WO2007009911A1

WO2007009911A1 - PYRIDO [2 , 3-D] PYRIMIDINE-2 , 4-DIAMINE COMPOUNDS AS PTPlB INHIBITORS

Info

Publication number: WO2007009911A1
Application number: PCT/EP2006/064091
Authority: WO
Inventors: Steven Joseph Berthel; Adrian Wai-Hing Cheung; Kyungjin Kim; Shiming Li; Kshitij Chhabilbhai Thakkar; Weiya Yun
Original assignee: F. Hoffmann-La Roche Ag
Priority date: 2005-07-21
Filing date: 2006-07-11
Publication date: 2007-01-25
Also published as: ATE449097T1; DE602006010564D1; EP1910359A1; ES2336603T3; CA2614443A1; KR20080018957A; CA2614443C; JP2009501758A; MX2008000885A; AU2006271809A1; IL188475A0; KR100962723B1; BRPI0613604A2; JP4880684B2; AU2006271809B2; CN101243081A; EP1910359B1; US20100280021A1; US20070021445A1; US20090062276A1

Abstract

The present invention is concerned with compounds of formula (I) wherein R1, R2, R3, R4 and X are as described in the description and claims. The compounds are inhibitors of PTP1B. Accordingly, the compounds can be used for treating or preventing PTP-1B mediated diseases, including diabetes, obesity, and diabetes-related diseases.

Description

PYRIDO [2,3-D] PYRIMIDINE-2,4-DIAMINE COMPOUNDS AS

PTP1 B INHIBITORS

The present invention comprises pyridopyrimidinediamine derivatives of the formula (I):

wherein X is a group X-1 of the formula:

or X is a group X-2 of the formula:

or X is a group X-3 of the formula:

CS 12.5.06 R¹ and R² are each independently selected from the group consisting of hydrogen, lower alkyl, methoxy lower alkyl and hydroxy lower alkyl, except that R¹ and R² may not both be hydrogen; R³ is hydrogen, lower alkyl or phenyl; R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl, carboxy, or together with R⁵ forms a 5-7 membered carbocyclic ring;

R⁵ when not in a ring with R⁴ 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 R⁶ forms a 5 or 6 membered aromatic ring;

R⁶ when not in a ring with R⁵ 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;

R⁷ 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;

R⁸ and R⁹ 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; R¹⁰ and R¹¹ 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 R¹² is hydrogen or aryl;

and the pharmaceutically acceptable salts or esters of the foregoing.

The compounds of the present invention are potent inhibitors of PTP1 B.

Accordingly, the invention also encompasses pharmaceutical compositions and methods of treating or preventing PTP- 1 B mediated diseases, including diabetes, obesity, and diabetes- related diseases.

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. PTP1 B 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- 1 B is a negative regulator of the insulin signaling pathway, suggesting that inhibitors of this enzyme may be beneficial in the treatment of diabetes.

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, Feb. 2003.

Inhibitors of PTP- 1 B 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. 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.

"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.

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.

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.

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 C-1-3 alkoxy. "Hydroxyalkoxy" means a lower alkoxy group which is mono- or disubstituted with hydroxy.

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.

The term "aryl" means a monocylic 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.

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.

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.

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.

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.

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.

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.

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.

The term "aryl lower alkoxy" means a lower alkoxy group in which one hydrogen atom is replaced by an aryl group. Benzyloxy is preferred.

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.

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 R⁴ or R⁵ are carboxy, which readily hydrolyze in v/Vo 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.

In more detail, the present invention is concerned with compounds of the formula (I):

wherein X is a group X-1 of the formula:

or X is a group X-2 of the formula:

or X is a group X-3 of the formula:

R¹ and R² are independently selected from the group consisting of hydrogen, lower alkyl, methoxy lower alkyl and hydroxy lower alkyl, except that R¹ and R² may not both be hydrogen;

R³ is hydrogen, lower alkyl or phenyl; R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl, carboxy or together with R⁵ forms a 5-7 membered carbocyclic ring;

R⁵ when not fused in a ring with R⁴ 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, perfluoro lower alkyl, lower alkylamino, lower alkanoylamino, sulfonylamino, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylcarbonyl, heteroaryl, or together with R⁶ forms a second fused 5 or 6 membered aromatic ring;

R⁶ when not fused in a ring with R⁵ 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;

R⁸ and R⁹ 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, lower alkylamino, lower alkanoylamino, sulfonylamino, cycloalkyl, heterocyclyl, heterocyclyloxy and heterocyclylcarbonyl;

Q is a 3-6 membered cycloalkyl ring; and

R¹² is hydrogen or aryl;

or the pharmaceutically acceptable salts or esters thereof.

Preferred compounds are those of the formula (Ia):

wherein R^a is hydrogen and R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl or carboxy, and R¹, R², R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined above. Preferably, R⁶, R⁷ and R⁸ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl. More preferably, R⁷ is hydrogen or flourine. It is also preferred, that one of R⁶ and R⁸ is hydrogen or flourine. Preferably, one of R⁶ and R⁸ is hydrogen or fluorine and the other is halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl. Most preferably, R⁶, R⁷ and R⁸ are hydrogen.

Other preferred compounds as defined above are those, wherein R⁵ and R⁹ are each independently selected from the group consisting of 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. Preferably, R⁵ and R⁹ are each independently selected from the group consisting of chlorine, fluorine, trifluoromethyl, C1 -4 alkyl, C1 -3 alkylthio, C1 -3 alkylsulfonyl, C1 -3 alkoxy, phenoxy, phenoxy mono-substituted with fluorine, chlorine or oxygen, and C1 -3 alkoxy substituted with hydroxy, methoxy or ethoxy.

It is preferred, that R¹ or R² is hydrogen. Preferably, the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

Preferred compounds are those, wherein R⁶, R⁷ and R⁸ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl. Preferably, R⁷ is hydrogen or flourine. Preferably, one of R⁶ and R⁸ is hydrogen or flourine. More preferably, one of R⁶ and R⁸ is hydrogen or fluorine and the other is halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl. Most preferably, R⁶, R⁷ and R⁸ are hydrogen.

Preferred compounds as defined above are those, wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl. Preferably, R⁵ and R⁹ are each independently selected from the group consisting of 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. Preferably, the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

Furthermore, it is preferred that R⁵ and R⁹ are each independently selected from the group consisting of chlorine, fluorine, trifluoromethyl, C1 -4 alkyl, C1 -3 alkylthio, C1 -3 alkylsulfonyl, C1 -3 alkoxy, phenoxy, phenoxy mono-substituted with fluorine, chlorine or oxygen, and C1 -3 alkoxy substituted with hydroxy, methoxy or ethoxy. Preferably, the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C 1 -3 alkyl. Preferred compounds of formula (I) as defined above are those, wherein R⁴ and

R⁵ form a 5-7 membered carbocyclic ring. Preferably, R¹ or R² is hydrogen.

Preferably, R⁷ is hydrogen or flourine. Preferably, one of R⁶ and R⁸ is hydrogen.

Preferably, one of R⁶ and R⁸ is hydrogen or fluorine and the other is halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl. More preferably, R⁶, R⁷ and R⁸ are hydrogen. In such compounds, it is preferred that the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl. Preferably, R⁵ and

R⁹ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, alkoxy lower alkoxy, nitro, hydroxy, hydroxy lower alkoxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and perfluoro lower alkyl.

Preferably, the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C 1 -3 alkyl.

Another preferred embodiment of the present invention is related to compounds of the formula (Ib):

wherein R¹, R², R³, R⁴, P, R¹⁰ and R¹¹ are as defined above. Preferably, R¹ or R² is hydrogen. Preferably, R3 is hydrogen and R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl or carboxy. Preferably, R¹⁰ and R¹¹ are each independently lower alkyl, lower alkoxy, perfluoro lower alkyl or halogen. More preferably, the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl. More preferably, the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C 1 -3 alkyl.

Another preferred embodiment of the present invention is related to compounds of of the formula (Ic):

wherein R¹, R², R³, R⁴, Q and R¹² are as defined above. Preferably, R¹ or R² is hydrogen. Preferably, R³ is hydrogen and R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl or carboxy. Preferably, R¹² is unsubstituted or substituted phenyl. It is preferred that R¹² is mono-substituted phenyl. Preferably, the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

Preferred compounds are those selected from the group consisting of N4-Methyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Chloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-tert-Butyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-chloro-6-fluorophenyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine, 7-Cyclohexyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-Methoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-(2-nitro-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 6,N4-Dimethyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-thiophen-2-yl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-6,7-diphenyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,6-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-dimethyl-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine, 7-(2-Chloro-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Methyl-7-(2,4,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-Bromo-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-Benzyloxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-(2-p-tolyloxy-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-6-propyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine,

N4-Methyl-7-(2,4-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,6-Dichloro-4-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

N8-Methyl-5,6-dihydro-benzo[h]pyrimido[4,5-b]quinoline-8,10-diamine, N4-Methyl-7-naphthalen-1 -yl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-lodo-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Fluoro-6-methoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-(2-Ethoxy-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Fluoro-6-isopropoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Fluoro-6-propoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-(2,3,5,6-tetramethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-phenyl-6-propyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 6-Ethyl-N4-methyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

6-Methanesulfonyl-N4-methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-(2,3,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dichloro-3-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,4-Bis-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,6-Bis-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,5-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-(2,3,6-trichloro-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-4-methyl-phenol,

N9-Methyl-6,7-dihydro-5H-10,12,13-triaza-benzo[3,4]cyclohepta[1 ,2- b]naphthalene-9,1 1 -diamine trifluoroacetic acid salt,

6-lsopropyl-N4-methyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-phenol trifluoroacetic acid salt,

7-(2,5-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-(2,4-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2,3-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-6-phenethyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Cyclopentyloxy-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

2-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenoxy]- ethanol trifluoroacetic acid, 3-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenoxy]- propan-1 -ol trifluoroacetic acid,

7-(2-Chloro-6-ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2-Amino-4-methylamino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-6- carboxylic acid trifluoroacetic acid salt,

N4-Methyl-7-(1 -phenyl-cyclopropyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Methyl-7-(1 -phenyl-cyclopentyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Methyl-7-(1 -phenyl-cyclohexyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, potassium 2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-benzoate, 7-(2,4-Diethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Ethyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Ethyl-6-methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Ethyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2,6-Dichloro-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Bromo-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, N4-Ethyl-7-(2-fluoro-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Chloro-6-fluoro-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Ethyl-7-(2,3,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2-[2-Amino-7-(2,6-dichloro-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol,

N4-Methyl-7-(2-piperidin-1 -yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine,

N4-Methyl-7-(2-morpholin-4-yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine- 2,4-diamine trifluoroacetic acid salt,

7-(2,4-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Methyl-7-[2-(4-methyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Ethoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-(2-Methoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-(2-Dimethylamino-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine, N4-Methyl-7-(2-methylamino-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-[2-(2-Dimethylamino-ethoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, N4-Methyl-7-(2-phenoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

N4-Methyl-7-(2-methylsulfanyl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt, 2-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl- phenoxy]-ethanol trifluoroacetic acid salt,

7-[2-(2-Methoxy-ethoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-[2-(2-pyrrolidin-1 -yl-ethoxy)-6-trifluoromethyl-phenyl]-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-lsopropoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

N4-Methyl-7-(2-propoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, 7-[2-(2-Diethylamino-ethoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-[2-(2-morpholin-4-yl-ethoxy)-6-trifluoromethyl-phenyl]-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-fluoro-6-pyrrolidin-1 -yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Fluoro-6-piperidin-1 -yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

2-(2-amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenol,

7-(2-Fluoro-6-morpholino-4-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine,

7-(2-Fluoro-6-phenylsulfanyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-(2-Fluoro-6-phenoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid,

7-(2-Fluoro-6-imidazol-1 -yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-[2-(4-Benzyl-piperazin-1 -yl)-6-fluoro-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine- 2,4-diamine trifluoroacetic acid salt,

7-(2-Fluoro-6-methylamino-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Dimethylamino-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, 7-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt,

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, 7-(2-Fluoro-6-thiomorpholin-4-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-[2-(3-Aminomethyl-piperidin-1 -yl)-6-fluoro-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-Fluoro-6-(2-methoxymethyl-pyrrolidin-1 -yl)-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(4-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Cyclohexyloxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt, N4-Methyl-7-[2-(2-methyl-pyrrolidin-1 -yl)-6-trifluoromethyl-phenyl]-pyrido[2,3- d]pyrimidine-2,4-diamine,

7-[2-(2,5-Dimethyl-pyrrolidin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]- pyrrolidin-3-ol trifluoroacetic acid salt,

1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]- piperidin-4-ol trifluoroacetic acid salt,

2-[2-Amino-7-(2-phenoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4- ylamino]-ethanol trifluoroacetic acid salt, {1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl- phenyl]-pyrrolidin-2-yl}-methanol trifluoroacetic acid salt,

7-[2-(2-Methoxymethyl-pyrrolidin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl- pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]- piperidin-3-ol trifluoroacetic acid salt,

7-[2-(4-Cyclohexyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(4-Ethyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, {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,

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, N4-Methyl-7-[2-(4-phenyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(4-Benzyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]- 4-phenyl-piperidin-4-ol trifluoroacetic acid salt,

7-[2-(4-Benzyl-piperidin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(4-Cyclopentyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 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,

7-[2-(4-lsopropyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(2-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(3-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(3-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-[2-(4-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-(2-p-tolyloxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-[2-(Biphenyl-4-yloxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2-[2-Amino-7-(2-pyrrolidin-1 -yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4- ylamino]-ethanol trifluoroacetic acid salt,

4-[2-amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-propan-

1 -ol trifluoroacetic acid salt, 2-[2-Amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol, N4-Propyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

4-[2-Amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-butan-1 - ol trifluoroacetic acid salt,

2-[2-Amino-7-(2-fluoro-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]- ethanol,

2-[2-Amino-7-(2-bromo-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol, 5,N-4-Dimethyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetate, and N-4-Methyl-5,7-diphenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetate, and pharmaceutically acceptable salts and esters thereof.

Particularly preferred compounds are those selected from the group consisting of

N4-Methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

2-chloro-6-fluorophenyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-Fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine,

7-(2-Chloro-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dichloro-3-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,4-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Methyl-7-(2-phenoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-[2-(4-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-(2-Cyclohexyloxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt,

7-[2-(2-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-[2-(3-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-[2-(4-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, and

N4-Methyl-7-(2-p-tolyloxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, and pharmaceutically acceptable salts and esters thereof.

It is preferred that the lower alkyl, methoxy lower alkyl, and hydroxy lower alkyl groups of R¹ and R² 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 R¹ or R² is hydrogen.

R³ and R⁴ are preferably hydrogen. Preferred substituents for R⁵ and R⁹ 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 R⁶ and R⁸ 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. R⁷ is preferably hydrogen, lower alkyl and perfluoro lower alkyl. Hydrogen is most preferred. Compounds of formula (I) are individually preferred, pharmaceutically acceptable salts thereof are individually preferred and pharmaceutically acceptable esters thereof are individually preferred, with the compounds of formula (I) being particularly preferred.

The compounds of formula (I) can have one or more asymmetric C atoms and can therefore exist as an enantiomeric mixture, mixture of stereoisomers or as optically pure compounds.

It will be appreciated that the compounds of general formula (I) in this invention may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo.

Another preferred embodiment of the present invention is concerned with a process for the preparation of compounds as defined above, comprising reacting a compound of formula (II)

with a compound HN(R¹, R²), wherein R¹, R², R³, R⁴ and X are as defined above.

Another embodiment of the present invention is related to compounds as defined above, when manufactured by a process as defined above.

Reaction conditions for the process are known in the art or from the description, schemes and examples given below. The invention is also concerned with pharmaceutical compositions comprising a compound of formula (I) as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Another embodiment of the present invention relates to compounds as defined above for use as therapeutic active substances, particularly for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are modulated by PTP- 1 B inhibitors, particularly diseases which are associated with high blood glucose concentration, particularly type 1 diabetes, type 2 diabetes, diabetes related diseases, impaired glucose tolerance, impaired insulin sensitivity or obesity.

The invention also embraces a method for the therapeutic and/or prophylactic treatment of diseases which are modulated by PTP- 1 B inhibitors, particularly for the therapeutic and/or prophylactic treatment of diseases which are associated with high blood glucose concentration, particularly type 1 diabetes, type 2 diabetes, diabetes related diseases, impaired glucose tolerance, impaired insulin sensitivity or obesity, which method comprises administering a compound of formula (I) as defined above to a human being or animal.

The invention furthermore relates to the use of compounds of formula (I) as defined above for the therapeutic and/or prophylactic treatment of diseases which are modulated by PTP- 1 B inhibitors, particularly diseases which are associated with high blood glucose concentration, especially type 1 diabetes, type 2 diabetes, diabetes related diseases, impaired glucose tolerance, impaired insulin sensitivity or obesity.

The invention also relates to the use of compounds of formula (I) as defined above for the preparation of medicaments for the therapeutic and/or prophylactic treatment of diseases which are modulated by PTP- 1 B inhibitors, particularly diseases which are associated with high blood glucose concentration, especially type 1 diabetes, type 2 diabetes, diabetes related diseases, impaired glucose tolerance, impaired insulin sensitivity or obesity. Of the diseases mentioned above, diabetes is the preferred medical indication, particularly type Il diabetes.

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.

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.

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.

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. 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.

The methods for preparing the compounds of this invention are described in the following schemes: SCHEME 1

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 Il 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 Il 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.

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, 1 149; (c) from substituted phenoltriflates (in turn prepared from substituted phenols), see e.g. Garrido, F. et a/., Tet. Lett. 2001 , 42, 265; (d) from substituted aryl iodides, see e.g. Cacchi, S. et a/., Org. Letters. 2003, 5, 289.

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 = CH₃, A = 2,4,6-trimethyl) exemplify the typical reaction conditions described in SCHEME 1 :

Compound I: To 6-chloro-2,4-diaminopyrimidine (5.0 g, 0.0347 mole) was added 25 ml_ of 25% aqueous MeNH₂ solution (0.182 mole, prepared from 40% aqueous MeNH₂ solution) in a sealed tube. The reaction was heated at 15O⁰C for 4.5 hours. TLC (1/9/90 v/v/v COnCNH₄OHZMeOHZCH₂CI₂) 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.NH₄OHZMeOHZCH₂CI₂) 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. ¹H NMR (DMSO-d₆, 300 MHz) δ 5.9 (broad s, 1 H), 5.5 (broad s, 2H), 5.3 (broad s, 2H), 4.76 (s, 1 H), 2.60 (broad s, 3H).

Compound II: To a 250 ml_ three-necked round bottom flask equipped with a magnetic stirrer, argon inlet and thermometer was added Λ/,Λ/-dimethylformamide (20 ml_, anhydrous). The flask was cooled in a dry iceZethylene 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 O⁰C. 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 4O⁰C 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 9O⁰C 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, cone. NH₄OH/MeOH/CH₂CI₂) gave 1.23 g (7.36 mmole, 47% yield) of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde Il as a light brown solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 9.68 (s, 1 H), 9.1 (broad s, 1 H), 6.85 (broad s, 2H), 6.5 (broad s, 2H), 2.80 (broad s, 3H).

Compound IV: A mixture of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde Il (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 100⁰C oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography (Isco 120 g, NH₄OH/MeOH/CH₂CI₂) 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 = CH₃, A = 2,4,6-trimethyl) as a light yellow solid; LR-MS for Ci₇H₁₉N₅ (M₊H)⁺ at m/z = 294. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.3 (d, 1 H), 8.09 (broad s, 1 H), 6.87-6.95 (m, 3H), 6.38 (broad s, 2H), 2.97 (broad s, 3H), 2.26 (s, 3H), 1.97 (s, 6H).

SCHEME 2

VII

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, Cl or CF₃) 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 Vl 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, 67, 193.

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 = CH₃, B = F, D = CH₂CH₃) exemplify the typical conditions used in the Friedlander condensation described in SCHEME 2:

A mixture of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde Il (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 100⁰C oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography (Isco 120 g,

NH₄OH/MeOH/CH₂CI₂) 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 = CH₃, B = F, D = CH₂CH₃) as a light brown solid; LRMS for Ci₆H₁₆FN₅O (M+H)⁺ at m/z = 314. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.37 (d, 1 H), 8.20 (broad s, 1 H), 7.40 (q, 1 H), 7.07 (d, 1 H), 6.97 (d, 1 H), 6.90 (t, 1 H), 6.47 (broad s, 2H), 4.05 (q, 2H), 2.97 (d, 3H), 1.18 (t, 3H).

SCHEME 3

VlIl

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.

The following procedures used in the synthesis of N4-Methyl-7-o-tolyl-pyrido[2,3- d]pyrimidine-2,4-diamine (IV, R1 = CH₃, A = 2-CH₃) exemplify the typical conditions described in SCHEME 3.

Compound VIII: A mixture of 2'-methylacetophenone (III, A = 2-CH₃, 5 g, 37.3 mmol) and Λ/,Λ/-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-CH₃) as a light brown oil. LRMS for Ci₂H₁₅NO (M₊H)⁺ at m/z = 190 Compound IX: A mixture of 1 -(o-tolyl)-3-dimethylamino-propenone (2.7 g, 14.3 mmol) and 2,4,6-triaminopyrimidine (VIII, A = CH₃, 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 = CH₃, 368 mg, 1 1 %) as a light brown solid; LRMS for Ci₄Hi₃N₅ (M+H)⁺ at m/z = 252.

Compound IV: To 7-o-Tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (IX, A = CH₃, 400 mg, 1.59 mmole) in Λ/,Λ/-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 = CH₃, A = 2-CH₃) as a light brown solid; EI-HRMS m/e calcd for Ci₅Hi₅N₅ (M)⁺ 265.1327, found 265.1322. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.37 (d, 1 H), 8.11 (broad s, 1 H), 7.42 (d, 1 H), 7.3 (m, 3H), 7.16 (d, 1 H), 6.42 (broad s, 2H), 2.97 (d, 3H), 2.37 (s, 3H).

SCHEME 4

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 Xl 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, 1 187. Conversion of N-2-pivaloyl pyrido[2,3- d]pyrimidin-4-ol Xl 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.

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 = CH₃, A = 2-F, 6- CF₃) exemplify the typical conditions described in SCHEME 4.

Compound VIII: A mixture of 2'-fluoro-6'-(trifluoromethyl)acetophenone (25.3 g, 0.123 mol) and Λ/,Λ/-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.

Compound X: A mixture of crude 1 -(2-fluoro-6-(trifluoromethyl)phenyl)-3- dimethylamino-propenone VIII (31.2 g, 1 19 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 25⁰C, 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 Ci₄H₈F₄N₄O (M₊H)⁺ at m/z = 325.

Compound Xl: 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 Xl (13.0 g, 52% yield) as a yellow solid; LR-MS for Ci₉Hi₆F₄N₄O₂ (M₊H)⁺ at m/z = 409.

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 Xl (7.10 g, 17.4 mmol) cooled in an ice bath was slowly added Λ/,Λ/-diisopropylethylamine (13.0 mL, 74.6 mmol). The reaction was then heated to 35⁰C 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-di methyl- 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 <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

Ci₅H₁₁F₄N₅ (M₊H)⁺ at m/z = 338. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.40 (d, 1 H), 8.30 (broad s, 1 H), 7.7 (m, 3H), 7.1 1 (d, 1 H), 6.60 (broad s, 2H), 2.97 (d, 3H).

SCHEME 5

Vl XIII SCHEME 5 describes a special scenario in which pyrido[2,3-d]pyrimidine-2,4- diamine analogs Vl containing highly electron-deficient C-7 phenyl with o-,o'- disubstitution and o-fluoro group (B could be, but not limited to, F, Cl or CF₃) 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 1 H-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- methylpiperazine, 1 -cyclohexylpiperazine, 1 -ethylpiperazine, 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-phenylphenol.

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 = CF₃, Nu = piperidine) exemplify the typical conditions described in SCHEME 5.

A mixture of 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine (Vl, B = CF₃, 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 19O⁰C 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 = CF₃, Nu = piperidine) as a light brown solid; LRMS for C₂oH₂iF₃N₆ (M+H)⁺ at m/z = 403. ¹H

NMR (DMSO-d₆, 300 MHz) δ 8.28 (d, 1 H), 8.09 (broad s, 1 H), 7.56 (t, 1 H), 7.44 (m, 2H), 6.97 (d, 1 H), 6.40 (broad s, 2H), 2.97 (d, 3H), 2.6-2.9 (m, 4H), 1.0-1.4 (m, 6H).

EXAMPLES

Example 1

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 Ci₂H₁₅NO (M+H)⁺ at m/z = 190.

H₃C.

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, 1 1 %) as a light brown solid; LRMS for Ci₄H₁₃N₅ (M₊H)⁺ at m/z = 252.

Step 3: To 7-o-Tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine (400 mg, 1.59 mmole) in Λ/,Λ/-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 Ci₅H₁₅N₅ (M)⁺ 265.1327, found 265.1322.

In an analogous manner, there were obtained:

Example 2

From 2'-trifluoromethylacetophenone: N4-Methyl-7-(2-trifluoromethyl-phenyl)- pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for Ci₅Hi₂F₃N₅ (M+H)⁺ at m/z = 320.

Example 3

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 Ci₄H₁₁CI₂N₅ (M+H)⁺ at m/z = 320.

Example 4

From 2'-chloroacetophenone: 7-(2-Chloro-phenyl)-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C₁₄H₁₂CIN₅ (M+H)⁺ at m/z = 286.

Example 5

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 C₁₄H₁₁F₂N₅ (M+H)⁺ at m/z = 288.

Example 6

From pinacolone: 7-tert-Butyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for Ci₂Hi₇N₅ (M+H)⁺ at m/z = 232.

Example 7

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 Ci₄HnCIFN₅ (M₊H)⁺ at m/z = 304.

Example 8

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 Ci₅HnF₄N₅ (M₊H)⁺ at m/z = 338.

Example 9

From 1 -cyclohexyl-ethanone: 7-Cyclohexyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine as a light yellow solid; LR-MS for Ci₄Hi₉N₅ (M+H)⁺ at m/z = 258.

Example 10

From 2'-Methoxyacetophenone: 7-(2-Methoxy-phenyl)-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine as a light brown solid; LRMS for Ci₅Hi₅N₅O (M+H)⁺ at m/z = 282.

Example 11

From 2'-Nitroacetophenone: N4-Methyl-7-(2-nitro-phenyl)-pyrido[2,3-d]pyrimidine- 2,4-diamine as a light brown solid; LRMS for Ci₄Hi₂N₆O₂ (M+H)⁺ at m/z = 297.

Example 12

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 Ci₆H₁₄F₃N₅ (M₊H)⁺ at m/z = 334.

Example 13

From 2-acetylthiophene: N4-Methyl-7-thiophen-2-yl-pyrido[2,3-d]pyrimidine-2,4- diamine as a light brown solid; LRMS for Ci₂HnN₅S (M+H)⁺ at m/z = 258.

Example 14

From deoxybenzoin: N4-Methyl-6,7-diphenyl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for C₂₀Hi₇N₅ (M+H)⁺ at m/z = 328.

Example 15

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 Ci₆H₁₇N₅ (M⁺) 279.1484, found 279.1474.

Example 16

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 Ci₇H₁₉N₅ (M-H)⁺ 292.1562, found 292.1563.

Example 17

Step 1 : A mixture of 2'-fluoro-6'-(trifluoromethyl)acetophenone (25.3 g, 0.123 mol) and Λ/,Λ/-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.

H₃C

Step 2: A mixture of crude 1 -(2-fluoro-6-(trifluoromethyl)phenyl)-3-dimethylamino- propenone (31.2 g, 1 19 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 25⁰C, filtered, washed with glacial acetic acid and dried in vacuo Xo 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 Ci₄H₈F₄N₄O (M₊H)⁺ at m/z = 325.

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 Ci₉Hi₆F₄N₄O₂ (M+H)⁺ at m/z = 409.

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 Λ/,Λ/-diisopropylethylamine (13.0 ml_, 74.6 mmol). The reaction was then heated to 35⁰C 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 <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 Ci₅HnF₄N₅ (M+H)⁺ at m/z = 338.

Example 18

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 Ci₄H₁₁CIFN₅ (M+H)⁺ at m/z = 304.

Preparation of 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde

Step 1 : To 6-chloro-2,4-diaminopyrimidine (5.0 g, 0.0347 mole) was added 25 ml of 25% aqueous MeNH₂ solution (0.182 mole, prepared from 40% aqueous MeNH₂ solution) in a sealed tube. The reaction was heated at 15O⁰C for 4.5 hours. TLC (1/9/90 v/v/v COnCNH₄OHZMeOHZCH₂CI₂) 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.NH₄OHZMeOHZCH₂CI₂) to give 3.98 g of an impure material. Recrystallization of the impure material from 45 ml of hot ethanol gave 1.57 g (1 1.3 mmole, 33% yield) of 2,4-diamino-6- methylaminopyrimidine as an off-white solid. ¹H NMR (DMSO-d₆, 300 MHz) δ 5.9 (broad s, 1 H), 5.5 (broad s, 2H), 5.3 (broad s, 2H), 4.76 (s, 1 H), 2.60 (broad s, 3H).

Step 2: To a 250 ml three-necked round bottom flask equipped with a magnetic stirrer, argon inlet and thermometer was added Λ/,Λ/-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 O⁰C. 2,4-diamino-6-methylaminopyrimidine I (2.20 g, 15.8 mmole) was then added carefully as a slurry in Λ/,Λ/-dimethylforamide (20 ml, anhydrous) (Exothermic!). The reaction was transferred to a 4O⁰C 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 9O⁰C 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, NH₄OH/MeOH/CH₂CI₂) gave 1.23 g (47% yield) of 2,4-diamino-6- methylaminopyrimidine-5-carbaldehyde Il as a light brown solid. ¹H NMR (DMSO- d₆, 300 MHz) δ 9.68 (s, 1 H), 9.1 (broad s, 1 H), 6.85 (broad s, 2H), 6.5 (broad s, 2H), 2.80 (broad s, 3H).

Example 19

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 100⁰C oil bath for 18 h. The reaction was cooled to room temperature, concentrated in vacuo and purified by silica gel chromatography (Isco 120 g, NH₄OH/MeOH/CH₂CI₂) 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 Ci₇H₁₉N₅ (M₊H)⁺ at m/z = 294. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.3 (d, 1 H), 8.09 (broad s, 1 H), 6.87-6.95 (m, 3H), 6.38 (broad s, 2H), 2.97 (broad s, 3H), 2.26 (s, 3H), 1.97 (s, 6H).

In an analogous manner, there were obtained:

Example 20

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 Ci₄Hi₂BrN₅ (M+H)⁺ at m/z = 330.

Example 21

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_2IH₁₉N₅O (M+H)⁺ at m/z = 358.

Example 22

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 Ci₆H₁₇N₅O (M+H)⁺ at m/z = 296.

Example 23

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 C₂i H₁₉N₅O (M+H)⁺ at m/z = 358.

Example 24

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 Ci₈H₁₈F₃N₅ (M₊H)⁺ at m/z = 362.

Example 25

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 Ci₆Hi₇N₅ (M+H)⁺ at m/z = 280.

Example 26

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 Ci₅H₁₀CI₂F₃N₅ (M+H)⁺ at m/z = 388.

Example 27

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 Ci₆H₁₅N₅ (M+H)⁺ at m/z = 278.

Example 28

From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and ^"T- acetonaphthone: N4-Methyl-7-naphthalen-1 -yl-pyrido[2,3-d]pyrimidine-2,4-diamine as a light brown solid; LRMS for Ci₈Hi₅N₅ (M+H)⁺ at m/z = 302.

Example 29

From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and 2'- iodoacetophenone: 7-(2-lodo-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt as a light brown solid; LRMS for Ci₄H₁₂IN₅ (M+H)⁺ at m/z = 378.

Example 30

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 Ci₅H₁₄FN₅O (M+H)⁺ at m/z = 300.

Example 31

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 Ci₆Hi₆FN₅O (M₊H)⁺ at m/z = 314.

Example 32

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 Ci₇H₁₈FN₅O (M+H)⁺ at m/z = 328.

Example 33

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 Ci₇H₁₈FN₅O (M+H)⁺ at m/z = 328.

Example 34

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 Ci₈H₂I N₅ (M+H)⁺ at m/z = 308.

Example 35

H₂N

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 Ci₇Hi₉N₅ (M+H)⁺ at m/z = 294.

Example 36

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 Ci₆Hi₇N₅ (M+H)⁺ at m/z = 280.

Example 37

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 Ci₆Hi₄F₃N₅O₂S (M+H)⁺ at m/z = 398.

Example 38

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 Ci₇H₁₉N₅ (M+H)⁺ at m/z = 294.

Example 39

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 Ci₄H₁₀CI₂FN₅ (M+H)⁺ at m/z = 338.

Example 40

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 Ci₆H₁₁F₆N₅ (M₊H)⁺ at m/z = 388.

Example 41

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 C₁₆H₁₁F₆N₅ (M₊H)⁺ at m/z = 388.

Example 42

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 C₁₆H₁₇N₅ (M₊H)⁺ at m/z = 280. Example 43

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 Ci₄H₁₀CI₃N₅ (M+H)⁺ at m/z = 354.

Example 44

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 Ci₅Hi₅N₅O (M+H)⁺ at m/z = 282.

Example 45

H₂N

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 Ci₇Hi₇N₅ (M+H)⁺ at m/z = 292.

Example 46

From 2,4-diamino-6-methylaminopyrimidine-5-carbaldehyde and isovalerophenone: 6-lsopropyl-N4-methyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt as a light brown solid; LRMS for Ci₇Hi₉N₅ (M+H)⁺ at m/z = 294.

Example 47

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 Ci₄Hi₃N₅O (M+H)⁺ at m/z = 268.

Example 48

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 Ci₄H₁₁CI₂N₅ (M₊H)⁺ at m/z = 320.

Example 49

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 C₁₄H₁₁CI₂N₅ (M+H)⁺ at m/z = 320.

Example 50

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 Ci₄H₁₁CI₂N₅ (M₊H)⁺ at m/z = 320.

Example 51

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 C₂₂H₂₁N₅ (M+H)⁺ at m/z = 356.

Example 52

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 C₁₉H₂₀FN₅O (M+H)⁺ at m/z = 354.

Example 53

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 Ci₆Hi₆FN₅O₂ (M+H)⁺ at m/z = 330.

Example 54

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 Ci₇Hi₈FN₅O₂ (M+H)⁺ at m/z = 344.

Example 55

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 Ci₆Hi₆CIN₅O (M₊H)⁺ at m/z = 330.

Example 56

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 Ci₆Hi₂F₃N₅O₂ (M+H)⁺ at m/z = 364.

Example 57

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 Ci₇Hi₇N₅ (M+H)⁺ at m/z = 292.

Example 58

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 Ci₉H₂iN₅ (M+H)⁺ at m/z = 320. Example 59

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 C20H23N5 (M+H)⁺ at m/z = 334.

Example 60

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 Ci₅Hi₃N₅O₂ (M+H)⁺ at m/z = 296.

Example 61

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 Ci₈H₂iN₅ (M+H)⁺ at m/z = 308. Example 62

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.

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 100⁰C 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 Ci₆H₁₄F₃N₅ (M+H)⁺ at m/z = 334.

In an analogous manner, there were obtained:

Example 63

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 Ci₇H₁₆F₃N₅ (M₊H)⁺ at m/z = 348.

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 Ci₆H₁₇N₅ (M+H)⁺ at m/z = 280.

Example 65

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 Ci₅H₁₃CI₂N₅ (M₊H)⁺ at m/z = 334.

Example 66

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 Ci₅H₁₄BrN₅ (M₊H)⁺ at m/z = 344.

Example 67

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 Ci₆Hi₃F₄N₅ (M₊H)⁺ at m/z = 352.

Example 68

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 Ci₅H₁₃CIFN₅ (M₊H)⁺ at m/z = 318.

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 Ci₈H_2I N₅ (M₊H)⁺ at m/z = 308.

Example 70

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 Ci₅Hi₃CI₂N₅O (M+H)⁺ at m/z = 350.

Example 71

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 Λ/,Λ/-dimethylformamide (4 ml) or 1 -methyl-2-pyrrolidinone (4 ml) in a sealed tube was heated in a 19O⁰C 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 C₂QH₂IF₃N₆ (M+H)⁺ at m/z = 403.

In an analogous manner, there were obtained: Example 72

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 Ci₉H₁₉F₃N₆O (M₊H)⁺ at m/z = 405.

Example 73

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 Ci₉H₁₉F₃N₆ (M+H)⁺ at m/z = 389.

Example 74

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 C₂₀H₂₂F₃N₇ (M+H)⁺ at m/z = 418.

Example 75

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 Ci₇H₁₆F₃N₅O (M₊H)⁺ at m/z = 364.

Example 76

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 Ci₆H₁₄F₃N₅O (M₊H)⁺ at m/z = 350.

Example 77

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 Ci₇H₁₇F₃N₆ (M+H)⁺ at m/z = 363.

Example 78

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 Ci₆Hi₅F₃N₆ (M₊H)⁺ at m/z = 349.

Example 79

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 Ci₉H₂IF₃N₆O (M+H)⁺ at m/z = 407.

Example 80

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 C₂IH₁₆F₃N₅O (M+H)⁺ at m/z = 412.

Example 81

H₂N

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 Ci₆H₁₄F₃N₅S (M+H)⁺ at m/z = 366.

Example 82

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 Ci₇Hi₆F₃N₅O₂ (M+H)⁺ at m/z = 380.

Example 83

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 Ci₈Hi₈F₃N₅O₂ (M+H)⁺ at m/z = 394.

Example 84

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 C2iH₂3F₃N₆O (M₊H)⁺ at m/z = 433.

Example 85

From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine, 2-propanol and sodium hydride: 7-(2-lsopropoxy-6-trifluoromethyl- phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt as a light brown solid; LRMS for Ci₈H₁₈F₃N₅O (M+H)⁺ at m/z = 378.

Example 86

H₂N

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 Ci₈Hi₈F₃N₅O (M+H)⁺ at m/z = 378.

Example 87

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 C₂IH₂SF₃N₆O (M+H)⁺ at m/z = 435.

Example 88

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 C₂i H₂₃F₃N₆O₂ (M₊H)⁺ at m/z = 449.

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 Ci₈Hi₉FN₆ (M+H)⁺ 339.1730, found 339.1728.

Example 90

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 Ci₉H₂iFN₆ (M⁺) 352.1812, found 352.1813.

Example 91

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 Ci₄H₁₂FN₅O (M⁺) 285.1029, found 285.1026.

Example 92

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 Ci₈H₁₉FN₆O (M+H)⁺ at m/z = 355.

Example 93

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 brwon solid; (ES)⁺-HRMS m/e calcd for C₂₀Hi₆FN₅S (M+H)⁺ 378.1 183, found 378.1 181.

Example 94

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 C₂₀Hi₆FN₅O (M₊H)⁺ 362.1412, found 362.1410.

Example 95

From 7-(2,6-Difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine and 1 H-lmidazole: 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 Ci₇H₁₄FN₇ (M₊H)⁺ 336.1368, found 336.1370.

Example 96

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 C₂₅H₂₆FN₇ (M₊H)⁺ 444.2307, found 444.2305.

Example 97

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 Ci₅H₁₅FN₆ (M+H)⁺ 299.1415, found 299.1417.

Example 98

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 Ci₆H₁₇FN₆ (M+H)⁺ 313.1572, found 313.1570.

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 Ci₉H₂₂FN₇ (M₊H)⁺ 368.1994, found 368.1992.

Example 100

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 C₂₂H₂₅FN₆O₂ (M₊H)⁺ 425.2098, found 425.2096.

Example 101

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 Ci₈H₁₉FN₆S (M₊H)⁺ 371.1449, found 371.1451.

Example 102

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 C₂₀H₂₄FN₇ (M+H)⁺ 382.2150, found 382.2152.

Example 103

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 C₂₀H₂₃FN₆O (M+H)⁺ 383.1990, found 383.1993.

Example 104

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 C₂₁ H₁₅F₄N₅O (M+H)⁺ at m/z = 430.

Example 105

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 C₂IH₂₂F₃N₅O (M+H)⁺ at m/z = 418.

Example 106

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 C₂₀H₂₁F₃N₆ (M₊H)⁺ at m/z = 403.

Example 107

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 C21 H₂₃F₃N₆ (M₊H)⁺ at m/z = 417.

Example 108

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 Ci₉Hi₉F₃N₆O (M+H)⁺ at m/z = 405.

Example 109

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 C₂₀H₂IF₃N₆O (M+H)⁺ at m/z = 419.

Example 110

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 C₂₂Hi₈F₃N₅O₂ (M+H)⁺ at m/z = 442.

Example 111

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 C₂₀H_2IF₃N₆O (M+H)⁺ at m/z = 419.

Example 112

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 C₂i H₂₃F₃N₆O (M+H)⁺ at m/z = 433.

Example 113

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 C₂₀H₂IF₃N₆O (M+H)⁺ at m/z = 419.

Example 114

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 C₂₅H₃OF₃N₇ (M+H)⁺ at m/z = 486.

Example 115

From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine and 1 -ethylpiperazine: 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 C₂IH₂₄F₃N₇ (M+H)⁺ at m/z = 432.

Example 116

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 C₂₄H₂₂F₃N₇O₂ (M+H)⁺ at m/z = 498.

Example 117

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 C₃₂H₂₈F₅N₇ (M+H)⁺ at m/z = 606.

Example 118

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 C₂₅H₂₄F₃N₇ (M+H)⁺ at m/z = 480.

Example 119

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 C₂₆H₂₆F₃N₇ (M+H)⁺ at m/z = 494.

Example 120

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 026H₂SF₃N₆O (M+H)⁺ at m/z = 495.

Example 121

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 C₂ZH₂₇F₃N₆ (M+H)⁺ at m/z = 493.

Example 122

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 C₂₄H₂SF₃N₇ (M+H)⁺ at m/z = 472.

Example 123

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 C₂₄H₂₉F₃N₈O (M₊H)⁺ at m/z = 503.

Example 124

From 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine and 1 -isopropylpiperazine: 7-[2-(4-lsopropyl-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 C22H26F3N7 (M+H)⁺ at m/z = 446.

Example 125

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 C21 H₁₅F₄N₅O (M+H)⁺ at m/z = 430.

Example 126

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 C₂₁ H₁₅F₄N₅O (M+H)⁺ at m/z = 430.

Example 127

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 C₂i H₁₅CIF₃N₅O (M+H)⁺ at m/z = 446.

Example 128

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_2IH₁₅CIF₃N₅O (M+H)⁺ at m/z = 446.

Example 129

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 C₂₂Hi₈F₃N₅O (M+H)⁺ at m/z = 426.

Example 130

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 C27H20F3N5O (M+H)⁺ at m/z = 488.

Example 131

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 C₂oH₂iFN₆O (M+H)⁺ at m/z = 419.

Example 132

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 Ci₉H₁₇F₃N₄O₂ (M₊H)⁺ at m/z = 391.

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 35⁰C 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 O⁰C. 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 Ci₇H₁₆F₃N₅O (M₊H)⁺ at m/z = 364.

In an analogous manner, the following compounds were also obtained:

Example 133

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 Ci₆H₁₄F₃N₅O (M₊H)⁺ at m/z = 350.

Example 134

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 Ci₇H₁₆F₃N₅ (M₊H)⁺ at m/z = 348.

Example 135

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 Ci₈H₁₈F₃N₅O (M+H)⁺ at m/z = 378.

Example 136

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 Ci₆Hi₃F₄N₅O (M₊H)⁺ at m/z = 368.

Example 137

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 Ci₈Hi₇BrN₄O₂ (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 Ci₅Hi₄BrN₅O (M+H)⁺ at m/z = 360.

Example 138

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 Ci₅H₁₅N₅ (M+H)⁺ at m/z = 266.

Example 139

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 C₂₀Hi₇N₅ (M₊H)⁺ at m/z = 328.

Example 140

In vitro inhibition of PTP1 B Enzymes

Human PTP1 B (1 -321 ) was cloned from a human cDNA library using conventional molecular biology techniques. The cDNA sequence was identical to the published human PTP1 B sequence (Accession number M33689). The protein was expressed and purified from E. coli as described by Barford D. et.al J. MoI Biol (1994) 239, 726-730.

PTPase assays

The measurement of PTPase activity was carried out using one of two methods: The first method for the measurement of PTP1 B inhibitory activity a tyrosine phosphorylated peptide based on the amino acid sequence of insulin receptor tyrosine auto phosphorylation site 1146 (TRDI(pY)E) was used as substrate. The reaction conditions were as follows:

PTP1 B (0.5-2nM ) was incubated with compound for 15 min in buffer containing 37.5 mM Bis-Tris buffer pH 6.2, 14OmMNaCI, 0.05% BSA and 2mM DTT. The reaction was started by the addition of 50μM 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).

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 dephosphoryated product becomes fluorescent and the fluorescense read (Excitiation:360mM/Emmission: 46OnM).

For kinetic experiments, the same buffer conditions were used except that the reaction was started using enzyme and the reaction stopped after 10 minutes.

The IC50 values (in μM) for the PTP1 B inhibitory activity of the compounds in the present application are in the range of about 0.14μM to about 80μM. The following Table lists IC50 results for several of the above exemplified compounds:

Example 141

Glucose Uptake Assay

The day before the assay the SKMC media was changed to high glucose DMEM ,

25mM Hepes, pH 7.0 and 2% Charcoal/dextran treated FBS for 19 hours. On the morning of the assay, cells were starved for max. 2 hours in low glucose

(5.5mM glucose) DMEM, 25 mM Hepes, pH 7.0 and 0.5% BSA. The starvation medium was removed and replaced with test medium (15OmMNaCI, 25mM 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. 10μM Cytochalasin B (CB) was added to appropriate wells to stop the active glucose transport (i.e., GLUT 1 & 4 ). At this point 2-Deoxy-D(U-¹⁵C)glucose (Amersham, Code CFB195, 200uCi/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 Pl (or compounds) in order to evaluate only active glucose transport. Fold increase was calculated by dividing values in the presence of Pl (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.

In vivo inhibition of PTP1 B: 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:

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.

B6.C-m Lep^db/++/J: Mice homozygous for the diabetes spontaneous mutation {Lepή¹⁰) 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 Lepf^b homozygotes.

B6.V-Lep°^b/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: 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.

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 160-190mg/dl.

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:

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 5ml/kg. An oral glucose challenge (1 -2g/kg) is administered four hours following treatment. Blood is collected from the tail vein into a 2OuI 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.

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 5ml/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

Mice that have type 2 diabetes are generated by maintaining them on a high fat diet for 4-6 months (Diabetes vol. 37 Sept 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 2h, 4h, 6h, 8h post treatment.

Compounds are considered active if the compounds demonstrated AUC (Area under the curve) show a statistically significant (p < 0.05) glucose lowering (>15%) compared to the vehicle treated animals.

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 < 0.05) glucose, insulin and triglyceride lowering compared to the vehicle treated animals. Example A

Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

Ingredients

Per tablet

Kernel:

Compound of formula (I) 10.0 mg 200.0 mg

Microcrystalline cellulose 23.5 mg 43.5 mg

Lactose hydrous 60.0 mg 70.0 mg

Polyvinylpyrrolidone K30 12.5 mg 15.0 mg

Sodium starch glycolate 12.5 mg 17.0 mg

Magnesium stearate 1.5 mg 4.5 mg

(Kernel Weight) 120.0 350.0 mg mg Film Coat:

Hydroxypropyl methyl cellulose 3.5 mg 7.0 mg

Polyethylene glycol 6000 0.8 mg 1.6 mg

Talc 1.3 mg 2.6 mg

Iron oxide (yellow) 0.8 mg 1.6 mg

Titanium dioxide 0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcristalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magesiumstearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution / suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in a conventional manner:

Ingredients Per capsule

Compound of formula (I) 25.0 mg

Lactose 150.0 mg

Maize starch 20.0 mg

Talc 5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg

Polyethylene glycol 400 150.0 mg

Acetic Acid q.s. ad pH 5.0

Water for injection solutions ad 1.0 ml

The active ingredient is dissolved in a mixture of polyethylene glycol 400 and water for injection (part). The pH is adjusted to 5.0 by acetic acid. The volume is adjusted to 1.0 ml by addition of the residual amount of water. The solution is filtered, filled into vials using an appropriate overage and sterilized.

Example D

Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:

Capsule contents

Compound of formula (I) 5.0 mg

Yellow wax 8.0 mg

Hydrogenated Soya bean oil 8.0 mg

Partially hydrogenated plant oils 34.0 mg

Soya bean oil H O.O mg

Weight of capsule contents 165.0 mg

Gelatin capsule

Gelatin 75.0 mg

Glycerol 85% 32.0 mg

Karion 83 8.0 mg (dry matter)

Titanium dioxide 0.4 mg

Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in a conventional manner:

Compound of formula (I) 50.0 mg

Lactose, fine powder 1015.0 mg

Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg

Sodium carboxymethyl cellulose 14.0 mg

Polyvinylpyrrolidone K 30 10.0 mg

Magnesium stearate 10.0 mg

Flavoring additives 1.0 mg

The active ingredient is mixed with lactose, microcristalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavouring additives and filled into sachets.

Claims

Claims:

1. Compounds of the formula (I):

wherein X is a group X-1 of the formula:

or X is a group X-2 of the formula:

or X is a group X-3 of the formula:

R¹ and R² are independently selected from the group consisting of hydrogen, lower alkyl, methoxy lower alkyl and hydroxy lower alkyl, except that R¹ and R² may not both be hydrogen; R ₅3 is hydrogen, lower alkyl or phenyl;

R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl, carboxy or together with R⁵ forms a 5-7 membered carbocyclic ring;

Q is a 3-6 membered cycloalkyl ring; and

R¹² is hydrogen or aryl;

or the pharmaceutically acceptable salts or esters thereof.

2. Compounds of claim 1 of the formula (Ia):

wherein R^a is hydrogen and R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl or carboxy, and R¹, R², R⁵, R⁶, R⁷, R⁸ and R⁹ are as defined in claim 1.

3. Compounds of claim 2 wherein R⁶, R⁷ and R⁸ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl.

4. Compounds of claim 3 wherein R⁷ is hydrogen or flourine.

5. Compounds of claim 4 wherein one of R⁶ and R⁸ is hydrogen or flourine.

6. Compounds of claim 4 wherein one of R⁶ and R⁸ is hydrogen or fluorine and the other is halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl.

7. Compounds of claim 5 wherein R⁶, R⁷ and R⁸ are hydrogen.

8. Compounds of any of claims 2 to 7 wherein R⁵ and R⁹ are each independently selected from the group consisting of 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.

9. Compounds of any of claims 5 to 7 wherein R⁵ and R⁹ are each independently selected from the group consisting of chlorine, fluorine, trifluoromethyl, C1 -4 alkyl, C1 -3 alkylthio, C1 -3 alkylsulfonyl, C1 -3 alkoxy, phenoxy, phenoxy mono- substituted with fluorine, chlorine or oxygen, and C1 -3 alkoxy substituted with hydroxy, methoxy or ethoxy.

10. Compounds of claim 2 wherein R¹ or R² is hydrogen.

1 1. Compound of claim 10 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

12. Compounds of claim 10 wherein R⁶, R⁷ and R⁸ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl.

13. Compounds of claim 10 wherein R⁷ is hydrogen or flourine.

14. Compounds of claim 13 wherein one of R⁶ and R⁸ is hydrogen or flourine.

15. Compounds of claim 13 wherein one of R⁶ and R⁸ is hydrogen or fluorine and the other is halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl.

16. Compounds of claim 14 wherein R⁶, R⁷ and R⁸ are hydrogen.

17. Compounds according to claim 16 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

18. Compounds of any of claims 10 to 15 wherein R⁵ and R⁹ are each independently selected from the group consisting of 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.

19. Compounds of claim 18 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

20. Compounds of claim 16 wherein R⁵ and R⁹ are each independently selected from the group consisting of chlorine, fluorine, trifluoromethyl, C1 -4 alkyl, C1 -3 alkylthio, C1 -3 alkylsulfonyl, C1 -3 alkoxy, phenoxy, phenoxy mono-substituted with fluorine, chlorine or oxygen, and C1 -3 alkoxy substituted with hydroxy, methoxy or ethoxy.

21. Compounds of claim 20 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

22. Compounds of claim 1 wherein R⁴ and R⁵ form a 5-7 membered carbocyclic ring.

23. Compounds of claim 22 wherein R¹ or R² is hydrogen.

24. Compounds of claim 23 wherein R⁷ is hydrogen or flourine.

25. Compounds of claim 24 wherein one of R⁶ and R⁸ is hydrogen.

26. Compounds of claim 24 wherein one of R⁶ and R⁸ is hydrogen or fluorine and the other is halogen, lower alkyl, lower alkoxy, hydroxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl or perfluoro lower alkyl.

27. Compounds of claim 25 wherein R , R and R are hydrogen.

28. Compounds according to claim 27 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

29. Compounds of claim 23 wherein R⁵ and R⁹ are each independently hydrogen, halogen, lower alkyl, lower alkoxy, alkoxy lower alkoxy, nitro, hydroxy, hydroxy lower alkoxy, hydroxy lower alkyl, lower alkylthio, lower alkyl sulfinyl, lower alkyl sulfonyl, and perfluoro lower alkyl.

30. Compounds of claim 23 or 25 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

31. Compounds of claim 1 of the formula (Ib):

wherein R¹, R², R³, R⁴, P, R¹⁰ and R are as defined in claim 1.

32. Compounds of claim 31 wherein R¹ or R² is hydrogen.

33. Compounds of claim 32 wherein R3 is hydrogen and R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl or carboxy.

34. Compounds of claim 32 or 33 wherein R¹⁰ and R¹¹ are each independently lower alkyl, lower alkoxy, perfluoro lower alkyl or halogen.

35. Compounds of claim 34 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

36. Compounds of claim 34 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

37. Compounds of claim 1 of the formula (Ic):

wherein R¹, R², R³, R⁴, Q and R¹² are as defined in claim 1.

38. Compounds of claim 37 wherein R¹ or R² is hydrogen.

39. Compounds of claim 38 wherein R³ is hydrogen and R⁴ is hydrogen, lower alkyl, lower alkylsulfonyl, phenyl or carboxy.

40. Compounds of claim 38 wherein R¹² is unsubstituted or substituted phenyl.

41. Compounds of claim 38 wherein R¹² is mono-substituted phenyl.

42. Compounds of claim 38 or 40 wherein the R¹ or R² which is substituted is substituted with C1 -4 alkyl or hydroxy C1 -3 alkyl.

43. Compounds of any of claims 1 to 42, selected from the group consisting of N4-Methyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Chloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Difluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-tert-Butyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-chloro-6-fluorophenyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine,

7-Cyclohexyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Methoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-(2-nitro-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 6,N4-Dimethyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-thiophen-2-yl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-6,7-diphenyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-dimethyl-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine,

7-(2-Chloro-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-(2,4,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Bromo-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Benzyloxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Ethoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-(2-p-tolyloxy-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, N4-Methyl-6-propyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine,

N4-Methyl-7-(2,4-dimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dichloro-4-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, N8-Methyl-5,6-dihydro-benzo[h]pyrimido[4,5-b]quinoline-8,10-diamine, N4-Methyl-7-naphthalen-1 -yl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-Fluoro-6-isopropoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-(2-Fluoro-6-propoxy-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Methyl-7-phenyl-6-propyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

6-Ethyl-N4-methyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2,4-diamine trifluoroacetic acid salt, N4-Methyl-7-(2,3,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,6-Dichloro-3-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-4-methyl-phenol,

7-(2,3-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, N4-Methyl-6-phenethyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Cyclopentyloxy-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, 2-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenoxy]- ethanol trifluoroacetic acid,

3-[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenoxy]- propan-1 -ol trifluoroacetic acid,

N4-Methyl-7-(1 -phenyl-cyclopropyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Methyl-7-(1 -phenyl-cyclopentyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, N4-Methyl-7-(1 -phenyl-cyclohexyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, potassium 2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-benzoate,

7-(2,4-Diethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Ethyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, N4-Ethyl-6-methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine,

N4-Ethyl-7-o-tolyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Bromo-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

N4-Ethyl-7-(2-fluoro-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Chloro-6-fluoro-phenyl)-N4-ethyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, N4-Ethyl-7-(2,3,6-trimethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2-[2-Amino-7-(2,6-dichloro-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol,

N4-Methyl-7-(2-piperidin-1 -yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine, N4-Methyl-7-(2-morpholin-4-yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt,

7-(2,4-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-Methoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, 7-(2-Dimethylamino-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine,

N4-Methyl-7-(2-methylamino-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-[2-(2-Dimethylamino-ethoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2-(2-amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-fluoro-phenol,

7-(2-Fluoro-6-morpholino-4-yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine, 7-(2-Fluoro-6-phenylsulfanyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-(2-Fluoro-6-imidazol-1 -yl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-[2-(4-Benzyl-piperazin-1 -yl)-6-fluoro-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt,

7-(2-Dimethylamino-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt,

7-[2-Fluoro-6-(4-methyl-piperazin-1 -yl)-phenyl]-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt,

7-(2-Cyclohexyloxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-

7-[2-(2,5-Dimethyl-pyrrolidin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]- pyrrolidin-3-ol trifluoroacetic acid salt,

1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]- piperidin-4-ol trifluoroacetic acid salt, 2-[2-Amino-7-(2-phenoxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4- ylamino]-ethanol trifluoroacetic acid salt,

{1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl- phenyl]-pyrrolidin-2-yl}-methanol trifluoroacetic acid salt,

7-[2-(4-Cyclohexyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-[2-(4-Ethyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

{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,

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,

N4-Methyl-7-[2-(4-phenyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(4-Benzyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 1 -[2-(2-Amino-4-methylamino-pyrido[2,3-d]pyrimidin-7-yl)-3-trifluoromethyl-phenyl]-

4-phenyl-piperidin-4-ol trifluoroacetic acid salt,

7-[2-(4-Cyclopentyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

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,

7-[2-(4-lsopropyl-piperazin-1 -yl)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-[2-(2-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(3-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 7-[2-(3-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-[2-(4-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

2-[2-Amino-7-(2-pyrrolidin-1 -yl-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4- ylamino]-ethanol trifluoroacetic acid salt, 4-[2-amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-propan-

1 -ol trifluoroacetic acid salt,

2-[2-Amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol,

N4-Propyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetic acid salt, 4-[2-Amino-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-butan-1 - ol trifluoroacetic acid salt,

2-[2-Amino-7-(2-bromo-phenyl)-pyrido[2,3-d]pyrimidin-4-ylamino]-ethanol, 5,N-4-Dimethyl-7-phenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetate, and

N-4-Methyl-5,7-diphenyl-pyrido[2,3-d]pyrimidine-2,4-diamine trifluoroacetate, and pharmaceutically acceptable salts and esters thereof.

44. Compounds of any of claims 1 to 43, selected from the group consisting of N4-Methyl-7-(2-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2,6-Dichloro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 2-chloro-6-fluorophenyl-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine, 7-(2-Fluoro-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine, 7-(2-Chloro-6-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,6-Dichloro-3-fluoro-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2,4-Dimethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4-diamine,

7-(2-lsopropoxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, 7-[2-(4-Fluoro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt,

7-(2-Cyclohexyloxy-6-trifluoromethyl-phenyl)-N4-methyl-pyrido[2,3-d]pyrimidine-

2,4-diamine trifluoroacetic acid salt,

7-[2-(4-Chloro-phenoxy)-6-trifluoromethyl-phenyl]-N4-methyl-pyrido[2,3- d]pyrimidine-2,4-diamine trifluoroacetic acid salt, and N4-Methyl-7-(2-p-tolyloxy-6-trifluoromethyl-phenyl)-pyrido[2,3-d]pyrimidine-2,4- diamine trifluoroacetic acid salt, and pharmaceutically acceptable salts and esters thereof.

45. A process for the preparation of compounds according to any of claims 1 to 44, comprising reacting a compound of formula (II)

with a compound HN(R ,R ), wherein R , R , R , R and X are as defined in any of claims 1 to 44.

46. Compounds according to any of claims 1 to 44, when manufactured by a process according to claim 45.

47. Pharmaceutical compositions comprising a compound according to any of claims 1 to 44 and a pharmaceutically acceptable carrier and/or adjuvant.

48. Compounds according to any of claims 1 to 44 for use as therapeutic active substances.

49. Compounds according to any of claims 1 to 44 for use as therapeutic active substances for the treatment and/or prophylaxis of diseases which are modulated by PTP- 1 B inhibitors.

50. A method for the therapeutic and/or prophylactic treatment of diseases which are modulated by PTP- 1 B inhibitors, particularly for the therapeutic and/or prophylactic treatment of diseases which are associated with high blood glucose concentration, particularly type 1 diabetes, type 2 diabetes, diabetes related diseases, impaired glucose tolerance, impaired insulin sensitivity or obesity, which method comprises administering a compound according to any of claims 1 to 44 to a human being or animal.

51. The use of compounds according to any of claims 1 to 44 for the therapeutic and/or prophylactic treatment of diseases which are modulated by PTP- 1 B inhibitors.

52. The use of compounds according to any of claims 1 to 44 for the therapeutic and/or prophylactic treatment of diabetes.

53. The use of compounds according to any of claims 1 to 44 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of diseases which are modulated by PTP- 1 B inhibitors.

54. The use of compounds according to any of claims 1 to 44 for the preparation of medicaments for the therapeutic and/or prophylactic treatment of diabetes.

55. The invention as hereinbefore defined.