CZ20002106A3 - Triazine inhibitors of angiogenesis - Google Patents

Abstract

Compounds of formula (I) or pharmaceutically acceptable salts thereof acceptable salts or prodrugs thereof are effective in the treatment of treatment of pathological conditions arising from angiogenesis or exacerbated by angiogenesis. Pharmaceutical preparations containing these compounds and their use as mammalian angiogenesis inhibitor.

Description

TRIAZINE ANGIOGENESIS INHIBITORS

Technical field

The present invention relates to substituted triazines that are effective in treating pathological conditions that arise or are exacerbated by angiogenesis, to pharmaceutical compositions containing these compounds, and to methods of inhibiting angiogenesis in mammals.

BACKGROUND OF THE INVENTION

Angiogenesis is the process by which new blood vessels are formed. It is essential for normal body activities involving the reproduction, development and treatment of injuries. Although this process is not fully understood, it is believed to involve complex interactions of molecules that regulate the growth of endothelial cells (primary cells of capillary blood vessels). Under normal conditions, these molecules appear to maintain microvascularity at rest (namely, one of the non-capillary growths) for long periods that may last weeks or in some cases decades. If necessary (as during wound treatment), these same cells may undergo rapid proliferation and conversion over a 5 day period (Folkman, J. and Shing, Y., The Journal of Biological Chemistry, 267 (16), 10931-). 10934, (1992) and Folkman, J. and Klagsbrun, M., Science, 235, 442-447 (1987).

Although angiogenesis is a highly regulated process under normal conditions, many diseases (characterized as angiogenic diseases) are caused by persistent, unregulated angiogenesis. Otherwise, unregulated angiogenesis can either directly cause individual diseases or exacerbate existing pathological conditions. For example, ocular neovascularization has been implicated as the most common cause of blindness and is prevalent in approximately twenty ocular diseases. In certain current conditions, such as arthritis, newly formed capillary blood vessels attack the joints and destroy cartilage. In diabetes, new capillaries formed in the retina invade the vitreous, bleed and cause blindness. The growth and metastasis of solid tumors also depend on angiogenesis (Folkman, J., Cancer Research, 46, 467-473 (1986), Folkman, J., Journal of the National Cancer Institute, 82, 4-6 (1989). that, for example, tumors that grow to a size greater than 2 mm must have their own blood supply, and must also induce the growth of new capillary blood vessels by inducing the growth of new blood vessels once they have become attached to the tumor, to enter into circulation and metastasize to distant places such as · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Liver, lung or bone (Weidner, N., et al., The New England Journal of Medicines, 324 (1), 18 (1991)).

Several angiogenesis inhibitors are currently under investigation for the treatment of angiogenic diseases (Gasparini, G. and Harris, A.L., J. Clin. Oncol., 13 (3): 765-782, 1995), but these compounds are not yet preferred. For example, Suramine is a potent inhibitor of angiogenesis, but at the doses required for antitumor activity it causes severe systemic toxicity in humans. Compounds such as retinoids, interferons and antiestrogens are relatively safe when used in human subjects but have weak anti-angiogenic effects. Thus, there is a continuing need for compounds effective in treating angiogenic diseases in mammals.

SUMMARY OF THE INVENTION

In one embodiment of the present invention, compounds having formula (I) are provided:

NR ¹ R ²

R ³ R ⁴ N

I, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R ¹ , R ² , R ³ and R ⁴ are independently selected from the group consisting of hydrogen, C 1 -C ₂₀ alkyl and C 1 -C ₂ oalkanoyl; or R ¹ and R ^2, taken together with the nitrogen to which they are attached, form a ring independently selected from the group consisting of morpholine, piperidine, piperazine and pyrrolidine; or R ³ and R ^4, taken together with the nitrogen atom to which they are attached, form a ring independently selected from the group consisting of morpholine, piperidine, piperazine and pyrrolidine;

substituent A is selected from the group consisting of heterocycle, (heterocycle) -C 1 -C ₂ alkyl, C 3 -C 10 cycloalkyl, C 6 -C 18 spiroalkyl and -BLY;

B and Y are independently aryl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, heterocycle or C 6 -C 15 Spiroalkyl;

• · · · · ·

L is a covalent bond, -C (= W) -, C 1 -C 20 alkylene, -NR ⁵ -, -NR ⁶ C (X) NR ⁷ -, C 2 -C 20 alkynylene, C 2 -C 20 alkenylene, -O-, -S (O) t - , -NR ⁶ C (X) -, -C (X) NR ⁶ , -NR ⁶ SO ² NR ⁷ -, NR ⁶ SO ² -, -SO ₂ NR ⁶ - or -OfC 1 R ² );

R ⁵ is hydrogen, C 1 -C 20 alkyl, C 1 -C 20 alkanoyl and C 1 -C 20 arylalkyl; R ⁶ and R ⁷ are independently hydrogen, C 1 -C 20 alkyl and aryl-C 1 -C ₂₀ alkyl; R ¹ and R ² are as defined above;

W is O, S or (= N-O-R ⁶ );

X is O or S; index t is 0-2;

each L is indicated with its left end attached to B and its right end attached to Y; and at each occurrence, aryl, cycloalkyl, cycloalkenyl, heterocycle, spiroalkyl, alkylene and (heterocycle) alkyl may be optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C ₂ alkoxy, C ₁ -C ₂ alkyl, amino, aryl , azido, cyano, halogen, Cr C ₂ ohalogenalkylu, heterocycle, nitro, or the substituents R ¹⁰ and R ^11, wherein (CH _{2) n} R ¹⁰ and R ¹¹ joined together form ⁱⁿ which a and D are independently oxygen or S (O) _t and the index n is 2-3, with the proviso that if B and Y are unsubstituted phenyl and L is a covalent bond, then at least one of R ¹ , R ² , R ³ and R ⁴ is other than a hydrogen atom and with the proviso that if L is a covalent bond and one of B or Y is unsubstituted imidazole and the other is unsubstituted phenyl, then at least one of R ¹ , R ² , R ³ and R ⁴ is other than hydrogen atom.

In another embodiment of the invention, methods of treating a disease comprising administering an effective amount of a compound having formula (I) are provided.

In yet another embodiment of the invention, pharmaceutical compositions comprising compounds of formula (I) are disclosed.

The compounds of the present invention include, but are not limited to, compounds selected from the group consisting of:

6- [1- (diphenylmethyl) -3-azetidinyl] -1,3,5-triazine-2,4-diamine,

6- (1-phenyl-4-piperidinyl) -1,3,5-triazine-2,4-diamine, trans-6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine,

6- [3- (1H-pyrrol-1-yl) phenyl] -1,3,5-triazine-2,4-diamine, cis / trans-6- (3-phenylcyclobutyl) -1,3,5- triazine-2,4-diamine,

6- [1,1'-biphenyl] -2-yl-1,3,5-triazine-2,4-diamine,

6- (4'-Nitro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine,

6- [4- (4-Pentylcyclohexyl) phenyl] -1,3,5-triazine-2,4-diamine,

6- (4-Phenoxyphenyl) -1,3,5-triazine-2,4-diamine,

N-cyclohexyl-N - [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] urea, (4,6-diamino-1,3,5-triazin-2-yl) N - [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] -N '-phenyl urea,

6- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) -1,3,5-triazine-2,4-diamine; 6- (4'-pentyl [1,1 '') -biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine,

6- [4 '- (pentyloxy) [1,1'-biphenyl] -4-yl] -1,3,5-triazine-2,4-diamine, 6- (6-methoxy-2-benzothiazolyl) - 1,3,5-triazine-2,4-diamine,

6- (4'-amino [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (5-oxazolyl) phenyl] -1, 3,5-triazine-2,4-diamine,

6- [4 - [[5- (trifluoromethyl) -2-pyridinyl] oxy] phenyl] -1,3,5-triazine-2,4-diamine, 4 '- (4,6-diamino-1,3, 5-triazin-2-yl) [1,1'-biphenyl] -4-carbonitrile, 6- (4'-methoxy [1,1'-biphenyl] -4-yl) -1,3,5-triazine- 2,4-diamine,

6- (4'-fluoro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine; N - [4- (4,6-diamino-1,3) 5-triazin-2-yl) phenyl] benzenesulfonamide

6- [1 - ([1,1'-biphenyl] -4-yl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine; diamino-1,3,5-triazin-2-yl) phenyl] -2-naphthalenesulfonamide,

^{2,5-dichloro-N} - [4- (4,6-diamino-l, 3,5-triazin-2-yl) phenyl] benzenesulfonamide, 6- (1-phenyl lcyklohexy 1) -1,3,5 -triazine-2,4-diamine, 6- [1- (4-methoxyphenyl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine, 6- [2- [4- (trifluoromethyl)] phenyl] -4-thiazolyl] -1,3,5-triazine-2,4-diamine,

6- [1- (4-methoxyphenyl) cyclohexyl] -1,3,5-triazine-2,4-diamine,

6- [4- (2-thienyl) phenyl] -1,3,5-triazine-2,4-diamine,

6- [4- (phenylethynyl) phenyl] -1,3,5-triazine-2,4-diamine,

N - (6- [1,1'-biphenyl] -4-yl-1,3,5-triazine-2,4-diyl) bis [acetamide], N - (4-amino-6- [1,1'- -biphenyl] -4-yl-1,3,5-triazin-2-yl) acetamide, N - [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] - 1-naphthalenesulfonamide, 6- (4'-azido [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (4-morpholinylsulfonyl) phenyl] ] -1,3,5-triazine-2,4-diamine,

6- [4- (2-furanyl) phenyl] -1,3,5-triazine-2,4-diamine,

N '- [6- (4-phenoxyphenyl) -1,3,5-triazine-2,4-diyl] bis [acetamide], N - [4-amino-6- (4-phenoxyphenyl) -1,3], 5-triazin-2-yl] acetamide, 6- (5-phenyl-2-furanyl) -1,3,5-triazine-2,4-diamine, 6- (5-phenyl-2-thienyl) -1, 3,5-triazine-2,4-diamine, N, N- [6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diyl] bis [acetamide], N- [4-amino-6] - (4-Phenylcyclohexyl) -1,3,5-triazin-2-yl] acetamide, 6- (4-phenyl-1-naphthalenyl) -1,3,5-triazine-2,4-diamine, 6- [4- (phenylthio) phenyl] -1,3,5-triazine-2,4-diamine,

6- (2-quinolinyl) -1,3,5-triazine-2,4-diamine,

6- (3-quinolinyl) -1,3,5-triazine-2,4-diamine,

6- (benzo [b] thien-2-ylmethyl) -1,3,5-triazine-2,4-diamine, 6- (2,2-dimethyl-2H-1-benzopyran-6-yl) -1, 3,5-triazine-2,4-diamine, 6- (1-isoquinolinyl) -1,3,5-triazine-2,4-diamine, (6- (2,3-dihydro-1,4-benzodioxine- 2-yl) -1,3,5-triazine-2,4-diatin, 6- (tricyclo [3.3.1.1 ^3,7 ] decan-1-yl) -1,3,5-triazine- 2,4-diamine, (+/-) -4- (4,6-diamino-1,3,5-triazin-2-yl) -α-phenylbenzenemethanol, 6- (2,3-dihydro-1,4) -benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine, 6- (1-azabicyclo [2.2.2] octan-4-yl) -1,3,5-triazine- 2,4-diamine, 6- [4- (phenylsulfinyl) phenyl] 1,3,5-triazine-2,4-diamine, 6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2 4-diamine, [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] phenylmethanone, oxime, 6-pyrazinyl-1,3,5-triazine-2,4-diamine ,

2,4-diamino-6 - [(4-phenylethenyl) phenyl] -1,3,5-triazine,

2,4-diamino-6 - [(4- (2-nitrophenyl) ethenyl) phenyl] -1,3,5-triazine, 6- [1,1'-biphenyl] -4-yl-7H, 7'-dimethyl- 1,3,5-triazine-2,4-diamine,

6- [1,1'-biphenyl] -4-yl-N-methyl-1,3,5-triazine-2,4-diamine, 6- (bicyclo [2.2.1] hept-2-yl) ) -1,3,5-triazine-2,4-diamine

6- [1,1'-biphenyl] -4-yl-N, N-diethyl-1,3,5-triazine-2,4-diamine, 6- (2'-nitro [1,1-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- (6-methyl-3-pyridinyl) -1,3,5-triazine-2,4-diamine, 6- (6 -chloro-3-pyridinyl) -1,3,5-triazine-2,4-diamine, 6- (5-bromo-3-pyridinyl) -1,3,5-triazine-2,4-diamine; · 1 · 1 · · · · · · · · · · · · · · · · · · · · · ·

6- (2,3-dihydro-2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine,

6- [4 - [(4-chlorophenyl) methoxy] phenyl] -1,3,5-triazine-2,4-diamine,

6- [4- (1-piperidinylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine,

6- (1-benzoyl-4-piperidinyl) -1,3,5-triazine-2,4-diamine, 6- [1- (phenylmethyl) -4-piperidinyl] -1,3,5-triazine-2, 4-diamine, N, (N-diacetyl-6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, N -acetyl-6- [4- (phenylsulfanyl) phenyl] -1,3,5-triazine-2,4-diamine and 6- (2-piperidin-1-ylphenyl) -1,3,5-triazine-2,4-diamine.

Explanation of terms

The term "alkanoyl" as used herein refers to an alkyl group having 1 20 carbon atoms attached to the parent molecule via a carbonyl group.

The term "alkoxy" as used herein refers to an alkyl group having 1-20 carbon atoms attached to the parent molecule via an oxygen atom.

The term "alkyl" as used herein refers to a monovalent group having 1 20 carbon atoms derived from a straight or branched saturated hydrocarbon chain. The alkyl groups of this invention may be substituted with 1-3 substituents independently selected from aryl or heterocycle.

The term "alkylene" as used herein refers to a divalent group having 1 20 carbon atoms derived from a straight or branched saturated hydrocarbon chain. The alkylene groups of this invention may be optionally substituted with an oxo group, a thioxo group, (= AOR ⁶ ) or -OR ⁶ .

The term "alkenylene" as used herein refers to an unsaturated divalent group having 2-20 carbon atoms derived from an unbranched or branched alkene chain.

The term "alkynylene" as used herein refers to an unsaturated divalent group having 2-20 carbon atoms derived from an unbranched or branched alkyne chain.

The term "amino" as used herein refers to the group -NH ₂ .

The term "aryl" as used herein refers to a monocyclic or bicyclic carbocyclic ring derived from one or two aromatic rings. Aryl groups

of this invention may be optionally substituted with 1-4 substituents independently selected from alkoxy, alkyl, amino, aryl, azido, cyano, halogen, haloalkyl, heterocycle or nitro.

The term "arylalkyl" as used herein refers to an aryl group attached to the parent molecule via an alkyl group.

The term "azido" as used herein refers to the group -N 3.

The term "cyano" as used herein refers to the group -CN.

The term "cycloalkyl" as used herein refers to a saturated monovalent group having 3-10 carbon atoms derived from a cyclic or bicyclic hydrocarbon. The cycloalkyl groups of this invention may be optionally substituted with 1-3 substituents independently selected from alkyl, aryl or heterocycle.

The term "cycloalkenyl," as used herein, refers to an unsaturated monovalent group of 4-10 carbon atoms derived from a cyclic or bicyclic alkene. The cycloalkenyl groups of this invention may be optionally substituted with 1-3 substituents independently selected from alkyl, aryl or heterocycle.

The term "halogen" as used herein refers to F, Cl, Br or I.

The term "haloalkyl" as used herein refers to an alkyl group to which at least one halogen atom is attached.

The term "heterocycle" as used herein refers to a 4-membered, 5-membered, 6-membered or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur. 4-membered and 5-membered rings have 0-2 double bonds and 6-membered and 7-membered rings have 0-3 double bonds. These heterocycles include benzimidazolyl, benzofuranyl, benzothiazolyl, benzothienyl, benzoxazolyl, dihydrothienyl, dihydroindolyl, dihydrofuranyl, dihydropyranyl, dithiazolyl, furyl, homopiperidinyl, imidazolyl, imidazolinyl, imidazolidinyl, isothiazolol, isothiazolol, isothiazolol, , oxazolyl, piperazinyl, piperidinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, pyridazinyl, pyrimidinyl, pyrimidyl, quinolinyl, tetrahydrofuranyl, tetrahydroisoquinolyl, tetrahydroquinolyl, thiothienyl, thiothienyl, tetothienyl, tetothienyl, tetothienyl, tetothienyl, tetothienyl, tetrazinyl , thiomorpholinyl, triazolyl, oxadiazolyl, and the like.

Heterocycles also include bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings are fused to one or two rings independently selected from an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring or other monocyclic heterocyclic rings. These heterocycles include benzofuryl, benzothienyl, indolyl, isoquinolyl, quinolyl, tetrahydroquinolyl, and the like.

Heterocycles also include compounds of the formula wherein X * is selected from -CH ₂ -, -CH ₂ O- and -O-, and Y * is selected from -C (O) - and - (C (R) ₂₎ - wherein R is hydrogen or alkyl having 1-4 carbon atoms and the index v is 1-3. These heterocycles include 1,3benzodioxolyl, 1,4-benzodioxanyl, and the like. The heterocycles of this invention may be optionally substituted with 1-4 substituents independently selected from alkoxy, alkyl, amino, aryl, azido, cyano, halogen, haloalkyl, heterocycle, nitro, or from R ¹⁰ and R ¹¹ , wherein R ¹⁰ and R ¹¹ are taken together to form

wherein A and D are independently oxygen or S (O) _t and the index n is 2-3

The term "(heterocycle) alkyl" as used herein refers to an alkyl group substituted with a heterocycle. The (heterocyclic) alkyl of the invention may be optionally substituted with an aryl or a heterocycle.

The term "hydroxy" as used herein refers to the -OH group.

The term "nitro" as used herein refers to the group -NO ₂ .

The term "oxo" as used herein refers to a group (—O).

The term "pharmaceutically acceptable prodrug" as used herein refers to those prodrugs of the compounds of the present invention which, within the scope of sound medical judgment, are suitable for use in contact with human tissue or lower animals and not causing toxicity, irritation, allergic reactions, etc., proportional to the reasonable benefit / risk ratio and effective for their intended use, as well as forms of the zwitterionic compounds of the invention, if possible.

The term "prodrug" as used herein refers to compounds that are rapidly transformed in vivo to the parent compound of the above formula, eg, by hydrolysis in blood. Full information on this can be found in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series and Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.

«·« «•« «« « ·· · ·· ··

The term "spiroalkyl," as used herein, refers to an alkylene diradical. Both ends are bonded to the same carbon atom of the parent group to form a spirocyclic group. The spiroalkyl groups of this invention may be optionally substituted with 1-2 substituents independently selected from alkyl, aryl or heterocycle.

The term "thioxo" as used herein refers to a group (= S).

Chiral or asymmetric centers may exist in the compounds of the present invention. The present invention contemplates various stereoisomers and mixtures thereof.

The individual stereoisomers of the compounds of the present invention are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers, or by preparing mixtures of enantiomeric compounds followed by resolution into enantiomers, which is well known to the skilled artisan. These methods of resolving into enantiomers are illustrated by (1) coupling the (±) labeled enantiomer racemate to chiral auxiliaries, separating the resulting diastereoisomers by recrystallization or chromatography and releasing the optically pure product from the auxiliary, or (2) directly separating the mixture of optical enantiomers on chiral chromatography columns. Pure enantiomers are designated herein by "R" or "S" depending on the configuration of the substituents around the chiral carbon atom.

Geometric isomers may also exist in the compounds of the present invention. The present invention contemplates various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or the arrangement of substituents around a carbocyclic ring. Substituents around the carbon-carbon double bond are denoted as Z and E configurations, with the term "Z" representing substituents on the same side of the carbon-carbon double bond and the term "E" representing substituents on opposite sides of the carbon-carbon double bond . The arrangement of substituents around the carbocyclic ring is denoted cis and trans, where the term "cis" represents substituents on the same side of the plane of the ring and the term "trans" represents substituents that are opposite to each other in the plane of the ring. Mixtures of compounds wherein the substituents are arranged on both sides of the plane of the ring, i. on the same and on the opposite they have the designation cis! trans.

Determination of endothelial cell migration

Determination of endothelial cell migration was performed as described

Polverinim et al., Methods Enzymol, 198: 440-450 (1991). Human microvascular endothelial cells (abbreviated as HMVEC) were introduced overnight in DMEM (Dulbecco's Modified Eagle Medium) containing 0.1% bovine serum albumin (BSA). The cells were then treated with trypsin and resuspended in DMEM 0.1% BSA to a concentration of 1.5 χ 10 ⁶ cells / ml. Cells are added to the bottom of a modified 48-tube Boyden chamber (Nucleopore Corporation, Cabin John, MD). The chamber was assembled and inverted, and the cells were firmly attached to polycarbonate chemotaxis membranes (5 µm pore size) which were soaked in 0.1% gelatin overnight and dried for 2 hours at 37 ° C. The chamber was then re-inverted and fibroblast core growth factor (bFGF) and test compounds were added to the upper chamber tubes (for a total volume of 50 µl); the apparatus was then incubated for 4 hours at 37 ° C. Membranes were isolated, fixed and stained (DiffQuick, Fisher Scientific, Pittsburgh, PA) and the number of cells that migrated into the upper chamber was counted per 10 strong fields. Primary migration of DMEM + 0.1% BSA was subtracted and data reported as the number of cells migrated to 10 strong fields (400X) or, if results from multiple experiments were pooled, data were reported as percent inhibition compared to a reliable control. The results are shown in Table 1.

Table 1

Inhibitory activity against bFGF induced by microvascular endothelial cell migration in human subjects

Example % inhibition at (nM) Irsogladin 53% (600nM) 1 20 (600) 3 100 (600) 4 62 (600) 6 95 (600) 7 100 (600) 8 30 (600) 9 29 (613) 10 29 (613) 12 36 (600)

····················

Table 1 continued

Inhibitory activity against bFGF induced by microvascular endothelial cell migration in human subjects

13 53% (600nM) 47 65 (600) 48 55 (600) 49 14 (600) 50 100 (600) 51 100 (600) 52 100 (600) 53 85 (600) 55 84 (600) 56 30 (600) 58 100 (600) 60 100 (600) 63 79 (500) 65 32 (200) 68 73 (500) 69 39 (500) 74 82 (500) 75 16 (500) 76 33 (500) 77 50 (500)

The compounds of the present invention including, but not limited to, the compounds specified in the Examples have anti-angiogenic activity. Compounds acting as angiogenic inhibitors are effective in the treatment of primary and metastatic solid tumors and breast cancers; colon; rectum; lung; oropharynx; hypopharynx; esophagus; stomach; pancreas; liver; gallbladder; bile duct; small intestine; urinary tract including kidney, bladder and urothelium; female genitalia including suppository, uterus, ovum, choriocarcinoma and gestational trophoblastic disease; male genital tract including prostate, seminal vesicles, testes, and germ cell tumors; endocrine glands including thyroid, adrenal gland and pituitary; skin including hemangioma, melanoma, bone or soft tissue sarcoma, and Kaposi's sarcoma; brain, nerve, eye and meningitis tumors including astrocytoma, glioma, glioblastoma, retionblastoma, neuroma, neuroblastoma, Schwannoma and meningioma; a solid tumor resulting from hematopoietic malignancies such as leukemia and including chlorine, plasmacytoma, mycosis fungoides plaques and tumors and cutaneous lymphoma / T-cell leukemia; lymphoma including Hodgkin's lymphoma and non-Hodgkin's lymphoma; prophylaxis of autoimmune disease including rheumatoid arthritis, immune arthritis and degenerative arthritis; ophthalmic diseases including diabetic retinopathy, premature retinopathy, corneal graft rejection, retrolentic fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration and insufficient oxygen supply; abnormal neovascularization conditions of the eye; skin diseases including psoriasis; blood vessel diseases including haemagioma and capillary proliferation within atherosclerotic plaques; Osler-Webber syndrome; myocardial angiogenesis; neovascularization plaques; teleangiektazie; hemophiliac joints; angiofibroma; wound granulation; diseases characterized by excessive or abnormal stimulation of endothelial cells including intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma and hypertrophic scar (namely, a keloid scar) and diseases that have angiogenesis as a pathological consequence including cat scratch disease (Rochele minalia quintosa) and ulcer (Helacterobacteria) . Another use is as a fertility regulating agent that inhibits mature egg release and placental attachment.

The compounds of the present invention may also be useful in preventing metastasis from the tumors described above, either when used alone or in combination with radiotherapy and / or other chemotherapeutic treatments conventionally applied to cancer patients. For example, when used in the treatment of solid tumors, the compounds of the present invention can be administered with chemotherapeutic agents such as α-interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristin) and dexamethasone), PRO-MACE / MOPP (prednisone, methotrexate (w / leukovine rescue), doxorubicin, cyclophosphamide, taxol, etoposide / mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibos, TNP, destioone, pentanone sulphate, TNP, destioone factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan, thalidomide, SP-PG, and the like. Other chemotherapeutic agents include alkylating agents such as nitrogen mustard including mechloethamine, melphane, chlorambucil, cyclophosphamide and ifosfamide; nitrosoureas · «· ros ros ros ros ros * * * * * * * * * * * * * 'Including carmustine, lomustine, semustine and streptozocin; alkylsulfonates including busulfan; triazines including dacarbazine; ethyenimines including thiotepa and hexamethylmelamine; folic acid analogs including methotrexate; pyrimidine analogs including 5-fluorouracil, cytosinarabinoside; purine analogs including 6-mercaptopurine and k-thioguanine; anti-tumor antiobiotics including actinomycin D; anthracyclines including doxorubicin, bleomycin, mitomycin C and methramycin; hormones and hormone antagonists including tamoxifen and corticosteroids; and a variety of agents including cisplatin and brechinar.

The compounds of the present invention may be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The term "pharmaceutically acceptable salt" as used herein refers to those salts, which are within the scope of reasonable medical judgment, suitable for use in contact with human or lower animal tissues without toxic action, irritation, causing allergic reactions, and the like. and are proportionate to a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art, e.g., S. M. Berge, et al., Describe in detail pharmaceutically acceptable salts in J. Pharmaceutical Sciences, 1977, 66: 1 et seq. Salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base with a suitable acid. Representative acid addition salts include, but are not limited to, acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, bisulfate, butyrate, camphate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrogen chloride, hydrogen chloride, hydrogen chloride, hydrogen chloride, hydrogen chloride, hydrogen chloride, , 2-hydroxyethanesulfonate (isethionate), lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, thiocyanate p-toluenesulfonate and undecanoate. Also, nitrogen-containing basic groups may be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are also obtained in this manner. Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and orthophosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid, and citric acid.

Base addition salts may be prepared in situ during the final isolation and purification of the compounds of this invention by reacting a carboxylic acid moiety with a suitable base, such as a hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, alkali metal or alkaline earth metal cations such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like, and non-toxic quaternary ammonium and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine , dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, and the like. Other representative organic amines useful for forming base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like. Preferred salts of the compounds of the invention include phosphate, tris and acetate.

The compounds of the invention may be combined with a pharmaceutically acceptable sustained release matrix, such as biodegradable polymers, to form a therapeutic composition. A sustained-release matrix, as used herein, is a matrix made of substances, commonly polymers, that are degradable by enzymatic or acid-base hydrolysis or dissolution. Once incorporated into the body, the matrix acts by enzymes and body fluids. The sustained-release matrix is selected as desired from biologically compatible substances such as liposomes, polylactides (polylactic acid), polyglycolides (glycolic acid polymer), polylactide co-glycolide (lactic-glycolic acid copolymer) polyanhydrides, poly (ortho) esters, polypeptides , hyaluronic acid, collagen, chondroitin sulfate, carboxylic acids, fatty acids, phospholipids, polysaccharides, nucleic acids, polyamino acids, amino acids such as phenylalanine, tyrosine, isoleucine, polynucleotides, polyvinylpropylene, polyvinylpyrrolidone and silicone. Preferred biodegradable matrices are either polylactide or polyglycolide or polylactide co-glycolide (co-polymer of lactic acid and glycolic acid).

The compounds of the invention or combinations thereof may be combined with pharmaceutically acceptable excipients or carriers to form therapeutic compositions. A pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, solvent, coating agent, or co-formulation of any type. The composition may be administered parenterally, subligually, intracistemally, intravaginally, intraperitoneally, rectally, buccally, or topically (using a powder, ointment, drops, transdermal patch or iontophoresis device).

The term "parenteral" as used herein refers to routes of administration that include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and 44 · ···· 44 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 4 · 44 Pharmaceutical preparations for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions or emulsions, as well as sterile dusting powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous aqueous carriers, diluents, solvents or carriers include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coatings such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These preparations may also contain adjuvants such as preservatives, detergents, emulsifiers and dispersants. Prevention of the action of microorganisms may be achieved by the inclusion of various antibacterial and antifungal agents such as paraben, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, etc. Prolonged absorption of injectable pharmaceutical forms may be induced by inclusion of agents such as aluminum monostearate and gelatin that delay absorption. Injectable depot forms are made by forming microencapsulated drug matrices in biodegradable polymers such as polylactide-polyglycolide, poly (orthoesters) and poly (anhydrides). The rate of drug release can be controlled according to the ratio of drug to polymer and the origin of the individual polymers used. Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues. Injectable formulations may be sterilized, for example, by filtration through a bacterial retention filter or by incorporation of sterile agents in the form of sterile solid preparations which may be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.

Topical administration includes application to the skin, mucosa and lung surface. Topical formulations, including those for inhalation, may be formulated as dry powders, which may be compressed or not compressed. In uncompressed powder formulations, the active ingredient in finely divided form can be used in admixture with a pharmaceutically acceptable inert carrier containing particles up to, e.g., up to 100 microns in diameter. Suitable inert carriers include sugars such as lactose. Suitably, at least 95% by weight of the active ingredient particles have an effective particle size in the range of 0.01 to 10 microns. For topical administration to the eye, the compound of the invention is delivered in a pharmaceutically acceptable ophthalmic carrier so that the compound is maintained in contact with the ocular surface for a period of time sufficient to allow the compound to be present.

9 · 90 · · · · * · * f f f f f f f f f f f f f f f f f f · ♦ compounds penetrate the comal and internal eye areas such as the anterior chamber, posterior chamber, vitreous humor, aqueous humor, cornea, iris / ciliar, lens, choroid / sclera. Pharmaceutically acceptable ophthalmic vehicles may be, for example, ointments, vegetable oils, or coatings. Alternatively, the compounds of the invention may be injected directly into the vitreous humor and aqueous humor.

The formulation may be compressed and contain a compressed gas such as nitrogen or a liquefied propellant gas. Indeed, the medium of the liquefied propellant and the overall formulation is preferably such that the active ingredient does not dissolve to any significant dimension in this. The compressed formulation may also contain a surfactant, such as a liquid or solid nonionic surfactant, or may be a solid anionic surfactant. It is preferred to use a solid anionic surfactant in the form of the sodium salt.

Formulations for rectal or vaginal administration are preferably rectal suppositories, which may be prepared by admixing a compound of the invention with suitable non-irritating excipients or carriers, such as cocoa w-polyethylene glycol or waxy rectal suppositories, which are solid at room temperature but liquid at body temperature; therefore it dissolves in the rectum or vaginal cavity to release the active compound.

The compositions of the present invention may also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monolameral or multi-lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposomal form may contain, according to the compound of the present invention, stabilizing agents, preservatives, excipients, and the like. Preferred lipids are phospholipids and phosphatidylcholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, e.g., Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), 33 et seq., Which is incorporated herein by reference.

When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be used in pure form or, where possible, in the form of a pharmaceutically acceptable salt and together or without a pharmaceutically acceptable excipient. By "therapeutically effective amount" of a compound of the invention is meant a sufficient amount of a compound of the invention to treat angiogenic diseases (eg, to reduce tumor growth or to slow or stop tumor metastasis) in a reasonable manner.

the benefit / risk ratio applicable to any medical treatment. However, it is clear that the overall daily use of the compounds and compositions of the present invention is at the discretion of the attending physician after reasonable medical judgment. The specific, therapeutically effective dose level for any individual patient will depend on various factors including the disease being treated and the severity of the disease; the activity of the specific compound used; use of a specific preparation; the patient's age, body weight, general health, sex and lifestyle; the time of administration, the mode of administration and the rate of excretion of the specific compound used; the duration of the treatment; drugs used in combination or in accordance with the specific compound used; and similar factors well known in medical practice. For example, it is well known in the art that starting with lower doses of a compound than is required to achieve a therapeutic effect, and gradually increasing the dose level until the desired effect is achieved.

The total daily dose of the compounds of this invention administered topically or systematically to humans or other mammals in single or divided doses may be, for example, from 0.01 to 200 mg / kg body weight per day or more usually from 1 to 300 mg / kg body weight. If desired, the effective daily dose for administration may be divided into multiple doses. Single doses of formulations may contain such amounts or fractions thereof to form a daily dose. It is understood that agents that may be combined with a compound of the present invention for inhibiting, treating or preventing angiogenic diseases are not limited to those listed above, but include substantially any agent effective for treating or preventing angiogenic diseases.

Preparation of the compounds of the invention

Abbreviations

Abbreviations used in the descriptions of the schemes and examples that follow are: DMSO for dimethylsulfoxide, DME for dimethoxyethane, EtOAc for ethyl acetate, and THF for tetrahydrofuran.

· * * * * * * «« ««

Methods of synthesis

The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes which illustrate the methods by which the compounds of the invention may be prepared.

Scheme 1

Reaction 1: A-CO 1 R + R 1 R ₂

ΊτΎ

NH NH 2B

NR3R4.

R3

Reaction 2: A-CN + ^{R 2 R, N} y y ^c cN - ¹

NH

As shown in Scheme 1, the triazine ring of compounds of formula (I) was prepared by condensation of esters with biguanide (reaction 1) or by condensation of nitriles and cyanoguanide (reaction 2). Reaction 2 was carried out in a polar solvent that boiled at a high temperature such as

2-methoxyethanol, and in the presence of a strong base such as potassium hydroxide. Reaction 1 was carried out in an alcohol, preferably methanol. Ester and nitrile precursors were purchased from commercial sources or prepared using known chemical transformations.

• · · · · · · · · · · ·

Scheme 2

JÍR1R2 li

R3R4N Ν A li

R3R4N N A

R1.R2.R3. and R 4 areHR 1 R 2 R 3. and R 4 are H: R ₂ is alkanoyl nr, r ₂

N

Λ Λ

Rj1 ^ N ^ N A

NR1R2

Λκ

Λ X

R ₃ R, hr ^ N ^× ^ A

R1.R2.R3. and R4JSOUH

R1 and R3 are H;

R2 and R4 are alkanoyl

As shown in Scheme 2, selective monoacylation to obtain compounds of formula (I) was achieved by heating the diaminotriazine precursor with a carboxylic acid anhydride at an elevated temperature, preferably at 80-90 ° C. It was possible to proceed differently

2,4-diacylation by heating the diaminotriazine precursor with carboxylic acid anhydride at high temperatures, preferably at 140-160 ° C.

* · · · · · · · · · · · · · · · · ·

Scheme 3

R3R4

NR1R2 iAn

A A

ON

Sn (CH ₃ hr

A is-B-L-Y;

B and Y are optionally substituted aryl or heterocycle; and

L is a covalent bond or alkynyl

As shown in Scheme 3, 2,4-diamino-6-bromaryl-triazines were converted to compounds of formula (I) using metal-catalyzed transient coupling reactions (palladium catalyst such as tetrakis (triphenylphosphine) palladium). Also, conversion of Example 20A to 2,4-diamino-6- (trialkylstannyl) aryl-triazine by reaction with an organotin, preferably hexamethyldicin, in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium followed by cross-coupling with aryl bromides provides an alternative method of preparing a compound of formula (AND). Reaction of Example 20A with ethynyl tin, such as trimethyl (phenylethylyl) tin in the presence of a palladium catalyst such as tetrakis (triphenylphosphine) palladium, affords compounds of formula (I).

Scheme 4

A is -B-L-Y,

B is cyclohexyl,

Y is optionally substituted aryl, and L is a covalent bond

As shown in Scheme 4, compounds of formula (I) were prepared by Friedel Crafts alkylation of aryl groups with cycloalkenylnitrile followed by treatment of the nitrile intermediate of Scheme 1 above (Reaction 2).

Scheme 5

θγΑ

OCH ₂ CH ₃

NR ,!

iAn

Λ A

R ₃ R4N n

1R2

A is -B-L-Y;

B is an optionally substituted heterocycle; Y is optionally substituted aryl, and L is a covalent bond

As shown in Scheme 5, piperidinylarylesters were converted to compounds of formula (I) by arylation of isonipecotinic acid esters with triaryl bismuth in the presence of cupric acylates.

Scheme 6

NR _n R ₂ IA

A A

RjR, N ^ N

A is-B-L-Y;

B is cyclobutyl,

Y is aryl, and

L is a covalent bond

As shown in Scheme 6, compounds of Formula (I) were prepared by condensing bistosylates with malonic esters to cycloalkane rings, monodecarboxylated at elevated temperature, and further processed according to Scheme 1 (Reaction 1).

Scheme 7

Suzuki's cupping

NR3R4

or

A is B-L-Y B is aryl or heterocycle L is a covalent bond, and Y is aryl

As shown in Scheme 7, diaminotriazines having alkyl substituents on amino groups can be prepared by a regulated and, in some way, sequential replacement of chlorines from the triazine ring. Heteroaryl, 6-aryl or cycloalkyl substituents may be introduced first by nucleophilic addition, eg, by Grignard's reagent to cyanuric chloride, or after nitrogen, eg by Suzuki Pd-boric acid-catalyzed cross coupling.

The present invention will be better understood in conjunction with the following examples which illustrate methods by which the compounds of the invention may be prepared and are not intended to limit the scope of the invention, which is fully defined in the appended claims.

Examples

Example 1

6- [1- (Diphenylmethyl) -3-azetidinyl] -1,3,5-triazine-2,4-diamine

A solution of 1- (diphenylmethyl) -3-azetidinecarbonitrile (500 mg, 2.01 mmol), dicyandiamide (220 mg, 2.62 mmol) and KOH (34 mg, 0.604 mmol) in 2-methoxyethanol (10 mL) was heated at reflux for 4 hours, diluted with water and cooled to room temperature. The precipitate is washed with water and dried in vacuo to give the desired compound.

Melting point: 126-128 ° C;

MS (DCI / NH 3) m / e 333 (M + H) ⁺ ;

• · ······ · · · · · ·

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.3 (d, 4H), 7.2 (t, 4H), 7.05 (t, 2H), 6.5-6.7 (br s 4H), 4.35 (s, 1H), 3.2-3.3 (m, 3H), 3.1-3.15 (m, 2H);

Calcd for C19H20N6O * 0.75H2O: C, 65.97; H, 6.26; N, 24.29. Found: C, 65.67; H, 5.65; N, 23.84.

Example 2

6- (1-phenyl-4-piperidinyl) -1,3,5-triazine-2,4-diamine

Example 2A

A solution of triphenylbismuth (5.02 g, 11.4 mmol), copper acetate (1.79 g, 9.85 mmol) and ethyl isonipecotate (1.5 mL, 9.7 mmol) in dichloromethane (100 mL) was stirred at room temperature. temperature for 18 hours, diluted with water and filtered through Celite®. The organic layer was dried (MgSO4) and concentrated. The residue is purified by flash chromatography on silica gel (0-2% acetone / dichloromethane) to give the desired compound.

MS (DCI / NH 3) m / e 234 (M + H) ⁺ .

Example 2B

The title compound is prepared according to the procedure of Inorganic Synthesis, Volume 7, 56-58 (1963).

Example 2C

6- (1-Phenyl-4-piperidinyl) -1,3,5-triazine-2,4-diamine

A solution of Example 2A (0.464 g, 1.99 mmol) and 2B (0.211 g, 2.09 mmol) in methanol (4 mL) was stirred at room temperature for 16 hours. The precipitate is rinsed with methanol, dried in vacuo and recrystallized from dioxane / ethanol to give the desired compound.

Melting point: 202-204 ° C;

MS (DCI / NH 3) m / e 271 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.19 (t, 2H), 6.94 (d, 2H), 6.72 (t, 1H), 6.56 (br s, 4H), 4 11 (q, 2H), 3.77 (m, 2H), 2.75 (dt, 2H), 2.41 (m, 1H), 1.79 (m, 2H);

Calcd for C 14 H 18 N 6 · 0.67H 2 O: C, 59.58; H, 6.90; N, 27.78. Found: C,

59.27; H, 6.79; N, 25.51.

• ·

Example 3

Trans-6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine

Example 3A

4-phenylhexenecarbonitrile

A solution of cyclohexenecarbonitrile (9 mL, 80.6 mmol) and benzene (75 mL) was treated portionwise at a temperature with AlCl 3 (13 g, 97 mmol) then stirred at room temperature for 2 hours. The mixture was poured into ice and extracted with ethyl acetate. The extract was washed successively with water and brine, dried (MgSO ₄ ), and concentrated. The residue was distilled at 125 ° C (0.6 mm Hg) to give the desired compound.

MS (DCI / NH 3) m / e 203 (Μ + ΝΗ 4Λ)

Example 3B trans-6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, the compound of Example 3A was treated according to the procedure of Example 1.

MS (DCI / NH 3) m / e 270 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO- d 6) δ 7.20-7.32 (m, 4H), 7.12-7.18 (m, 1H), 6.57 (br s, 4H), 2, 46 (tt, 1H), 2.32 (tt, 1H), 1.80-1.93 (m, 4H), 1.41-1.66 (m, 4H);

Calcd for C15H19N5: C, 66.88; H, 7.11; N, 26.00. Found: C, 66.85; H, 7.00; N, 26.08.

Example 4

6- (3- (1H-pyrrol-1-yl) phenyl) -1,3,5-triazine-2,4-diamine

3- (1H-pyrrol-1-yl) -benzonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Melting point: 164-170 ° C;

MS (DCI / NH 3) m / e 253 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.35 (s, 1H), 8.15 (d, 1H), 7.7 (dd, 1H), 7.6-7.5 (m, IH) )

7.3 (t, 3H), 7.0-6.8 (br s, 4H), 6.3-6.25 (m, 2H);

Calcd for C13H12N6: C, 61.89; H, 4.79; N, 33.31. Found: C, 62.20; H, 4.56;

N, 32.39.

· · · ·

In · «· · · · · · ·

Example 5 cis / trans-6- (3-phenylcyclobutyl) -1,3,5-triazine-2,4-diamine

A solution of cis / trans-methyl- (3-phenylcyclobutane-1-carboxylate) prepared according to the method of J. Am. Chem. Soc., 1985, 107, 7247-7257, was treated according to the procedure of Example 2C to obtain the desired compounds.

Mp 98-102 ° C;

1 H NMR (300 MHz, DMSO-d 6) δ 7.31 (m, 4H), 7.19 (m, 1H), 6.60 (m, 4H), 3.62 (m, 0.4H), 3.43 (m, 0.4H), 3.18 (m, 0.8H), 2.88 (m, 0.8H), 2.56 (m, 1.2H), 2.38 (m, 2.4H);

Anal Calcd For C 11 H 15 N 3 O 2 O 2 CH 2 CO 2 CH 2 CH 3: C, 63.14; H, 6.71; N, 24.54. Found: C, 62.75; H, 6.73; N, 24.48.

Example 6

6- [1,1-Biphenyl] -2-yl-1,3,5-triazine-2,4-diamine

[1,1'-Biphenyl] -2-carbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

MS (DCI / NH 3) m / e 264 (M + H) ⁺ ;

Δ H NMR (300 MHz, DMSO-δ) δ 7.63-7.2 (m, 5H), 7.37-7.27 (m, 4H), 6.6 (br s, 4H); Calcd for C15H13N5: C, 68.42; H, 4.97; N, 26.59. Found: C, 67.85; H, 4.94; N, 26.50.

Example 7

6- (4'-Nitro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 4'-nitro [1,1'-biphenyl] -4-carbonitrile was processed as in Example 1.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 309 (M + H) +;

Δ NMR (300 MHz, DMSO-d 6) δ 8.5-8.4 (m, 4H), 8.1 (d, 2H), 7.95 (d, 2H), 6.85 (br s, 4H);

Calcd for C15H12N6O2: C, 58.43; H, 3.92; N, 27.42. Found: C, 58.46; H,

3.76; N, 27.12.

Example 8 trans-6- [4- (4-pentylcyclohexyl) phenyl] -1,3,5-triazine-2,4-diamine

4- (trans-4-pentylcyclohexyl) benzonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 340 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO- d ₆ ) δ 8.2 (d, 2H), 7.3 (d, 2H), 6.75 (bs, 4H), 1.85 (d, 4H), 1.551 4 (m, 2H), 1.37-1.2 (m, 10H), 1.1-1.05 (m, 2H), 0.85 (t, 3H);

Calcd for C20H29N5: C, 70.76; H, 8.61; N, 20.62. Found: C, 70.71; H, 8.73; N, 20.67.

Example 9

6- (4-Phenoxyphenyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 4-phenoxybenzonitrile was treated as in Example 1.

Mp 198-200 ° C;

MS (DCI / NH 3) m / e 280 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.3-8.2 (m, 2H), 7.5-7.4 (m, 2H), 7.2 (t, 1H), 7.17 -7.0 (m, 4H), 6.9-6.65 (br s, 4H);

Calcd for C15H13N5O. C, 64.51; H, 4.69; N, 25.07. Detected. C, 63.84; H, 4.67; N, 24.90.

Example 10

N-cyclohexyl-N '- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] urea

Example 10A ··· «· * ··

4-Aminobenzonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

MS (DCI / NH 3) m / e 203 (M + H) +

Example 10B

N -cyclohexyl-N '- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] urea

A mixture of Example 10A (1.0 g; 4.9 mmol), cyclohexyl isocyanate (610 mg, 4.9 mmol) and triethylamine (0.68 mL, 4.9 mmol) in dioxane were stirred overnight at room temperature. The precipitate is washed with water and dried in vacuo to give the desired compound.

MS (DCI / NH 3) m / e 328 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO- d 6) δ 8.4 (s, 1H), 8.23 (t, 1H), 8.8-8.75 (m, 1H), 7.55-7.45 (m, 1H), 7.25-7.2 (t, 1H), 7.0-6.8 (br s, 4H), 6.0 (d, 1H), 3.55-3 4 (m, 1H), 1.9-1.8 (m, 2H), 1.71.6 (m, 2H), 1.59-1.5 (m, 1H), 1,2- 0.5 (m, 5H);

Calcd for C15H21N7O: C, 58.70; H, 6.47; N, 29.95. Found: C, 58.49; H, 6.59; N, 29.49.

Example 11 (4,6-Diamino-1,3,5-triazin-2-yl) phenylmethenone

To obtain the desired compound, 4-cyanobenzophenone is treated according to the procedure of Example 1.

Mp > 250 ° C;

1 H NMR (300 MHz, DMSO-d 6) δ 8.4 (d, 2H), 7.9 (d, 2H), 7.8 (m, 2H), 7.7 (m, 1H), 7, Δ (t, 2H), 6.9 (br s, 4H);

MS (DCI / NH 3) m / e 292 (M + H);

Calcd for C ₁₆ H ₁₃ N ₅ O: C, 65.97; H, 4.50; N, 24.04. Detected. C, 65.74; H, 4.32; N, 23.93.

Example 12 N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] -N'-phenylurea

The compound of Example 10A was treated according to the procedure of Example 10B, but the phenylisocyanate was replaced with cyclohexylisocyanate to obtain the desired compound.

.....

1 H NMR (300 MHz, DMSO- d 6) δ 8.8 (s, 1H), 8.65 (s, 1H), 8.35 (t, 1H), 7.9 (d, 1H), 7, 6-7.5 (m, 1H), 7.49-7.44 (m, 2H), 7.35 (t, 1H), 7.29 (t, 2H), 7.0 (t, 1 H), 6.8-6.7 (br s, 4H); Calcd for C16H15N7O: C, 59.80; H, 4.70; N, 30.51. Found: C, 59.61; H, 4.72; N, 29.91.

Example 13

6- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) -1,3,5-triazine-2,4-diamine

A mixture of 2,4-diamino-6-chloro-1,3,5-triazine (2 g, 14 mmol), 1,4-dioxa-8azaspiro [4.5] decane (3 g, 21 mmol) and KOH (100 g). mg (1.8 mmol) in dioxane (10 mL) and ethanol (40 mL) were heated at reflux overnight, diluted with water and filtered. The precipitate is washed with water and dried in vacuo to give the desired compound.

Mp 209-211 ° C;

MS (DCI / NH 3) m / e 253 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-4) δ 6.14 (br s, 4H), 3.90 (s, 4H), 3.75-3.68 (m, 4H), 1.58-1, 51 (m, 4 H);

Calcd for C 10 H 16 N 6 O 2: C, 47.61; H, 6.39; N, 33.31. Found: C, 47.45; H, 6.34; N, 33.24.

Example 14

6- (4-Pentyl [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

4'-Pentyl-1,1'-biphenyl] -4-carbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 242-244 ° C;

MS (DCI / NH 3) m / e 334 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.3 (d, 2H), 8.75 (d, 2H), 8.65 (d, 2H), 7.3 (d, 2H), 6.756, 82 (br s, 4H), 2.6 (t, 2H), 1.6-1.7 (m, 2H), 1.3-1.4 (m, 4H), 0.95 (t, 3H) );

Calcd for C20H23N5 * 0.25H2O: C, 71.61; H, 7.09; N, 20.03. Found: C, 71.80; H, 7.00; N, 20.45.

• ·

Example 15

6- [4'-Pentyloxy [1,1'-biphenyl] 4-yl] -1,3,5-triazine-2,4-diamine

4 '(Pentyloxy) [1,1'-biphenyl] -4-carbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 246-249 ° C;

MS (DCI / NH 3) m / e 350 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 8.3 (d, 2H), 7.75-7.65 (m, 4H), 7.07 (d, 2H), 6.85-6, 7 (br s, 4H), 4.05 (t, 2H), 1.8-1.7 (m, 2H), 1.5-1.3 (m, 4H), 0.9 (t, 3H) );

Calcd for C20H23N5O: C, 68.75; H, 6.63; N, 20.04. Found: C, 68.64; H, 6.77; N, 19.94.

Example 16

6- (6-methoxy-2-benzothiazolyl) -1,3,5-triazine-2,4-diamine

6-Methoxy-2-benzothiazolecarbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 275 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.98 (d, 1H), 7.71 (d, 1H), 7.17 (dd, 1H), 7.16 (br s, 2H), 6.95 (br s, 2H); 3.85 (s, 3H);

Calcd for C11H10N6OS: C, 48.17; H, 3.67; N, 30.64. Found: C, 48.07; H, 3.75; N, 30.72.

Example 17

6- (4'-amino [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

The 4'amino [1,1'-biphenyl] -4-carbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 279 (M + H) ⁺ ;

¹ H NMR (300 MHz, DMSO-d 6) δ 8.25 (d, 2H), 7.65 (d, 2H), 7.45 (d, 2H), 6.8-6.6 (m, 6H) 1.5 (s, 2H);

• ·

..........

Calcd for C15H14N6: C, 64.73; H, 5.07; N, 30.20. Found: C, 64.34; H, 5.18;

N, 29.91.

Example 18

6- [4- (5-oxazolyl) phenyl] -1,3,5-triazine-2,4-diamine

4- (5-oxazolyl) -benzonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

MS (DCI / NH 3) m / e 255 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.55 (s, 1H), 8.37 (d, 2H), 7.9-7.8 (t, 3H), 6.9-6.7 (br s, 4H);

Calcd for C11H10N6O: C, 56.69; H, 3.96; N, 33.05. Detected. C, 56.40; H, 4.02; N, 33.11.

Example 19

6- [4 - [[5- (trifluoromethyl) -2-pyridinyl] oxy] phenyl] -1,3,5-triazine-2,4-diamine

To obtain the title compound, 4 - [[5 (trifluoromethyl) -2-pyridinyl] oxy] benzonitrile was treated as in Example 1.

MS (DCI / NH 3) m / e 349 (M + H) ⁺ ;

¹ H NMR (300 MHz, DMSO-d 6) δ 8.6 (s, 1H), 8.6-8.5 (m, 3H), 7.4-7.3 (m, 3H), 6.9 -6.7 (br s, 4H);

Calcd for C15H11F3N6O: C, 51.73; H, 3.18; N, 24.13. Found: C, 51.67; H, 3.20; N, 23.83.

Example 20

4 '- (4,6-diamine-1,3,5-triazin-2-yl) [1,1'-biphenyl] -4-carbonitrile

Example 20A

To obtain the desired compound, 4-bromobenzonitrile was treated according to the procedure of Example 1.

MS (DCI / NH 3) m / e 267 (M + H) ⁺ .

• ·

• ·

Example 20B

A solution of Example 20A (0.76 g, 2.9 mmol) and tetrakis (triphenylphosphine) palladium (0.17 g, 0.15 mmol) in dry, degassed dimethylacetamide (45 mL) was heated at 100 ° C, allowed to cool. treated with hexamethyldicine (1.0 g, 3.1 mmol), heated at 100 ° C for 3 hours, treated with ethyl acetate, washed sequentially with 1M NaOH and brine, dried (MgSO ₄ ) and concentrated to afford the desired compound.

MS (DCI / NH ₃ ) m / e 352 (M + H) < + & gt ^; .

Example 20C

4 '- (4,6-diamino-1,3,5-triazin-2-yl) [1,1'-biphenyl] -4-carbonitrile

A solution of Example 1B (0.95 g, 2.7 mmol), 4-bromobenzonitrile (0.55 g, 3.0 mmol) and tetrakis (triphenylphosphine) palladium (0.20 g, 0.17 mmol) in dry, degassed dimethylacetamide (45 mL) was heated at 100 ° C for 3 hours, cooled to room temperature, treated with ethyl acetate, washed sequentially with 1M NaOH and brine, dried (MgSO ₄ ) and concentrated. The residue is recrystallized from dioxane / ethanol to give the desired compound.

Mp > 260 ° C;

MS (DCI / NH ₃ ) m / e 289 (M + H) ^< ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 8.36 (d, 2H), 7.96 (s, 4H), 7.88 (d, 2H), 6.81 (br s, 4H); Calcd for C16H12N6 * 0.75H2O: C, 63.67; H, 4.51; N, 27.84. Found: C,

64.06; H, 4.38; N, 27.17.

Example 21

6- (4-Methoxy [1,1-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

A solution of Example 20A (0.749 g, 2.8 mmol) and tetrakis (triphenylphosphine) palladium (0.15 g, 0.13 mmol) in dry, degassed dimethylacetamide (45 mL) was heated to 100 ° C, allowed to react gradually with 4-methoxyphenylboronic acid (0.648 g, 4.3 mmol) in absolute ethanol (15 mL) and saturated NaHCO ₃ (30 mL), heated at 100 ° C for 3 hours, cooled to room temperature, allowed to react with ethyl acetate, washed with brine, dried (MgSO ₄ ) and concentrated. The residue is recrystallized from dioxane / ethanol to give the desired compound.

• ·

Mp > 260 ° C;

MS (DCI / NH 3) m / e 294 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 8.31 (d, 2H), 7.72 (t, 4H), 7.03 (d, 2H), 6.86 (br s, 4H), 3.81 (s, 3H);

Calcd for C16H15N500.33H2O: C, 64.21; H, 5.27; N, 23.40. Found: C, 64.26; H, 5.35; N, 23.43,

Example 22

6- (4'-Fluoro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, Example 20A and 4-fluorophenylboronic acid were treated according to the method of Example 24.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 282 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 8.32 (d, 2H), 7.77 (m, 4H), 7.32 (t, 2H), 6.75 (br s, 4H); Calcd for C15H12FN5O * 0.25H2O: C, 63.04; H, 4.41; N, 24.50. Found: C, 63.41; H, 4.49; N, 24.17.

Example 23

N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] benzenesulfonamide

A solution of Example 10A (575 mg, 2.8 mmol) and benzenesulfonyl chloride (554 mg, 3.1 mmol) in pyridine (5 mL) were heated at reflux for 4 hours, stirred overnight at room temperature, treated with water and extracted with ethyl acetate. The extract was washed with water and brine, dried (MgSO ₄ ) and concentrated. The residue is recrystallized from ethanol to give the desired compound.

Mp 197-199 ° C;

MS (DCI / NH 3) m / e 343 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.20 (br s, 1H), 8.03-8.01 (m, 1H), 7.94-7.91 (m, 1H), 7 , 80-7.78 (m, 2H), 7.60-7.50 (m, 3H), 7.34-7.25 (m, 1H), 7.22-7.19 (m, 1H) ;

Calcd for C ₁₅ H ₄ N ₆ O ₂ S · C ₂ H ₅ OH: C, 52.56; H, 5.18; N, 21.63. Found: C, 52.47; H, 5.24; N, 21.54.

* ·

Example 24

6- [1 - ([1,1'-Biphenyl] -4-yl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine

Example 24A

A mixture of 4-bromobiphenyl (19.16 g, 82 mmol) in THF (820 mL) at -78 ° C was treated with tert-butyllithium (100 mL of a 1.7 M solution in pentane, 170 mmol), stirred for 8 minutes, treated with bismuth trichloride (8.62 g, 27.4 mmol) in THF (100 mL), stirred for an additional 3 hours, treated with saturated aqueous NH 4 Cl and extracted with ethyl acetate.

The extract was washed with water and brine, dried over (MgSO 4) and concentrated. The residue is dried in a vacuum oven to give the desired compound.

¹³ CNMR (300 MHz, CDCl 3) δ 153.83, 141.04, 140.69,138.07, 129.21, 128.75, 127.33, 127.07.

Example 24B

6- [1 - ([1,1'-Biphenyl] -4-yl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine

To obtain the desired compound, the compound of Example 24A and ethyl isonipecotate were treated according to the method of Examples 2A and 2C.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 347 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.58 (m, 2H), 7.47 (d, 2H), 7.39 (m, 2H), 7.23 (m, 1H), 6 97 (d, 2H), 6.59 (br s, 4H), 3.61 (m, 1H), 1.78 (m, 4H), 1.58 (m, 4H).

Example 25

N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] -2-naphthalenesulfonamide

6- (4-Aminophenyl) -1,3,5-triazine-2,4-diamine was processed according to the procedure of Example

23, but to obtain the desired compound, 2-naphthalenesulfonyl chloride is replaced with benzenesulfonyl chloride.

Mp 230-233 ° C;

MS (DCI / NH ₃ ) m / e 393 (M + H) ^< ^{+ &gt};;

^! 1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.55 (s, 1H), 8.5 (s, 1H), 8.2-8.05 (m, 3H), 8.0 (d, 1H) )

7.9-7.85 (m, 1 H), 7.8-7.75 (m, 1 H), 7.74-7.6 (m, 2 H), 7.3-7.2 (m, 2 H) 1, 6.9-6.65 (br s, 4H);

Anal Calcd For C 18 H 16 N 6 O 2 S 2 O 2 O 2 · C: C, 57.23; H, 5.37; N, 16.02. Found: C, 57.11; H, 5.33; N, 16.28.

Example 26

2,5-dichloro-N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] benzenesulfonamide

To obtain the desired compound, the compound of Example 10A was treated according to the procedure of Example 23 but replacing 2,5-dichlorobenzenesulfonyl chloride with benzenesulfonyl chloride.

Mp 230-233 ° C;

MS (DCI / NH 3) m / e 411 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 10.5 (s, 1H), 8.05 (m, 3H), 7.75-7.7 (m, 2H), 7.35 (t, 1 H), 7.25-7.2 (m, 1H), 6.8-6.7 (br s, 4H);

Calcd for C15H12Cl2N6O2S * 0.5CH3CH2OH C, 44.24; H, 3.48; N, 19.35. Found: C, 44.43; H, 3.26; N, 19.44.

Example 27

6- (1-Phenylcyclohexyl) -1,3,5-triazine-2,4-diamine

1 phenylcyclohexanecarbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 153-155 ° C;

MS (DCI / NH 3) m / e 270 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.4-7.3 (m, 2H), 7.15 (t, 2H), 7.2-7.1 (m, 1H), 6, 6-6.5 (br s, 4H), 2.7-2.6 (m, 2H), 1.75-1.6 (m, 2H), 1.6-1.2 (m, 6H) ;

Calcd for C15H19N5: C, 66.89; H, 7.1; N, 26.00. Found: C, 66.94; H,

7.20; N, 26.04.

Example 28

6- [1- (4-Methoxyphenyl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine

Tris (4'-methoxy [1,1'-biphenyl] bismuth), prepared as described in the example

24A, and ethyl isonipecotate are processed according to the method of Examples 2A and 2C to obtain the desired compound.

* »• · · ·

Mp 204-205 ° C;

MS (DCI / NH 3) m / e 301 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 6.92 (d, 2H), 6.81 (d, 2H), 6.58 (m, 4H), 3.59 (m, 2H), 2, 62 (m, 2H), 2.35 (m, 1H), 1.82 (m, 4H).

Example 29

6- [2- [4- (Trifluoromethyl) phenyl] -4-thiazolyl] -1,3,5-triazine-2,4-diamine

To obtain the desired compound, ethyl 2- [4- (trifluoromethyl) phenyl] thiazole-4-carboxylate) and the compound of Example 2B were treated as in Example 2C.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 339 (M + H) ⁺ ;

Δ H NMR (300 MHz, DMSO-d 6) δ 8.42 (s, 1H), 8.19 (d, 2H), 7.91 (d, 2H), 6.82 (br s, 4H); Calcd for C 13 H 9 F 3 N 6 S: C, 46.15; H, 2.68; N, 24.84. Found: C, 45.85; H, 2.64; N, 24.44.

Example 30

6- [1- (4-methoxyphenyl) cyclohexyl] -1,3,5-triazine-2,4-diamine

1- (4-Methoxyphenyl) cyclohexanecarbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 159-163 ° C;

MS (DCI / NH 3) m / e 300 (M + H) ⁺ ;

Δ NMR (300 MHz, DMSO-d 6) δ 7.15 (d, 2H), 6.8 (d, 2H), 6.6 (br s, 4H), 3.7 (s, 3H), 2, 7-2.6 (m, 2H), 1.7-1.6 (m, 2H), 1.6-1.2 (m, 6H);

Calcd for C16H21N5O: C, 64.19; H, 7.07; N, 23.39. Found: C, 64.13; H, 7.07; N, 23.25.

Example 31

6- [4- (2-thienyl) phenyl] -1,3,5-triazine-2,4-diamine

A solution of Example 20A (500 mg, 1.9 mmol) and 2-tri-n-butyltin thiophene (840 mg, 2.2 mmol) in dry, degassed dimethylacetamide (15 mL) was treated with tetrakis (triphenylphosphine) palladium (115 mL). mg, 0.1 mmol), heated at 100 ° C for 3 hours, cooled, treated with 1N NaOH and extracted with ethyl acetate. The extract was washed with brine, dried (MgSO ₄ ) and concentrated. The residue is recrystallized from ethanol / dioxane to give the desired compound.

Mp > 260 ° C;

MS (DCI / NH ₃ ) m / e 270 (M + H) ^< ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 8.31-8.24 (m, 2H), 7.8-7.72 (m, 2H), 7.62-7.59 (m, 2H) ,

7.2-7.16 (m, 1H), 6.92 (br s, 4H);

Calcd for C13H11N5S: C, 57.97; H, 4.11; N, 26.00. Found: C, 57.91; H, 4.06; N, 25.83.

Example 32

6- [4- (phenylethynyl) phenyl] -1,3,5-triazine-2,4-diamine

Example 32A

To obtain the desired compound, 4-bromobenzonitrile and trimethyl (phenylthynyl) tin were treated as in Example 31.

MS (DCI / NH 3) m / e 221 (M + NH ₄ ) ⁺ .

Example 32B

6- [4- (phenylethynyl) phenyl] -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 4 (phenylethynyl) benzonitrile was treated according to the procedure of Example 1.

Mp 248-249 ° C;

MS (DCI / NH 3) m / e 289 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.30 (d, 2H), 7.67 (d, 2H), 7.61-7.58 (m, 2H), 7.5-7.43 (m,

3H), 6.82 (br s, 4H);

Calcd for C17H13N5: C, 71.06; H, 4.56; N, 24.37. Found: C, 70.79; H, 4.73;

N, 24.08.

»» »

* «• · · ·

Example 33

N, N '- (6- [1,1'-Biphenyl] -4-yl-1,3,5-triazine-2,4-diyl) bis [acetamide]

Example 33A

To obtain the desired compound, 4-phenylbenzonitrile was treated according to the procedure of Example 1.

MS (DCI / NH 3) m / e 264 (M + H) ⁺ .

Example 33B

N, N - (6- [1,1'-biphenyl] -4-yl-1,3,5-triazine-2,4-diyl) bis [acetamide]

A solution of Example 33A (0.26g, 0.99 mmol) in acetic anhydride (10 mL) was refluxed for 20 hours and cooled to room temperature. The precipitate is washed with saturated sodium bicarbonate and dried in vacuo to afford the desired compound. Mp > 260 ° C;

MS (DCI / NH ₃ ) m / e 348 (M + H) ^< ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 10.79 (s, 2H), 8.43 (d, 2H), 7.91 (d, 2H), 7.79 (d, 2H), 7, 52 (m, 2H), 7.41 (m, 1H), 2.41 (s, 6H);

Calcd for C19H17N5O2: C, 65.70; H, 4.93; N, 20.16. Found: C, 65.63; H, 4.84; N, 20.18.

Example 34

N - (4-amino-6- [1,1'-biphenyl] -4-yl-1, 3, 5-triazin-2-yl) acetamide

A solution of Example 33A (0.38g, 1.4 mmol) in acetic anhydride (4 mL) was heated at 80 ° C for 20 h, treated with ethyl acetate and cooled to room temperature. The precipitate was collected by vacuum filtration, washed with aqueous sodium carbonate, and dried in vacuo to afford the desired compound.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 306 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 10.22 (s, 1H), 8.39 (d, 2H), 7.83 (d, 2H), 7.77 (d, 2H), 7, 53 (m, 3H), 7.41 (m, 2H), 2.36 (s, 3H);

• 9

Anal Calcd For C 11 H 15 N 5 O 5 • CH 2 Cl 2: C, 65.86; H, 5.02; N, 22.07. Found: C, 65.82; H, 4.97; N, 22.37.

Example 35: N- [4- (4,6-Diamino-1,3,5-triazin-2-yl) phenyl] -1-naphthalenesulfonamide

The compound of Example 10A was treated according to the procedure of Example 23, but 1-naphthalenesulfonyl chloride was substituted for benzenesulfonyl chloride to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 393 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 10.8 (s, 1H), 8.8 (d, 1H), 8.3 (d, 1H), 8.2 (d, 1H), 8, 1 (d, 1H), 8.0 (s, 1H), 7.83-7.6 (m, 4H), 7.2 (t, 1H), 7.15-7.1 (m, 1H) 6.83-6.7 (m, 4H); Anal Calcd For C 18 H 16 N 6 O 2 S 2 H 2 O: C, 55.59; H, 4.42; N, 20.47. Found: C, 55.57; H, 4.42;

N, 20.52.

Example 36

6- (4-azido [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

Example 36A

A solution of 4'-amino [1,1-biphenyl] -4-carbonitrile (0.490 g, 2.53 mmol) in trifluoroacetic acid (12.5 mL) was gradually treated with sodium nitrite (0.338 g, 4.90 mmol). and sodium azide (0.33 g, 5.1 mmol), stirred at room temperature for 10 minutes, treated with water, and extracted with ethyl acetate. The extract was dried (MgSO 4) and concentrated to give the desired compound.

MS (DCI / NH 3) m / e 238 (Μ + ΝΗ 4Λ)

Example 36B

6- (4-azido [1,1-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

The compound of Example 36A was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 230 ° C (decomp.);

·· »·

MS (DCI / NH 3) m / e 305 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.32 (d, 2H), 7.79 (m, 4H), 7.24 (d, 2H), 6.74 (bds, 4H); Calcd for C15H12N8 * 0.33H2O: C, 58.07; H; 4.11; N, 36.12. Found: C, 58.15; H, 3.84; N, 33.09.

Example 37

6- [4- (4-Morpholinylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine

Example 37A

A solution of 4-cyanobenzenesulfonyl chloride (600 mg, 2.98 mmol), morpholine (300 mg, 3.44 mmol) and pyridine (350 μΐ, 342 mg, 4.33 mmol) in dichloromethane (10 mL) was stirred overnight at room temperature The reaction was quenched with saturated NH 4 Cl and extracted with ethyl acetate. The extract was washed with water and brine, dried (MgSO ₄ ) and concentrated to give the desired compound.

MS (DCENH 3) m / e 270 (M + NKQs)

Example 37B

4- (2,4-Diamino-1,3,5-triazin-2-yl) -N- (4-morpholinyl) benzenesulfonamide

The compound of Example 37 was treated as in Example 1 to obtain the desired compound.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 337 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.46 (d, 2H), 7.83 (d, 2H), 6.91 (br s, 4H), 3.65-3.60 (m, 4H), 2.94-2.88 (m, 4H);

Calcd for C13H16N6O3S: C, 46.42; H, 4.79; N, 24.98. Found: C, 46.21; H, 4.69; N, 25.24.

Example 38

6- [4- (2-furanyl) phenyl-1,3,5-triazine-2,4-diamine • 9,999,999,99 9,99 9 9,99 99 * <> » 9 9 9 9 9 9 99 99 99 99 99 99

6- (4-Bromophenyl) -1,3,5-triazine-2,4-diamine was processed according to the procedure of Example 31, but 2-tri-n-butyltinfuran was substituted for 2-tri-butyltin thiophene to obtain the desired compound.

MS (DCI / NH ₃ ) m / e 254 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 8.3 (d, 2H), 7.8 (d, 3H), 7.05 (d, 1H), 6.8-6.7 (br s, 4H), 6.65-6.6 (m, 1H);

Calcd for C 13 H 11 N 5 O: C, 60.30; H, 5.57; N, 24.30. Found: C, 59.83; H,

5.44; N, 24.86.

Example 39

N, N- [6- (4-Phenoxyphenyl) -1,3,5-triazine-2,4-diyl] bis [acetamide]

The compound of Example 9 was treated according to the procedure of Example 33B to obtain the desired compound.

Mp 243-245 ° C;

MS (DCI / NH 3) m / e 364 (M + H) ⁺ ;

¹ H NMR (300 MHz, DMSO-d 6) δ 10.74 (s, 2H), 8.38 (d, 2H), 7.47 (t, 2H), 7.24 (t, 1H), 7, 14 (dd, 4H), 2.38 (s, 6H);

Calcd for C19H17N5O3: C, 62.80; H, 4.72; N, 19.27. Found: C, 62.56; H,

4.82; N, 19.40.

Example 40

N- [4-amino-6- (4-phenoxyphenyl) -1,3,5-triazin-2-yl] acetamide

The compound of Example 9 was treated according to the procedure of Example 34 to obtain the desired compound.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 322 (M + H) ⁺ ;

Δ NMR (300 MHz, DMSO-d ₆ ) δ 10.21 (s, 1H), 8.32 (d, 2H), 7.46 (t, 2H), 7.37 (bds, 2H),

7.13 (d, 2H), 7.08 (d, 2H), 2.32 (s, 3H);

Calcd for C17H15N5O2: C, 63.54; H, 4.71; N, 21.79. Found: C, 63.25; H,

4.79; N, 21.84.

4 · «· 9

C · · «

ν · ····

Example 41

6- (5-phenyl-2-furanyl) -1,3,5-triazine-2,4-diamine

Example 41 A

Methyl (5-bromo-2-fluoro), phenylboronic acid and tetrakis (triphenylphosphine) palladium were treated as in Example 21 to obtain the desired compound.

MS (DCI / NH ₃ ) m / e 203 (M + H) &lt; + & gt ^; .

Example 41B

6- (5-phenyl-2-furanyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, the compounds of Examples 41A and 2B were treated as in Example 2C.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 254 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.80 (d, 2H), 7.52-7.44 (m, 2H), 7.41-7.37 (m, 1H), 7, 23 (dd, 1H), 7.16 (dd, 1H), 6.78 (br s, 4H);

Calcd for C 13 H 11 N 5 O: C, 61.65; H, 4.37; N, 27.65. Found: C, 61.33; H, 4.37; N, 27.42.

Example 42

6- (5-phenyl-2-thienyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, methyl (5-phenylthiophene-2-carboxylate) was treated according to the procedure of Example 41A and 41B.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 270 (M + H) +;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 7.80 (d, 1H), 7.71-7.76 (m, 2H), 7.56 (d, 1H), 7.31-7, 49 (m, 3H), 6.78 (bds, 4H);

Calcd for C ₁₃ H ₁₁ N ₅ S * 0.5H ₂ O: C, 56.09; H, 4.34; N, 25.16. Found: C,

56.35; H, 4.01; N, 25.27.

Example 43

A, ^N '- [6- (4-phenylcyclohexyl) -l, 3,5-triazine-2,4-diylJbis [acetamide]

To obtain the desired compound, the compound of Example 3 was treated according to the procedure of Example 33B.

Mp 235-236 ° C;

MS (DCI / NH ₃₎ m / e 354 (M + H) ^+;

1 H NMR (300 MHz, DMSO-d 6) δ 10.61 (s, 2H), 7.30 (m, 4H), 7.18 (m, 1H), 2.63 (m, 1H), 2, 56 (m, 1H), 2.36 (s, 6H), 1.98 (m, 4H), 1.63 (m, 4H);

Calcd for C19H23N5O2 * 0.25H2O: C, 63.76; H, 6.62; N, 19.57. Found: C, 63.83, H, 6.52; N, 19.27.

Example 44

N- [4-amino-6- (4-phenylcyclohexyl) -1,3,5-triazin-2-yl] acetamide

To obtain the desired compound, the compound of Example 3 was treated according to the procedure of Example 34.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 312 (M + H) ⁺ ;

Δ NMR (300 MHz, DMSO-d 6) δ 10.02 (s, 1H), 7.28 (m, 7H), 2.54 (m, 1H), 2.44 (m, 1H), 2.25 (s, 3H), 1.96 (m, 4H), 1.59 (m, 4H);

Calcd for C17H21N5O. C, 65.57; H, 6.80; N, 22.49. Found: C, 65.37; H, 6.85; N, 22.74.

Example 45

6- (4-phenyl-1-naphthalenyl) -1,3,5-triazine-2,4-diamine

Example 45A

A solution of 4-methoxy-1-naphthalenecarbonitrile (3.5 g, 19 mmol) in dichloromethane (15 mL) at -78 ° C was treated with BBr ₃ (5 g, 20 mmol) in dichloromethane (15 mL), stirred

at room temperature for 18 hours, allowed to react with water. Extract with ethyl acetate. The extract was washed with water and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by silica gel flash chromatography (30% ethyl acetate / hexanes) to give the desired compound.

MS (DCI / NH 3) m / e 187 (M + NH ₄ ) ⁺ .

Example 45B

A solution of Example 45A (1.0 g, 5.9 mmol), triethylamine (1 mL, 7.2 mmol) and N-phenyltrifluoromethanesulfonamide (2.1 g, 5.9 mmol) in dichloromethane (15 mL) at 0 The ° C was stirred overnight at room temperature. The reaction was then treated with ethyl acetate and washed sequentially with 10% HCl, 20% KOH, water and brine, dried (MgSO 4) and concentrated to afford the desired compound.

MS (DCI / NH 3) m / e 319 (M + NH ₄ ) ⁺ .

Example 45C

To obtain the desired compound, the compound of Example 45B and phenylboronic acid were treated as in Example 21.

MS (DCI / NH 3) m / e 247 (M + NH ₄ ) ⁺ .

Example 45D

6- (4-phenyl-1-naphthalenyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, the compound of Example 45C was treated according to the procedure of Example 1.

Mp 239-240 ° C;

MS (DCI / NH ₃ ) m / e 314 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 8.84-8.80 (m, 1H), 7.97 (d, 1H), 7.85-7.81 (m, 1H), 7.697, 48 (m, 8H), 6.84 (bds, 4H);

Calcd for C19H15N5: C, 72.82; H, 4.82; N, 22.34. Found: C, 72.68; H, 4.77;

N, 22.35.

Example 46

6- [4- (phenylthio) phenyl] -1,3,5-triazine-2,4-diamine

Example 46A

A solution of 4-bromobenzonitrile (1.0 g, 5.5 mmol), thiophenol (644 mg, 5.8 mmol), K 2 CO 3 (1.9 g, 13.7 mmol) and CuI (1.05 g, 5.5) mmol) in DMF (20 mL) was heated at reflux for 24 h, treated with ethyl acetate and filtered through Celite®. The filtrate was washed with water and brine, dried (MgSO ₄ ) and concentrated. The residue was purified by flash column chromatography on silica gel (5% ethyl acetate / hexanes) to afford the desired compound.

MS (DCI / NH 3) m / e 229 (M + NH 4).

Example 46B

6- [4- (phenylthio) phenyl] -1,3,5-triazine-2,4-diamine

The compound of Example 46A was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 213-215 ° C;

MS (DCI / NH 3) m / e 296 (M + H) ⁺ ;

¹ H NMR (300 MHz, DMSO-d 6) δ 8.19 (d, 2H), 7.44-7.41 (m, 5H), 7.32 (d, 2H), 6.77 (bds, 4H) );

Calcd for C15H13N5S: C, 60.99; H, 4.43; N, 23.71. Found: C, 60.70; H,

4.32; N, 23.55.

Example 47

6- (2-quinolinyl) -1,3,5-triazine-2,4-diamine

2-Quinolinecarbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

MS (DCI / NH 3) m / e 239 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.5 (d, 1H), 8.35 (d, 1H), 8.15-8.0 (m, 2H), 7.9-7.8 (m, 1

H), 7.75-7.7 (m, 1H), 7.1-7.0 (br s, 2H), 7.0-6.9 (br s, 2H);

Calcd for C12H10N6: C, 60.49; H, 4.23; N, 35.27. Found: C, 60.24; H, 3.94;

N, 35.12.

Example 48

6- (3-quinolinyl) -1,3,5-triazine-2,4-diamine

3-Quinolinecarbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH ₃ ) m / e 239 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO- d ₆ ) δ 9.7 (d, 1H), 9.1 (d, 1H), 8.2-8.1 (m, 2H), 6.9-6, 85 (m, 1H), 6.8-6.7 (m, 1H), 7.05-6.9 (br s, 4H);

Calcd for C ₂₂ H ₁₀ N ₆ : C, 60.49; H, 4.23; N, 35.27. Found: C, 60.32; H, 4.06; N, 35.54.

Example 49

6- (benzo [b] thien-2-ylmethyl) -1,3,5-triazine-2,4-diamine

Benzo [b] thiophene-2-acetonitrile was worked up to obtain the title compound.

Mp 216-218 ° C;

MS (DCI / NH ₃ ) m / e 258 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 7.97-7.92 (m, 1H), 7.87-7.80 (m, 1H), 7.48 (s, 1H), 7.47 32 (m, 2H), 6.65 (br s, 4H), 3.90 (s, 2H);

Calcd for C12H11N5S: C, 56.01; H, 4.30; N, 27.21. Found: C, 55.97; H, 4.19; N, 27.31.

Example 50

6- (2,2-Dimethyl-2H-1-benzopyran-6-yl) -1,3,5-triazine-2,4-diamine

2,2-Dimethyl-2H-1-benzopyran-6-carbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

MS (DCI / NH 3) m / e 270 (M + H) ⁺ ;

^! 1 H NMR (300 MHz, DMSO-d 6) δ 8.05 (dd, 1H), 7.95 (d, 1H), 6.9 (d, 1H), 6.78-6.75 (br s,

4H), 6.70 (d, 1H), 5.80 (d, 1H), 1.20 (s, 6H);

Calcd for C14H15N5O: C, 62.44; H, 5.61; N, 26.00. Detected. C, 62.19; H,

5.70; N, 25.54.

• ·

Example 51

6- (2,3-dihydro-1,4-benzodioxin-2-yl) -1,3,5-triazine-2,4-diamine

2,3-dihydro-1,4-benzodioxine-2-carbonitrile was treated as in Example 1 to obtain the title compound.

MS (DCI / NH 3) m / e 246 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 7.0-6.75 (m, 8H), 3.5 (t, 1H), 3.3 (d, 2H);

Calcd for C11H11N5O2: C, 53.81; H, 4.52; N, 28.55. Found: C, 53.80; H, 4.36; N, 28.40.

Example 52

6- (tricyclo [3.3.1.1 ^3,7 ] decan-1-yl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, methyl (tricyclo [3.3.1.1 ^3,7 ] decane-1-carboxylate) and the compound of Example 2B were treated as in Example 2C.

Mp 261-262 ° C;

MS (DCI / NH 3) m / e 246 (M + H) ⁺ ;

Δ NMR (300 MHz, DMSO-d 6) δ 6.47 (br s, 4H), 2.05-1.95 (m, 3H), 1.9-1.88 (m, 6H), 1,771.60 (m, 6H);

Calcd for C 13 H 19 N 5: C, 63.64; H, 7.80; N, 28.54. Found: C, 63.48; H, 7.66; N, 28.34.

Example 53

6- (1-isoquinolinyl) -1,3,5-triazine-2,4-diamine

The isoquinolinecarbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 239 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.7 (d, 1H), 8.2 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7, Δ (dt, 1H), 7.65 (dt, 1H), 6.9 (bs, 4H);

Calcd for C12H10N6 * 0.3H2O: C, 60.49; H, 4.23; N, 35.27. Found: C, 59.55; H, 4.35; N, 34.03.

Example 54 (+/-) -4- (4,6-Diamino-1,3,5-triazin-2-yl) -α-phenylbenzenemethanol

A mixture of Example 11 (150 mg, 0.515 mmol) and sodium borohydride (6 mg, 0.15 mmol) in ethanol (5 mL) was heated at reflux for 30 minutes, then stirred overnight at room temperature. The precipitate is washed with water and dried in vacuo to give the desired compound.

Mp 214-216 ° C;

MS (DCI / NH 3) m / e 294 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.2 (d, 2H), 7.5 (d, 2H), 7.4 (d, 2H), 7.3 (t, 2H), 7, 2 (m, 1H), 6.7 (br s, 4H), 6.0 (d, 1H), 5.75 (d, 1H);

Calcd for C16H15N5O: C, 65.51; H, 5.15; N, 23.87. Found: C, 65.33; H, 4.91; N, 23.65.

Example 55

6- (2,3-Dihydro-1,4-benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine

2,3-dihydro-1,4-benzodioxine-6-carbonitrile was treated as in Example 1 to obtain the title compound.

Mp 241-244 ° C;

MS (DCI / NH 3) m / e 246 (M + H) ⁺ ;

Ή NMR (300 MHz, DMSO-d 6) δ 8.8-8.75 (m, 2H), 6.95-6.9 (m, 1H), 6.9-6.8 (br s, 4H) 4.25-4.33 (m, 4H);

Calcd for C11H11N5O2: C, 53.87; H, 4.52; N, 28.56. Found: C, 53.93; H, 4.27; N, 28.41.

Example 56

6- (1-azabicyclo [2.2.2] octan-4-yl) -1,3,5-triazine-2,4-diamine

........

1azabicyclo [2.2.2] octane-4-carbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 245 ° C;

MS (DCI / NH 3) m / e 221 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 6.6-6.5 (br s, 4H), 3.35 (s, 2H), 2.9 (t, 5H), 1.7 (t, 5H); Calcd for C 10 H 11 N 6: C, 54.53; H, 7.32; N, 38.15. Found: C, 54.40; H, 7.38; N, 38.25.

Example 57

6- [4- (phenylsulfinyl) phenyl] -1,3,5-triazine-2,4-diamine

A mixture of Example 49 (102 mg, 0.34 mmol) and Oxone ® (106 mg, 0.17 mmol) in acetic acid (2 mL) was stirred overnight at room temperature, treated with saturated NaHCO ₃ and extracted with ethyl acetate. . The extract was washed with water and brine, dried (MgSO 4) and concentrated. The residue is recrystallized from ethanol to give the desired compound.

Mp 253-255 ° C;

MS (DCI / NH 3) m / e 312 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.36 (d, 2H), 7.81 (d, 2H), 7.75-7.72 (m, 2H), 7.607.52 (m, 3H) ), 6.82 (br s, 4H);

Calcd for C 15 H 13 N 5 OS · 0.25H 2 O: C, 57.03; H, 4.30; N, 22.17. Found: C, 57.47; H, 4.04; N, 21.81.

Example 58

6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 4- (phenylsulfonyl) benzonitrile was treated according to the procedure of Example 1 (J. Org. Chem. 1989, 54,4691).

Mp > 250 ° C;

MS (DCI / NH 3) m / e 328 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO- d 6) δ 8.41 (d, 2H), 8.08 (d, 2H), 7.96 (d, 2H), 7.71-7.60 (m, 3H) )

6.92 (brs, 4H);

Calcd for C 15 H 13 N 5 O 2 S · 0.25H 2 O: C, 54.28; H, 4.10; N, 21.10. Found: C,

54.28; H, 3.92; N, 20.82.

• «• · · ·

Example 59

E / N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] phenylmethanone, oxime

A mixture of Example 11 (300 mg, 1.03 mmol) and hydroxylamine hydrochloride (70 mg, 1.0 mmol) in 1: 1 ethanol / pyridine (10 mL) was heated at reflux for 3 hours, stirred overnight at room temperature. , react with water and filter. The precipitate is washed with water and dried to obtain the desired compound.

Melting point: 97-107 ° C;

MS (DCI / NH ₃₎ m / e 307 (M + H) ^+;

¹ H NMR (300 MHz, DMSO-d 6) δ 11.42 (s, 0.5H), 11.41 (s, 0.5H), 8.35 (d, 1H), 8.2 (d, 1H) )

7.3-7.5 (m, 7H), 6.8 (brs, 4H);

Calcd for C 16 H 14 N 6 O • CH 3 CH 2 OH: C, 61.35; H, 5.72; N, 23.84. Found: C, 61.67; H, 5.29; N, 23.37.

Example 60

6-pyrazinyl-1,3,5-triazine-2,4-diamine

Pyrazinecarbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 190 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 6.9 (br s, 2H), 7.1 (br s, 2H), 8.75-8.8 (m, 2H), 9.3 (s , 1H); Calcd for C7H7N7: C, 44.44; H, 3.72; N, 51.82. Found: C, 44.40; H, 3.62; N, 51.79.

Example 61

2,4-diamino-6 - [(4-phenylethenyl) phenyl] -1,3,5-triazine

Example 61A

A solution of benzyltriphenylphosphonium chloride (22.8 g, 58 mmol) in THF (100 mL) at room temperature was treated with lithium hexamethyldisilazide (1M in toluene, 53 mL, 53 mL, heated at reflux for 15 min.). minutes, cooled to room temperature, treated with 4-cyanobenzaldehyde (7 g, 53 mmol) in THF (40 mL), stirred overnight at room temperature, acidified with 10% HCl and filtered. The filtrate was extracted with ethyl acetate, dried (MgSO ₄ ) and concentrated. The residue was dissolved in hot ethyl acetate and filtered through a silica gel column to give the desired compound.

Example 61B

The compound of Example 61 A was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 216-217 ° C;

MS (DCI / NH 3) m / e 290 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.25 (d, 2H), 7.75 (d, 2H), 7.65 (d, 2H), 7.2-7.4 (m, 5H) 6.75 (br s, 4H);

Anal Calcd For C ₁₇ H ₁₅ N ₅ · 0.5CH ₃ CO ₂ CH ₂ CH 3: C, 68.45; H, 5.74; N, 21.00. Found: C, 68.50; H, 5.49; N, 21.43.

Example 62

2,4-diamino-6 - [(4- (2-nitrophenyl) ethenyl) phenyl] -1,3,5-triazine 4-nitrobenzyltriphenylphosphonium bromide was processed to obtain the desired compound according to the procedure of Example s61Aa61B.

Mp > 250 ° C;

MS (DCI / NH 3) m / e 335 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.25 (t, 4H), 7.9 (d, 2H), 7.8 (d, 2H), 7.6 (m, 2H), 6, Δ (br s, 4H);

Calcd for C 11 H 11 N 2 O 2: C, 61.07; H, 4.22; N, 25.14. Found: C, 60.78; H, 4.12; N, 24.89.

Example 63

6- (1,1'-Biphenyl] -4-yl-N, N-dimethyl-1,3,5-triazine-2,4-diamine

Example 63A

2- [1,1'-Biphenyl] -4-yl-4,6-dichloro-1,3,5-triazine

A mixture of 4-phenyl-phenylmagnesium bromide (prepared from 4-bromobiphenyl (7.75 g, 33 mmol) and magnesium turnings (0.83 g, 35 mmol) in 40 mL of ether) and cyanuric chloride (4.00 g, 21.7 mmol) ) in benzene (90 mL) was stirred at 0 ° C for 90 minutes. The reaction mixture was evaporated to dryness and the residue was purified by silica gel flash chromatography (50% hexanes / methylene chloride) to give the desired compound (2.80 g, 43%).

MS (DCI / NH 3) m / e 301 (M + H) ⁺ .

Example 63B

6- [1,1'-Biphenyl] -4-yl-N, N-dimethyl-1,3,5-triazine-2,4-diamine

A mixture of Example 63A (0.52 g, 1.72 mmol) and N-methylamine (30 mmol) in tetrahydrofuran (25 mL) was stirred at room temperature for 72 hours. The reaction mixture was reduced in volume and diluted with water. The precipitate was combined, washed with water and ether, and dried. Purification by reverse phase HPLC afforded the desired compound.

Mp 198-200 ° C;

MS (DCI / NH 3) m / e 292 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 8.37 (m, 2H), 7.74 (m, 4H), 7.51 (m, 2H), 7.39 (m, 1H), 7 22 (bdm, 2H); 2.82 (m, 6H);

Calcd for C17H17N5 * 0.25H2O: C, 69.01; H, 5.96; N, 23.67. Found: C,

69.37; H, 5.85; N, 23.63.

Example 64

6- [1,1'-Biphenyl] -4-yl-N-methyl-1,3,5-triazine-2,4-diamine

Example 64A

4- [1,1'-Biphenyl] -4-yl-6-chloro-1,3,5-triazin-2-amine

A mixture of 2- [1,1'-biphenyl] -4-yl-4,6-dichloro-1,3,5-triazine (Example 63A) (0.804 g, 2.67 mmol) in 40 mL of ether and concentrated ammonium hydroxide ( 2 mL, 30 mmol) in tetrahydrofuran (30 mL) was stirred at 0 ° C for 60 min and at room temperature for 20 min. The reaction mixture was reduced in volume, diluted with water, and the precipitate was combined, washed with water and ether, and dried to afford the desired compound (0.090 g, 12%).

MS (DCI / NH 3) m / e 282 (M + H) ⁺ .

Example 64B

6- [1,1'-Biphenyl] -4-yl-N-methyl-1,3,5-triazine-2,4-diamine

Example 64A (0.090 g, 0.32 mmol) and N -methylamine (6 mmol) in tetrahydrofuran (9 mL) were stirred at room temperature for 24 hours. The reaction mixture was reduced in volume and diluted with water. The precipitate was combined, washed with water and ether and dried to give the desired compound. (0.062 g, 70%).

M.p .: 237-238 ° C;

MS (DCI / NH ₃ ) m / e 278 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 8.39 (d, 1H), 8.32 (d, 1H), 7.77 (m, 4H), 7.51 (t, 2H), 41 (m, 1H); 7.25 (q, 1H); 6.79 (bds, 2H); 2.79 (d, 3H);

Calcd for C 16 H ₁₅ N ₅ · 0.5C ₄ H ₈ O 2. C, 67.27; H, 5.96; N, 21.79. Found: C, 67.20; H, 5.71; N, 22.05.

Example 65

6- (bicyclo [2.2.1] hept-2-yl) -1,3,5-triazine-2,4-diamine

Example 65A

6- (bicyclo [2.2.1] hept-2-en-5-yl) -1,3,5-triazine-2,4-diamine

The bicyclo [2.2.1] hept-2-ene-5-carbonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

MS (DCI / NH 3) m / e 204 (M + H) ⁺ .

Example 65B

6- (bicyclo [2.2.1] hept-2-yl) -1,3,5-triazine-2,4-diamine

The solution of Example 65A in methanol was reduced with hydrogen gas and palladium on charcoal, filtered and evaporated to give the desired compound.

Mp 216-217 ° C;

MS (DCI / NH 3) m / e 206 (M + H) ⁺ ;

¹ H NMR (300 MHz, DMSO-d 6) δ 6.52 (bds, 4H), 2.83 (m, 1H), 2.39 (m, 1H), 2.21 (m, 1H),

2.04 (m, 1H), 1.91 (m, 1H), 1.6-1.2 (m, 5H), 6.52 (m, 1H);

• · · · ·

Calcd for C10H15N5: C; 58.52, H; 7.37, N; 34.12. Found: C; 58.59, H; 7.40, N; 34,00.

Example 66

6- [1,1'-Biphenyl] -4-yl-4'-diethyl-], 3,5-triazine-2,4-diamine

A mixture of 2,4-di-N-ethylamino-6-chloro-1,3,5-triazine (0.55 g, 2.7 mmol) and tetrakis (triphenylphosphine) palladium (0.19 g, 0.16 mmol) in dry, degassed dimethylacetamide (45 mL) is heated at 100 ° C, treated sequentially with 4- (phenyl) phenylboronic acid (Yabroff et al., Journal of the American Chemical Society, Volume 56, 1934, 18501856) (0 , 80 g, 4.0 mmol) in absolute ethanol (15 mL) and saturated aqueous sodium bicarbonate (30 mL) and the reaction mixture was maintained at 100 ° C for 3 days. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The organic layer was washed with brine, dried (MgSO ₄ ), concentrated and dried in vacuo. The residue was recrystallized from 2: 1 dioxane / ethanol to give 0.15 g (17%) of the title compound as a white solid. Mp 183-184 ° C;

MS (DCI / NH 3) m / e 320 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.36 (m, 2H), 7.78 (d, 2H), 7.73 (d, 2H), 7.49 (m, 2H), 7, 38 (m, 1H); 7.28 (m, 2H); 3.40 (m, 4H); 1.16 (m, 6H);

Calcd for C18H18N5O4.204O2: C, 70.91; H, 6.55; N, 8.28. Found: C, 71.21; H, 6.50; N, 21.13.

Example 67

6- (2'-Nitro- [1,1-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 4-cyano-2'-nitrobiphenyl was treated according to the procedure of Example 1.

Mp > 250 ° C;

1 H NMR (300 MHz, DMSO-d 6) δ 8.3 (d, 2H,> 9 Hz), 8.05 (dd, 1H), 7.8 (m, 1H), 7.6-7.7 (m,

2H), 7.45 (d, 2H), 6.8 (br s, 4H);

MS (DCI / NH 3) m / e 309 (M + H) ⁺ ;

Calcd for C15H12N6O2: C, 58.44; H, 3.92; N, 27.26. Found: C, 58.46; H,

3.99; N, 27.15.

• · · · · · · · · · · · · · · ·

Example 68

6- (6-methyl-3-pyridinyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 6-methyl-nicotinonitrile was treated according to the procedure of Example 1.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 203 (M + H) ⁺ ;

¹ H NMR (300 MHz, DMSO-d 6) δ 9.23 (d, 1H), 8.39 (dd, 1H, J = 11), 7.38 (d, 1H), 6.81 (br s, 4H), 2.56 (s, 3H);

Calcd for C8H10Ng: C, 53.45; H, 4.98; N, 41.55. Found: C, 53.46; H, 4.94; N, 41.84.

Example 69

6- (6-chloro-3-pyridinyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, methyl (6-chlomicotinate) and imidodicarbonimide diamide (2B) were treated according to the procedure of Example 2C.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 223, 225 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 9.17 (d, 1H), 8.46 (dd, 1H, J = 11), 7.62 (d, 1H), 6.91 (br s, 4H);

Calcd for C 8 H 11 ClNg. C, 43.15; H, 3.16; N, 37.74. Found: C, 43.05; H, 3.08; N, 37.50.

Example 70

6- (5-bromo-3-pyridinyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 5-bromonicotinonitrile was treated according to the procedure of Example 1.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 267 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d ₆ ) δ 9.3 (d, 1H), 8.82 (d, 1H, J = 3 Hz), 8.62-8.64 (m, 1H) , 6.87.1 (br s, 1H);

Calcd for C & HyBrNe: C, 35.98; H, 2.64-, N, 31.47. Found: C, 35.89; H, 2.53; N, 31.22.

Example 71

6- (2,3-dihydro-2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, 6-cyano-2,3-dihydro-2,2,3,3-tetrafluoro-1,4-benzodioxane was treated according to the procedure of Example 1.

Mp 176-179 ° C;

MS (DCI / NH 3) m / e 275 (M + H) + ^. ;

Ή NMR (300 MHz, DMSO-d 6) δ 7.98 (d, 1H), 7.71 (d, 1H), 7.17 (dd, 1H), 7.16 (br s, 2H), 6 95 (br s, 2H); 3.85 (s, 3H);

Anal Calcd for C ₇ F4N5O2: C; 41.65, H; 2.22, N; 22.08. Found: C; 41.55, H; 2.10, N; 22.09.

Example 72

6- [4 - [(4-chlorophenyl) methoxy] phenyl] -1,3,5-triazine-2,4-diamine

4 - ((4-chlorophenyl) methoxy] benzonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp 246-248 ° C;

MS (DCI / NH 3) m / e 342 (M + H) ⁺ ;

Δ NMR (300 MHz, DMSO-d 6) δ 7.45 (s, 4H), 7.25 (d, 2H), 6.9 (d, 2H), 6.6 (br s, 4H), Δ (s, 2H), 3.55 (s, 2H);

Calcd for C17H16ClN5O: C, 59.74; H, 4.72; N, 20.49. Found: C, 59.64; H, 4.64; N, 20.49.

Example 73

6- (4- (1-piperidinylsulfonyl) phenyl) -1,3,5-triazine-2,4-diamine

Example 73A 1 - [(4-Cyanophenyl) sulfonyl] piperidine

A mixture of 4-cyanobenzenesulfonyl chloride (0.51 g, 2.5 mmol) and piperidine (0.60 mL, 517 mg, 6.04 mmol) in 10 mL of methylene chloride was stirred overnight at room temperature. The organic layer was washed sequentially with water, 5% HCl and brine, dried (Na 2 SO ₄ ) and concentrated.

The resulting white solid (0.61 g, 96%) was used without further purification.

Example 73B

6- [4- (1-piperidinylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine

The product of Example 73 A was treated as in Example 1 to obtain the desired compound.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 335 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.43 (d, 2H), 7.84 (d, 2H), 6.90 (bds, 4H), 2.90-2.97 (m, 4H) 1.50-1.59 (m, 4H), 1.32-1.42 (m, 2H);

Calcd for C14H18N6O2S: C, 50.28; H, 5.42; N, 25.13. Found: C, 50.43; H, 5.32; N, 25.12.

Example 74

6- (1-benzoyl-4-piperidinyl) -1,3,5-triazine-2,4-diamine

Example 74A

-benzoyl-4-piperidinecarbonitrile

A mixture of 1-benzoyl-4-piperidone (2.0 g, 9.8 mmol), tosylmethylisocyanide (2.5 g, 12.8 mmol) and ethanol (1.0 mL, 17.1 mmol) in 30 mL of DME was added. is cooled in an ethanol / ice water bath and tert-butoxide is added in an amount to maintain a temperature of <10 ° C. Remove the ice bath and stir the reaction at room temperature overnight. The solids were removed by filtration, rinsed with DME, and the filtrate was evaporated. The residue was dissolved in EtOAc, washed with water and brine, dried (MgSO ₄ ), filtered through a silica gel column and concentrated to give 2.14 g (66%) of a slightly yellow oil.

• v «·

Example 74B

6- (1-benzoyl-4-piperidinyl) -1,3,5-triazine-2,4-diamine

To obtain the desired compound, the product of Example 74A was treated as in Example 1.

Mp 246-248 ° C;

MS (DCI / NH 3) ml 299 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 7.43-7.49 (m, 3H), 7.33-7.39 (m, 2H), 6.58 (bds, 4H), 4,444.52 (bm, 1H), 3.55-3.67 (bm, 1H), 2.79-3.27 (bm, 2H), 1.53-1.94 (bm, 5H);

Calcd for C 18 H 18 N 6 O: C, 60.38; H, 6.08; N, 28.16. Found: C, 60.09; H, 6.02; N, 28.29.

Example 75

6- [1- (phenylmethyl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine

A-Benzyl-4-piperidone was treated according to the procedure of Examples 74A and 74B to obtain the desired compound.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 285 (M + H) ⁺ ;

¹ H NMR (300 MHz, DMSO- d 6) δ 7.19-7.32 (m, 5H), 6.50 (bds, 4H), 3.44 (s, 2H), 2.78-2.86 (m, 2H), 2.16-2.28 (m, 1H), 1.90-1.99 (m, 2H), 1.63-1.76 (m, 4H);

Calcd for C18H20N6 * H2O: C, 59.58; H, 7.33; N, 27.79. Detected. C, 60.06; H, 7.19; N, 27.94.

Example 76

N, N-diacetyl-6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine

6- [4- (Phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (Example 58) was treated according to the procedure of Example 33B to obtain the desired compound.

Mp > 260 ° C;

MS (DCI / NH 3) m / e 412 (M + H) ⁺ ;

1 H NMR (300 MHz, DMSO-d 6) δ 8.52 (d, 2H, J = 8Hz), 8.18 (d, 2H, J = 8Hz), 8.01 (m, 2H), 7 73 (m, 1H), 7.68 (m, 2H), 2.37 (s, 6H);

c *

Calcd for C19H17N5O4: C, 55.47; H, 4.16; N, 17.02. Found: C, 55.47; H,

4.19; N, 17.11.

·· ····

Example 77

A-acetyl-6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine

6- [4- (Phenylsulfonyl) phenyl] 1,3,5-triazine-2,4-diamine (Example 58) was treated according to the procedure of Example 34 to obtain the desired compound.

Mp > 260 ° C;

MS (DCI / NH ₃ ) m / e 370 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 8.5 1 (d, 2H), 8.27 (d, 2H), 8.06 (d, 2H), 7.78 (t, 1H), 7 68 (t, 2H); 2.56 (s, 3H);

Calcd for C 11 H 15 N 5 O 4 O 4 H 2 O: C, 53.96; H, 4.26; N, 18.51. Found: C, 53.75; H, 3.91; N, 18.83.

Example 78

6- [2- (1-piperidinyl) phenyl] -1,3,5-triazine-2,4-diamine

2- (1-piperidinyl) benzonitrile was treated according to the procedure of Example 1 to obtain the desired compound.

Mp > 250 ° C;

MS (DCI / NH ₃ ) m / e 271 (M + H) ^&lt; ^{+ &gt};;

1 H NMR (300 MHz, DMSO-d 6) δ 7.27 (d, 2H), 6.93 (d, 2H), 6.89 (m, 1H), 6.63 (bds, 4H), 3, 88 (m, 4H), 1.47 (bdm, 6H);

Calcd for C14H18N6: C; 62.20, H; 6.71, N; 31.09. Found: C; 61.88, H; 6.36, N; 31.37.

Claims (30)

PATENT CLAIMS 1. Compounds having formula (I): NR ¹ R ² R ³ R ⁴ NNA Or a pharmaceutically acceptable salt or prodrug thereof, wherein R ¹ , R ² , R ³ and R ⁴ are independently selected from the group consisting of hydrogen, C 1 -C 20 alkyl and C 1 -C 20 alkanoyl; or R and R, taken together with the nitrogen to which they are attached, form a ring independently selected from the group consisting of morpholine, piperidine, piperazine and pyrrolidine; or R ³ and R ^4, taken together with the nitrogen to which they are attached, form a ring independently selected from the group consisting of morpholine, piperidine, piperazine, and pyrrolidine; A is selected from the group consisting of heterocycle, (heterocycle) -C 1 -C 20 -alkyl, C 3 -C 10 cycloalkyl, C ₆ -C ₁₅ spiroalkyl, and -BLY; B and Y are independently aryl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, heterocycle or C 8 -C 8 spiroalkyl; L is a covalent bond, -C (= W) -, C 1 -C ₂ alkylene, -NR ⁵ -, -NR ⁶ C (X) NR ⁷ -, C ₂ -C ₂₀ alkynylene, C ₂ -C 20. alkenylene, -0-, -S (0) R, -NR ⁶ C (X) -, -C (X) NR ^6, NR ⁶ SO 2 NR ⁷ -, -NR ⁶ SO ₂ -, -SO ₂ NR 6 or - CXCRV); R ⁵ is hydrogen, C 1 -C 20 alkyl, C 1 -C 20 alkanoyl and C 1 -C 20 arylalkyl; R ⁶ and R ⁷ are independently hydrogen, C 1 -C 20 alkyl and aryl-C 1 -C 20 -alkyl; R ¹ and R ² are as defined above; W is O, S or (= NOR ⁶ ); X is O or S; index t is 0-2; Each L is indicated with its left end attached to B and its right end attached to Y; and at each occurrence, aryl, cycloalkyl, cycloalkenyl, heterocycle, spiroalkyl, alkylene and (heterocyclic) alkyl may be optionally substituted with 1-3 substituents independently selected from the group consisting of C 1 -C ₂ alkoxy, C 1 -C ₂ alkyl, amino , aryl, azido, cyano, halo, C ₂ ohalogenalkylu, heterocycle, nitro, or the substituents R ¹⁰ and R ^11, wherein R ¹⁰ and R ¹¹ together (CH _{2) n} generate wherein a and D are independently oxygen or S (O) _t and the index n is 2-3, with the proviso that if B and Y are unsubstituted phenyl and L is a covalent bond, then at least one of R ¹ , R ² , R ³ and R ⁴ is other than hydrogen and with the proviso that if L is a covalent bond and one of B or Y is unsubstituted imidazole and the other is unsubstituted phenyl, then at least one of R ¹ , R ² , R ³ and R ⁴ is other than hydrogen. 2. A compound selected from the group consisting of: 6- [1- (diphenylmethyl) -3-azetidinyl] -1,3,5-triazine-2,4-diamine, 6- (1-phenyl-4-piperidinyl) -1,3,5-triazine-2, 4-diamine, trans-6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine, 6- [3- (1H-pyrrol-1-yl) phenyl] -1,3,5-triazine-2,4-diamine, cis / trans-6- (3-phenylcyclobutyl) -1,3,5- triazine-2,4-diamine, 6- [1,1'-Biphenyl] -2-yl-1,3,5-triazine-2,4-diamine, 6- (4'-nitro [1,1'-biphenyl] -4-yl) -1 , 3,5-triazine-2,4-diamine, 6- [4- (4-pentylcyclohexyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- (4-phenoxyphenyl) -1,3,5-triazine-2,4-diamine, N-cyclohexyl-N '- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] urea, (4,6-diamino-1,3,5-triazine-2- yl) phenylmethenone, N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] -N'-phenyl urea, 6- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) -1,3,5-triazine-2,4-diamine 6- (4'-Pentyl [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4 '- (pentyloxy) [1,1-biphenyl] -4-yl] -1,3,5-triazine-2,4-diamine, 6- (6-methoxy-2-benzothiazolyl) -1,3,5-triazine-2,4-diamine, 6- (4'-amino [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (5-oxazolyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- [4 - [[5- (trifluoromethyl) -2-pyridinyl] oxy] phenyl] -1,3,5-triazine-2,4-diamine, 4 '- (4,6-diamino-1,3, 5-triazin-2-yl) [1,1'-biphenyl] -4-carbonitrile, 6- (4'-methoxy [1,1'-biphenyl] -4-yl) -1,3,5-triazin-2 6- (4'-fluoro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine N - [4- (4,6-diamino) -1,3,5-triazin-2-yl) phenyl] benzenesulfonamide 6- [1 - ([1,1'-biphenyl] -4-yl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine, N- [4- (4,6-diamino) -1,3,5-triazin-2-yl) phenyl] -2-naphthalenesulfonamide 2,5-dichloro-N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] benzenesulfonamide, 6- (1-phenylcyclohexyl) -1,3,5-triazine -2,4-diamine, 6- [1- (4-methoxyphenyl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine, 6- (2- [4- (trifluoromethyl) phenyl] -4-thiazolyl] -1,3,5-triazine-2,4-diamine, 6- [1- (4-methoxyphenyl) cyclohexyl] -1,3,5-triazine-2,4-diamine, 6- [4- (2-thienyl) phenyl] -1,3,5-triazine-2, 4-diamine, 6- [4- (phenylethynyl) phenyl] -1,3,5-triazine-2,4-diamine, N, N - (6- [1,1'-biphenyl] -4-yl-1,3,5-triazine-2,4-diyl) bis [acetamide], N - (4-amino-6- [1] 1,1-biphenyl] -4-yl-1,3,5-triazin-2-yl) acetamide, N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] 1-naphthalenesulfonamide, 6- (4'-azido [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (4-morpholinylsulfonyl)] phenyl] -1,3,5-triazine-2,4-diamine, 6- [4- (2-furanyl) phenyl] -1,3,5-triazine-2,4-diamine, A, A- [6] - (4-phenoxyphenyl) -1,3,5-triazine-2,4-diyl] bis [acetamide], N- [4-amino-6- (4-phenoxyphenyl) -1,3,5-triazine-2] -yl] acetamide, 6- (5-phenyl-2-furanyl) -1,3,5-triazine-2,4-diamine, 6- (5-phenyl-2-thienyl) -1,3,5-triazine-2,4-diamine, N, N - [6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diyl] bis [acetamide], N - [4-amino-6- (4-phenylcyclohexyl) -1,3] 5-triazin-2-yl] acetamide 6- (4-phenyl-1-naphthalenyl) -1,3,5-triazine-2,4-diamine, 6- [4- (phenylthio) phenyl] -1,3,5-triazine-2,4-diamine, 6- (2-quinolinyl) -1,3,5-triazine-2,4-diamine, ··· ·········· · · · · · · · · · · · · · · · · · · · 6- (3-quinolinyl) -1,3,5-triazine-2,4-diamine, 6- (benzo [b] thien-2-ylmethyl) -1,3,5-triazine-2,4-diamine, 6- (2,2-dimethyl-2H-1-benzopyran-6-yl) -1,3,5-triazine-2,4-diamine, 6- (1-isoquinolinyl) -1,3,5-triazine-2,4-diamine, (6- (2,3-dihydro-1,4-benzodioxin-2-yl) -1,3,5- triazine-2,4-diamine, 6- (tricyclo [3.3.1.1 ^3,7 ] decan-1-yl) -1,3,5-triazine-2,4-diamine, (+/-) -4- (4,6- diamino-1,3,5-triazin-2-yl) -α-phenylbenzenemethanol, 6- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine, 6- (1-azabicyclo [2.2.2] octan-4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (phenylsulfinyl) phenyl] 1,3,5-triazine-2,4-diamine, 6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] phenylmethanone , oxime, 6-pyrazinyl-1,3,5-triazine-2,4-diamine, 2,4-diamino-6 - [(4-phenylethenyl) phenyl] -1,3,5-triazine, 2,4-diamino-6 - [(4- (2-nitrophenyl) ethenyl) phenyl] -1,3,5-triazine, 6- [1,1'-biphenyl] -4-yl- N, N-dimethyl-1,3,5-triazine-2,4-diamine, 6- [1,1'-biphenyl] -4-yl-N-methyl-1,3,5-triazine-2,4-diamine, 6- (bicyclo [2.2.1] hept-2-yl) -1,3,5-triazine-2,4-diamine, 6- [1,1'-biphenyl] -4-yl-N (N-diethyl-1,3,5-triazine-2,4-diamine), 6- (2'-nitro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- (6-methyl-3-pyridinyl) -1,3,5-triazine-2,4-diamine, 6- (6-chloro-3-pyridinyl) -1,3,5-triazine-2,4-diamine, 6- (5-bromo-3-pyridinyl) -1,3,5-triazine-2,4-diamine, 6- (2,3-dihydro-2,2,3,3-tetrafluoro-1,4-benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine, 6- [4 - [(4-chlorophenyl) methoxy] phenyl] -1,3,5-triazine-2,4-diamine, 6- [4- (1-piperidinylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- (1-benzoyl-4-piperidinyl) -1,3,5-triazine-2,4-diamine, 6- [1- (phenylmethyl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine, N, N-diacetyl-6- [4- (phenylsulfonyl) phenyl] -1,3 5-triazine-2,4-diamine, N-acetyl-6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, and 6- (2-Piperidin-1-yl-phenyl) -1,3,5-triazine-2,4-diamine. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ·· · ·· · 63 The compound of claim 1, wherein R ¹ , R ² , R ³ and R ⁴ are hydrogen. A compound according to claim 3, wherein A is heterocycle, (heterocycle) -C 1 -C 20 -alkyl, C 3 -C 2 cycloalkyl and C 6 -C 18 spiroalkyl, wherein the heterocycle, (heterocycle) -C 1 -C 20 alkyl, cycloalkyl, (heterocycle) alkyl and spiroalkyl may be optionally substituted. A compound according to claim 4 selected from the group consisting of: 6- (1,4-dioxa-8-azaspiro [4,5] dec-8-yl) -1,3,5-triazine-2,4-diamine, 6- (2-quinolinyl) -1,3,5-triazine-2,4-diamine, 6- (3-quinolinyl) -1,3,5-triazine-2,4-diamine, 6- (benzo [b] thien-2-ylmethyl) -1,3,5-triazine-2,4-diamine, 6- (2,2-dimethyl-2H-1-benzopyran-6-yl) -1,3,5-triazine-2,4-diamine, 6- (2,3-dihydro-1,4-benzodioxin-2-yl) -1,3,5-triazine-2,4-diamine, 6- (tricyclo [3.3.1.1 ^3,7 ] decan-1-yl) -1,3,5-triazine-2,4-diamine, 6- (1-isoquinolinyl) -1,3,5-triazine-2,4-diamine, 6- (2,3-dihydro-1,4-benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine, 6- (1-azabicyclo [2.2.2] octan-4-yl) -1,3,5-triazine-2,4-diamine, 6-pyrazinyl-1,3,5-triazine-2,4-diamine, 6- (6-methoxy-2-benzothiazolyl) -1,3,5-triazine-2,4-diamine; 6- (5-bromo-3-pyridinyl) -1,3,5-triazine-2,4- diamine, 6- (6-chloro-3-pyridinyl) -1,3,5-triazine-2,4-diamine, 6- (2,3-dihydro-2,2,3,3-tetrafluoro-1,4) -benzodioxin-6-yl) -1,3,5-triazine-2,4-diamine a 6- (6-methyl-3-pyridinyl) -1,3,5-triazine-2,4-diamine. A compound according to claim 3 wherein A is -BLY or C 3 -C 10 -cycloalkyl, B and Y are independently aryl, C 3 -C 10 cycloalkyl, C 4 -C 10 cycloalkenyl, C 6 -C 15 spiroalkyl or heterocycle and aryl, cycloalkyl, cycloalkenyl, spiroalkyl or heterocycle may be optionally substituted. The compound of claim 6, wherein L is a covalent bond or alkylene. A compound according to claim 7 selected from the group consisting of: 6- [1- (diphenylmethyl) -3-azetidinyl] -1,3,5-triazine-2,4-diamine, 6- (1-phenyl-4-piperidinyl) ) -1,3,5-triazine-2,4-diamine, trans-6- (4-phenylcyclohexyl) -1,3,5-triazine-2,4-diamine, 6- [3- (1H-pyrrol-1-yl) phenyl] -1,3,5-triazine-2,4-diamine, cis / trans-6- (3-phenylcyclobutyl) -1,3,5- triazine-2,4-diamine, 6- [1,1'-biphenyl] -2-yl-1,3,5-triazine-2,4-diamine, 6- (4'-nitro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (4-pentylcyclohexyl) phenyl] -1, 3,5-triazine-2,4-diamine, 6- (4'-pentyl [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6 - [ 4 '- (pentyloxy) [1,1'-biphenyl] -4-yl] -1,3,5-triazine-2,4-diamine, 6- (4'-amino [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (5-oxazolyl) phenyl] -1,3,5-triazine-2,4-diamine, 4 '- (4,6-diamino-1,3,5-triazin-2-yl) [1,1'-biphenyl] -4-carbonitrile, 6- (4'-methoxy [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- (4'-fluoro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [1 - ([1,1'-biphenyl] -4-yl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine, 6- (1-Phenylcyclohexyl) -1,3,5-triazine-2,4-diamine, 6- [1- (4-methoxyphenyl) -4-piperidinyl] -1,3,5-triazine-2,4- diamine, 6- [2- [4- (trifluoromethyl) phenyl] -4-thiazolyl] -1,3,5-triazine-2,4-diamine, 6- [1- (4-methoxyphenyl) cyclohexyl] -1, 3,5-triazine-2,4-diamine, 6- [4- (2-thienyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- (4'-Azido [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine, 6- [4- (2-furanyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- (5-phenyl-2-furanyl) -1,3,5-triazine-2,4 -diamin, 6- (5-phenyl-2-thienyl) -1,3,5-triazine-2,4-diamine, 6- (4-phenyl-1-naphthalenyl) -1,3,5-triazine-2,4-diamine, 6- (bicyclo [2.2.1] hept-2-yl) -1,3,5-triazine-2,4-diamine, 6- (2-Piperidin-1-ylphenyl) -1,3,5-triazine-2,4-diamine, <RTIgt; · · · · 6- [1- (phenylmethyl) -4-piperidinyl] -1,3,5-triazine-2,4-diamine a 6- (2'-Nitro [1,1'-biphenyl] -4-yl) -1,3,5-triazine-2,4-diamine. The compound of claim 6, wherein L is -O- or -O (CR 1 R ² ) -, wherein R ¹ and R ² are as defined above. A compound according to claim 9 selected from the group consisting of: 6- (4-phenoxyphenyl) -1,3,5-triazine-2,4-diamine, 6- [4 - [[5- (trifluoromethyl) -2-pyridinyl] oxy] phenyl] -1,3,5-triazine-2,4-diamine and 6- [4 - [(4-chlorophenyl) methoxy] phenyl -1,3,5-Triazine-2,4-diamine. The compound of claim 6, wherein L is -NR ⁶ SO ^{2 -} and R ⁶ is hydrogen. A compound according to claim 11 selected from the group consisting of: A- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl) benzenesulfonamide, A- [4- (4, 6- diamino-1,3,5-triazin-2-yl) phenyl) -2-naphthalenesulfonamide, 2,5-dichloro-N- [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] benzenesulfonamide and N- [4- (4,6-diamino-1,3, 5-triazin-2-yl) phenyl] -1-naphthalenesulfonamide. The compound of claim 6, wherein L is -NR ⁶ C (X) NR ⁷ -, X is O, and R ⁶ and R ⁷ are hydrogen. A compound according to claim 13 selected from the group consisting of: N-cyclohexyl-N - [4- (4,6-diamino-1,3,5-triazin-2-yl) phenyl] urea and N - [4- ( 4,6-diamino-1,3,5-triazin-2-yl) phenyl] -N-phenylurea. • · The compound of claim 6, wherein L is C 2 -C 20 alkynylene. A compound according to claim 15 having the formula 6- [4- (phenylethynyl) phenyl] -1,3,5-triazine-2,4 diamine. The compound of claim 6, wherein L is C ₂ -C ₂ oalkenylene. A compound according to claim 17 selected from the group consisting of: (E) -2,4-diamino-6- [4- (2- (4-nitrophenyl) ethenyl) phenyl] -1,3,5-triazine and (E) ) -2,4-diamino-6- [4- (2-phenylethenyl) phenyl] -1,3,5-triazine. The compound of claim 6, wherein L is -S (O) _t - and the index t is 0-2. A compound according to claim 19 selected from the group consisting of: 6- [4- (4-morpholinylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- [4- (phenylthio) phenyl] - 1,3,5-triazine-2,4-diamine, 6- [4- (phenylsulfinyl) phenyl] -1,3,5-triazine-2,4-diamine, 6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine and 6- [4- (1-piperidinylsulfonyl) phenyl] -1,3,5-triazine-2,4- diamine. The compound of claim 6, wherein L is -C (W) - and W is (= O), (= S) or (= N-OR ⁶ ). A compound according to claim 21 selected from the group consisting of: (E / Z) -2,4-diamino-6 - [(4-benzoyl) phenyl] -1,3,5-triazine oxime, (4,6-diamino) -1,3,5-triazin-2-yl) phenylmethenone 4 4 4 4 4 4 • 44 44> 4 4 (+/-) -4- (4,6-diamino-1,3,5-triazin-2-yl) -α-phenylbenzenemethanol and 6- (1-benzoyl) -4-piperidinyl) -1,3,5-triazine-2,4-diamine. The compound of claim 1, wherein R ¹ , R ² , R ³ and R ⁴ are independently hydrogen, C 1 -C 20 alkyl or C 1 -C 20 alkanoyl. The compound of claim 23, wherein A is -BLY, B and Y are independently aryl, C ₃ -C ₁₀ cycloalkyl, C ₄ -C ₁₀ cycloalkenyl, C 6 -C 18 spiroalkyl or heterocycle, and the aryl, cycloalkyl, cycloalkenyl, spiroalkyl or heterocycle may be optionally substituted . The compound of claim 24, wherein L is a covalent bond. A compound according to claim 25 selected from the group consisting of: N, N- (6- [1,1'-biphenyl] -4-yl-1,3,5-triazine-2,4-diyl) bis [acetamide] N, N- (4-amino-6- [1,1-biphenyl] -4-yl-1,3,5-triazin-2-yl) acetamide, N, N - [6- (4-phenylcyclohexyl)] - -1,3,5-triazin-2,4-diyl] bis [acetamide], N- [4-amino-6- (4-phenylcyclohexyl) -1,3,5-triazin-2-yl] acetamide , 6- [1,1'-biphenyl] -4-yl-N, N-diethyl-1,3,5-triazine-2,4-diamine, 6- [1,1'-biphenyl] -4-yl-N, N-dimethyl-1,3,5-triazine-2,4-diamine, 6- [1,1'-biphenyl] -4-yl-Y-methyl-1,3,5-triazine-2,4-diamine, N, N -diacetyl-6- [4- (phenylsulfonyl) phenyl] -1,3,5-triazine-2,4-diamine and N-acetyl-6- [4- (phenylsulfonyl) phenyl] -1,3, 5-triazine-2,4-diamine. The compound of claim 23, wherein L is -O-. The compound of claim 27 selected from the group consisting of: N, N - [6- (4-Phenoxyphenyl) -1,3,5-triazine-2,4-diyl] bis [acetamide] and N - [4-amino-6- (4-phenoxyphenyl) -1] 3,5-triazin-2-yl] acetamide. 29. A method of ameliorating an angiogenic disease, comprising administering a compound of claim 1. 30. The method of claim 29, wherein the disease is selected from the group consisting of cancer, diabetic retinopathy, and macular degeneration.