Abstract:
The present invention comprises pyridopyrimidinediamine compounds of the general formula I: 
     
       
                 
         
             
             
         
       
     
     The compounds of the present invention are potent inhibitors of PTP1B. Accordingly, the invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP-1B mediated diseases, including diabetes, obesity, and diabetes-related diseases.

Description:
PRIORITY TO RELATED APPLICATIONS 
       [0001]    This application is a continuation of U.S. application Ser. No. 11/488,863, filed Jul. 18, 2006, now Pending; which claims the benefit of U.S. Provisional Application No. 60/701,467, filed Jul. 21, 2005, which is hereby incorporated by reference in its entirety. 
     
    
     BACKGROUND OF THE INVENTION 
       [0002]    Protein tyrosine phosphatases (PTPases) are key enzymes in processes that regulate cell growth and differentiation. The inhibition of these enzymes can play a role in the modulation of multiple signaling pathways in which tyrosine phosphorylation dephosphorylation plays a role. PTP1B is a particular protein tyrosine phosphatase that is often used as a prototypical member of that class of enzymes. Kennedy et al., 1999, Science 283: 1544-1548 showed that protein tyrosine phosphatase PTP-1B is a negative regulator of the insulin signaling pathway, suggesting that inhibitors of this enzyme may be beneficial in the treatment of diabetes. 
         [0003]    PTPase inhibitors are recognized as potential therapeutic agents for the treatment of diabetes. See, e.g. Moeller et al., 3(5):527-40, Current Opinion in Drug Discovery and Development, 2000; or Zhang, Zhong-Yin, 5:416-23, Current Opinion in Chemical Biology, 2001. The utility of PTPase inhibitors as therapeutic agents has been a topic of discussion in several review articles, including, for example, Expert Opin Investig Drugs 12(2):223-33, February 2003. 
         [0004]    Inhibitors of PTP-1B have utility in controlling or treating Type 1 and Type 2 diabetes, in improving glucose tolerance, and in improving insulin sensitivity in patients in need thereof. 
       SUMMARY OF THE INVENTION 
       [0005]    The present invention comprises pyridopyrimidinediamine compounds of the general formula I: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0006]    The compounds of the present invention are potent inhibitors of PTP1B. Accordingly, the invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP-1B mediated diseases, including diabetes, obesity, and diabetes-related diseases. 
     
    
     DETAILED DESCRIPTION OF THE INVENTION 
       [0007]    The present invention comprises compounds of the formula I: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    wherein X is a group X-1 of the formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or X is a group X-2 of the formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    or X is a group X-3 of the formula: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0000]    R 1  and R 2  are each independently selected from the group consisting of hydrogen, lower alkyl, methoxy lower alkyl and hydroxy lower alkyl, except that
 
R 1  and R 2  may not both be hydrogen;
 
R 3  is hydrogen, lower alkyl or phenyl;
 
R 4  is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl, carboxy, or together with R 5  forms a 5-7 membered carbocyclic ring;
 
R 5  when not in a ring with R 4  is hydrogen, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, hydroxy, carboxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, cyano, nitro, lower alkanoyl, aryl, aroyl, aryloxy, arylthio, lower alkylamino, lower alkanoylamino, sulfonylamino, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heteroaryl, or together with R 6  forms a 5 or 6 membered aromatic ring;
 
R 6  when not in a ring with R 5  is hydrogen, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, hydroxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, cyano, nitro, lower alkanoyl, aryl, aroyl, aryloxy, lower alkylamino, lower alkanoylamino, sulfonylamino, cycloalkyl, heterocyclyl, heterocyclyloxy or heterocyclylcarbonyl;
 
R 7  is hydrogen, lower alkyl, lower alkoxy, alkoxy lower alkyl, alkoxy lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, perfluoro lower alkyl, lower alkanoyl, aroyl or lower alkanoylamino;
 
R 8  and R 9  are each independently selected from the group consisting of hydrogen, lower alkyl, substituted lower alkyl, lower alkoxy, substituted lower alkoxy, hydroxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, aminosulfonyl, cyano, nitro, lower alkanoyl, aryl, aroyl, aryloxy, arylthio, lower alkylamino, lower alkanoylamino, sulfonylamino, cycloalkyl, cycloalkoxy, heteroaryl, heterocyclyl, heterocyclyloxy and heterocyclylcarbonyl;
 
P is a 5 or 6 membered heteroaromatic ring containing from 1 to 2 hetero atoms selected from the group consisting of oxygen, sulfur and nitrogen;
 
R 10  and R 11  are each independently selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, perfluoro lower alkyl, halogen, aryl lower alkyl, aryl and aryl lower alkoxy;
 
Q is a 3-6 membered cycloalkyl ring; and
 
R 12  is hydrogen or aryl;
 
and the pharmaceutically acceptable salts or esters of the foregoing.
 
         [0008]    It is preferred that the lower alkyl, methoxy lower alkyl, and hydroxy lower alkyl groups of R 1  and R 2  have up to 4 carbon atoms with C1-4 alkyl and hydroxy C1-3 alkyl being more preferred; and it is most preferable that one of R 1  or R 2  is hydrogen. 
         [0009]    R 3  and R 4  are preferably hydrogen. Preferred substituents for R 5  and R 9  are hydrogen, halogen, lower alkyl, lower alkoxy, alkoxy lower alkoxy, nitro, hydroxy, hydroxy lower alkoxy, hydroxy lower alkyl, lower alkylthio, lower alkylamino, lower alkyl sulfonyl, lower alkyl sulfinyl, perfluoro lower alkyl, cycloalkyl, cycloalkoxy, aryl, heteroaryl, aryloxy, arylthio and heterocyclyl. Chlorine, fluorine, trifluoromethyl, C1-4 alkyl, C1-3 alkylthio, C1-3 alkylsulfonyl, C1-3 alkoxy, C1-3 alkoxy substituted with a group selected from hydroxy, methoxy and ethoxy, phenoxy and phenoxy mono-substituted with fluorine, chlorine or oxygen are still more preferred. Preferred substituents for R 6  and R 8  are hydrogen, halogen, lower alkyl, lower alkoxy, alkoxy lower alkoxy, nitro, hydroxy, hydroxy lower alkoxy, hydroxy lower alkyl, lower alkylthio, lower alkylamino, lower alkyl sulfonyl, and perfluoro lower alkyl. Hydrogen, chlorine, fluorine, trifluoromethyl, C1-4 alkyl, C1-3 alkylthio, C1-3 alkylsulfonyl, C1-3 alkoxy, C1-3 alkoxy substituted with a group selected from hydroxy, methoxy and ethoxy are further preferred. Hydrogen is more preferred. R 7  is preferably hydrogen, lower alkyl and perfluoro lower alkyl. Hydrogen is most preferred. 
         [0010]    As used in this specification, the term “lower alkyl”, alone or in combination (for example, as part of “lower alkanoyl,” below), means a straight-chain or branched-chain alkyl group containing a maximum of six carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec. butyl, isobutyl, tert.butyl, n-pentyl, n-hexyl and the like. 
         [0011]    “Substituted lower alkyl” means lower alkyl as defined substituted by one or more groups selected independently from cycloalkyl, nitro, aryloxy, aryl, heteroaryl, hydroxy, halogen, cyano, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and substituted amino, e.g., dimethylamino. Preferred substituents are hydroxy, halogen, nitro, lower alkoxy, phenoxy, phenyl and lower alkylthio. Examples of substituted lower alkyl groups include 2-hydroxyethyl, 2-methoxypropyl, 3-oxobutyl, cyanomethyl, trifluoromethyl, 2-nitropropyl, benzyl, including p-chloro-benzyl and p-methoxy-benzyl, and 2-phenyl ethyl. The term “hydroxy lower alkyl” means a lower alkyl group which is mono- or di-substituted with hydroxy. 
         [0012]    The term “cycloalkyl” means an unsubstituted or substituted 3- to 6-membered carbocyclic ring. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, substituted lower alkyl, aroyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, aryl, heteroaryl and substituted amino. Preferred substitutents are hydroxy, halogen, lower alkoxy, lower alkyl, phenyl and benzyl. 
         [0013]    The term “heterocyclyl” means an unsubstituted or substituted 5- to 6-membered carbocyclic ring in which one or two of the carbon atoms has been replaced by heteroatoms independently selected from O, S and N. “Heterocyclyl carbonyl” means a heterocyclyl group which is bonded to the rest of the molecule via a carbonyl group. Preferred heterocyclyl groups are pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl. Substituents useful in accordance with the present invention are hydroxy, halogen, cyano, lower alkoxy, lower alkanoyl, lower alkyl, substituted lower alkyl, substituted lower alkoxy, aroyl, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cycloalkyl, aryl, heteroaryl and substituted amino. Preferred substitutents useful in accordance with the present invention are hydroxy, halogen, lower alkoxy, lower alkyl and benzyl. 
         [0014]    The term “lower alkoxy” means a lower alkyl group (as defined above) bonded through an oxygen atom. Examples of unsubstituted lower alkoxy groups are methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy and the like. “Substituted lower alkoxy” means a lower alkoxy group substituted as described for lower alkyl. “Alkoxy lower alkoxy” means a lower alkoxy group substituted with a C1-3 alkoxy. “Hydroxyalkoxy” means a lower alkoxy group which is mono- or disubstituted with hydroxy. 
         [0015]    The term “lower alkylthio” means a lower alkyl group bonded through a divalent sulfur atom, for example, a methyl mercapto or an isopropyl mercapto group. The term “lower alkylsulfinyl” means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfinyl group. The term “lower alkylsulfonyl” means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfonyl group. 
         [0016]    The term “aryl” means a monocyclic aromatic group, such as phenyl, which is unsubstituted or substituted by one to three conventional substituent groups preferably selected from lower alkyl, lower alkoxy, hydroxy lower alkyl, hydroxy, hydroxyalkoxy, halogen, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, cyano, nitro, perfluoro lower alkyl, alkanoyl, phenyl, aroyl, aryl alkynyl, heteroaryl, lower alkynyl and lower alkanoylamino. Examples of aryl groups that may be used in accordance with this invention are unsubstituted phenyl, m- or o-nitrophenyl, p-tolyl, m- or p-methoxyphenyl, 3,4-dimethoxyphenyl, p-chlorophenyl, p-cyanophenyl, m-methylthiophenyl, 2-methyl-5-nitrophenyl, 2,6-dichlorophenyl, m-perfluorophenyl, and the like. 
         [0017]    The term “aryloxy” means an aryl group, as hereinbefore defined which is bonded via an oxygen atom. “Arylthio” is aryl bonded via a sulfur atom. 
         [0018]    The term “heteroaryl” means an unsubstituted or substituted 5- or 6-membered monocyclic heteroaromatic ring containing one to three heteroatoms which are independently N, S or O. Examples are pyridyl, thienyl, pyrimidinyl, oxazolyl, and furyl. Substituents as defined above for “aryl” are included in the definition of heteroaryl. 
         [0019]    The term “perfluoro lower alkyl” means a lower alkyl group wherein all the hydrogens of the lower alkyl group are replaced by fluorine. Preferred perfluoro lower alkyl groups are trifluoromethyl and pentafluoroethyl. 
         [0020]    The term “lower alkanoyl” means lower alkyl groups bonded to the rest of the molecule via a carbonyl group and embraces in the sense of the foregoing definition groups such as acetyl, propionyl and the like. The term “perfluoro lower alkanoyl” means a perfluoro lower alkyl group which is bonded to the rest of the molecule via a carbonyl group. “Lower alkanoylamino” means a lower alkanoyl group bonded to the rest of the molecule via an amino group. 
         [0021]    The term “aminosulfonyl” means an amino group bound to the rest of the molecule through the sulfur atom of a sulfonyl group wherein the amino may be optionally further mono- or di-substituted with methyl or ethyl. 
         [0022]    The term “sulfonylamino” means a sulfonyl group bound to the rest of the molecule through the nitrogen atom of an amino group wherein the sulfonyl group may be optionally further substituted with methyl or ethyl. 
         [0023]    The term “aroyl” means an aryl or heteroaryl group as defined bonded to the rest of the molecule via a carbonyl group. Examples of aroyl groups are benzoyl, 3-cyanobenzoyl, and the like. 
         [0024]    The term “aryl lower alkoxy” means a lower alkoxy group in which one hydrogen atom is replaced by an aryl group. Benzyloxy is preferred. 
         [0025]    The term “pharmaceutically acceptable salts” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formulas I, I-A and I-B, and are formed from suitable non-toxic organic or inorganic acids, or organic or inorganic bases. Sample acid-addition salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Sample base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide. The chemical modification of a pharmaceutical compound (i.e., drug) into a salt is a technique well known to pharmaceutical chemists to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. See, e.g., H. Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems (6th Ed. 1995) at pp. 196 and 1456-1457. 
         [0026]    Likewise, the term “pharmaceutically acceptable esters” refers to the well known practice in the pharmaceutical arts of preparing the non-toxic ester of a pharmaceutically active organic acid molecule, such as for example in the present invention where R 4  or R 5  are carboxy, which readily hydrolyze in vivo to thereby provide the active parent acid principle. It is accordingly understood that the claims presented hereinafter to compounds within Formula I include within their equivalent scope a corresponding pharmaceutically acceptable salt or ester. 
         [0027]    Intravenous, intramuscular, oral or inhalation administrations are preferred forms of use. The dosages in which the compounds of the invention are administered in effective amount depend on the nature of the specific active ingredient, the age and requirements of the patient and the mode of administration. Dosages may be determined by any conventional means, e.g., by dose-limiting clinical trials. In general, dosages of about 0.1 to 20 mg/kg body weight per day are preferred, with dosages of 0.5-10 mg/kg per day being particularly preferred. 
         [0028]    The invention further comprises pharmaceutical compositions that contain a pharmaceutically effective amount of a compound of the invention and a pharmaceutically acceptable carrier. Such compositions may be formulated by any conventional means. Tablets or granulates can contain a series of binders, fillers, carriers or diluents. Liquid compositions can be, for example, in the form of a sterile water-miscible solution. Capsules can contain a filler or thickener in addition to the active ingredient. Furthermore, flavor-improving additives as well as substances usually used as preserving, stabilizing, moisture-retaining and emulsifying agents as well as salts for varying the osmotic pressure, buffers and other additives can also be present. The previously mentioned carrier materials and diluents can comprise any conventional pharmaceutically acceptable organic or inorganic substances, e.g., water, gelatine, lactose, starch, magnesium stearate, talc, gum arabic, polyalkylene glycols and the like. 
         [0029]    Oral unit dosage forms, such as tablets and capsules, preferably contain from 1 mg to 250 mg of a compound of this invention. The compounds of the invention may be prepared by conventional means. 
         [0030]    In accordance with this invention, the compounds herein as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses associated with high blood glucose concentration. A preferred indication associated with the present invention is that associated with diabetes. 
         [0031]    The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration, the dosage for adults may vary from about 1 mg to about 1000 mg per day of a compound of formula I, or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses, and in addition, the upper limit can also be exceeded when this is found to be indicated. 
         [0032]    The methods for preparing the compounds of this invention are described in the following schemes: 
         [0000]    
       
                 
         
             
             
         
       
     
         [0033]    SCHEME 1 describes a general method for the synthesis of pyrido[2,3-d]pyrimidine-2,4-diamine analogs IV bearing R1 group at N-4 and substituted (A group) phenyl at C-7. Alkylamine displacement of 6-chloro-2,4-diaminopyrimidine to give 2,4-diamino-6-alkylaminopyrimidine I was carried out using similar procedures described by Elion, G. B. et al.,  J. Am. Chem. Soc.  1953, 75, 4311. 2,4-diamino-6-alkylaminopyrimidine I was then formylated to give 2,4-diamino-6-alkylaminopyrimidine-5-carbaldehyde II according to the procedures described by Delia, T. J. et al.,  Heterocycles  1983, 20, 1805. Friedlander condensation of 2,4-diamino-6-alkylaminopyrimidine-5-carbaldehyde II and substituted acetophenone III was carried out in a similar fashion as described by Evens, G. et al.,  J. Org. Chem.  1975, 40, 1438 and Perandones, F. et al.,  J. Heterocyclic Chem.  1998, 35, 413 to give the desired product IV. 
         [0034]    Substituted acetophenones III used in the Friedlander condensation reactions (SCHEME 1) are either commercially available or could be prepared using conventional synthetic methods: (a) from substituted benzoic acids, see e.g. Jorgenson, M. J.  Org. React.  1970, 18, 1; (b) from substituted benzaldehydes, see e.g. Tanouchi, T. et al.,  J. Med. Chem.  1981, 24, 1149; (c) from substituted phenoltriflates (in turn prepared from substituted phenols), see e.g. Garrido, F. et al.,  Tet. Lett.  2001, 42, 265; (d) from substituted aryl iodides, see e.g. Cacchi, S. et al.,  Org. Letters.  2003, 5, 289. 
         [0035]    The following procedures used in the synthesis of N4-Methyl-7-(2,4,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine (IV, R1=CH 3 , A=2,4,6-trimethyl) exemplify the typical reaction conditions described in SCHEME 1: 
         [0036]    Compound I: To 6-chloro-2,4-diaminopyrimidine (5.0 g, 0.0347 mole) was added 25 mL of 25% aqueous MeNH 2  solution (0.182 mole, prepared from 40% aqueous MeNH 2  solution) in a sealed tube. The reaction was heated at 150° C. for 4.5 hours. TLC (Jan. 9, 1990 v/v/v conc.NH 4 OH/MeOH/CH 2 Cl 2 ) analysis indicated complete disappearance of starting material. The reaction was then cooled to room temperature and concentrated to give a crude oil. The crude was absorbed onto silica gel using methanol as solvent. The crude material on silica gel was purified using silica gel chromatography (conc.NH 4 OH/MeOH/CH 2 Cl 2 ) to give 3.98 g of an impure material. Recrystallization of the impure material from 45 mL of hot ethanol gave 1.57 g (11.3 mmole, 33% yield) of 2,4-diamino-6-methylaminopyrimidine I as an off-white solid.  1 H NMR (DMSO-d 6 , 300 MHz) δ 5.9 (broad s, 1H), 5.5 (broad s, 2H), 5.3 (broad s, 2H), 4.76 (s, 1H), 2.60 (broad s, 3H). 
         [0037]    Compound II: To a 250 mL three-necked round bottom flask equipped with a magnetic stirrer, argon inlet and thermometer was added N,N-dimethylformamide (20 mL, anhydrous). The flask was cooled in a dry ice/ethylene glycol bath and phosphorus oxychloride (1.97 mL, 21.14 mmol) was added slowly at a rate so as to keep the internal temperature below 0° C. 2,4-diamino-6-methylaminopyrimidine I (2.20 g, 15.8 mmole) was then carefully added as a slurry in N,N-dimethylformamide (20 mL, anhydrous) (Exothermic!). The reaction was transferred to a 40° C. oil bath and stirred for 1.5 hours. The reaction was quenched with ice (˜70 g) and sodium hydroxide pellets (4 g) was added to make the solution slightly basic (pH ˜8). The mixture was then heated in a 90° C. oil bath until methylamine gas was no longer evolved from the mixture. Sodium hydroxide pellets were added as needed to keep the pH of mixture ˜8. The reaction was then cooled to room temperature and concentrated to give a crude solid. The crude was absorbed onto silica gel using methanol as solvent. Silica gel chromatography (Isco 120 g, conc. NH 4 OH/MeOH/CH 2 Cl 2 ) gave 1.23 g (7.36 mmole, 47% yield) of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde II as a light brown solid.  1 H NMR (DMSO-d 6 , 300 MHz) δ 9.68 (s, 1H), 9.1 (broad s, 1H), 6.85 (broad s, 2H), 6.5 (broad s, 2H), 2.80 (broad s, 3H). 
         [0038]    Compound IV: A mixture of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde II (100 mg, 0.60 mmole), 2′,4′,6′-trimethylacetophenone (III, A=2,4,6-trimethyl, 200 mg, 1.23 mmole), potassium hydroxide pellet (100 mg, 1.79 mmole) and ethanol (4 mL) in a sealed tube was heated in a 100° C. oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography (Isco 120 g, NH 4 OH/MeOH/CH 2 Cl 2 ) to give 81 mg (46% yield) of N4-Methyl-7-(2,4,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine (IV, R1=CH 3 , A=2,4,6-trimethyl) as a light yellow solid; LR-MS for C 17 H 19 N 5  (M+H) +  at m/z=294.  1 H NMR (DMSO-d 6 , 300 MHz) δ 8.3 (d, 1H), 8.09 (broad s, 1H), 6.87-6.95 (m, 3H), 6.38 (broad s, 2H), 2.97 (broad s, 3H), 2.26 (s, 3H), 1.97 (s, 6H). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0039]    SCHEME 2 shows the special cases of Friedlander condensation reaction when highly electron-deficient acetophenones V containing 2′-fluoro group (B could be, but not limited to, F, C 1  or CF 3 ) are used as substrates. In these special cases, analog VII in which the 2′-F was displaced by the alcoholic solvent could be isolated while the expected product VI might or might not be isolated. Examples of alcohol used in the fluoride displacement include, but not limited to, methanol, ethanol, 2-propanol, 1-propanol, cyclopentanol, ethylene glycol and 1,3-propanediol. Aromatic nucleophilic substitution reactions with fluoride ion acting as the leaving group have previously been reviewed by Vlasov, V. M.  J. Fluorine Chem.  1993, 61, 193. 
         [0040]    The following procedures used in the synthesis of 7-(2-Fluoro-6-ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine (VII, R1=CH 3 , B═F, D=CH 2 CH 3 ) exemplify the typical conditions used in the Friedlander condensation described in SCHEME 2: 
         [0041]    A mixture of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde II (100 mg, 0.60 mmole), 2′,6′-difluoroacetophenone (V, 200 mg, 1.23 mmole), potassium hydroxide pellet (100 mg, 1.79 mmole) and ethanol (4 mL) in a sealed tube was heated in a 100° C. oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography (Isco 120 g, NH 4 OH/MeOH/CH 2 Cl 2 ) to give 81 mg (46% yield) of 7-(2-Fluoro-6-ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine (VII, R1=CH 3 , B═F, D=CH 2 CH 3 ) as a light brown solid; LRMS for C 16 H 16 FN 5 O (M+H) +  at m/z=314.  1 H NMR (DMSO-d 6 , 300 MHz) δ 8.37 (d, 1H), 8.20 (broad s, 1H), 7.40 (q, 1H), 7.07 (d, 1H), 6.97 (d, 1H), 6.90 (t, 1H), 6.47 (broad s, 2H), 4.05 (q, 2H), 2.97 (d, 3H), 1.18 (t, 3H). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0042]    SCHEME 3 describes an alternative general synthesis of pyrido[2,3-d]pyrimidine-2,4-diamine analogs IV bearing R1 group at N-4 and substituted (A group) phenyl at C-7. Condensation of substituted acetophenone III with dimethylformamide dimethyl acetal was carried out in a similar fashion as described in Tseng, S-S. et al.,  J. Heterocyclic Chem.  1987, 24, 837 and Moyroud, J. et al.,  Heterocycles  1996, 43, 221 to give dimethylamino-propenone VIII. Condensation of dimethylamino-propenone VIII with 2,4,6-triaminopyrimidine was carried out with slight modifications as described in Troschutz, R. et al.,  Arch. Pharm.  1994, 327, 221 to give pyrido[2,3-d]pyrimidine-2,4-diamine IX. Treatment of pyrido[2,3-d]pyrimidine-2,4-diamine IX with sodium hydride and alkyl iodide in dimethylformamide gave the desired product IV. 
         [0043]    The following procedures used in the synthesis of N4-Methyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (IV, R1=CH 3 , A=2-CH 3 ) exemplify the typical conditions described in SCHEME 3. 
         [0044]    Compound VIII: A mixture of 2′-methylacetophenone (III, A=2-CH 3 , 5 g, 37.3 mmol) and N,N-dimethylformamide dimethyl acetal (10 mL, 75.3 mmol) was heated at reflux for 48 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a dark brown oil. Silica gel chromatography (Isco 120 g, ethyl acetate/hexanes) gave 4.66 g (66% yield) of 1-(o-tolyl)-3-dimethylamino-propenone (VIII, A=2-CH 3 ) as a light brown oil. LRMS for C 12 H 15 NO (M+H) +  at m/z=190 
         [0045]    Compound IX: A mixture of 1-(o-tolyl)-3-dimethylamino-propenone (2.7 g, 14.3 mmol) and 2,4,6-triaminopyrimidine (VIII, A=CH 3 , 1.61 g, 12.9 mmol) in glacial acetic acid (25 mL) was heated at reflux for 19 h. Concentration gave a crude which was taken up in hot methanol and absorbed onto silica gel. Silica gel chromatography (Isco 120 g, methylene chloride/methanol/ammonium hydroxide) gave a slightly impure material which was recrystallized from hot aqueous ethanol to give 7-o-Tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (IX, A=CH 3 , 368 mg, 11%) as a light brown solid; LRMS for C 14 H 13 N 5  (M+H) +  at m/z=252. 
         [0046]    Compound IV: To 7-o-Tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (IX, A=CH 3 , 400 mg, 1.59 mmole) in N,N-dimethylformamide (5 mL) in an ice bath was carefully added sodium hydride (60% in mineral oil, 58 mg, 1.45 mmole). To the chilled mixture was added iodomethane (79 μL, 1.27 mmole) and the mixture was stirred at room temperature for 6 h. Concentration gave a crude which was taken up in hot methanol and absorbed onto silica gel. Silica gel chromatography (Isco 120 g, methylene chloride/methanol/ammonium hydroxide) afforded 20 mg (5% yield) of N4-Methyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (IV, R1=CH 3 , A=2-CH 3 ) as a light brown solid; EI-HRMS m/e calcd for C 15 H 15 N 5  (M)+265.1327, found 265.1322.  1 H NMR (DMSO-d 6 , 300 MHz) δ 8.37 (d, 1H), 8.11 (broad s, 1H), 7.42 (d, 1H), 7.3 (m, 3H), 7.16 (d, 1H), 6.42 (broad s, 2H), 2.97 (d, 3H), 2.37 (s, 3H). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0047]    SCHEME 4 describes an alternative general synthesis of pyrido[2,3-d]pyrimidine-2,4-diamine analogs IV bearing R1 group at N-4 and substituted (A group) phenyl at C-7. Condensation of substituted acetophenone III with dimethylformamide dimethyl acetal was carried out in a similar fashion as described in Tseng, S-S. et al.,  J. Heterocyclic Chem.  1987, 24, 837 and Moyroud, J. et al.,  Heterocycles  1996, 43, 221 to give dimethylamino-propenone VIII. Condensation of dimethylamino-propenone VIII with 2,4-diamino-6-hydroxypyrimidine was carried out with slight modifications as described in Troschutz, R. et al.,  Arch. Pharm.  1994, 327, 221 to give 2-amino-pyrido[2,3-d]pyrimidin-4-ol X. 2-amino-pyrido[2,3-d]pyrimidin-4-ol X was previously reported to be formed from the condensation of 4-diamino-6-hydroxypyrimidine with 3-ketoaldehydes by Robins, R. K. et al.,  J. Am. Chem. Soc.  1958, 80, 3449. Protection of 2-amino-pyrido[2,3-d]pyrimidin-4-ol X as the N-2 pivaloyl pyrido[2,3-d]pyrimidin-4-ol XI was carried out in a similar fashion as described by Taylor, E. C. et al.  Heterocycles  1993, 36, 1883 and Taylor, E. C. et al.  Syn. Commun.  1988, 18, 1187. Conversion of N-2-pivaloyl pyrido[2,3-d]pyrimidin-4-ol XI to its 4-chloro analog XII was achieved using a similar procedure as described by Ife, R. J. et al.  J. Med. Chem.  1995, 38, 2763. Treatment of 2-N-pivaloyl-4-chloro-pyrido[2,3-d]pyrimidine XII with alkylamine gave the desired pyrido[2,3-d]pyrimidine-2,4-diamine analog IV. 
         [0048]    The following procedures used in the synthesis of 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine (IV, R1=CH 3 , A=2-F, 6-CF 3 ) exemplify the typical conditions described in SCHEME 4. 
         [0049]    Compound VIII: A mixture of 2′-fluoro-6′-(trifluoromethyl)acetophenone (25.3 g, 0.123 mol) and N,N-dimethylformamide dimethyl acetal (200 mL, 1.51 mol) was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give 31.2 g (97% yield) of 1-(2-fluoro-6-(trifluoromethyl)phenyl)-3-dimethylamino-propenone VIII as a brown oil. This compound was used in the next step as a crude oil without further purification. 
         [0050]    Compound X: A mixture of crude 1-(2-fluoro-6-(trifluoromethyl)phenyl)-3-dimethylamino-propenone VIII (31.2 g, 119 mmol) and 2,4-diamino-6-hydroxypyrimidine (13.6 g, 108 mmol) in glacial acetic acid (350 mL) was heated at reflux for 2 days. The slurry was cooled to 25° C., filtered, washed with glacial acetic acid and dried in vacuo to afford 2-amino-7-(2-fluoro-6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-4-ol X (20.1 g, 57%) as a yellow solid; LR-MS for C 14 H 8 F 4 N 4 O (M+H) +  at m/z=325. 
         [0051]    Compound XI: A mixture of 2-amino-7-(2-fluoro-6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-4-ol X (20.0 g, 61.7 mmol) and trimethylacetic anhydride (33.0 mL, 161 mmol) in pyridine (200 mL) was heated to reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated in vacuo and recrystallization of the crude solid from hot ethyl acetate gave N-[7-(2-fluoro-6-(trifluoromethyl)phenyl)-4-hydroxy-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide XI (13.0 g, 52% yield) as a yellow solid; LR-MS for C 19 H 16 F 4 N 4 O 2  (M+H) +  at m/z=409. 
         [0052]    Compound IV: To a mixture of phosphorous oxychloride (70 mL, 753 mmol) and N-[7-(2-fluoro-6-(trifluoromethyl)phenyl)-4-hydroxy-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide XI (7.10 g, 17.4 mmol) cooled in an ice bath was slowly added N,N-diisopropylethylamine (13.0 mL, 74.6 mmol). The reaction was then heated to 35° C. for 18 h. After cooling to room temperature, the excess phosphorous oxychloride was distilled off in vacuo to afford N-[4-chloro-7-(2-fluoro-6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide XII as a brown oil. To the above crude XII was added chilled 2-propanol (300 mL) and the solution was saturated with methylamine gas while maintaining the internal temperature&lt;20° C. The resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo, taken up in hot methanol and absorbed onto silica gel. Silica gel chromatography (Merck Silica gel 60, 230-400 mesh, methylene chloride/methanol/ammonium hydroxide) afforded 2.32 g (40% yield) of 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine IV as a light yellow solid. LR-MS for C 15 H 11 F 4 N 5  (M+H) +  at m/z=338.  1 H NMR (DMSO-d 6 , 300 MHz) δ 8.40 (d, 1H), 8.30 (broad s, 1H), 7.7 (m, 3H), 7.11 (d, 1H), 6.60 (broad s, 2H), 2.97 (d, 3H). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0053]    SCHEME 5 describes a special scenario in which pyrido[2,3-d]pyrimidine-2,4-diamine analogs VI containing highly electron-deficient C-7 phenyl with o-,o′-disubstitution and o-fluoro group (B could be, but not limited to, F, C 1  or CF 3 ) was treated with a number of nucleophiles under harsh conditions to give the corresponding pyrido[2,3-d]pyrimidine-2,4-diamine analogs XIII through the displacement of the o-fluoro group. Aromatic nucleophilic substitution reactions with fluoride ion acting as the leaving group have previously been reviewed by Vlasov, V. M.  J. Fluorine Chem.  1993, 61, 193. Examples of nucleophiles used in the fluoride displacement reaction include, but not limited to, amines, alcohols, phenols, methanethiolate, benzenethiol and 1H-imidazole. Examples of amines used include, but not limited to, morpholine, dimethylamine, methylamine, thiomorpholine, pyrrolidine, 2-methylpyrrolidine, 2,5-dimethylpyrrolidine, 3-hydroxypyrrolidine, L-prolinol, (2-methoxymethyl)pyrrolidine, piperidine, piperidine-2-carboxylic acid ethyl ester, 4-hydroxypiperidine, 3-hydroxypiperidine, 3-methylamino-piperidine, 4-hydroxy-4-phenylpiperidine, 4-benzylpiperidine, N-methyl piperazine, 1-cyclohexylpiperazine, 1-ethyl piperazine, 1-benzylpiperazine, 1-phenylpiperazine, 1-(2-furoyl)piperazine, 1-cyclopentylpiperazine and 1-isopropylpiperazine. Examples of alcohols used include, but not limited to, methanol, ethanol, 2-propanol, 1-propanol, cyclopentanol, cyclohexanol, ethylene glycol, 1,3-propanediol, 2-dimethylaminoethanol, 2-diethylaminoethanol, 2-methoxyethanol, 1-(2-hydroxyethyl)pyrrolidine and 1-(2-hydroxyethyl)morpholine. Examples of phenols used include, but not limited to, phenol, p-cresol, 4-chlorophenol, 3-chlorophenol, 4-fluorophenol, 3-fluorophenol, 2-fluorophenol and 4-phenyl phenol. 
         [0054]    The following procedures used in the synthesis of N4-Methyl-7-(2-piperidin-1-yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine (XIII, B═CF 3 , Nu=piperidine) exemplify the typical conditions described in SCHEME 5. 
         [0055]    A mixture of 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine (VI, B═CF 3 , 30 mg, 0.089 mmole), piperidine (39 mg, 0.46 mmole) and potassium carbonate (60 mg, 0.43 mmole) in N,N-dimethylformamide (4 mL) or 1-methyl-2-pyrrolidinone (4 mL) in a sealed tube was heated in a 190° C. oil bath overnight. After cooling to room temperature, the reaction was concentrated in vacuo and purified by silica gel chromatography (Merck Silica gel 60, 230-400 mesh, methylene chloride/methanol/ammonium hydroxide) to give 23 mg (41% yield) of N4-Methyl-7-(2-piperidin-1-yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine (XIII, B═CF 3 , Nu=piperidine) as a light brown solid; LRMS for C 20 H 21 F 3 N 6  (M+H) +  at m/z=403.  1 H NMR (DMSO-d 6 , 300 MHz) δ 8.28 (d, 1H), 8.09 (broad s, 1H), 7.56 (t, 1H), 7.44 (m, 2H), 6.97 (d, 1H), 6.40 (broad s, 2H), 2.97 (d, 3H), 2.6-2.9 (m, 4H), 1.0-1.4 (m, 6H). 
       EXAMPLES 
     Example 1 
       [0056]    
       
                 
         
             
             
         
       
     
         [0057]    Step 1: A mixture of 2′-methylacetophenone (5 g, 37.3 mmol) and N,N-dimethylformamide dimethyl acetal (10 mL, 75.3 mmol) was heated to reflux for 48 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give a dark brown oil. Silica gel chromatography (Isco Silica gel 120 g, ethyl acetate/hexanes) gave 4.66 g (66% yield) of 1-(o-tolyl)-3-dimethylamino-propenone as a light brown oil. LRMS for C 12 H 15 NO (M+H) +  at m/z=190. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0058]    Step 2: A mixture of 1-(o-toyl)-3-dimethylamino-propenone (2.7 g, 14.3 mmol) and 2,4,6-triaminopyrimidine (1.61 g, 12.9 mmol) in glacial acetic acid (25 mL) was heated to reflux for 19 h. Concentration gave a crude which was taken up in hot methanol and absorbed onto silica gel. Silica gel chromatography (Isco silica gel 120 g, methylene chloride/methanol/ammonium hydroxide) gave a slightly impure material which was recrystallized from hot aqueous ethanol to give 7-o-Tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (368 mg, 11%) as a light brown solid; LRMS for C 14 H 13 N 5  (M+H) +  at m/z=252. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0059]    Step 3: To 7-o-Tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (400 mg, 1.59 mmole) in N,N-dimethylformamide (5 ml) in an ice bath was carefully added sodium hydride (60% in mineral oil, 58 mg, 1.45 mmole). To the chilled mixture was added iodomethane (79 μL, 1.27 mmole) and the mixture was stirred at room temperature for 6 h. Concentration gave a crude which was taken up in hot methanol and absorbed onto silica gel. Silica gel chromatography (Isco silica gel 120 g, methylene chloride/methanol/ammonium hydroxide) afforded 20 mg (5% yield) of N4-Methyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; EI-HRMS m/e calcd for C 15 H 15 N 5  (M)+265.1327, found 265.1322. 
         [0000]    In an analogous manner, there were obtained: 
       Example 2 
       [0060]    
       
                 
         
             
             
         
       
     
         [0061]    From 2′-trifluoromethylacetophenone: N4-Methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 15 H 12 F 3 N 5  (M+H) +  at m/z=320. 
       Example 3 
       [0062]    
       
                 
         
             
             
         
       
     
         [0063]    From 2′,6′-dichloroacetophenone: 7-(2,6-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a brown solid; LRMS for C 14 H 11 Cl 2 N 5  (M+H) +  at m/z=320. 
       Example 4 
       [0064]    
       
                 
         
             
             
         
       
     
         [0065]    From 2′-chloroacetophenone: 7-(2-Chloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 14 H 12 ClN 5  (M+H) +  at m/z=286. 
       Example 5 
       [0066]    
       
                 
         
             
             
         
       
     
         [0067]    From 2′,6′-difluoroacetophenone: 7-(2,6-Difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as an off-white solid; LR-MS for C 14 H 11 F 2 N 5  (M+H) +  at m/z=288. 
       Example 6 
       [0068]    
       
                 
         
             
             
         
       
     
         [0069]    From pinacolone: 7-tert-Butyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 12 H 17 N 5  (M+H) +  at m/z=232. 
       Example 7 
       [0070]    
       
                 
         
             
             
         
       
     
         [0071]    From 2′-chloro-6′-fluoroacetophenone: 2-chloro-6-fluorophenyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid; LR-MS for C 14 H 11 ClFN 5  (M+H) +  at m/z=304. 
       Example 8 
       [0072]    
       
                 
         
             
             
         
       
     
         [0073]    From 2′-fluoro-6′-trifluoromethylacetophenone: 7-(2-Fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid; LR-MS for C 15 H 11 F 4 N 5  (M+H) +  at m/z=338. 
       Example 9 
       [0074]    
       
                 
         
             
             
         
       
     
         [0075]    From 1-cyclohexyl-ethanone: 7-Cyclohexyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid; LR-MS for C 14 H 19 N 5  (M+H) +  at m/z=258. 
       Example 10 
       [0076]    
       
                 
         
             
             
         
       
     
         [0077]    From 2′-Methoxyacetophenone: 7-(2-Methoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 15 H 15 N 5 O (M+H) +  at m/z=282. 
       Example 11 
       [0078]    
       
                 
         
             
             
         
       
     
         [0079]    From 2′-Nitroacetophenone: N4-Methyl-7-(2-nitro-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 14 H 12 N 6 O 2  (M+H) +  at m/z=297. 
       Example 12 
       [0080]    
       
                 
         
             
             
         
       
     
         [0081]    From 2′-(trifluoromethyl)propiophenone: 6,N4-Dimethyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 16 H 14 F 3 N 5  (M+H) +  at m/z=334. 
       Example 13 
       [0082]    
       
                 
         
             
             
         
       
     
         [0083]    From 2-acetylthiophene: N4-Methyl-7-thiophen-2-yl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 12 H 11 N 5 S (M+H) +  at m/z=258. 
       Example 14 
       [0084]    
       
                 
         
             
             
         
       
     
         [0085]    From deoxybenzoin: N4-Methyl-6,7-diphenyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 20 H 17 N 5  (M+H) +  at m/z=328. 
       Example 15 
       [0086]    
       
                 
         
             
             
         
       
     
         [0087]    From 2′,6′-dimethylacetophenone in step 1 and iodomethane in step 3: 7-(2,6-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a yellow solid; EI-HRMS m/e calcd for C 16 H 17 N 5  (M + ) 279.1484, found 279.1474. 
       Example 16 
       [0088]    
       
                 
         
             
             
         
       
     
         [0089]    From 2′,6′-dimethylacetophenone in step 1 and iodoethane in step 3: 7-(2,6-dimethyl-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a yellow solid; EI-HRMS m/e calcd for C 17 H 19 N 5  (M−H) +  292.1562, found 292.1563. 
       Example 17 
       [0090]    
       
                 
         
             
             
         
       
     
         [0000]    
       
                 
         
             
             
         
       
     
         [0091]    Step 1: A mixture of 2′-fluoro-6′-(trifluoromethyl)acetophenone (25.3 g, 0.123 mol) and N,N-dimethylformamide dimethyl acetal (200 mL, 1.51 mol) was heated at reflux for 16 h. The reaction mixture was cooled to room temperature and concentrated in vacuo to give 31.2 g (97% yield) of 1-(2-fluoro-6-(trifluoromethyl)phenyl)-3-dimethylamino-propenone as a brown oil. This compound was used in the next step as a crude without further purification. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0092]    Step 2: A mixture of crude 1-(2-fluoro-6-(trifluoromethyl)phenyl)-3-dimethylamino-propenone (31.2 g, 119 mmol) and 2,4-diamino-6-hydroxypyrimidine (13.6 g, 108 mmol) in glacial acetic acid (350 mL) was heated at reflux for 2 days. The slurry was cooled to 25° C., filtered, washed with glacial acetic acid and dried in vacuo to afford 2-amino-7-(2-fluoro-6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-4-ol (20.1 g, 57%) as a yellow solid; LR-MS for C 14 H 8 F 4 N 4 O (M+H) +  at m/z=325. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0093]    Step 3: A mixture of 2-amino-7-(2-fluoro-6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-4-ol (20.0 g, 61.7 mmol) and trimethylacetic anhydride (33.0 mL, 161 mmol) in pyridine (200 mL) was heated to reflux for 2 days. After cooling to room temperature, the reaction mixture was concentrated in vacuo and recrystallization of the crude from hot ethyl acetate gave N-[7-(2-fluoro-6-(trifluoromethyl)phenyl)-4-hydroxy-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (13.0 g, 52% yield) as a yellow solid; LR-MS for C 19 H 16 F 4 N 4 O 2  (M+H) +  at m/z=409. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0094]    Step 4: To a mixture of phosphorous oxychloride (70 mL, 753 mmol) and N-[7-(2-fluoro-6-(trifluoromethyl)phenyl)-4-hydroxy-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (7.10 g, 17.4 mmol) cooled in an ice bath was slowly added N,N-diisopropylethylamine (13.0 mL, 74.6 mmol). The reaction was then heated to 35° C. for 18 h. After cooling to room temperature, the excess phosphorous oxychloride was distilled off in vacuo to afford N-[4-chloro-7-(2-fluoro-6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide as a brown oil. To the above crude brown oil was added chilled 2-propanol (300 mL) and the solution was saturated with methylamine gas while maintaining the internal temperature&lt;20° C. The resulting mixture was stirred at room temperature for 18 h. The mixture was concentrated in vacuo, taken up in hot methanol and absorbed onto silica gel. Silica gel chromatography (Merck Silica gel 60, 230-400 mesh, methylene chloride/methanol/ammonium hydroxide) afforded 2.32 g (40% yield) of 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid. LR-MS for C 15 H 11 F 4 N 5  (M+H) +  at m/z=338. 
       Example 18 
       [0095]    
       
                 
         
             
             
         
       
     
         [0096]    Using the same four-step sequence as shown above but starting from 2′-chloro-6′-fluoroacetophenone gave 7-(2-Chloro-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid; LR-MS for C 14 H 11 ClFN 5  (M+H) +  at m/z=304. 
       Preparation of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde 
       [0097]    
       
                 
         
             
             
         
       
     
         [0098]    Step 1: To 6-chloro-2,4-diaminopyrimidine (5.0 g, 0.0347 mole) was added 25 ml of 25% aqueous MeNH 2  solution (0.182 mole, prepared from 40% aqueous MeNH 2  solution) in a sealed tube. The reaction was heated at 150° C. for 4.5 hours. TLC (Jan. 9, 1990 v/v/v conc.NH 4 OH/MeOH/CH 2 Cl 2 ) analysis indicated complete disappearance of starting material. The reaction was then cooled to room temperature and concentrated to give a crude oil. The crude was absorbed onto silica gel using methanol as solvent. The crude material on silica gel was purified using silica gel chromatography (silica gel, conc.NH 4 OH/MeOH/CH 2 Cl 2 ) to give 3.98 g of an impure material. Recrystallization of the impure material from 45 ml of hot ethanol gave 1.57 g (11.3 mmole, 33% yield) of 2,4-diamino-6-methylaminopyrimidine as an off-white solid.  1 H NMR (DMSO-d 6 , 300 MHz) δ 5.9 (broad s, 1H), 5.5 (broad s, 2H), 5.3 (broad s, 2H), 4.76 (s, 1H), 2.60 (broad s, 3H). 
         [0000]    
       
                 
         
             
             
         
       
     
         [0099]    Step 2: To a 250 ml three-necked round bottom flask equipped with a magnetic stirrer, argon inlet and thermometer was added N,N-dimethylformamide (20 ml, anhydrous). The flask was cooled in a dry ice/ethylene glycol bath and phosphorus oxychloride (1.97 ml, 21.14 mmol) was added slowly at a rate so as to keep the internal temperature below 0° C. 2,4-diamino-6-methylaminopyrimidine I (2.20 g, 15.8 mmole) was then added carefully as a slurry in N,N-dimethylforamide (20 ml, anhydrous) (Exothermic!). The reaction was transferred to a 40° C. oil bath and stirred for 1.5 hours. The reaction was quenched with ice (˜70 g) and sodium hydroxide pellets (4 g) was added to make the solution slightly basic (pH ˜8). The mixture was then heated in a 90° C. oil bath until methylamine gas was no longer evolved from the mixture. Sodium hydroxide pellets were added as needed to keep the pH of mixture ˜8. The reaction was then cooled to room temperature and concentrated to give a crude solid. The crude was absorbed onto silica gel using methanol as solvent. Silica gel chromatography (Isco silica gel 120 g, NH 4 OH/MeOH/CH 2 Cl 2 ) gave 1.23 g (47% yield) of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde II as a light brown solid.  1 H NMR (DMSO-d 6 , 300 MHz) δ 9.68 (s, 1H), 9.1 (broad s, 1H), 6.85 (broad s, 2H), 6.5 (broad s, 2H), 2.80 (broad s, 3H). 
       Example 19 
       [0100]    
       
                 
         
             
             
         
       
     
         [0101]    A mixture of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde (100 mg, 0.60 mmole), 2′,4′,6′-trimethylacetophenone (200 mg, 1.23 mmole), potassium hydroxide pellet (100 mg, 1.79 mmole) and ethanol (4 ml) in a sealed tube was heated in a 100° C. oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography (Isco 120 g, NH 4 OH/MeOH/CH 2 Cl 2 ) to give 81 mg (46% yield) of N4-Methyl-7-(2,4,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid; LR-MS for C 17 H 19 N 5  (M+H) +  at m/z=294.  1 H NMR (DMSO-d 6 , 300 MHz) δ 8.3 (d, 1H), 8.09 (broad s, 1H), 6.87-6.95 (m, 3H), 6.38 (broad s, 2H), 2.97 (broad s, 3H), 2.26 (s, 3H), 1.97 (s, 6H). 
         [0000]    In an analogous manner, there were obtained: 
       Example 20 
       [0102]    
       
                 
         
             
             
         
       
     
         [0103]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′-bromoacetophenone: 7-(2-Bromo-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid; LRMS for C 14 H 12 BrN 5  (M+H) +  at m/z=330. 
       Example 21 
       [0104]    
       
                 
         
             
             
         
       
     
         [0105]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′-benzyloxyacetophenone: 7-(2-Benzyloxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 21 H 19 N 5 O (M+H) +  at m/z=358. 
       Example 22 
       [0106]    
       
                 
         
             
             
         
       
     
         [0107]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′-ethoxyacetophenone: 7-(2-Ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 17 N 5 O (M+H) +  at m/z=296. 
       Example 23 
       [0108]    
       
                 
         
             
             
         
       
     
         [0109]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2-tolyloxyacetophenone: N4-Methyl-7-(2-p-tolyloxy-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 19 N 5 O (M+H) +  at m/z=358. 
       Example 24 
       [0110]    
       
                 
         
             
             
         
       
     
         [0111]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 1-(2-Trifluoromethyl-phenyl)-pentan-1-one: N4-Methyl-6-propyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 18 H 18 F 3 N 5  (M+H) +  at m/z=362. 
       Example 25 
       [0112]    
       
                 
         
             
             
         
       
     
         [0113]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,4′-dimethylacetophenone: N4-Methyl-7-(2,4-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 16 H 17 N 5  (M+H) +  at m/z=280. 
       Example 26 
       [0114]    
       
                 
         
             
             
         
       
     
         [0115]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-dichloro-4′-(trifluoromethyl)acetophenone: 7-(2,6-Dichloro-4-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 15 H 10 Cl 2 F 3 N 5  (M+H) +  at m/z=388. 
       Example 27 
       [0116]    
       
                 
         
             
             
         
       
     
         [0117]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and α-tetralone: N8-Methyl-5,6-dihydro-benzo[h]pyrimido[4,5-b]quinoline-8,10-diamine as a light brown solid; LRMS for C 16 H 15 N 5  (M+H) +  at m/z=278. 
       Example 28 
       [0118]    
       
                 
         
             
             
         
       
     
         [0119]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 1′-acetonaphthone: N4-Methyl-7-naphthalen-1-yl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 18 H 15 N 5  (M+H) +  at m/z=302. 
       Example 29 
       [0120]    
       
                 
         
             
             
         
       
     
         [0121]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′-iodoacetophenone: 7-(2-Iodo-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 14 H 12 IN 5  (M+H) +  at m/z=378. 
       Example 30 
       [0122]    
       
                 
         
             
             
         
       
     
         [0123]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-difluoroacetophenone using methanol as solvent: 7-(2-Fluoro-6-methoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 15 H 14 FN 5 O (M+H) +  at m/z=300. 
       Example 31 
       [0124]    
       
                 
         
             
             
         
       
     
         [0125]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-difluoroacetophenone using ethanol as solvent: 7-(2-Ethoxy-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 16 FN 5 O (M+H) +  at m/z=314. 
       Example 32 
       [0126]    
       
                 
         
             
             
         
       
     
         [0127]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-difluoroacetophenone using 2-propanol as solvent: 7-(2-Fluoro-6-isopropoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 17 H 18 FN 5 O (M+H) +  at m/z=328. 
       Example 33 
       [0128]    
       
                 
         
             
             
         
       
     
         [0129]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-difluoroacetophenone using 1-propanol as solvent: 7-(2-Fluoro-6-propoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 17 H 18 FN 5 O (M+H) +  at m/z=328. 
       Example 34 
       [0130]    
       
                 
         
             
             
         
       
     
         [0131]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,3′,5′,6′-tetramethylacetophenone: N4-Methyl-7-(2,3,5,6-tetramethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LR-MS for C 18 H 21 N 5  (M+H) +  at m/z=308. 
       Example 35 
       [0132]    
       
                 
         
             
             
         
       
     
         [0133]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and valerophenone: N4-Methyl-7-phenyl-6-propyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 17 H 19 N 5  (M+H) +  at m/z=294. 
       Example 36 
       [0134]    
       
                 
         
             
             
         
       
     
         [0135]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and butyrophenone: 6-Ethyl-N4-methyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 17 N 5  (M+H) +  at m/z=280. 
       Example 37 
       [0136]    
       
                 
         
             
             
         
       
     
         [0137]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2-methanesulfonyl-1-(2-trifluoromethyl-phenyl)ethanone: 6-Methanesulfonyl-N4-methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 14 F 3 N 5 O 2 S (M+H) +  at m/z=398. 
       Example 38 
       [0138]    
       
                 
         
             
             
         
       
     
         [0139]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,3′,6′-trimethylacetophenone: N4-Methyl-7-(2,3,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 17 H 19 N 5  (M+H) +  at m/z=294. 
       Example 39 
       [0140]    
       
                 
         
             
             
         
       
     
         [0141]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-dichloro-3′-fluoroacetophenone: 7-(2,6-Dichloro-3-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 14 H 10 Cl 2 FN 5  (M+H) +  at m/z=338. 
       Example 40 
       [0142]    
       
                 
         
             
             
         
       
     
         [0143]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′4′-bis(trifluoromethyl)acetophenone: 7-(2,4-Bis-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 16 H 11 F 6 N 5  (M+H) +  at m/z=388. 
       Example 41 
       [0144]    
       
                 
         
             
             
         
       
     
         [0145]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-bis(trifluoromethyl)acetophenone: 7-(2,6-Bis-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 16 H 11 F 6 N 5  (M+H) +  at m/z=388. 
       Example 42 
       [0146]    
       
                 
         
             
             
         
       
     
         [0147]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,5′-dimethylacetophenone: 7-(2,5-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 16 H 17 N 5  (M+H) +  at m/z=280. 
       Example 43 
       [0148]    
       
                 
         
             
             
         
       
     
         [0149]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,3′,6′-trichloroacetophenone: N4-Methyl-7-(2,3,6-trichloro-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 14 H 10 Cl 3 N 5  (M+H) +  at m/z=354. 
       Example 44 
       [0150]    
       
                 
         
             
             
         
       
     
         [0151]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′-hydroxy-5′-methylacetophenone: 2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-4-methyl-phenol as a light brown solid; LR-MS for C 15 H 15 N 5 O (M+H) +  at m/z=282. 
       Example 45 
       [0152]    
       
                 
         
             
             
         
       
     
         [0153]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 1-benzosuberone: N9-Methyl-6,7-dihydro-5H-10,12,13-triaza-benzo[3,4]cyclohepta[1,2-b]naphthalene-9,11-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 17 H 17 N 5  (M+H) +  at m/z=292. 
       Example 46 
       [0154]    
       
                 
         
             
             
         
       
     
         [0155]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and isovalerophenone: 6-Isopropyl-N4-methyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 17 H 19 N 5  (M+H) +  at m/z=294. 
       Example 47 
       [0156]    
       
                 
         
             
             
         
       
     
         [0157]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′-hydroxyacetophenone: 2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-phenol trifluoroacetic acid salt as a light brown solid; LRMS for C 14 H 13 N 5 O (M+H) +  at m/z=268. 
       Example 48 
       [0158]    
       
                 
         
             
             
         
       
     
         [0159]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,5′-dichloroacetophenone: 7-(2,5-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 14 H 11 Cl 2 N 5  (M+H) +  at m/z=320. 
       Example 49 
       [0160]    
       
                 
         
             
             
         
       
     
         [0161]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,4′-dichloroacetophenone: 7-(2,4-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 14 H 11 Cl 2 N 5  (M+H) +  at m/z=320. 
       Example 50 
       [0162]    
       
                 
         
             
             
         
       
     
         [0163]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,3′-dichloroacetophenone: 7-(2,3-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 14 H 11 Cl 2 N 5  (M+H) +  at m/z=320. 
       Example 51 
       [0164]    
       
                 
         
             
             
         
       
     
         [0165]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 4-butyrylbiphenyl: N4-Methyl-6-phenethyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 22 H 21 N 5  (M+H) +  at m/z=356. 
       Example 52 
       [0166]    
       
                 
         
             
             
         
       
     
         [0167]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-difluoroacetophenone using cyclopentanol as solvent: 7-(2-Cyclopentyloxy-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 19 H 20 FN 5 O (M+H) +  at m/z=354. 
       Example 53 
       [0168]    
       
                 
         
             
             
         
       
     
         [0169]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-difluoroacetophenone using ethylene glycol as solvent: 2-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenoxy]-ethanol trifluoroacetic acid as a light brown solid; LRMS for C 16 H 16 FN 5 O 2  (M+H) +  at m/z=330. 
       Example 54 
       [0170]    
       
                 
         
             
             
         
       
     
         [0171]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,6′-difluoroacetophenone using 1,3-propanediol as solvent: 3-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenoxy]-propan-1-ol trifluoroacetic acid as a light brown solid; LRMS for C 17 H 18 FN 5 O 2  (M+H) +  at m/z=344. 
       Example 55 
       [0172]    
       
                 
         
             
             
         
       
     
         [0173]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde, 2′-chloro-6′-fluoroacetophenone using ethanol as solvent: 7-(2-Chloro-6-ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 16 ClN 5 O (M+H) +  at m/z=330. 
       Example 56 
       [0174]    
       
                 
         
             
             
         
       
     
         [0175]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and methyl 2-(trifluoromethyl)benzoylacetate: 2-Amino-4-methylamino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-6-carboxylic acid trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 12 F 3 N 5 O 2  (M+H) +  at m/z=364. 
       Example 57 
       [0176]    
       
                 
         
             
             
         
       
     
         [0177]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 1-(1-phenyl-cyclopropyl)-ethanone: N4-Methyl-7-(1-phenyl-cyclopropyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 17 H 17 N 5  (M+H) +  at m/z=292. 
       Example 58 
       [0178]    
       
                 
         
             
             
         
       
     
         [0179]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 1-(1-phenyl-cyclopentyl)-ethanone: N4-Methyl-7-(1-phenyl-cyclopentyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 19 H 21 N 5  (M+H) +  at m/z=320. 
       Example 59 
       [0180]    
       
                 
         
             
             
         
       
     
         [0181]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 1-(1-phenyl-cyclohexyl)-ethanone: N4-Methyl-7-(1-phenyl-cyclohexyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 20 H 23 N 5  (M+H) +  at m/z=334. 
       Example 60 
       [0182]    
       
                 
         
             
             
         
       
     
         [0183]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2-acetylbenzoic acid: potassium 2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-benzoate as a light brown solid; LRMS for C 15 H 13 N 5 O 2  (M+H) +  at m/z=296. 
       Example 61 
       [0184]    
       
                 
         
             
             
         
       
     
         [0185]    From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2′,4′-diethylacetophenone: 7-(2,4-Diethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as an orange solid; LR-MS for C 18 H 21 N 5  (M+H) +  at m/z=308. 
       Example 62 
       [0186]    
       
                 
         
             
             
         
       
     
         [0187]    By using the 2-step procedure used in the preparation of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde (Example 19), substituting the use of methylamine with ethylamine in step 1, gave 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0188]    A mixture of 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde (40 mg, 0.22 mmole), 2′-(trifluoromethyl)acetophenone (75 mg, 0.40 mmole), potassium hydroxide pellet (100 mg, 1.79 mmole) and ethanol (4 ml) in a sealed tube was heated in a 100° C. oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by reversed phase HPLC to give 24 mg (24% yield) of N4-Ethyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 14 F 3 N 5  (M+H) +  at m/z=334. 
         [0000]    In an analogous manner, there were obtained: 
       Example 63 
       [0189]    
       
                 
         
             
             
         
       
     
         [0190]    From 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde and 2′-(trifluoromethyl)propiophenone: N4-Ethyl-6-methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 17 H 16 F 3 N 5  (M+H) +  at m/z=348. 
       Example 64 
       [0191]    
       
                 
         
             
             
         
       
     
         [0192]    From 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde and 2′-methylacetophenone: N4-Ethyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 17 N 5  (M+H) +  at m/z=280. 
       Example 65 
       [0193]    
       
                 
         
             
             
         
       
     
         [0194]    From 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde and 2′,6′-dichloroacetophenone: 7-(2,6-Dichloro-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 15 H 13 Cl 2 N 5  (M+H) +  at m/z=334. 
       Example 66 
       [0195]    
       
                 
         
             
             
         
       
     
         [0196]    From 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde and 2′-bromoacetophenone: 7-(2-Bromo-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 15 H 14 BrN 5  (M+H) +  at m/z=344. 
       Example 67 
       [0197]    
       
                 
         
             
             
         
       
     
         [0198]    From 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde and 2′-fluoro-6′-(trifluoromethyl)acetophenone: N4-Ethyl-7-(2-fluoro-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 13 F 4 N 5  (M+H) +  at m/z=352. 
       Example 68 
       [0199]    
       
                 
         
             
             
         
       
     
         [0200]    From 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde and 2′-chloro-6′-fluoroacetophenone: 7-(2-Chloro-6-fluoro-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 15 H 13 ClFN 5  (M+H) +  at m/z=318. 
       Example 69 
       [0201]    
       
                 
         
             
             
         
       
     
         [0202]    From 2,4-diamino-6-ethylaminopyrimidine-5-carbaldehyde and 2′,3′,6′-trimethylacetophenone: N4-Ethyl-7-(2,3,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 18 H 21 N 5  (M+H) +  at m/z=308. 
       Example 70 
       [0203]    
       
                 
         
             
             
         
       
     
         [0204]    Using the 2-step procedure used in the preparation of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde (Example 19), substituting the use of methylamine with ethanolamine in step 1, gave 2,4-Diamino-6-(2-hydroxy-ethylaminopyrimidine-5-carbaldehyde. From 2,4-Diamino-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbaldehyde and 2′,6′-dichloroacetophenone: 2-[2-Amino-7-(2,6-dichloro-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol as an orange solid; LR-MS for C 15 H 13 Cl 2 N 5 O (M+H) +  at m/z=350. 
       Example 71 
       [0205]    
       
                 
         
             
             
         
       
     
         [0206]    To a mixture of 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine (30 mg, 0.089 mmole), piperidine (39 mg, 0.46 mmole) and potassium carbonate (60 mg, 0.43 mmole) in N,N-dimethylformamide (4 ml) or 1-methyl-2-pyrrolidinone (4 ml) in a sealed tube was heated in a 190° C. oil bath overnight. After cooling to room temperature, the reaction was concentrated in vacuo and purified by reversed phase HPLC to give 23 mg (41% yield) of N4-Methyl-7-(2-piperidin-1-yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 20 H 21 F 3 N 6  (M+H) +  at m/z=403. 
         [0000]    In an analogous manner, there were obtained: 
       Example 72 
       [0207]    
       
                 
         
             
             
         
       
     
         [0208]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and morpholine: N4-Methyl-7-(2-morpholin-4-yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 19 H 19 F 3 N 6 O (M+H) +  at m/z=405. 
       Example 73 
       [0209]    
       
                 
         
             
             
         
       
     
         [0210]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and pyrrolidine: 7-(2,4-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 19 H 19 F 3 N 6  (M+H) +  at m/z=389. 
       Example 74 
       [0211]    
       
                 
         
             
             
         
       
     
         [0212]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and N-methylpiperazine: N4-Methyl-7-[2-(4-methyl-piperazin-1-yl)-6-trifluoromethyl-phenyl]-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 20 H 22 F 3 N 7  (M+H) +  at m/z=418. 
       Example 75 
       [0213]    
       
                 
         
             
             
         
       
     
         [0214]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and sodium ethoxide: 7-(2-Ethoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 17 H 16 F 3 N 5 O (M+H) +  at m/z=364. 
       Example 76 
       [0215]    
       
                 
         
             
             
         
       
     
         [0216]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and sodium methoxide: 7-(2-Methoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 14 F 3 N 5 O (M+H) +  at m/z=350. 
       Example 77 
       [0217]    
       
                 
         
             
             
         
       
     
         [0218]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and dimethylamine: 7-(2-Dimethylamino-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 17 H 17 F 3 N 6  (M+H) +  at m/z=363. 
       Example 78 
       [0219]    
       
                 
         
             
             
         
       
     
         [0220]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and methylamine: N4-Methyl-7-(2-methylamino-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 15 F 3 N 6  (M+H) +  at m/z=349. 
       Example 79 
       [0221]    
       
                 
         
             
             
         
       
     
         [0222]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-dimethylaminoethanol and sodium hydride: 7-[2-(2-Dimethylamino-ethoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 19 H 21 F 3 N 6 O (M+H) +  at m/z=407. 
       Example 80 
       [0223]    
       
                 
         
             
             
         
       
     
         [0224]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, phenol and sodium hydride: N4-Methyl-7-(2-phenoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 16 F 3 N 5 O (M+H) +  at m/z=412. 
       Example 81 
       [0225]    
       
                 
         
             
             
         
       
     
         [0226]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, sodium methanethiolate: N4-Methyl-7-(2-methylsulfanyl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 16 H 14 F 3 N 5 S (M+H) +  at m/z=366. 
       Example 82 
       [0227]    
       
                 
         
             
             
         
       
     
         [0228]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, ethylene glycol and sodium hydride: 2-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenoxy]-ethanol trifluoroacetic acid salt as a light brown solid; LRMS for C 17 H 16 F 3 N 5 O 2  (M+H) +  at m/z=380. 
       Example 83 
       [0229]    
       
                 
         
             
             
         
       
     
         [0230]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-methoxyethanol and sodium hydride: 7-[2-(2-Methoxy-ethoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 18 H 18 F 3 N 5 O 2  (M+H) +  at m/z=394. 
       Example 84 
       [0231]    
       
                 
         
             
             
         
       
     
         [0232]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 1-(2-hydroxyethyl)pyrrolidine and sodium hydride: N4-Methyl-7-[2-(2-pyrrolidin-1-yl-ethoxy)-6-trifluoromethyl-phenyl]-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 23 F 3 N 6 O (M+H) +  at m/z=433. 
       Example 85 
       [0233]    
       
                 
         
             
             
         
       
     
         [0234]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-propanol and sodium hydride: 7-(2-Isopropoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 18 H 18 F 3 N 5 O (M+H) +  at m/z=378. 
       Example 86 
       [0235]    
       
                 
         
             
             
         
       
     
         [0236]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 1-propanol and sodium hydride: N4-Methyl-7-(2-propoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 18 H 18 F 3 N 5 O (M+H) +  at m/z=378. 
       Example 87 
       [0237]    
       
                 
         
             
             
         
       
     
         [0238]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-diethylaminoethanol and sodium hydride: 7-[2-(2-Diethylamino-ethoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 25 F 3 N 6 O (M+H) +  at m/z=435. 
       Example 88 
       [0239]    
       
                 
         
             
             
         
       
     
         [0240]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, N-(2-hydroxyethyl)morpholine and sodium hydride: N4-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)-6-trifluoromethyl-phenyl]-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 23 F 3 N 6 O 2  (M+H) +  at m/z=449. 
       Example 89 
       [0241]    
       
                 
         
             
             
         
       
     
         [0242]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, and pyrrolidine: 7-(2-fluoro-6-pyrrolidin-1-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a dark-yellow solid; (ES) + -HRMS m/e calcd for C 18 H 19 FN 6  (M+H) +  339.1730, found 339.1728. 
       Example 90 
       [0243]    
       
                 
         
             
             
         
       
     
         [0244]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and piperidine: 7-(2-Fluoro-6-piperidin-1-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a yellow solid; EI-HRMS m/e calcd for C 19 H 21 FN 6  (M + ) 352.1812, found 352.1813. 
       Example 91 
       [0245]    
       
                 
         
             
             
         
       
     
         [0246]    Obtained as a by-product from 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, phenol and sodium hydride: 2-(2-amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenol as a yellow solid; EI-HRMS m/e calcd for C 14 H 12 FN 5 O (M + ) 285.1029, found 285.1026. 
       Example 92 
       [0247]    
       
                 
         
             
             
         
       
     
         [0248]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and morpholine: 7-(2-Fluoro-6-morpholino-4-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a yellow solid; LRMS for C 18 H 19 FN 6 O (M+H) +  at m/z=355. 
       Example 93 
       [0249]    
       
                 
         
             
             
         
       
     
         [0250]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and Benzenethiol: 7-(2-Fluoro-6-phenylsulfanyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 20 H 16 FN 5 S (M+H) +  378.1183, found 378.1181. 
       Example 94 
       [0251]    
       
                 
         
             
             
         
       
     
         [0252]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and Phenol: 7-(2-Fluoro-6-phenoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 20 H 16 FN 5 O (M+H) +  362.1412, found 362.1410. 
       Example 95 
       [0253]    
       
                 
         
             
             
         
       
     
         [0254]    From 7-(2,6-Difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1H-Imidazole: 7-(2-Fluoro-6-imidazol-1-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light yellow solid; (ES) + -HRMS m/e calcd for C 17 H 14 FN 7  (M+H) +  336.1368, found 336.1370. 
       Example 96 
       [0255]    
       
                 
         
             
             
         
       
     
         [0256]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-Benzyl-piperazine: 7-[2-(4-Benzyl-piperazin-1-yl)-6-fluoro-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 25 H 26 FN 7  (M+H) +  444.2307, found 444.2305. 
       Example 97 
       [0257]    
       
                 
         
             
             
         
       
     
         [0258]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and Methylamine: 7-(2-Fluoro-6-methylamino-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 15 H 15 FN 6  (M+H) +  299.1415, found 299.1417. 
       Example 98 
       [0259]    
       
                 
         
             
             
         
       
     
         [0260]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and Dimethylamine: 7-(2-Dimethylamino-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 16 H 17 FN 6  (M+H) +  313.1572, found 313.1570. 
       Example 99 
       [0261]    
       
                 
         
             
             
         
       
     
         [0262]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-Methyl-piperazine: 7-[2-Fluoro-6-(4-methyl-piperazin-1-yl)-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 19 H 22 FN 7  (M+H) +  368.1994, found 368.1992. 
       Example 100 
       [0263]    
       
                 
         
             
             
         
       
     
         [0264]    From 7-(2,6-Difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and Piperidine-2-carboxylic acid ethyl ester: 1-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenyl]-piperidine-2-carboxylic acid ethyl ester trifluoroacetic acid salt as a yellow solid; (ES) + -HRMS m/e calcd for C 22 H 25 FN 6 O 2  (M+H) +  425.2098, found 425.2096. 
       Example 101 
       [0265]    
       
                 
         
             
             
         
       
     
         [0266]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and Thiomorpholine: 7-(2-Fluoro-6-thiomorpholin-4-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 18 H 19 FN 6 S (M+H) +  371.1449, found 371.1451. 
       Example 102 
       [0267]    
       
                 
         
             
             
         
       
     
         [0268]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and C-Piperidin-3-yl-methylamine: 7-[2-(3-Aminomethyl-piperidin-1-yl)-6-fluoro-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 20 H 24 FN 7  (M+H) +  382.2150, found 382.2152. 
       Example 103 
       [0269]    
       
                 
         
             
             
         
       
     
         [0270]    From 7-(2,6-difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 2-Methoxymethyl-pyrrolidine: 7-[2-Fluoro-6-(2-methoxymethyl-pyrrolidin-1-yl)-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a brown solid; (ES) + -HRMS m/e calcd for C 20 H 23 FN 6 O (M+H) +  383.1990, found 383.1993. 
       Example 104 
       [0271]    
       
                 
         
             
             
         
       
     
         [0272]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 4-fluorophenol and sodium hydride: 7-[2-(4-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 15 F 4 N 5 O (M+H) +  at m/z=430. 
       Example 105 
       [0273]    
       
                 
         
             
             
         
       
     
         [0274]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, cyclohexanol and sodium hydride: 7-(2-Cyclohexyloxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 22 F 3 N 5 O (M+H) +  at m/z=418. 
       Example 106 
       [0275]    
       
                 
         
             
             
         
       
     
         [0276]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 2-methylpyrrolidine (racemic): N4-Methyl-7-[2-(2-methyl-pyrrolidin-1-yl)-6-trifluoromethyl-phenyl]-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C 20 H 21 F 3 N 6  (M+H) +  at m/z=403. 
       Example 107 
       [0277]    
       
                 
         
             
             
         
       
     
         [0278]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 2,5-dimethylpyrrolidine (mixture of cis- and trans-): 7-[2-(2,5-Dimethyl-pyrrolidin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 23 F 3 N 6  (M+H) +  at m/z=417. 
       Example 108 
       [0279]    
       
                 
         
             
             
         
       
     
         [0280]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and racemic 3-hydroxypyrrolidine: 1-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-pyrrolidin-3-ol trifluoroacetic acid salt as a light brown solid; LRMS for C 19 H 19 F 3 N 6 O (M+H) +  at m/z=405. 
       Example 109 
       [0281]    
       
                 
         
             
             
         
       
     
         [0282]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 4-hydroxypiperidine: 1-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-piperidin-4-ol trifluoroacetic acid salt as a light brown solid; LRMS for C 20 H 21 F 3 N 6 O (M+H) +  at m/z=419. 
       Example 110 
       [0283]    
       
                 
         
             
             
         
       
     
         [0284]    From 2-[2-Amino-7-(2-fluoro-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol, phenol and sodium hydride: 2-[2-Amino-7-(2-phenoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol trifluoroacetic acid salt as a light brown solid; LRMS for C 22 H 18 F 3 N 5 O 2  (M+H) +  at m/z=442. 
       Example 111 
       [0285]    
       
                 
         
             
             
         
       
     
         [0286]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and (L)-prolinol: {1-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-pyrrolidin-2-yl}-methanol trifluoroacetic acid salt as a light brown solid; LRMS for C 20 H 21 F 3 N 6 O (M+H) +  at m/z=419. 
       Example 112 
       [0287]    
       
                 
         
             
             
         
       
     
         [0288]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and (S)-2-(methoxymethyl)pyrrolidine: 7-[2-(2-Methoxymethyl-pyrrolidin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 23 F 3 N 6 O (M+H) +  at m/z=433. 
       Example 113 
       [0289]    
       
                 
         
             
             
         
       
     
         [0290]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and racemic 3-hydroxypiperidine: 1-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-piperidin-3-ol trifluoroacetic acid salt as a light brown solid; LRMS for C 20 H 21 F 3 N 6 O (M+H) +  at m/z=419. 
       Example 114 
       [0291]    
       
                 
         
             
             
         
       
     
         [0292]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-cyclohexylpiperazine: 7-[2-(4-Cyclohexyl-piperazin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 25 H 30 F 3 N 7  (M+H) +  at m/z=486. 
       Example 115 
       [0293]    
       
                 
         
             
             
         
       
     
         [0294]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-ethyl piperazine: 7-[2-(4-Ethyl-piperazin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 24 F 3 N 7  (M+H) +  at m/z=432. 
       Example 116 
       [0295]    
       
                 
         
             
             
         
       
     
         [0296]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-(2-furoyl)piperazine: {4-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-piperazin-1-yl}-furan-2-yl-methanone trifluoroacetic acid salt as a light brown solid; LRMS for C 24 H 22 F 3 N 7 O 2  (M+H) +  at m/z=498. 
       Example 117 
       [0297]    
       
                 
         
             
             
         
       
     
         [0298]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-(4,4′-difluorobenzhydryl)piperazine: 7-(2-{4-[Bis-(4-fluoro-phenyl)-methyl]-piperazin-1-yl}-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 32 H 28 F 5 N 7  (M+H) +  at m/z=606. 
       Example 118 
       [0299]    
       
                 
         
             
             
         
       
     
         [0300]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-phenylpiperazine: N4-Methyl-7-[2-(4-phenyl-piperazin-1-yl)-6-trifluoromethyl-phenyl]-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 25 H 24 F 3 N 7  (M+H) +  at m/z=480. 
       Example 119 
       [0301]    
       
                 
         
             
             
         
       
     
         [0302]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-benzylpiperazine: 7-[2-(4-Benzyl-piperazin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 26 H 26 F 3 N 7  (M+H) +  at m/z=494. 
       Example 120 
       [0303]    
       
                 
         
             
             
         
       
     
         [0304]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 4-hydroxy-4-phenylpiperidine: 1-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-4-phenyl-piperidin-4-ol trifluoroacetic acid salt as a light brown solid; LRMS for C 26 H 25 F 3 N 6 O (M+H) +  at m/z=495. 
       Example 121 
       [0305]    
       
                 
         
             
             
         
       
     
         [0306]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 4-benzylpiperidine: 7-[2-(4-Benzyl-piperidin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 27 H 27 F 3 N 6  (M+H) +  at m/z=493. 
       Example 122 
       [0307]    
       
                 
         
             
             
         
       
     
         [0308]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-cyclopentylpiperazine: 7-[2-(4-Cyclopentyl-piperazin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 24 H 28 F 3 N 7  (M+H) +  at m/z=472. 
       Example 123 
       [0309]    
       
                 
         
             
             
         
       
     
         [0310]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and N-isopropyl-1-piperazineacetamide: 2-{4-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-piperazin-1-yl}-N-isopropyl-acetamide trifluoroacetic acid salt as a light brown solid; LRMS for C 24 H 29 F 3 N 8 O (M+H) +  at m/z=503. 
       Example 124 
       [0311]    
       
                 
         
             
             
         
       
     
         [0312]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)—N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1-isopropylpiperazine: 7-[2-(4-Isopropyl-piperazin-1-yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 22 H 26 F 3 N 7  (M+H) +  at m/z=446. 
       Example 125 
       [0313]    
       
                 
         
             
             
         
       
     
         [0314]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-fluorophenol and sodium hydride: 7-[2-(2-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 15 F 4 N 5 O (M+H) +  at m/z=430. 
       Example 126 
       [0315]    
       
                 
         
             
             
         
       
     
         [0316]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 3-fluorophenol and sodium hydride: 7-[2-(3-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 15 F 4 N 5 O (M+H) +  at m/z=430. 
       Example 127 
       [0317]    
       
                 
         
             
             
         
       
     
         [0318]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 3-chlorophenol and sodium hydride: 7-[2-(3-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 15 ClF 3 N 5 O (M+H) +  at m/z=446. 
       Example 128 
       [0319]    
       
                 
         
             
             
         
       
     
         [0320]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 4-chlorophenol and sodium hydride: 7-[2-(4-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 21 H 15 ClF 3 N 5 O (M+H) +  at m/z=446. 
       Example 129 
       [0321]    
       
                 
         
             
             
         
       
     
         [0322]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, p-cresol and sodium hydride: N4-Methyl-7-(2-p-tolyloxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 22 H 18 F 3 N 5 O (M+H) +  at m/z=426. 
       Example 130 
       [0323]    
       
                 
         
             
             
         
       
     
         [0324]    From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 4-phenylphenol and sodium hydride: 7-[2-(Biphenyl-4-yloxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for C 27 H 20 F 3 N 5 O (M+H) +  at m/z=488. 
       Example 131 
       [0325]    
       
                 
         
             
             
         
       
     
         [0326]    From 2-[2-Amino-7-(2-fluoro-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol and pyrrolidine: 2-[2-Amino-7-(2-pyrrolidin-1-yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol trifluoroacetic acid salt as a light brown solid; LRMS for C 20 H 21 FN 6 O (M+H) +  at m/z=419. 
       Example 132 
       [0327]    
       
                 
         
             
             
         
       
     
         [0328]    Using steps 1-3 of the four-step sequence of Example 17 but starting from 2′-(trifluoromethyl)acetophenone gave N-[7-(2-(trifluoromethyl)phenyl)-4-hydroxy-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide as a light brown solid. LR-MS for C 19 H 17 F 3 N 4 O 2  (M+H) +  at m/z=391. 
         [0000]    
       
                 
         
             
             
         
       
     
         [0329]    To a mixture of phosphorous oxychloride (26 ml, 280 mmol) and N-[7-(2-(trifluoromethyl)phenyl)-4-hydroxy-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide (2.5 g, 6.4 mmol) cooled in an ice bath was slowly added N,N-diisopropylethylamine (5.2 ml, 29.9 mmol). The reaction was then heated in a 35° C. oil bath for 24 h. After cooling to room temperature, phosphorous oxychloride was distilled off in vacuo to afford N-[4-chloro-7-(6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide as a brown oil. To a portion of the crude N-[4-chloro-7-(6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide prepared above (750 mg, 1.84 mmol) in a sealed tube was added 2-propanol (60 ml), N,N-diisopropylethylamine (1.50 ml, 8.63 mmol) and 3-amino-1-propanol (270 mg, 3.60 mmol) at 0° C. The reaction was stirred at room temperature for three days. The reaction was concentrated in vacuo and purified by reversed phase HPLC to give 139 mg (16% yield) of 4-[2-amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-propan-1-ol trifluoroacetic acid salt as a white solid; LRMS for C 17 H 16 F 3 N 5 O (M+H) +  at m/z=364. 
         [0000]    In an analogous manner, the following compounds were also obtained: 
       Example 133 
       [0330]    
       
                 
         
             
             
         
       
     
         [0331]    From N-[4-chloro-7-(6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide and ethanolamine: 2-[2-Amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol as a light brown solid; LR-MS for C 16 H 14 F 3 N 5 O (M+H) +  at m/z=350. 
       Example 134 
       [0332]    
       
                 
         
             
             
         
       
     
         [0333]    From N-[4-chloro-7-(6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide and n-propylamine: N4-Propyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a white solid; LRMS for C 17 H 16 F 3 N 5  (M+H) +  at m/z=348. 
       Example 135 
       [0334]    
       
                 
         
             
             
         
       
     
         [0335]    From N-[4-chloro-7-(6-(trifluoromethyl)phenyl)-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide and 4-amino-1-butanol: 4-[2-Amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-butan-1-ol trifluoroacetic acid salt as a white solid; LRMS for C 18 H 18 F 3 N 5 O (M+H) +  at m/z=378. 
       Example 136 
       [0336]    
       
                 
         
             
             
         
       
     
         [0337]    From N-[7-(2-fluoro-6-(trifluoromethyl)phenyl)-4-chloro-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide and ethanolamine: 2-[2-Amino-7-(2-fluoro-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol as a light brown solid; LRMS for C 16 H 13 F 4 N 5 O (M+H) +  at m/z=368. 
       Example 137 
       [0338]    
       
                 
         
             
             
         
       
     
         [0339]    Analogously, substituting 2′-bromoacetophenone for 2′-(trifluoromethyl)acetophenone in the above procedures gave N-[7-(2-bromophenyl)-4-hydroxy-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide as a light brown solid. LR-MS for C 18 H 17 BrN 4 O 2  (M+H) +  at m/z=401. From the resulting N-[7-(2-bromophenyl)-4-chloro-pyrido[2,3-d]pyrimidin-2-yl]-2,2-dimethyl-propionamide and ethanolamine: 2-[2-Amino-7-(2-bromo-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol as a light brown solid; LRMS for C 15 H 14 BrN 5 O (M+H) +  at m/z=360. 
       Example 138 
       [0340]    
       
                 
         
             
             
         
       
     
         [0341]    A mixture of N-Methyl-pyrimidine-2,4,6-triamine (40 mg, 0.29 mmole) and 1-Phenyl-but-2-en-1-one (53 mg, 0.36 mmole) in 1-methyl-2-pyrrolidinone (2 mL) was heated at reflux overnight. The reaction mixture was blown to dryness and the crude was purified by reversed phase HPLC to give 10 mg (9% yield) of 5,N*4*-Dimethyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetate as a light brown solid; LR-MS for C 15 H 15 N 5  (M+H) +  at m/z=266. 
       Example 139 
       [0342]    
       
                 
         
             
             
         
       
     
         [0343]    A mixture of N-Methyl-pyrimidine-2,4,6-triamine (40 mg, 0.29 mmole), 1,3-Diphenyl-propenone (75 mg, 0.36 mmole) in 1-methyl-2-pyrrolidinone (2 mL) was heated at reflux overnight. The reaction was blown to dryness and the crude was purified by reversed phase HPLC to give 15 mg (12% yield) of N*4*-Methyl-5,7-diphenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetate as a light brown solid; LR-MS for C 20 H 17 N 5  (M+H) +  at m/z=328. 
       Example 140 
     In Vitro Inhibition of PTP1B 
     Enzymes 
       [0344]    Human PTP1B (1-321) was cloned from a human cDNA library using conventional molecular biology techniques. The cDNA sequence was identical to the published human PTP1B sequence (Accession number M33689). The protein was expressed and purified from  E. coli  as described by Barford D. et. al J. Mol. Biol (1994) 239, 726-730. 
       PTPase Assays 
       [0345]    The measurement of PTPase activity was carried out using one of two methods: 
         [0346]    The first method for the measurement of PTP1B inhibitory activity a tyrosine phosphorylated peptide based on the amino acid sequence of insulin receptor tyrosine autophosphorylation site 1146 (TRDI(pY)E) was used as substrate. The reaction conditions were as follows: 
         [0347]    PTP1B (0.5-2 nM) was incubated with compound for 15 min in buffer containing 37.5 mM Bis-Tris buffer pH 6.2, 140 mM NaCl, 0.05% BSA and 2 mM DTT. The reaction was started by the addition of 50 μM substrate. After 20 min at room temperature (22-25° C.), the reaction was stopped with KOH and the amount of free phosphate measured using Malachite Green as previously described (Harder et al. 1994 Biochem J. 298; 395). 
         [0348]    The second method was used for the measurement of general PTPase inhibitory activity across a panel of PTPases the substrate (6,8-difluoro-4-methylumbelliferyl phosphate (DiFMUP; from Molecular Probes) was used at the Km for each enzyme. The buffer conditions were identical as in the Malachite Green assay. The reaction was stopped with KOH. In this case the dephosphorylated product becomes fluorescent and the fluorescense read (Excitation: 360 mM/Emmission: 460 nM). 
         [0349]    For kinetic experiments, the same buffer conditions were used except that the reaction was started using enzyme and the reaction stopped after 10 minutes. 
         [0350]    The IC50 values (in μM) for the PTP1B inhibitory activity of the compounds in the present application are in the range of about 0.14 μM to about 80 μM. The following Table lists IC50 results for several of the above exemplified compounds: 
         [0000]    
       
         
               
               
               
             
               
               
               
             
           
               
                   
                   
               
               
                   
                 Example 
                 IC50 (μM) 
               
               
                   
                   
               
             
             
               
                   
               
             
          
           
               
                   
                 1 
                 1.66 
               
               
                   
                 3 
                 0.51 
               
               
                   
                 9 
                 1.41 
               
               
                   
                 13 
                 3.57 
               
               
                   
                 14 
                 2.56 
               
               
                   
                 27 
                 4.22 
               
               
                   
                 28 
                 1.15 
               
               
                   
                 56 
                 0.25 
               
               
                   
                 59 
                 10.80 
               
               
                   
                 80 
                 0.17 
               
               
                   
                 92 
                 2.33 
               
               
                   
                 107 
                 0.80 
               
               
                   
                 116 
                 0.30 
               
               
                   
                 121 
                 2.05 
               
               
                   
                 139 
                 52.44 
               
               
                   
                   
               
             
          
         
       
     
       Example 141 
     Glucose Uptake Assay 
       [0351]    The day before the assay the SKMC media was changed to high glucose DMEM, 25 mM Hepes, pH 7.0 and 2% Charcoal/dextran treated FBS for 19 hours. 
         [0352]    On the morning of the assay, cells were starved for max. 2 hours in low glucose (5.5 mM glucose) DMEM, 25 mM Hepes, pH 7.0 and 0.5% BSA. The starvation medium was removed and replaced with test medium (150 mM NaCl, 25 mM Hepes, pH 7.0) containing either 1% DMSO, or test compound diluted in DMSO or Porcine Insulin to a final concentrations of 1, 0.1, 0.05, 0.01 and 0.01 μM. Each assay point was performed in triplicate. The cells were incubated for 45 min at 37° C. 10 μM Cytochalasin B (CB) was added to appropriate wells to stop the active glucose transport (i.e., GLUT 1 &amp; 4). At this point 2-Deoxy-D(U- 15 C)glucose (Amersham, Code CFB195, 200 uCi/ml) was added to all wells to a final concentration of 0.8 μCi/ml. The cells were incubated for an additional 45 minutes at 37° C. in an incubator. Cells were then very gently washed for three times in PBS (RT). The cells were then lysed with the addition of 0.05% NaOH solution for 20 min at RT. The lysate was transferred to a scintillation vial containing 5 ml of scintillation fluid and counted in a Beckman LS6500 Scintillation counter. Analysis of results: The counts obtained with CB (passive glucose transport values) were subtracted from every value obtained with PI (or compounds) in order to evaluate only active glucose transport. Fold increase was calculated by dividing values in the presence of PI (or compounds) by the value obtained in the presence of DMSO (control). Compounds were considered to be active when they increase glucose uptake at least 25% of the Porcine Insulin response at 0.05 μM. 
         [0353]    In vivo inhibition of PTP1B: The anti-diabetic effect of compounds can be confirmed in well established rodent in vivo models of type 2 diabetes and obesity as set forth in the following procedures: 
       Example 142 
     Mouse Models 
       [0354]    Diet Induced Obese (DIO) Mouse Model: A majority of male C57BL/6J mice fed a diet consisting of 35.5% fat for 3 months develop obesity, hyperinsulinemia and hyperglycemia. DIO mice are probably a better model for human type-2 diabetes than are genetic mutations with multiple neuroendocrine abnormalities. Furthermore, the DIO mice probably develop type-2 diabetes in a manner similar to most cases of type-2 diabetes in humans, e.g. only those predisposed individuals who become obese after access to a diabetogenic diet. 
         [0355]    B6.C-m Lep db /++/J: Mice homozygous for the diabetes spontaneous mutation (Lepr db ) become identifiably obese around 3 to 4 weeks of age. Elevations of plasma insulin begin at 10 to 14 days and of blood sugar at 4 to 8 weeks. Homozygous mutant mice are polyphagic, polydipsic, and polyuric. The course of the disease is markedly influenced by genetic background. A number of features are observed on the C57BLKS background, including an uncontrolled rise in blood sugar, severe depletion of the insulin-producing beta-cells of the pancreatic islets, and death by 10 months of age. Exogenous insulin fails to control blood glucose levels and gluconeogenic enzyme activity increases. Peripheral neuropathy and myocardial disease are seen in C57BLKS Lepr db  homozygotes. 
         [0356]    B6.V-Lep ob /J: Mice homozygous for the obese spontaneous mutation, (Lep ob  commonly referred to as ob or ob/ob), are first recognizable at about 4 weeks of age. Homozygous mutant mice increase in weight rapidly and may reach three times the normal weight of wildtype controls. In addition to obesity, mutant mice exhibit hyperphagia, a diabetes-like syndrome of hyperglycemia, glucose intolerance, elevated plasma insulin, subfertility, impaired wound healing, and an increase in hormone production from both pituitary and adrenal glands. They are also hypometabolic and hypothermic. The obesity is characterized by an increase in both number and size of adipocytes. Although hyperphagia contributes to the obesity, homozygotes gain excess weight and deposit excess fat even when restricted to a diet sufficient for normal weight maintenance in lean mice. Hyperinsulinemia does not develop until after the increase body weight and is probably the result of it. Homozygotes do have an abnormally low threshold for stimulation of pancreatic islet insulin secretion even in very young preobese animals. Female homozygotes exhibit decreased uterine and ovarian weights, decreased ovarian hormone production and hypercytolipidemia in follicular granulosa and endometrial epithelial tissue layers (Garris et al., 2004). 
       Mouse Criteria: 
       [0357]    DIO Mouse Model: Mice used in these studies are at least 18 weeks of age and maintained on a high fat diet (BioServ F3282) for at least 12 weeks, The mice are weighed on the day prior to the study and sorted into treatment groups. Because of the variability in body weights, the DIO mice having the most extreme (i.e. highest or lowest) body weights are excluded. 
         [0358]    B6.C-m Lep db /++/J: Mice used in these studies are at least 9 weeks of age and maintained on Purina Lab Diet 5008 starting at 6 weeks of age. Two to three days prior to the study blood glucose levels of the mice are determined following a two hour fast. The mice are sorted into treatment groups. Because of the variability in blood glucose levels, the mice having the most extreme (i.e. highest or lowest) blood glucose levels are excluded with the goal of achieving an average blood glucose level between 160-190 mg/dl. 
         [0359]    B6.V-Lep ob /J: Mice used in these studies are at least 7 weeks of age and maintained on Purina Lab Diet 5001. Two to three days prior to the study blood glucose levels of the mice are determined following a two hour fast. The mice are sorted into treatment groups. Because of the variability in blood glucose levels, the mice having the most extreme (i.e. highest or lowest) blood glucose levels are excluded. In some instances mice are sorted based on body weights, the ob/ob mice having the most extreme (i.e. highest or lowest) body weights were excluded. 
       Experimental Parameters: 
       [0360]    Oral Glucose Tolerance Test (OGTT): Mice are placed into individual cages and fasted for 15 hours. After 15 hours the mice are treated orally by gavage with vehicle or compound using a dose volume of 5 ml/kg. An oral glucose challenge (1-2 g/kg) is administered four hours following treatment. Blood is collected from the tail vein into a 20 ul heparinized microhematocrit tube immediately prior to dosing with vehicle or compound, immediately prior to the OGTT and 0.5, 1, 1.5, 2 and sometimes up to 4 hours following the OGTT. The blood is transferred immediately to a microfuge tube. Blood glucose is measured with the YSI 2700 Select Glucose Analyzer. In some instances mice are fasted for only 2 hours prior to dosing with vehicle or compound and the OGTT is administered 4 hours post dose. 
         [0361]    Acute Efficacy Study: Mice are placed into individual cages and fasted for 2 hours. After 2 hours the mice are treated orally by gavage with vehicle or compound using a dose volume of 5 ml/kg. Blood is collected from the tail vein into a 20 ul heparinized microhematocrit tube immediately prior to dosing with vehicle or compound and 2, 4, 6 and 8 hours following treatment. The blood is transferred immediately to a microfuge tube. Blood glucose is measured with the YSI 2700 Select Glucose Analyzer 
         [0362]    Mice that have type 2 diabetes are generated by maintaining them on a high fat diet for 4-6 months (Diabetes vol. 37 September 1988). Male C57BL/6J mice (age 3-4 weeks) are placed on high fat diet for 4-6 months. At this time they are hyperglycemic and hyperinsulinemic and weighed 40-50 g. DIO mice (n=10) are weighed and fasted for a two hour period prior to oral treatment. Immediately prior to dosing a pre-dose blood glucose reading is taken by snipping off a portion of the tail and collecting blood from the tail vein. Mice are treated either with a single dose of compound (acute) or once a day for 5 days (sub-chronic). For the acute studies, glucose is generally measured at 2 h, 4 h, 6 h, 8 h post treatment. Compounds are considered active if the compounds demonstrated AUC (Area under the curve) show a statistically significant (p≦0.05) glucose lowering (&gt;15%) compared to the vehicle treated animals. 
         [0363]    For sub-chronic (5 day) studies mice are dosed once a day by gavage as described above. On day five, glucose is measured prior to dosing (0 time) and 2 hours after dosing. Insulin and triglycerides are measured at 2 hour post dose. Compounds are considered active if the compounds demonstrated AUC (Area under the curve) show a statistically significant (p&lt;0.05) glucose, insulin and triglyceride lowering compared to the vehicle treated animals.