_10′

)C(Z)R₁₁, N(R_10′

)S(O)₂R₇, C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b, C(Z)O(CR₁₀R₂₀)_vR_b, N(R_10′

)C(Z)(CR₁₀R₂₀)_vR_b;

N(R_10′

)C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b;

or N(R_10′

)OC(Z)(CR₁₀R₂₀)_vR_b; and

wherein

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, (CR₁₀R₂₀)_vOR₇, (CR₁₀R₂₀)_vS(O)_mR₇, (CR₁₀R₂₀)_v N(R_10′

)S(O)₂R₇, or (CR₁₀R₂₀)_vNR₄R₁₄; and

wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted;

R_b is hydrogen, C_1-10 alkyl, C_3-7 cycloalkyl, C_3-7 cycloalkylC_1-10 alkyl, aryl, arylC_1-10alkyl, heteroaryl, heteroarylC_1-10 alkyl, heterocyclic, or a heterocyclylC_1-10 alkyl moiety, which moieties excluding hydrogen, may all be optionally substituted;

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;

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;

R₈ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-4 alkyl, C_5-7 cycloalkenyl, C_5-7cycloalkenyl C_1-4 alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, or a heterocyclylC_1-4 alkyl moiety, and wherein these moieties, excluding hydrogen, may be optionally substituted independently at each occurrence;

R_9′

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

m is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;

v is independently selected at each occurrence from 0, or an integer having a value of 1 to 2.

v′

is independently selected at each occurrence from 0 or an integer having a value of 1 or 2;

R₄ and R₁₄ are each independently selected at each occurrence from hydrogen, C_1-10 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 heteroaryl C_1-4 alkyl;

or the R₄ and R₁₄ 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 nitrogen; and

wherein all of these moieties, excluding hydrogen, are 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 an optionally substituted 5 to 7 membered ring which optionally contains an additional heteroatom selected from oxygen, sulfur or NR_9′

;

R₅ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl or NR_4′

R_14′

, excluding the moieties SR₅ being SNR_4′

R_14′

, S(O)₂R₅ being SO₂H and S(O)R₅ being SOH;

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

R_10′

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

R₁₁ is independently selected at each occurrence from hydrogen, or C_1-4 alkyl;

R₁₂ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_3-7 cycloalkyl C_1-4 alkyl, C_5-7 cycloalkenyl, C_5-7cycloalkenyl C_1-4 alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, or heterocyclylC_1-4 alkyl, and wherein these moieties, excluding hydrogen, may be optionally substituted; and

R₁₃ is independently selected at each occurrence from hydrogen, C_1-4 alkyl, halo-substituted C_1-4 alkyl, C_2-4 alkenyl, C_2-4 alkynyl, C_3-7 cycloalkyl, C_3-7cycloalkylC_1-4 alkyl, C_5-7 cycloalkenyl, C_5-7cycloalkenyl C_1-4 alkyl, aryl, arylC_1-4 alkyl, heteroaryl, heteroarylC_1-4 alkyl, heterocyclyl, or a heterocyclylC_1-4 alkyl moiety, and wherein each of these moieties, excluding hydrogen, may be optionally substituted.

90. The process according to claim 89 wherein the phenyl ring is substituted one or more times independently at each occurrence by halogen, C_1-4 alkyl, halo-substituted-C_1-4 alkyl, SR₅, S(O)R₅, S(O)₂R₅, (CR₁₀R₂₀)_v′

OR₁₃, (CR₁₀R₂₀)_vC(Z)NR₄R₁₄, C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b, and (CR₁₀R₂₀)_vC(Z)OR₈.

91. The process according to claim 90 wherein R₈ is hydrogen, or C_1-4 alkyl, R₁₃ is hydrogen, or C_1-4 alkyl, such as methyl;

Rb is suitably hydrogen, C_1-4 alkyl, aryl, or heteroaryl.

92. The proves according to claim 78 wherein the phenyl ring is substituted by 2-methoxy, 3-methoxy, 4-methoxy, 2-chloro, 3-chloro, 4-chloro, 2-fluoro, 3- fluoro, 4-fluoro, 4-difluoro, 2,4,6-trifluoro, 3,4-difluoro, 3,5-difluoro, 2-methyl-4-fluoro, 2-methyl-4-chloro, 2-methylsulfanyl, 3-methylsulfanyl, 4-methylsulfanyl, 2-phenyl, 3-phenyl, 4-phenyl, 2-methyl, 3-methyl, 4-methyl, 3-fluoro-4-phenyl, 2-hydroxy, 3-hydroxy, 4-hydroxy, 2-methylsulfonyl, 3-methylsulfonyl, 4-methylsulfonyl, 3-N-cyclopropylamide, 2-methyl-3-fluoro-5-N-cyclopropylamide, 2-C(O)OH, 3-C(O)OH, 4-C(O)OH, 2-methyl-5-C(O)OH, 2-methyl-3-C(O)OH, 2-methyl-4-C(O)OH, 2-methyl-3-F-5-C(O)OH, 4-F-phenyl1-amide, 2-ethyl-5-C(O)OH, 2-ethyl-3-C(O)OH, 2-ethyl-4-C(O)OH, 2-methyl-5-dimethylamide, 2-methyl-4-dimethylamide, 5-dimethylamide, and 4-dimethylamide.

93. The process according to claim 89 wherein the phenyl ring is substituted one or more times independently at each occurrence by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

94. The process according to claim 93 wherein the phenyl is di-substituted independently at each occurrence by fluorine or methyl.

95. The process according to claim 87 wherein the aryl is phenyl, 2-methyl-4-fluorophenyl, 2-methylphenyl, 2-chlorophenyl, 2-fluorophenyl, 2-methyl-4-chlorophenyl, or 2-methyl-3-fluorophenyl.

96. The process according to claim 87 wherein the phenyl is substituted in the 4- or 5-position by C(Z)N(R_10′

)(CR₁₀R₂₀)_vR_b, Z is oxygen, and R_b is an optionally substituted C_1-10alkyl, or an optionally substituted heteroaryl.

97. The process according to claim 96 wherein the phenyl ring is also substituted one or more times independently at each occurrence by halogen, C_1-4 alkyl, or halo-substituted-C_1-4 alkyl.

98. The process according to claim 83 wherein the aryl is 4-methyl-N-1,3-thiazol-2-ylbenzamide, N-(4-fluorophenyl)-4-methylbenzamide, 4-methyl-N-isopropylbenzamide or 4-methyl-N-propylbenzamide.

13. A compound of the formula:

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 18 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 occurence, 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 N(R_10′

), q is 1 or 2, 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 maybe 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 (CH₂)_nN(R_2′

)(R_2″

), and R_2′

is an optionally substituted C_1-10 alkyl, cycloalkyl, heterocyclic, heterocyclyl C_1-10 alkyl, 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_3-7cycloalkylC_1-10alkyl, C_5-7cycloalkenyl, C_5-7 cycloalkenylC_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_1-10 alkyl;

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)ORj;

(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 heteroC_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_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_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_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 27 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(R_10′

)C(Z)OR₇.

30. The compound according to claim 13 wherein the (CH₂)_nN(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′

.

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)_nN(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)aminopropylamine, 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_2-10alkynyl, C_3-7cycloalkyl, C_3-7cycloalkylC_1-10alkyl, 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′

l)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_1-10 alkyl.

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;

5-chloro-7-{[3-(diethylamino)propyl]amino}-1-(2,6-difluorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H )-one trifluoroacetate;

5-chloro-1-(2,6-difluorophenyl)-7-[4-(1-pyrrolidinyl)-1-piperidinyl]-3,4-dihydropyrimido[4,5-d]pyrimidin-2( 1H)-one;

or

5-chloro-1-(2,6-difluorophenyl)-7-{[2-(dimethylamino)ethyl]amino}-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.

41. A compound of the formula:

42. The compound according to claim 41 wherein Rg is methyl.