KR20080013026A - Inhibitors of glycogen synthase kinase 3 - Google Patents

Abstract

New pyrimidine or pyridine based compounds, compositions and methods of inhibiting the activity of glycogen synthase kinase (GSK3) in vitro and of treatment of GSK3 mediated disorders in vivo are provided. The methods, compounds and compositions of the invention may be employed alone, or in combination with other pharmacologically active agents in the treatment of disorders mediated by GSK3 activity, such as diabetes, Alzheimer's disease and other neurodegenerative disorders, obesity, atherosclerotic cardiovascular disease, essential hypertension, polycystic ovary syndrome, syndrome X, ischemia, traumatic brain injury, bipolar disorder, immunodeficiency or cancer.

Description

Inhibitor of glycogen synthase kinase 3 {INHIBITORS OF GLYCOGEN SYNTHASE KINASE 3}

The present invention relates to novel pyrimidine and pyridine derivatives that inhibit the activity of glycogen synthase kinase 3: GSK3, pharmaceutical compositions containing the compounds, and the compounds and compositions alone or in combination with other agents. It relates to a method of use with a pharmaceutical active. The compounds and compositions provided by the present invention are useful for treating diseases mediated by GSK3 activity such as diabetes, Alzheimer's disease and other degenerative neurological diseases, obesity, atherosclerosis cardiovascular disease, idiopathic hypertension, polycystic ovary syndrome, syndrome X, ischemia, It is particularly useful for the treatment of cerebral ischemia, traumatic brain injury, bipolar disorder, immunodeficiency and cancer.

Glycogen synthase kinase 3 (GSK3) is a serine / creonine kinase with two isoforms α and β identified . See Woodgett, Trends Biochem. Sci. , 16 : 177-81 (1991). Both GSK3 isoforms are structurally active in resting cells. GSK3 is originally known as a kinase that inhibits glycogen synthase by direct phosphorylation. Upon insulin activation, GSK3 is inactive, activating possible other insulin-dependent phenomena such as glycogen synthase and glucose transport. As a result, GSK3 activity is also known to be inactivated by other growth factors that signal through receptor tyrosine kinases (RTKs), such as insulin. Examples of such signal molecules include IGF-1 and EGF. See Saito et al., Biochem . J., 303 : 27-31 (1994); Welsh et al., Biochem. J. , 294 : 625-29 (1993); and cross et al., Biochem. J. , 303 : 2126 (1994)].

Inhibitors of GSK3 activity are useful for the treatment of diseases mediated by GSK3 activity. In addition, the process of inhibition of GSK3 is similar to that of the growth factor signaling pathway, such that GSK3 inhibitors are useful for the treatment of diseases in which the pathway is insufficiently activated. Examples of diseases that can be treated with GSK3 inhibitors are described below.

diabetes

Diabetes mellitus is a serious metabolic disease (hyperglycemia) defined by the presence of chronically elevated levels of blood sugar. Such hyperglycemia is a result of the relative or absolute lack of peptide hormones, insulin. Insulin is produced and secreted by the β cells of the pancreas. Insulin has been reported to promote the use of glucose, protein synthesis, and the formation and storage of carbohydrate energy as glycogen. Glucose is stored in the body as glycogen in the form of polymerized glucose, which is converted back into glucose to meet metabolic requirements. Under normal conditions, insulin is secreted at both base and increased rates after glucose stimulation, maintaining metabolic homeostasis by the conversion of glucose to glycogen.

As used herein, the term diabetes mellitus is to encompass a variety of different hyperglycemic states. This includes type 1 diabetes (insulin-dependent diabetes mellitus (IDDM) and type 2 diabetes (non-insulin dependent diabetes mellitus (NIDDM)). Hyperglycemia present in an individual is associated with a deficiency level, a decrease level, or the absence of insulin, which is insufficient to maintain blood sugar levels within the physiological range.Usually, type 1 diabetes is generally an alternative dose of insulin by a genetic method. GSK3 inhibition stimulates insulin dependent phenomena, and consequently is useful for the treatment of type 1 diabetes.

Type 2 diabetes is a growing middle-aged disease. Type 2 is initially characterized by a decrease in sensitivity to insulin and an increased compensation of circulating insulin concentrations, the latter being necessary to maintain normal blood glucose levels. Increased insulin levels are achieved by increased secretion from pancreatic beta cells, and the resulting hyperinsulin is associated with cardiovascular complications of diabetes. As insulin resistance worsens, the demand for pancreatic beta cells continues to increase until the pancreas can no longer provide sufficient levels of insulin, resulting in an increase in glucose levels in the blood. Ultimately, hyperglycemia and hyperlipidemia occur, leading to long-term, fatal complications associated with diabetes, including cardiovascular disease, kidney failure and color blindness. The exact mechanisms that cause type 2 diabetes are unknown, but glucose transport into skeletal muscle is reduced, glucose production in the liver is increased, and insulin response is insufficient. Since dietary changes are often ineffective, most patients ultimately require drug administration to prevent and / or slow the progression of these complications. Most patients can be treated with one or more available oral antidiabetics, including sulfonylureas, to increase insulin secretion. Examples of sulfonylurea drugs include meformin, troglitazone, and insulin sensitizing drugs that inhibit glucose production in the liver. Despite the use of such agents, 30-40% of diabetic patients are not fully treated with these drugs and require subcutaneous insulin injections. In addition, each of these treatments has associated side effects. For example, sulfonylureas can cause hypoglycemia and troglitazone can cause severe hepatotoxicity. Thus, there is a need for new and improved drugs for the treatment of prediabetics and diabetics.

As mentioned above, GSK3 inhibition stimulates insulin dependency and consequently is useful for the treatment of type 2 diabetes. Recent data obtained using lithium salts provide evidence for this view. Lithium ions have recently been reported to inhibit GSK3 activity (Klein et al., PNAS 93 : 8455-9 (1996)). Since 1924, lithium has included the ability to reduce plasma glucose levels, increase glycogen uptake, increase insulin potency, upregulate glucose synthesis activity, and stimulate glycogen synthesis in skin, muscle and fat cells. It has been reported to have an antidiabetic effect. However, lithium is not widely accepted for use in the inhibition of GSK3 activity due to the possibility of demonstrated effects on GSK3 and other target molecules. The purine analogue 5-uredotuversidin is also a GSK3 inhibitor, which similarly stimulates glycogen synthesis and counteracts the inactivation of glycogen synthesis by glucagon and vasopressin in rat liver cells [Fluckiger-Isler et al., Biochem J 292 : 85-91 (1993); and Massillon et al., Biochem J 299 : 123-8 (1994). However, this compound is also known to inhibit other serine / threonine and tyrosine kinases (Massillon et al., Biochem J 299 : 123-8 (1994)).

One of the main goals in the management of patients with diabetes mellitus is to achieve blood glucose levels as close to normal as possible. In general, obtaining normal postprandial blood sugar levels is more difficult than normalizing hyperglycemia in a single fast. In addition, some epidemiological studies have suggested that postprandial hyperglycemia (PPHG) or hyperinsulin is an independent risk factor for the development of macrovascular complications of diabetes. Recently, several drugs with different pharmacokinetic profiles for the purpose of PPHG have been developed. These drugs include insulin lispro, amylin analogues, alpha-glucosidase inhibitors and meglitinide analogues. Insulin lispro has a faster onset and shorter duration of efficacy compared to normal human insulin. In clinical trials, the use of insulin lispro has been associated with improved control of PPHG and reduced incidence of hypoglycemic symptoms. Repaglinide, meglitinide analogs are short acting insulin stimulants that, when given before meals, stimulate endogenous insulin secretion and reduce postprandial hyperglycemia. Insulin lispro and repaglinide are associated with postprandial hyperinsulin. In contrast, amylin analogs reduce PPHG by slowly emptying the stomach and transporting nutrients to the absorbing surface of the intestines. Alpha glucosidase inhibitors, such as acarbose, miglitol and bogglibose, also reduce PPHG, primarily by interfering with carbohydrate digestive enzymes and delaying the absorption of glocose [Ref. Yamasaki et al., Tohoku J Exp Med 1997 Nov; 183 (3): 173-83]. GSK inhibitors of the invention are also useful for the treatment of fasting hyperglycemia and for the treatment of postprandial hyperglycemia, either alone or in combination with the agents set forth above.

Alzheimer's disease

GSK3 is also associated with biological pathways associated with Alzheimer's disease (AD). The pathological feature of AD consists of extracellular plaques of amyloid precursor protein (APP) in an abnormally processed form called β-amyloid peptide (β-AP) and mainly of hyperphosphorylated tau (tau) protein. Development of intracellular nerve fiber entanglement containing paired helical filaments (PHF). GSK3 is one of numerous kinases that have been found to phosphorylate tau protein in vitro for abnormal site properties of PHF tau and is the only kinase that has been demonstrated to do this in living cells and animals [Ref. Lovestone et al., C urrent Biology 4 : 1077-86 (1994); And Brownlees et al., Neuroreport 8 : 3251-3255 (1997). In addition, the GSK3 kinase inhibitor LiCl blocks tau hyperphosphorylation in cells (Stambolic et al., C urrent Biology 6 : 1664-8 (1996)). As such, GSK3 activity may contribute to the production of nerve fiber entanglement and consequently Alzheimer's disease progression. Recently GSK3β has been known to be associated with presenillin 1 (PS1), another important protein in AD etiology (Takashima et., PNAS 95 : 9637-9641 (1998)). Although mutations in the PS1 gene increase the production of β-AP, the authors also explained that PS1 variant proteins bind more tightly to GSK3β, enabling phosphorylation of tau that binds to the same region of PS1.

Interestingly, it is also known that another GSK3 substrate, β-catenin, binds to PS1 (Zhong et al., Nature 395 : 698-702 (1998)). Cytoplasmic β-catenin is aimed at degradation upon phosphorylation by GSK3, and reduced β-catenin activity is associated with increased sensitivity of neurons to β-AP induced neuronal cell death. As a result, the increased relationship between GSK3β and variant PS1 may account for diseases associated with decreased β-catenin levels and increased neuronal cell death observed in the brains of PS1 variant AD patients. Consistent with these observations, the infusion of GSK3 antisense (not sense) blocks the pathological effects of β-AP on neurons in vitro, and has been shown to delay the onset of cell death by 24 hours [Ref. Takashima et al. , PNAS 90 : 7789-93. (1993). In this study, intracellular GSK3 activity was doubled after this effect on cellular lethality (effects occurred within 3 to 6 hours after β-AP administration), indicating that genetic mechanisms could increase GSK3 activity. will be. Another evidence of the role of GSK3 on AD was provided by the observation that the protein expression level of GSK3 (but not specific activity in this case) is increased by 50% in the postsynaptosome supernatant of AD compared to normal brain tissue. Pei et al., J Neuropathol Exp 56 : 70-78 (1997). As such, certain inhibitors of GSK3 are likely to act to slow the progression of Alzheimer's disease.

Other central nervous system diseases

In addition to the effects of lithium described above, there have long been reports of the use of lithium to treat bipolar disorder (manic depression syndrome). Clinical response to lithium may reflect the involvement of GSK3 activity in the pathogenesis of bipolar disorder, in which case GSK3 inhibitors are associated with these indications. In this view, Valproate, another drug commonly used in the treatment of bipolar disorder, is also a GSK3 inhibitor (Chen et al., J. Neurochemistry 72 : 1327-1330 (1999)). One mechanism by which lithium and other GSK3 inhibitors may act to treat bipolar disorder is to increase the survival of the ideally high level of excitatory nerves induced by the neurotransmitter glutamate [Nonaka et al. , PNAS 95 : 2642-2647 (1998). Glutamate-induced neuronal excitability is also believed to be a major cause of neurodegeneration associated with acute injury such as cerebral ischemia, traumatic brain injury and bacterial infection. In addition, excessive glutamate signaling is chronic neurological disorder seen in diseases such as Alzheimer's disease, Huntington's chorea, Parkinson's disease, AIDS-related dementia, amyotrophic lateral sclerosis (AMS) and multiple sclerosis (MS). It is believed to be a factor of dexterity [References: Thomas, J. Am. Geriatr . Soc . 43 : 1279-89 (1995). As a result, GSK3 inhibitors are believed to be useful for the treatment of these and other degenerative neurological diseases.

Immune synergy

GSK3 phosphorylation transcription factor NF-AT and its promoters promote release from the nucleus, as opposed to the effects of calcineurin (Beals et al., Science 275 : 1930-33 (1997)). As such, GSK3 blocks early immune response gene activation via NF-AT, and GSK3 inhibitors may exhibit a tendency to allow or prolong activation of the immune response. Thus, GSK3 inhibitors are believed to extend the immunostimulatory effect and enhance the efficacy of certain cytokines, which may increase the potential efficacy of cytokines in tumor immunotherapy or indeed in general immunotherapy.

Other diseases

Lithium also has other biological effects. Lithium is a potential stimulator of hematopoiesis both in vivo and ex vivo (Hammond et al., Blood 55 : 26-28 (1980)). In dogs, lithium carbonate eliminated recurrent neutropenia and other normalized blood cell counts. Doukas et al. Exp Hematol 14 : 215-221 (1986)]. If this effect of lithium is mediated through inhibition of GSK3, GSK3 inhibitors can be applied more broadly.

Since inhibitors of GSK3 are useful for the treatment of various diseases, the identification of novel inhibitors of GSK3 is highly desirable.

Summary of the Invention

It has surprisingly been found that the activity of glycogen synthase kinase 3 (GSK3) can be inhibited in vivo or ex vivo by certain pyrimidine and pyridine-based derivatives. Accordingly, the present invention provides novel compounds, compositions and methods for inhibiting the activity of GSK3 in vitro and methods of treating GSK3 mediated diseases in vivo. In one aspect, the present invention provides novel compounds and pharmaceutically acceptable salts thereof having GSK3 inhibitory activity of formula

In the above formula,

W is optionally substituted carbon or nitrogen;

X and Y are independently selected from the group consisting of nitrogen, oxygen and optionally substituted carbon;

A is optionally substituted aryl or heteroaryl;

R ₁ , R ' ₁ , R ₂ , R' ₂ , R ₃ , R ' ₃ , R ₄ and R' ₄ are hydrogen, hydroxyl, optionally substituted lower alkyl, cyclolowalkyl, cyclic aminoalkyl, alkyl Independently selected from the group consisting of aminoalkyl, lower alkoxy, amino, alkylamino, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, aryl and heteroaryl, R ' ₁ , R ' ₂ , R' ₃ and R ' ₄ are independently selected from the group consisting of hydrogen and optionally substituted lower alkyl;

R ₅ and R ₇ are hydrogen, halo, optionally substituted lower alkyl, cycloalkyl, alkoxy, amino, aminoalkoxy, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heteroarylcarbonylamino, hetero Aralkylcarbonylamino, cycloimido, heterocycloimido, amidino, cycloamidino, heterocycloamidino, guanidinyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocycloalkyl, and arylsulfonami Independently selected from the group consisting of roads;

R ₆ is hydrogen, hydroxy, halo, carboxyl, nitro, amino, amido, amidino, imido, cyano, substituted or unsubstituted lower alkyl, lower alkoxy, alkylcarbonyl, arylcarbonyl, aralkyl Carbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, alkylaminocarbonyloxy, aryl Aminocarbonyloxy, formyl, lower alkylcarbonyl, lower alkoxycarbonyl, aminocarbonyl, aminoaryl, alkylsulfonyl, sulfonamido, aminoalkoxy, alkylamino, heteroarylamino, alkylcarbonylamino, alkylamino Carbonylamino, arylaminocarbonylamino, aralkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloamido, From the group consisting of cyclothioamido, cycloamidino, heterocycloamidino, cycloimido, heterocycloimido, guanidinyl, aryl, heteroaryl, heterocyclo, heterocycloalkyl, arylsulfonyl and arylsulfonamido Is selected.

Particularly preferred novel compounds of the present invention are provided as compounds of Formulas 4 and 5 and pharmaceutically acceptable salts thereof:

In the above formula,

X, R ₁ to R ₆ , and R ₈ to R ₁₄ are as described above and R ₁₇ is hydrogen, nitro, cyano, amino, alkyl, halo, haloloweralkyl, alkyloxycarbonyl, aminocarbonyl , Alkylsulfonyl and arylsulfonyl.

The methods, compounds and compositions of the present invention include diabetes, Alzheimer's disease and other degenerative neurological diseases, obesity, atherosclerosis cardiovascular disease, idiopathic hypertension, polycystic ovary syndrome, syndrome X, ischemia, especially cerebral ischemia, traumatic brain injury, bipolar disorder, It may be used alone or in combination with other pharmacologically active agents in the treatment of diseases mediated by GSK3 activity such as immunodeficiency and cancer.

In accordance with the present invention, compounds, compositions and methods are provided for inhibiting the activity of glycogen synthase kinase 3 (GSK3) in vivo or ex vivo. In one aspect, the present invention provides novel compounds and pharmaceutically acceptable salts thereof having GSK3 inhibitory activity of formula

(Formula 1)

In the above formula,

W is optionally substituted carbon or nitrogen;

X and Y are independently selected from the group consisting of nitrogen, oxygen and optionally substituted carbon;

A is optionally substituted aryl or heteroaryl;

R ₁ , R ' ₁ , R ₂ , R' ₂ , R ₃ , R ' ₃ , R ₄ and R' ₄ are hydrogen, hydroxyl, optionally substituted lower alkyl, cyclolowalkyl, cyclic aminoalkyl, alkyl Independently selected from the group consisting of aminoalkyl, lower alkoxy, amino, alkylamino, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, aryl and heteroaryl, R ' ₁ , R ' ₂ , R' ₃ and R ' ₄ are independently selected from the group consisting of hydrogen and optionally substituted lower alkyl;

R ₅ and R ₇ are hydrogen, halo, optionally substituted lower alkyl, cycloalkyl, alkoxy, amino, aminoalkoxy, alkylcarbonylamino, arylcarbonylamino, aralkylcarbonylamino, heteroarylcarbonylamino, hetero Aralkylcarbonylamino, cycloimido, heterocycloimido, amidino, cycloamidino, heterocycloamidino, guanidinyl, aryl, biaryl, heteroaryl, heterobiaryl, heterocycloalkyl, and arylsulfonami Independently selected from the group consisting of roads;

R ₆ is hydrogen, hydroxy, halo, carboxyl, nitro, amino, amido, amidino, imido, cyano, substituted or unsubstituted lower alkyl, lower alkoxy, alkylcarbonyl, arylcarbonyl, aralkyl Carbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylcarbonyloxy, arylcarbonyloxy, aralkylcarbonyloxy, heteroarylcarbonyloxy, heteroaralkylcarbonyloxy, alkylaminocarbonyloxy, aryl Aminocarbonyloxy, formyl, lower alkylcarbonyl, lower alkoxycarbonyl, aminocarbonyl, aminoaryl, alkylsulfonyl, sulfonamido, aminoalkoxy, alkylamino, heteroarylamino, alkylcarbonylamino, alkylamino Carbonylamino, arylaminocarbonylamino, aralkylcarbonylamino, heteroarylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, cycloamido, Group consisting of cyclothioamido, cycloamidino, heterocycloamidino, cycloimido, heterocycloimido, guanidinyl, aryl, heteroaryl, heterocyclo, heterocycloalkyl, arylsulfonyl and arylsulfonamido Is selected from.

In one preferred embodiment of the invention, at least one of X and Y is nitrogen. Representative compounds of this group include compounds wherein one of X and Y is nitrogen and the other of X and Y is oxygen or optionally substituted carbon. Preferably both X and Y are nitrogen.

Substituent A may be an aromatic ring having 3 to 10 carbon ring atoms and optionally one or more hetero ring atoms. Thus, in one embodiment, A can be an optionally substituted carbocyclic aryl. Alternatively, A is optionally substituted heteroaryl, such as substituted or unsubstituted pyridyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxdiazolyl, tetrazolyl, pyrazinyl, triazolyl, thio Phenyl, furanyl, quinolinyl, furinyl, naphthyl, benzothiazolyl, benzopyridyl and benzimidazolyl, which may be substituted with 1 to 3 substituents. Representative substituents are, for example, nitro, amino, cyano, halo, thioamido, amidino, oxamidino, alkoxyamidino, imdino, guanidino, sulfonamido, carboxyl, formyl, lower alkyl Halo lower alkyl, lower alkoxy, halo lower alkoxy, lower alkoxyalkyl, lower alkylamino lower alkoxy, lower alkylcarbonyl, lower aralkylcarbonyl, lower heteroaralkylcarbonyl, alkylthio, aminoalkyl and cyanoalkyl It may be independently selected from the group consisting of.

In a particularly preferred embodiment of the invention, A has the formula

In the above formula,

R ₈ and R ₉ are hydrogen, hydroxy, nitro, amino, cyano, halo, thioamido, amidino, oxamidino, alkoxyamidino, imdino, guanidinyl, sulfonamido, carboxyl, forform Mill, lower alkyl, amino lower alkyl, lower alkylamino lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, lower alkoxyalkyl, lower alkylamino lower alkoxy, lower alkylcarbonyl, lower aralkylcarbonyl, lower heteroaral Independently selected from the group consisting of kelccarbonyl, alkylthio, aryl and aralkyl. Most preferably, A is aminopyridyl, nitropyridyl, aminonitropyridyl, cyanopyridyl, cyanothiazolyl, aminocyanopyridyl, trifluoromethylpyridyl, methoxypyridyl, methoxynitro Pyridyl, methoxycyanopyridyl and nitrothiazolyl.

In another embodiment of the invention, at least one of R ₁ , R ' ₁ , R ₂ , R' ₂ , R ₃ , R ' ₃ , R ₄ and R' ₄ is hydrogen; Lower alkyl selected from the group consisting of halo lower alkyl, heterocycloaminoalkyl and lower alkylamino lower alkyl; Or lower alkylamino lower alkyl. Preferred embodiments of the invention are those in which R ₁ , R ' ₁ , R ₂ , R' ₂ , R ₃ , R ' ₃ and R ₄ are hydrogen and R' ₄ is hydrogen, methyl, ethyl, aminoethyl, dimethylaminoethyl And pyridyl ethyl, piperidinyl, pyrrolidinylethyl, piperazinylethyl and morpholinylethyl.

Other preferred compounds of the present invention include compounds of formula 1 selected from the group consisting of substituted and unsubstituted aryl, heteroaryl and biaryl, wherein at least one of R ₅ and R ₇ is substituted. In a preferred embodiment, at least one of R ₅ and R ₇ is a substituted or unsubstituted moiety of the formula:

Wherein R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ are hydrogen, nitro, amino, cyano, halo, thioamido, carboxyl, hydroxy, and optionally substituted lower alkyl, lower alkoxy, Halo lower alkyl, halo lower alkoxy, aminoalkyl, alkylamino, aminoalkylalkynyl, alkylaminoalkylalkynyl, alkylthio, alkylcarbonylamino, aralkylcarbonylamino, heteroaralkylcarbonylamino, arylcarbonylamino , Heteroarylcarbonylamino, aminocarbonyl, lower alkylaminocarbonyl, aminoaralkyl, loweralkylaminoalkyl, aryl, heteroaryl, cycloheteroalkyl, aralkyl, alkylcarbonyloxy, arylcarbonyloxy, aralkyl From the group consisting of carbonyloxy, arylcarbonyloxyalkyl, alkylcarbonyloxyalkyl, heteroarylcarbonyloxyalkyl, aralkylcarbonyloxyalkyl and heteroaralkylcarbonyloxyalkyl It is selected as a neutral. Particularly preferred compounds are those in which R ₁₀ , R ₁₁ , R ₁₃ and R ₁₄ are hydrogen and R ₁₂ is halo, lower alkyl, hydroxy, lower alkoxy, halolower alkyl, aminocarbonyl, alkylaminocarbonyl and cyano Compounds selected from; R ₁₁ , R ₁₃ and R ₁₄ are hydrogen, and R ₁₀ and R ₁₂ are selected from the group consisting of halo, lower alkyl, hydroxy, lower alkoxy, halo lower alkyl and cyano; R ₁₀ , R ₁₁ , R ₁₃ and R ₁₄ are hydrogen and R ₁₂ is heteroaryl; R ₁₀ , R ₁₁ , R ₁₃ and R ₁₄ are hydrogen and R ₁₂ is heterocycloalkyl; At least one of R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ is halo and the remainder is hydrogen. Preferably, at least one of R ₅ and R ₇ is dichlorophenyl, difluorophenyl, trifluoromethylphenyl, chlorofluorophenyl, bromochlorophenyl, ethylphenyl, methylchlorophenyl, imidazolylphenyl, cyanophenyl , Morpholinophenyl and cyanochlorophenyl.

In a preferred embodiment of the invention, R ₆ is alkyl, such as aralkyl, hydroxyalkyl, aminoalkyl, aminoaralkyl, carbonylaminoalkyl, alkylcarbonylaminoalkyl, arylcarbonylaminoalkyl, aralkylcarbonylamino Alkyl, aminoalkoxyalkyl and arylaminoalkyl; Substituted amino such as alkylamino, alkylcarbonylamino, alkoxycarbonylamino, arylalkylamino, arylcarbonylamino, alkylthiocarbonylamino, arylsulfonylamino, heteroarylamino, alkylcarbonylamino, arylcarbonyl Amino, heteroarylcarbonylamino, aralkylcarbonylamino, and heteroaralkylcarbonylamino; Or substituted carbonyl, such as substituted or unsubstituted aminocarbonyl, alkyloxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl and alkylaminoalkyloxycarbonyl. In other embodiments, R ₆ can be selected from the group consisting of amidino, guanidino, cycloimido, heterocycloimido, cycloamido, heterocycloamido, cyclothioamido and heterocyclolowalkyl . In another embodiment, R ₆ is aryl or heteroaryl, such as substituted or unsubstituted pyridyl, pyrimidinyl, piperazinyl, thiazolyl, indolyl, imidazolyl, oxdiazolyl, tetrazolyl, pyrazinyl, Triazolyl, thienyl, furanyl, quinolinyl, pyrroliopyridyl, benzothiazolyl, benzopyridyl, benzotriazolyl and benzimidazolyl. In other embodiments, R ₆ can be a monoketopipiperazinyl group having the structure:

Wherein R ₁₅ and R ₁₆ are hydrogen, lower alkyl, lower alkynyl, aryl, heteroaryl, aryl lower alkyl, lower alkyl aryl lower alkyl, halo lower alkyl, haloaryl lower alkyl, carbocyclic and heterocyclic Independently selected from the group consisting of; R ₈ may form a carbocyclic, heterocyclic or aryl ring with another R ₁₆ or R ₁₅ ; o is 1 to 6; In a representative embodiment of the invention according to this aspect, R ₁₅ is lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl or tertiary butyl, or R ₁₅ is R ₁₆ And together form a group having the structure:

Examples of preferred compounds of this group include 1- [2-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -4- ( 2,4-dichlorophenyl) -5-pyrimidinyl] -2-piperazinone, 1- [2-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-]-2- Pyridinyl} amino) ethyl] amino} -4- (2,4-dichlorophenyl) -5-pyrimidinyl] -4-ethyl-3-methyl-2-piperazinone, 1- [6-{[2 -({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -4- (2,4-dichlorophenyl) -3-pyridinyl] -4- Methyl-2-piperazinone, 1- [2-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -4- ( 2,4-dichlorophenyl) -5-pyrimidinyl] -4-methyl-2-piperazinone, 6-[(2-{[6- (2,4-dichlorophenyl) -5- (4-methyl -2-oxo-1-piperazinyl) -2-pyridinyl] amino} ethyl) amino] nicotinonitrile, 1- [6-{[2-({6-amino-5- [hydroxy (oxyde) ) Amino] -2-pyridinyl} amino) ethyl] a Mino} -2- (4-ethylphenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 6-[(2-{[6- (4-ethylphenyl) -5- (4- Methyl-2-oxo-1-piperazinyl) -2-pyridinyl] amino} ethyl) amino] nicotinonitrile, 6-({2-[[6- (4-ethylphenyl) -5- (4- Methyl-2-oxo-1-piperazinyl) -2-pyridinyl] (methyl) amino] ethyl} amino) nicotinonitrile, 6-[(2-{[4- (2,4-dichlorophenyl)- 5- (4-methyl-2-oxo-1-piperazinyl) -2-pyrimidinyl] amino} ethyl) amino] -nicotinonitrile, 1- [6-{[2-({6-amino- 5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4-difluorophenyl) -3-pyridinyl] -4-methyl-2-pipe Lazinone, 4- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -3- (4-methyl-2 -Oxo-1-piperazinyl) -2-pyridinyl] benzonitrile, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} Amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -4- Sopropyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridyl] -4-ethyl-2-piperazinone, 1- {6-{[2-({6-amino-5- [hydroxy (oxy)) amino ] -2-pyridinyl} amino) ethyl] amino} -2- [2- (trifluoromethyl) phenyl] 3-pyridinyl} -4-methyl-piperazinone, 1- [6-{[2- ({6-amino-5- [hydroxy (oxy)) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2-bromophenyl) -3-pyridinyl] -4-methyl- 2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) propyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy- (oxy)) amino]- 2-pyridinyl} amino) propyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl) -4-methyl-2-piperazinone, 1- [6-{[2-({ 6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) -l -Methylethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5 -[Hydroxy (oxy) amino] -2-pyridinyl} amino) -1-methylethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -4-methyl-2- Piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) -1,1-dimethylethyl] amino} -2 -(2,4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, l- [6-{[2-({6-amino-5- [hydroxy (oxy)) Amino] -2-pyridinyl} amino) ethyl] [2- (l-pyrrolidinyl) ethyl] amino} -2- (2,4-dichlorophenyl) 3-pyridyl] -4-methyl-2- Piperazinone, 1- [6- [3-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) propyl] -2- (2,4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-[[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino ) Ethyl] (methyl) amino] -2- (2,4-dichlorophenyl) -3-pyridinyl] -4-meth Methyl-2-piperazinone, 1- [6- [2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethoxy] -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy)) amino] -2 -Pyridinyl} oxy) ethyl] amino} -2- (2,4-dichlorophenyl) 3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6- Amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] [2- (4-morpholinyl) ethyl] amino} -2- (2,4-dichlorophenyl) -3 -Pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl ] Amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxygen) ) Amino] -2-pyridinyl} -amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -4-cyclopropyl-2-piperazinone, 1- [6- {[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino ) Ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -4-cyclohexyl-2-piperazinone, 1- [6-{[2-({6-amino-5 -[Hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (4-bromophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1 -[6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} -amino) ethyl] amino} -2- (2,4-dichlorophenyl)- 3-pyridinyl] -3,4-dimethyl-2-piperazinone, 1- (2- (2,4-dichlorophenyl) -6-{[2-({5- [hydroxy (oxy)) amino ] -6-methoxy-2-pyridinyl} amino) -ethyl] amino} -3-pyridinyl) -4-methyl-2-piperazinone, 1- (2- (2,4-dichlorophenyl)- 6-{[2-({5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -3-pyridinyl) -4-methyl-2-piperazinone, 4- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -3- (4-methyl-2-oxo-1- Piperazinyl) -2-pyridinyl] benzamide, 2- [6-{[2-({6-amino-5- [hydroxy] (Oxido) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] hexahydropyrrolo [1,2-a] pyrazine-3 ( 4H) -one, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4 -Dichlorophenyl) -3-pyridinyl] -4- (methylsulfonyl) -2-piperazinone, 4-acetyl-1- [6-{[2-({6-amino-5- [hydroxy ( Oxido) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -2-piperazinone, 2- [6-{[2- ({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] hexahydropyrrolo [1, 2-a] pyrazine-3 (4H) -one, 2- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) Ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] hexahydropyrrolo [1,2-a] pyrazine-3 (4H) -one, 2- [6-{[2- ({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl } Amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] hexapyrrolo [1,2-a] pyrazine-1 (2H) -one, 2- [6-{[ 2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) tyl) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] Hexahydropyrrolo [1,2-a] pyrazine-1 (2H) -one, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridine Diyl} -amino) ethyl] amino} -2- (2,4-difluorophenyl) -3-pyridinyl] -4-ethyl-2-piperazinone, 4- [6-{[2-({ 6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -3- (4-ethyl-2-oxo-1-piperazinyl) -2-pyridinyl ] Benzonitrile, 1- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) propyl] amino} -2- (2,4- Dichlorophenyl) -3-pyridinyl] -4-ethyl-2-piperazinone, 1- (6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridine Diyl} amino) ethyl] amino} -2-phenyl-3-pyridinyl) -4-methyl-2-pipera Xenon, 1- [6-{[2-({6-amino-5- [hydroxy- (oxy)) amino] -2-pyridinyl} amino) ethyl] amino} -2- (4-chlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 3-amino-1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-]-2- Pyridinyl} -amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -2-piperidinone, 1- [6-{[2-({6-amino-5 -[Hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (3-chlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4-dichlorophenoxy) -3 -Pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl ] -Amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -4- (2,2,2-trifluoroethyl) -2-piperazinone, 4- [6- {[ 2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] Mino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -3-morpholinone, 1- {6- [2- (6-amino-5-nitro-pyridin-2-ylamino) -Ethylamino]-[2,3 '] bipyridinyl-3-yl} -4-methyl-piperazin-2-one, 1- [6-{[2-({6-amino-5- [hydr Oxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2,4-dichlorophenyl) -3-pyridinyl] -2-piperidinone, 1- [6-{[ 2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} -amino) ethyl] amino} -2- (4-chloro-2-methylphenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (4-methoxyphenyl) -3-pyridinyl] -4-methyl-2-piperazinone, and 1- [6-{[2-({6-amino-5- [hydroxy (oxy)) amino ] -2-pyridinyl} amino) ethyl] amino} -2- (3-furyl) -3-pyridinyl] -4-methyl-2-piperazinone.

Examples of heterocyclo groups as used herein include the groups set forth below (at the point of attachment of the substituents, the other substituents set forth below are by an upper left-hand bond). Such heterocyclo groups may be further substituted and attached at various positions apparent to those skilled in the organic and medical chemistry arts associated with the disclosure herein:

Representative examples of heteroaryl groups include those set forth below. Such heteroaryl groups may be further substituted and attached at various positions apparent to those skilled in the organic and medical chemistry arts associated with the disclosure herein:

Representative examples of cycloimido groups and heterocycloimido groups include those set forth below. Such cycloimido groups and heterocycloimido groups can be further substituted and attached at various positions apparent to those skilled in the organic and medical chemistry arts associated with the disclosure herein:

Representative examples of substituted amidino groups and heterocycloamidino groups include those shown below. Such amidino and heterocycloamidino groups can be further substituted, as will be apparent to those skilled in the organic and medical chemistry arts associated with the disclosure herein:

Representative examples of substituted alkylcarbonylamino, alkyloxycarboniamino, aminoalkyloxycarbonylamino and arylcarbonylamino groups include those set forth below. These groups may be further substituted as will be apparent to those skilled in the organic and medical chemistry arts associated with the disclosure herein:

Representative examples of substituted aminocarbonyl groups include those set forth below. These groups may be heterocyclo groups which may be further substituted as will be apparent to those skilled in the organic and medical chemistry arts associated with the description herein:

Representative examples of substituted alkoxycarbonyl groups include those set forth below. Such alkoxycarbonyl groups may be further substituted as will be apparent to those skilled in the organic and medical chemistry arts associated with the description herein:

Particularly preferred compounds of the present invention include compounds having the formula (4) and pharmaceutically acceptable salts thereof:

(Formula 4)

Wherein X, R ₁ to R ₆ , and R ₈ to R ₁₄ are as described above. Examples of preferred compounds with this group are [4- (4-imidazolylphenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 4- [5 -Imidazolyl-2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile, 4- [2-({2- [ (6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -5-imidazolylpyrimidin-4-yl] benzenecarbonitrile, [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 4- [2-({2-[(5-nitro-2 -Pyridyl) amino] ethyl} amino) -7a-hydro-1,2,4-triazolo [1,5-a] pyrimidin-7-yl] benzenecarbonitrile, {2-[(6-amino- 5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5imidazolylpyrimidin-2-yl] amine, [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 6-[(2-{[4- (2, 4-dichlorophenyl) -5-imidazole Pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile, [5-benzotriazolyl-4 (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(5- Nitro (2-pyridyl)) amino] ethyl} amine, [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 -Dichlorophenyl) pyrimidin-5-yl] methan-1-ol, [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl } Amino) pyrimidin-5-yl] methan-1-ol, 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 ( 2,4-dichlorophenyl) pyrimidin-5-yl] isoindoline-1,3-dione, [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2- [ (6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, {2-[(6-amino-5 nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5-morpholin-4-ylpyrimidin-2-yl] -amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} {4- (2,4-dichlorophenyl) -5- [5 (trifluoromethyl) (1, 2,3, 4-tetrazolyl)] pyrimidin-2-yl} amine, 1- [2 [({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- ( 2,4-dichlorophenyl) pyrimidin-5-yl] pyrrolidone-2,5-dione, [4- (2,4-dichlorophenyl) -5-pyrazolylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, [4- (2,4-dichlorophenyl) -5- (4-methylimidazolyl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, [4- (2, 4-dichlorophenyl) -5- (2, 4-dimethylimidazolyl) pyrimidin-2-yl] { 2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 6-[(2- {[4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidine- 2-yl] amino} ethyl) amino] pyridine-3-carbonitrile, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl ) -5 (morpholin-4-ylmethyl) pyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] -ethyl} [4- (2 , 4-dichlorophenyl) -5-piperazinylpyrimidin-2-yl] amine, {2-[( 6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-ethylphenyl) -5-imidazolylpyrimidin-2-yl] amine, 1- [4- (2, 4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl]] hydropyridin-2-one, [5-benzimi Dazolyl-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, {2-[(6-amino- 5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] methylamine, {2-[(6-amino- 5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5- (4-pyridyl) pyrimidin-2-yl] amine, {2-[(6- Amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4-methylpiperazinyl) -pyrimidin-2-yl] amine, [4 -(2,4-dichlorophenyl) -5- (2-methylimidazolyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, {2 -[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4-(2,4-di Rorophenyl) -5- (2-methylimidazolyl) pyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- ( 2, 4-dichlorophenyl) -5- (4-phenylimidazolyl) pyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5- (2, 4-dimethylimidazolyl) pyrimidin-2-yl] amine, [4- (2,4-dichlorophenyl) -5-imidazole -2-ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amine, [4- (2,4-dichlorophenyl) -5 -Piperazinylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, [4- (2,4-dichlorophenyl) -5-imidazolylpyrid Midin-2-yl] [2- (dimethylamino) ethyl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 1- [2-({2-[(6-amino -5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] -4-methylpiperazin-2,6-dione, [4 -(2,4-dichlorophenyl) -5- (1-methylimidazol-2-yl) pyrimidin-2- Yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] Ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] -3-morpholin-4-ylpyrrolidone-2, 5-dione, 1- [4- (2,4- Dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -4-methyl-piperazine-2,6-dione, 1 -[2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] -3 -(Dimethylamino) pyrrolidone-2,5-dione, {5-imidazol-2-yl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} {2-[( 5-nitro (2-pyridyl)) amino] -ethyl} amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl ) -5- (1 methylimidazol-2-yl) pyrimidin-2-yl] amine, [4- (2,4-dichlorophenyl) -5- (4-methyl-piperazinyl) pyrimidine- 2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, [4- (2,4-dichlorophenyl) -5- (morpholine-4 -Ylmethyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} -amine, [4- (2,4-dichlorophenyl) -5- (4- Methylimidazol-2-yl) pyrimidin-2-yl] {2-[(5-nitro (2pyridyl)) amino] ethyl} amine, {2-[(6-amino-5-nitro (2 -Pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amine, {2-[(6 -Amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine, [4- (2- Chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, [4- (2 , 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} (2-pyrrolidinylethyl) amine, [4 -(2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] (2-morpholin-4-ylethyl) {2-[(5-nitro (2-pyridyl)) amino] Ethyl} amine, 6-[(2- {4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyridine Din-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chloro- 4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine, [4- (4-ethylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] { 2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, [5-((1E) -1-aza-2-morpholin-4-ylprop-1-enyl) -4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, N- [4- (2,4- Dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} -amino) pyrimidin-5-yl] acetamide, [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine, 6-[(2-{[ 4- (2, 4-dichlorophenyl) 5-imidazolylpyrimidin-2-yl] methylamino} ethyl) amino] pyridine-3-carbonitrile, 6-[(2-{[4- (2,4 -Dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methylamino} Yl) amino] pyridine-3carbonitrile, [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methyl {2-[(5-nitro (2-pyri) Dill)) amino] ethyl} amine, 6-[(2-{[4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) Amino] pyridine-3-carbonitrile, [4- (4-chlorophenyl) -5imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] Ethyl} amine, {2-[(6-amino-5nitro (2-pyridyl)) amino] ethyl} [4- (4-chloro-2-methylphenyl) -5-imidazol-2-ylpyrimidine- 2 day] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-bromo-2-chlorophenyl) -5imidazol-2-yl Pyrimidin-2-yl] amine, 6-[(2-{[4- (4-bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) Amino] pyridine-3-carbonitrile, 6- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl ) Pyrimidin-5-yl] -3-pyrrolino [3, 4b] Pyridine-5,7-dione, N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichloro Phenyl) pyrimidin-5-yl] -2- (methylamino) acetamide, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-bromo -2-chlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amine, 6-[(2-{[4- (4-bromo-2-chlorophenyl ) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] -amino} ethyl) amino] pyridine-3-carbonitrile, {2-[(6-amino-5-nitro ( 2-pyridyl)) amino] ethyl} [4- (2-chloro-4-fluorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amine, and 6 -[(2-{[4- (2,4-dichlorophenyl) -5- (5-chloro-2-oxohydropyridyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboni Tril is included.

Examples of particularly preferred compounds of the present invention include compounds having the formula (5) and pharmaceutically acceptable salts thereof:

(Formula 5)

Wherein X, R ₁ to R ₆ , and R ₈ to R ₁₄ are as described above, R ₁₅ is hydrogen, nitro, cyano, amino, alkyl, halo, haloloweralkyl, alkyloxycarbonyl, Aminocarbonyl, alkylsulfonyl and arylsulfonyl. Examples of compounds of this group include [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} Amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] amine , 6-[(2-{[6- (2, 4-dichlorophenyl) -5-imidazolyl-2-pyridyl] amino} ethyl) amino] pyridine-3-carbonitrile, {2-[(6 -Amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5-nitro (2-pyridyl)] amine, {2-[(6-amino- 5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5- (4-methylimidazolyl) (2-pyridyl)] amine, 6-[(2 -{[6- (2, 4-dichlorophenyl) -5- (4-methylimidazolyl) -2-pyridyl] amino} ethyl) -amino] pyridine-3-carbonitrile, and [4- (4 -Bromo-2-chlorophenyl) -5-imidazol-2-yl-pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine.

In another aspect, the present invention provides a composition comprising a compound of Formula 1 in an amount effective to modulate GSK3 activity in a human or animal subject with a pharmaceutically acceptable carrier.

In another embodiment, the present invention provides a method of inhibiting GSK3 activity in a human or animal subject, comprising administering to the human or animal subject a compound of Formula 1 in a GSK3 inhibitory amount.

The present invention further comprises administering to a human or animal subject with a GSK3-mediated disease a therapeutically effective amount of a compound of Formula 1, alone or in combination with other therapeutically active agents, a human or animal with a GSK3-mediated disease Provided are methods for treating a subject.

In another embodiment, the present invention provides a compound of formulas (1), (4) and (5) as described above for use as a medicament; Provided are methods for use in the manufacture of a medicament for the treatment of polycystic ovary syndrome, X syndrome, ischemia, in particular cerebral ischemia, traumatic brain injury, bipolar disorder, immunodeficiency or cancer.

The terms set forth below as used herein have the meanings defined below:

As used herein, “glycogen synthase kinase 3” and “GSK3” refer to proteins having more than 60% sequence homology to amino acids between positions 56 and 340 of the human GSK3 beta amino acid sequence (Genbank Accession No. L33801). Say. In order to determine the homology ratio of two amino acid sequences or two nucleic acids, the sequences are arranged for optimal comparison purposes (e.g., one polypeptide or nucleic acid with gaps having another polypeptide or nucleic acid for optimal alignment) May be introduced in the sequence of). The amino acid residues or nucleotides are then compared at the corresponding amino acid position or nucleotide position. When a position in one sequence is occupied by the same amino acid residue or nucleotide as the corresponding position in another sequence, the molecule is homologous at that position (ie, an amino acid or nucleic acid "homologous" as used herein is an amino acid or nucleic acid). Equal to "identity"). The homology ratio between two sequences is a function of the number of identical positions shared by the sequence (ie, homology (%) = number of identical positions (#) / number of total positions (#) x 100). GSK3 was originally described in Woodgett et al., Trends Biochem. Sci. , 16: 177-81 (1991), by phosphorylation of glycogen synthase. By inhibiting GSK3 kinase activity, the activity downstream of GSK3 can be inhibited or alternatively stimulated. For example, when GSK3 activity is inhibited, glycogen synthase may be activated to increase glycogen production. GSK3 is also known to act as a kinase in a variety of other situations, including, for example, phosphorylation of c-jun, β-catenin and tau proteins. It is understood that inhibition of GSK3 kinase activity can result in a variety of effects in a variety of biological situations. However, the present invention is not limited to any mechanism theory in its method of operation.

As used herein, “GSK3 inhibitor” refers to a compound that exhibits an IC ₅₀ of about 100 μM or less, preferably about 50 μM or less for GSK3, as measured in a cell-free assay for GSK3 inhibitory activity, generally described below. . "IC ₅₀ " refers to the concentration of an inhibitor that reduces the activity of an enzyme (eg, GSK3) to half its maximum level. Representative compounds of the present invention have been shown to exhibit inhibitory activity against GSK3. The compounds of the present invention preferably exhibit an IC ₅₀ of less than about 10 μM, preferably about 5 μM, more preferably about 1 μM, most preferably less than about 200 nM, as determined by the cell-free GSK3 kinase assay.

The term "optionally substituted" refers to the hydrogen being substituted with a monovalent or divalent radical. Examples of suitable substituents include hydroxyl, nitro, amino, imino, cyano, halo, thio, thioamido, amidino, imidino, oxo, oxamidino, methoxamidino, imdino, guanidino, sulfone Amido, carboxyl, formyl, lower alkyl, halo lower alkyl, lower alkoxy, halo lower alkoxy, lower alkoxyalkyl, alkylcarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl , Alkylthio, aminoalkyl, cyanoalkyl and the like.

The substituent itself may be substituted. The group substituted on the substituent is carboxyl, halo; Nitro, amino, cyano, hydroxyl, lower alkyl, lower alkoxy, aminocarbonyl, -SR, thioamido, -SO ₃ H, -SO ₂ R, where R is typically hydrogen, hydroxyl or lower alkyl Or cycloalkyl.

If the substituted substituents comprise a linear group, the substitution may be in the chain (eg, 2-hydroxypropyl, 2-aminobutyl, etc.) or the chain terminus (eg, 2-hydroxyethyl, 2-cyano). Profile, etc.). Substituted substituents can be branched or cyclic arrangements of straight chain, covalently bonded carbon or hetero atoms.

The term "lower alkyl" as used herein refers to, for example, one or more halogen, hydroxyl or other groups such as methyl, ethyl, propyl, isopropyl, n-butyl, tertiary butyl, neopentyl, trifluoromethyl, A linear or branched alkyl group having 1 to 10 carbon atoms, optionally substituted with pentafluoroethyl or the like.

"Alkylenyl" means a divalent linear or branched saturated aliphatic radical having 1 to 20 carbon atoms. Common alkylenyl groups used in the compounds of the present invention are lower alkylenyl groups having 1 to about 6 carbon atoms in the main chain. As used herein, "alkenyl" refers to a linear, branched or cyclic radical having one or more double bonds and having 2 to 20 carbon atoms.

As used herein, "lower alkoxy" means RO-, where R is lower alkyl. Representative lower alkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy and the like.

"Cycloalkyl" means monocyclic, polycyclic, heterocyclic or carbocyclic alkyl substituents. Common cycloalkyl substituents have 3 to 8 main chain (ie, ring) atoms in which each chain atom is a carbon or hetero atom. As used herein, the term “heterocycloalkyl” means a cycloalkyl substituent having 1 to 5, preferably 1 to 4 heteroatoms in the ring structure. Suitable heteroatoms used in the compounds of the present invention are nitrogen, oxygen and sulfur. Representative heterocycloalkyl moieties include morpholino, piperazinyl, piperadinyl, and the like. Carbocycloalkyl groups are cycloalkyl groups in which all ring atoms are carbon. When used with cycloalkyl substituents, the term "polycyclic" as used herein refers to fused and unfused alkyl cyclic structures.

As used herein, "halo" refers to a halogen radical such as fluorine, chlorine, bromine or iodine. "Haloalkyl" means an alkyl radical substituted with one or more halogen atoms. The term "haloalkoxy" means an alkoxy radical substituted with one or more halogen atoms. The term "halo lower alkoxy" means a lower alkoxy radical substituted with one or more halogen atoms.

, 나프틸 등에 융합된 헤테로시클릭 구조를 가짐)과 같은 방향족인 융합 및 융합되지 않은 시클릭 구조를 의미한다. 본 발명의 화합물에서 치환기로서 사용되는 아릴 부분의 예로는 페닐, 피리딜, 피리미디닐, 티아졸릴, 인돌릴, 이미다졸릴, 옥사디 아졸릴, 테트라졸릴, 피라지닐, 트리아졸릴, 티오페닐, 푸라닐, 퀴놀리닐, 푸리닐, 나프틸, 벤조티아졸릴, 벤조피리딜, 벤즈이미다졸릴 등이 포함된다."Aryl" is a monocyclic and polycyclic aromatic group having 3 to 14 carbon or hetero atoms of the main chain, and includes both carbocyclic aryl groups and heterocyclicaryl groups. Carbocyclic aryl groups are aryl groups in which all ring atoms in the aromatic ring are carbon. As used herein, the term “heteroaryl” refers to an aryl group having 1 to 4 heteroatoms as ring atoms in the aromatic ring, the remainder being carbon atoms. When used in connection with an aryl substituent, the term "polycyclic" as used herein means that the one or more cyclic structures are aromatic, for example benzodioxozo (phenyl group, ie

Fused and unfused cyclic structures). Examples of aryl moieties used as substituents in the compounds of the present invention include phenyl, pyridyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, Furanyl, quinolinyl, furinyl, naphthyl, benzothiazolyl, benzopyridyl, benzimidazolyl and the like.

As used herein, "aralkyl" refers to an alkyl group substituted with an aryl group. Generally, the aralkyl group used in the compound of the present invention has 1 to 6 carbon atoms inserted in the alkyl portion of the aralkyl group. Examples of suitable aralkyl groups used in the compounds of the present invention include benzyl, picolyl and the like.

As used herein, "amino" refers to -NH ₂ . As used herein, the term "alkylamino" means -NRR ', wherein R and R' are each independently selected from hydrogen or lower alkyl. As used herein, the term "arylamino" refers to the group -NRR 'wherein R is aryl and R' is hydrogen, lower alkyl, or aryl. As used herein, the term “aralkylamino” refers to an NRR ′ group wherein R is lower aralkyl and R ′ is hydrogen, lower alkyl, aryl, or lower aralkyl.

As used herein, the term "arylcycloalkylamino" means aryl-cycloalkyl-NH-, where cycloalkyl is a divalent cycloalkyl group. Typically, cycloalkyl has 3 to 6 backbone atoms, optionally 1 to about 4 heteroatoms. The term "aminoalkyl" refers to an alkyl group substituted at the terminal with an amino group.

The term "alkoxyalkyl" refers to a group -alk ₁ -O-alk ₂ where alk ₁ is alkylenyl or alkenyl and alk ₂ is alkyl or alkenyl. The term "lower alkoxyalkyl" means an alkoxyalkyl wherein alk ₁ is lower alkylenyl or lower alkenyl and alk ₂ is lower alkyl or lower alkenyl. The term "aryloxyalkyl" refers to an -alkylenyl-O-aryl group. The term "aralkoxyalkyl" means a group -alkylenyl-O-aralkyl, where aralkyl is lower aralkyl.

As used herein, the term “alkoxyalkylamino” refers to a group —NR— (alkoxyalkyl), wherein R is typically hydrogen, lower aralkyl, or lower alkyl. The term "amino lower alkoxyalkyl" means aminoalkoxyalkyl wherein the alkoxyalkyl is lower alkoxyalkyl.

The term "aminocarbonyl" refers to a -C (O) -NH ₂ group. "Substituted aminocarbonyl" means a group -C (O) -NRR 'wherein R is lower alkyl and R' is hydrogen or lower alkyl. The term "arylaminocarbonyl" refers to a group -C (O) -NRR 'wherein R is aryl and R' is hydrogen, lower alkyl or aryl. The term "aralkylaminocarbonyl" refers to a group -C (O) -NRR 'wherein R is lower aralkyl and R' is hydrogen, lower alkyl, aryl, or lower aralkyl.

As used herein, "aminosulfonyl" refers to the group -S (O) ₂ -NH ₂ . "Substituted aminosulfonyl" means a group -S (O) ₂ -NRR 'wherein R is lower alkyl and R' is hydrogen or lower alkyl. The term "aralkylaminosulfonylaryl" refers to the group -aryl-S (O) ₂ -NH-aralkyl (where aralkyl is lower aralkyl).

"Carbonyl" means a divalent -C (O)-group.

"Carbonyloxy" generally means -C (O) -O-. Such groups include esters, —C (O) —O—R, wherein R is lower alkyl, cycloalkyl, aryl, or lower aralkyl. The term "carbonyloxycycloalkyl" generally means both "carbonyloxycarbocycloalkyl" and "carbonyloxyheterocycloalkyl", ie R is carbocycloalkyl or heterocycloalkyl, respectively. The term "arylcarbonyloxy" means a C (O) -0-aryl, wherein aryl is monocyclic, polycyclic, carbocycloaryl or heterocycloaryl. The term "aralkylcarbonyloxy" refers to the group -C (O) -O-aralkyl (where aralkyl is lower aralkyl).

As used herein, the term "sulfonyl" refers to the group -S0 _2- . "Alkylsulfonyl" means substituted sulfonyl of the structure -SO ₂ R-, wherein R is alkyl. Alkylsulfonyl groups used in the compounds of the present invention are generally lower alkylsulfonyl groups having 1 to 6 carbon atoms in the main chain structure. As such, examples of common alkylsulfonyl groups used in the compounds of the invention include methylsulfonyl (ie, R is methyl), ethylsulfonyl (ie, R is ethyl), propylsulfonyl (ie, R is Profile). The term "arylsulfonyl" refers to an -S0 ₂ -aryl group. The term "aralkylsulfonyl" refers to the group -SO ₂ -aralkyl, wherein aralkyl is lower aralkyl. The term "sulfonamido" refers to the group -SO ₂ NH ₂ .

As used herein, the term "carbonylamino" refers to a divalent -NH-C (O) group wherein the hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced by a loweralkyl, aryl or loweraralkyl group. do. Such groups include carbamate esters (-NH-C (O) -OR) and amides -NH-C (O) -OR, wherein R is linear or branched lower alkyl, cycloalkyl, aryl or lower aralkyl Is included). The term "lower alkylcarbonylamino" means alkylcarbonylamino, wherein R is lower alkyl having from 1 to about 6 carbon atoms in the main chain structure. The term "arylcarbonylamino" means a group -NH-C (O) -R, wherein R is aryl. Similarly, the term "aralkylcarbonylamino" means carbonylamino (R is lower aralkyl).

As used herein, the term “guanidino” or “guanidyl” means a moiety derived from guanidine H ₂ NC (═NH) —NH ₂ . This moiety is a moiety bound at the nitrogen atom having a conventional double bond (the “2” position of guanidine, for example diaminomethyleneamino (H ₂ N) ₂ C═NH—) and a nitrogen atom having a conventional single bond. In one of them (the "1-" and / or "3" -position of guanidine, for example H ₂ NC (= NH) -NH-). The hydrogen atom at any nitrogen may be substituted with a suitable substituent, such as lower alkyl, aryl or lower aralkyl.

As used herein, the term "amidino" refers to RC (= N) -NR '-(radical in "N ¹ " nitrogen) and R (NR') C = N- (radical in "N ² " nitrogen) ( Wherein R and R 'may be hydrogen, lower alkyl, aryl, or lower aralkyl) moiety.

Compounds of the present invention can be readily synthesized using the methods described herein or methods well known in the art. For example, the synthesis of pyrimidines with various substituents is described in D. J. Brown, "The Pyrimidines," vol. 54, Wiley (1994). The compounds described herein were synthesized using both solution phase and resin based (ie solid phase) techniques.

The pyrimidine-based compound of the present invention can be easily synthesized in solution by reacting a carbonyl-containing derivative with N, N-dimethylformamide dimethyl acetal (DMFDMA). The intermediate enaminoketone obtained at various temperatures was then reacted with guanidine in the presence of an organic solvent and a suitable base such as sodium ethoxide, sodium methoxide, sodium hydroxide or cesium carbonate. This method is generally described in the following references: Heterocyclic chem ., 24 : 1669 (1987), P. Schenone et al., J. Heterocyclc chem ., 27: 295 (1990), R. Paul et al., J. Med. Chem ., 36 : 2716 (1993) and J. Zimmermann et al., Arch . Pharm ., 329 : 371 (1996).

Examples of suitable carbonyl-containing starting reagents for use in this scheme include β-ketoesters, alkyl aryl ketones, β-keto sulfones, α-nitro ketones, β-ketone nitriles, desoxybenzoin, aryl heteroarylmethyl ketones, and the like. This includes. Carbonyl-containing starting reagents may also be purchased or synthesized by known methods.

For example, β-keto esters are readily prepared by reacting an acid chloride or other activated carboxylic acid with potassium ethyl malonate in the presence of triethylamine, according to the methods described in the literature, which is incorporated herein by reference. (JR Clay et al., Synthesis, 1992: 290 (1992)). Alternatively, the preferred β-keto esters can be prepared by diprotonating the appropriate methyl ketone with a suitable base, such as sodium hydride, according to the methods described in the literature, which is incorporated herein by reference. It can be easily synthesized by condensation by Sircar et al., J. Med. Chem., 28: 1405 (1985).

Similarly, β-keto sulfones and α-nitro ketones can be prepared according to known methods described in the following references, which are incorporated herein by reference. NS Simpkins, “Sulphones in Organic Synthesis,” Pergamon. (1993) (β-keto sulfones) and M. Jung et. al., J. Org. Chem., 52: 4570 (1987) (α-nitro ketones). β-ketonitrile can be readily prepared by reacting α-halo ketone with sodium or potassium cyanide.

When the substrate is a double activated carbonyl compound (e.g., β-keto ester, β-keto sulfone, β-ketonitrile, etc.), the first condensation is typically at TH 70-80 ° C. for several hours, such as THF. Performed with a little excess of DMFDMA in the solvent. This method is described in more detail in Example 25 below (ie "Solution Method A").

When mono-activated substrates such as methyl ketones are involved, DMFDMA is often used as solvent at high temperatures (90-100 ° C.) for extended periods of time (eg overnight). After the condensation reaction is over, the solvent and excess DMFDMA are removed under vacuum. The resulting solid or oil is dissolved in a suitable solvent and heated with an equivalent molar amount of guanidine and base. This method is described in more detail in Example 60 below (ie "Solution Method B").

If an ester is formed, the corresponding carboxylic acid is obtained by alkaline or acidic hydrolysis of the resulting pyrimidine. The acid may then be further coupled to various alcohols or amines to provide various ester or amide derivatives.

Guanidines used in the synthesis of the compounds of the present invention may be purchased or may be synthesized by reacting the corresponding amines with guanidino transfer agents such as benzotriazole carboxamidinium 4-methylbenzenesulfonate. Such guanidino transporters are described in the following references, incorporated herein by reference: A. R. Katritzky et al., 1995, Synthetic communications, 25: 1173 (1995). As such, for example, benzotriazole carboxamidinium 4-methylbenzenesulfonate is reacted with an equivalent amount of amine and one equivalent of diisopropyl ethyl amine (DIEA) in acetonitrile at room temperature upon addition of diethyl ether. To obtain guanidinium 4-methylbenzenesulfonate. Amines containing nitrogen heterocyclic aryl can be prepared by nucleophilic substitution of halo substituted nitrogen heterocyclic aryl with a suitable diamine such as ethylenediamine or propylenediamine. Such diamines are particularly suitable for use as reaction solvents at reaction temperatures of about 25-125 ° C. Methods for preparing the specified amines are specified in the examples provided herein.

Other known synthetic methods can be used to prepare the compounds of the present invention. For example, 5-aryl 2-aminopyrimidine can be prepared by reacting guanidine with a vinamidinium salt, according to the methods described in the following references incorporated herein by reference: RM Wagner and C Jutz, Chem. Berichte, p. 2975 (1971). This method is illustrated in Example 67 below (ie "Solution Method C").

Similarly, 4-anilo-2-chloropyrimidine can be prepared by reacting aniline with 2,4-dichloropyrimidine. Similarly, aniline can be treated with 2,4-dichloropyrimidine to yield 4-anilo-2-chloropyrimidine. Further substitution with secondary amines yields 2-amino-4-anilinopyrimidines.

In addition to the solution step synthesis method, solid support synthesis methods (including resin based synthesis methods) can also be used to synthesize the compounds of the invention, in particular in parallel and combination synthesis methods. For example, the synthesis of tetrasubstituted pyrimidines can be initiated by loading aromatic carboxylic acid aldehydes, such as 4-formyl benzoic acid, with amino groups of suitable resins such as link amide resins (Nova Biochem, San Diego, Calif.) This method is described in more detail as “resin method A” in Example 2. lH— in the presence of a base (eg potassium carbonate) suitable for Knoevenagel Condensation of β-keto esters. An unsaturated intermediate is obtained which can be condensed with pyrazole-1-carboxamidine hydrochloride (Aldrich), and then the intermediate dihydropyrimidine is converted to 2,3-dichloro-5,6-dicyano in benzene. -1,4-benzoquinone (DDQ) can be used to oxidize to resin bound pyrimidine Finally heated with amine in 1-methylpyrrolidone (NMP) or other suitable solvent It is decomposed by the acid after the pyrazolo portion substituted as desired to give a pyrimidine. This synthesis method can be used to generate a pyrimidine with a substituent at the 4-position of the pyrimidine ring.

Resin method B, described in detail in Example 3, can be used to synthesize pyrimidine in which the 6-position is unsubstituted. Hydroxymethyl resins such as commercially available Sasrin resins (Bachem Biosciences, King of Prussia, PA) are treated with triphenylphosphine dibromide in dichloromethane to form hydroxymethyl groups on the resin. Conversion to bromomethyl group (K. Ngu et al., Tetrahedron Letters, 38: 973 (1997)). Bromine is then substituted by reaction with the primary amine in NMP (at room temperature or 70-80 ° C.). The amine is then coupled with a suitable aromatic compound containing an acetyl group. Such coupling can be performed with PyBOP® (Nova Biochem, San Diego, Calif.) And 4-methylmorpholine in NMP.

Resin method B can also be used to incorporate amino acid residues into the resulting pyrimidines. For example, amino resins can be coupled to 9-fluorenyl-methoxycarbonyl (FMOC) protected amino acids according to standard peptide synthesis conditions and methods. Further coupling to 4-acetylbenzoic acid followed by reaction with N, N-dimethylformamide dimethyl acetal and cyclization with guanidine to give pyrimidine derivatives incorporating amino acid residues.

Pyrimidines having a carboxamidophenyl group at position 6 and hydrogen at position 5 may be prepared from an amino (ie -NH ₂ ) containing resin such as a link amide resin (Novabiochem, San Diego, CA). . This method is described in more detail in Example 10 below (“Resin Method C”).

Compounds of the invention can also be prepared according to Resin Method F to produce 2,4-diaminopyrimidines. Resin bound amines can be derived from suitable primary amines, but aniline is generally not suitable. Substitution with secondary amines and partitioning of the product from the resin yields 2,4-diaminopyrimidine. For the second substitution, primary or secondary amines which may contain other functional groups such as unprotected hydroxy groups are suitable. The resulting dichloropyrimidine can be further substituted, for example, with ester groups at the 5 position. 2,6-dichloropyridine can be used in place of 2,4-dichloropyrimidine to produce 2,6-diaminopyridine. This method is described in more detail in Examples 17-19 below.

Resin method E can be used to produce 2,6-diaminopyridine. This method is similar to Resin Method D, except that 2,6-dichloropyridine is used as the electrophilic material and the final product is 2,6-diaminopyridine. Resin method E is described in more detail in Examples 20-21 below.

Resin method F can be used to synthesize 5-amino substituted compounds of the present invention. The resin bound amines react with halomethyl aryl ketones. The resulting resin bound aminomethyl ketone is then treated with DMFDMA (purified) and then cyclized to guanidine to yield 2,5-diamino-6-arylpyrimidine. Resin method F is described in more detail in Example 22 below.

Resin method G, which is described in more detail in Example 23, can be used to synthesize the compounds of the invention having carboxyl groups at the 5 position.

GSK3 inhibitor compounds of the present invention can be purified by known methods such as chromatography, crystallization and the like.

The compounds of the present invention preferably exhibit relatively significantly selective inhibitory activity against GSK3, compared to one or more other types of kinases. As used herein, the term "optional" means that the inhibitory potency against GSK3 is relatively high compared to one or more other types of kinases. Preferably, the GSK3 inhibitors of the invention are selective for GSK3 over two or more other types of kinases. Activity assays for GSK3 and other kinases are generally known. See, Havlicek et al., J Med. Claem., 40: 408-12 (1997). GSK3 selectivity can be quantified according to the following formula: GSK3 selectivity = IC _{50 (another kinase)} ÷ IC _{50 (GSK3)} where the GSK3 inhibitor is IC _{50 (another kinase)} > IC _{50 (GSK3)} As such, inhibitors that are selective for GSK3 indicate GSK3 selectivity that is one-fold greater than that of GSK3 and other kinases As used herein, the term “other kinase” refers to GSK3 and other kinases. This selectivity is generally measured by the cell-free assay described in Example 265.

In general, the GSK3 inhibitors of the present invention exhibit at least about two-fold selectivity for GSK3 (ie, IC _{50 (other kinases)} ÷ IC _{50 (GSK3)} ) compared to _{other kinases} , more commonly at least about five times Selectivity is shown. In general, the GSK3 inhibitors of the invention exhibit a selectivity of at least about 10, preferably at least about 100 times, more preferably at least about 1000 times, relative to one or more other kinases.

GSK3 inhibitory activity can be readily detected using the assays described herein, and assays generally known in the art. Examples of methods for identifying specific inhibitors of GSK3 include both cell-free and cell-based GSK3 kinase assays. Cell-free GSK3 kinase assays detect inhibitors that act in direct interaction with polypeptide GSK3, while cell-based GSK3 kinase assays may be directed by direct interaction with GSK3 itself, or by other mechanisms, such as modification of intracellular localization of GSK3 or Inhibitors can be identified that act by post-translational processes or interference with GSK3 expression necessary to produce mature active GSK3.

In general, cell-free GSK3 kinase assays (1) use GSK3 as a peptide substrate, radiolabeled ATP (such as γ ³³ P-ATP or γ ³² P-ATP, all of which are Amersham products based in Arlington Heights, IL). ), Incubating with magnesium ions, and optionally one or more candidate inhibitors; (2) incubating the mixture for a period of time to incorporate radiolabeled phosphate into the peptide substrate by GSK3 activity; (3) separate containers, commonly peptides Transfer some or all of the enzyme reaction mixture to a micro titration well containing a uniform amount of capture ligand capable of binding an anchor ligand on the substrate; (4) after washing to remove unreacted radiolabeled ATP; 5) can be readily performed by a method of quantifying the amount of ³³ P or ³² P remaining in each well. This amount represents the amount of radiolabeled phosphate incorporated into the peptide substrate. Inhibition is observed as a reduction of the incorporation of radiolabeled phosphate into the peptide substrate.

Suitable peptide substrates for use in cell-free assays can be peptides, polypeptides or synthetic peptide derivatives that can be phosphorylated by GSK3 in the presence of an appropriate amount of ATP. Suitable peptide substrates may be based on some of the various natural protein substrate sequences of GSK3 and may also contain N-terminal or C-terminal modifications or extensions, including spacer sequences and anchor ligands. As such, the peptide substrate may be present in the large polypeptide or may be an isolated peptide designed for phosphorylation by GSK3.

For example, the peptide substrate can be designed based on the sequence of the DNA binding protein CREB, such as the SGSG linked CREB peptide sequence in the CREB DNA binding protein described below. Wang et al., Anal . Biochem., 220: 397-402 (1994). In the assay reported by Wang et al., The C-terminal serine in the SXXXS motif of the CREB peptide is enzymatically phosphorylated by CAMP-dependent protein kinase (PKA) and the N-terminal serine in a motif that can be phosphorylated by GSK3. It is necessary to provide steps. Alternatively, a modified CREB peptide substrate can be used that has the same SXXXS motif and also contains an N-terminal anchor ligand, which can be synthesized with pre-phosphorylated C-terminal serine (such substrates are from Chiron Technologies, Clayton, Australia). Commercially available from Chiron Technologies PTY Ltd.). Phosphorylation of the second serine in the SXXXS motif during peptide synthesis eliminates the need to enzymatically phosphorylate residues into PKA as a separate step, and the incorporation of anchor ligands facilitates the capture of the peptide substrate after reaction with GSK3.

In general, the peptide substrate used in the kinase activity assay may contain one or more sites that can be phosphorylated by GSK3, and one or more sites that can be phosphorylated by kinases other than GSK3. As such, other sites can be prephosphorylated to produce motifs that can be phosphorylated by GSK3. As used herein, the term “prephosphorylated” means that the peptide substrate is phosphorylated with unradiolabeled phosphate prior to performing the kinase assay using the peptide substrate. Such prephosphorylation can be commonly performed during the synthesis of peptide substrates.

SGSG linked CREB peptides can be linked to anchor ligands such as biotin, where serine near the C terminus between P and Y is prephosphorylated. As used herein, the term “anchor ligand” is a ligand that can be attached to a peptide substrate to facilitate the capture of the peptide substrate on the capture ligand, which keeps the peptide substrate in place during the washing step while unreacted radiolabeled ATP serves to remove it. One example of an immobilized ligand is biotin. As used herein, the term "capture ligand" refers to a molecule capable of binding an anchor ligand with high affinity and attached to a solid structure. Examples of bound capture ligands include avidin or streptavidin coated microtiter wells or agarose beads. Beads with capture ligands may be further combined with scintillators to provide a means for detecting the captured radiolabeled peptide substrate, or scintillators may be added to the captured peptides in a later step.

The captured radiolabeled peptide substrate can be quantified in a scintillation counter by known methods. The signal detected in the scintillation counter will be proportional to GSK3 activity if the enzymatic reaction is made under conditions where some limited portion of the peptide substrate (eg less than 20%) is phosphorylated. If an inhibitor is present during the reaction, GSK3 activity will be reduced and therefore a small amount of radiolabeled phosphate will be incorporated into the peptide substrate. In this way, a low glare signal will be detected. As a result, the GSK3 inhibitory activity will be detected as a decrease in the flash signal compared to that observed in the negative control where no inhibitor is present during the reaction. This assay is described in more detail in Example 265 below.

Cell-based GSK3 kinase activity assays are commonly used for cells capable of expressing both GSK3 and GSK3 substrates, such as cells transformed with genes encoding GSK3 and its substrate (a prescriptive control sequence for expression of this gene). Inclusive). In performing cell based assays, cells capable of expressing genes are incubated in the presence of a compound of the invention. These cells are lysed and the proportion of the substrate in the phosphorylated form determines the amount of substrate recognized by the antibody, e.g., observing mobility for the unphosphorylated form on the SDS PAGE or specific for the phosphorylated form of the substrate. Is determined by. The degree of phosphorylation of the substrate is indicative of the inhibitory activity of the compound. In other words, inhibition is detected as a decrease in phosphorylation compared to assays performed without inhibitors. GSK3 inhibitory activity detected in cell based assays may be due to, for example, expression of GSK3 or inhibition of kinase activity of GSK3.

As such, cell based assays can also be used to specifically assay activity contemplated by GSK3 inhibition, such as inhibition of tau protein phosphorylation, the possibility of insulin signaling, and the like. For example, to assay the ability of a GSK3 inhibitor to inhibit Alzheimer's phosphorylation of a tau protein with which microtubules are involved, cells can be co-transformed with human GSK3β and human tau protein and then incubated with one or more candidate inhibitors. . Various mammalian cell lines and expression vectors can be used for this type of assay. For example, COS cells contain human tau protein coding sequences under the human GSK3β expression plasmid and initial SV40 promoter according to the protocol described herein (Stambolic et al., 1996, current Biology 6: 1664-68). Both expression plasmids such as pSG5 can be transformed (Goedert et al., EMBO J., 8: 393-399 (1989)). Alzheimer's phosphorylation of the tau protein can be readily detected with certain antibodies, such as AT8, available from Polymedco Inc. (Coatland Manor, NY) after lysis of the cells.

Similarly, the ability of GSK3 inhibitor compounds to enable insulin signaling by activating glycogen synthase can be readily identified using cell based glycogen synthase activity assays. This assay uses cells that respond to insulin stimulation by increasing glycogen synthase activity, such as the CHO-HIRC cell line overexpressing wild-type insulin receptors (about 100,000 binding sites / cells). CHO-HIRC cell line, see Moller et al., J: Biol. Chem., 265: 14979-14985 (1990) and Moller et al., Mol. Endocrinol., 4: 1183-1191 (1990). This assay can be performed by incubating serum-depleted CHO-HIRC cells in medium in the presence of various concentrations of a compound of the invention, followed by lysing the cells at the end of the incubation. Glycogen synthase activity is calculated as the maximum glycogen synthase activity ratio for each sample and described as a function of candidate GSK3 inhibitor concentration, as described by Thomas et al. Concentrations of candidate GSK3 inhibitors in which glycogen synthase activity was increased to half of the maximum level (ie, EC ₅₀ ) were determined by conjugating four variables to sigmoidal curves using a general curve conjugation method well known to those skilled in the art. Can be calculated. This is described in more detail in Example 66 below.

GSK3 inhibitors can be readily screened for in vivo activity using methods well known in the art. For example, candidate compounds with potential therapeutic activity in the treatment of type 2 diabetes can be readily identified by detecting the ability to improve glucose tolerance in animal models of type 2 diabetes. Specifically, candidate compounds may be prepared before administration of glucose pills in mice with diabetes (eg KK, db / db, ob / ob) or rats with diabetes (eg Zucker Fa / Fa or GK). Can be administered in a manner. After administration of the candidate compound and glucose, blood samples were removed at scheduled time intervals and serum glucose and insulin levels evaluated. Improved treatment of glucose without increased levels of secretion of endogenous insulin may be considered insulin sensitization and may exhibit compound efficacy. Details of this assay are provided in the Examples below.

The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Such salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsul Pate, Ethanesulfonate, Glucoheptanoate, Glycerophosphate, Hemisulphate, Heptanoate, Hexanoate, Fumarate, Hydrochloride, Hydrobromide, Hydroidide, 2-hydroxyethanesulfonate, Lactate , Maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, sulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, Tartrate, thiocyanate, p-tolenesulfonate and undecanoate. In addition, basic nitrogen-containing groups include lower alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; Dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; Long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide; Aralkyl halides such as benzyl, phenethyl bromide and the like. This gives a water soluble, fat soluble or dispersible product.

Examples of acids that can be used to form pharmaceutically acceptable acid addition salts include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Basic addition salts may be prepared in situ during the final isolation and purification of the compound of formula 1 or may be a suitable base such as hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation, ammonia, or organic primary, secondary Or by reacting the tertiary amine with the carboxylic acid moiety separately. Examples of pharmaceutically acceptable salts include cations of alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, non-toxic ammonium, quaternary ammonium and amine cations such as ammonium, tetramethylammonium, tetraethyl Ammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Examples of other organic amines useful for the formation of base addition salts include diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.

The compounds of the present invention can be administered in a variety of ways, including enteral, parenteral and topical modes of administration. For example, suitable modes of administration include oral, subcutaneous, transdermal, mucosal, ionic, intravenous, intraperitoneal, intranasal, subdural, rectal, and the like.

According to another embodiment of the present invention, there is provided a composition comprising a GSK3-inhibitor compound of the present invention, together with a pharmaceutically acceptable carrier or excipient.

Pharmaceutically acceptable excipients include treatments, drug delivery modifiers and adjuvants such as calcium phosphate, magnesium stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, decks. STROS, hydroxypropyl-β-cyclodextrin, polyvinylpyrrolidinone, low melting waxes, ion exchange resins, and the like, and combinations of two or more thereof. Other suitable pharmaceutically acceptable excipients are described herein. "Remington's Pharmaceutical Sciences," Mack Pub. Co., New Jersey (1991).

Pharmaceutical compositions containing a GSK3 inhibitor compound of the invention may be used in any form suitable for the intended method of administration, for example in the form of solutions, suspensions and emulsions. Liquid carriers are commonly used to prepare solutions, suspensions or emulsions. Liquid carriers that may be used in the practice of the present invention include water, saline, pharmaceutically acceptable organic solvent (s), pharmaceutically acceptable oils or fats, and the like, and combinations of two or more thereof. The liquid carrier may contain other suitable pharmaceutically acceptable additives such as solubilizers, emulsifiers, nutrients, buffers, preservatives, suspending agents, thickening agents, viscosity modifiers, stabilizers and the like. Examples of suitable organic solvents include monohydric alcohols such as ethanol and polyhydric alcohols such as glycols. Examples of suitable oils include soybean oil, coconut oil, olive oil, safflower oil, cottonseed oil and the like. For parenteral administration, the carrier may also be an oily ester such as ethyl oleate, isopropyl pyristate and the like. The compositions of the present invention may also be in the form of microparticles, microcapsules, liposome capsules, and the like, and combinations of two or more thereof.

The compounds of the present invention may be administered orally, parenterally, sublingually, by inhalational spray, or topically in the form of dosage units containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. . Topical administration may also use methods of transdermal administration, such as transdermal patches or iontophoretic devices. As used herein, the term parenteral method of administration includes subcutaneous injection, intravenous injection, intramuscular injection, sternum injection or infusion technique.

Injectable preparations, for example, sterile aqueous or oleaginous suspensions, may be formulated according to techniques known in the art using suitable dispersing, wetting or suspending agents. Injectable sterile preparations may also be injectable sterile solutions or suspensions in parenterally acceptable non-toxic diluents or solvents, for example solutions in 1,3-propanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, solidified oils can be used as the solvent or suspending medium. To this end, any mixed coagulant oil may be used, including synthetic monoglycerides or diglycerides. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

Suppositories for rectal administration of a drug can be prepared by mixing with the drug a suitable non-irritating excipient such as cocoa butter and polyethylene glycol, which is solid at room temperature but liquid at rectal temperature and can be dissolved and delivered in the rectum.

Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound may be mixed with one or more inert diluents such as sucrose, lactose or starch. Such dosage forms may also comprise, in normal use, additional substances other than inert diluents, such as lubricants such as magnesium stearate. In the case of capsules, tablets and pills, these dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared by enteric coating.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing an inert diluent such as water commonly used in the art. Such compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, cyclodextrins, sweetening agents, seasonings and flavoring agents.

According to another embodiment, the present invention provides a method of inhibiting GSK3 activity in a human or animal subject, comprising administering a GSK3 inhibitor compound having Formula 1, 4 or 5 in an amount effective to inhibit GSK3 activity in a subject. It provides a method comprising the steps. Another embodiment comprises administering to a human or animal subject with a GSK3-mediated disease, or cell, a compound or composition of the invention in an amount effective to inhibit GSK3 activity in the subject or cell, wherein the GSK3 Provided are methods for treating a mediated disease or cell. Preferably, the subject may be a human or non-human animal subject. Inhibition of GSK3 activity includes the detection of an inhibition of GSK3 activity compared to the expected GSK3 activity or compared to a control.

An effective amount of a compound of the invention is generally described herein by assaying the alleviation of symptoms in a subject suffering from GSK3-mediated disease or by other GSK3 kinase activity assays known to those of skill in the art. One of the assays includes an amount sufficient to detectably inhibit GSK3 activity.

GSK3-mediated diseases that can be treated in accordance with the present invention include biological or medical diseases that allow signaling via pathways in which GSK3 activity is considered or inhibition of GSK 3 is characteristically lacking among the diseases to be treated. Such symptoms or diseases may be caused by abnormal GSK3 activity or characterized by abnormal GSK3 activity. Examples of GSK3-mediated diseases include type 2 diabetes, Alzheimer's disease and other degenerative neurological disorders, obesity, atherosclerosis cardiovascular disease, idiopathic hypertension, polycystic ovary syndrome, X syndrome, ischemia, especially cerebral ischemia, traumatic brain injury, bipolar disorder , Immunodeficiency, cancer and the like.

Subjects can be successfully treated in accordance with the present invention to reduce or alleviate symptoms in a subject suffering from a medical or biological disease, to prevent further progression of these diseases, or to prevent these diseases. As such, the treatment of diabetes can reduce glucose or HbA1c levels in the patient. Similarly, treatment of Alzheimer's disease can reduce the rate of disease progression, as assayed by measuring a decrease in dementia growth rate.

The amount of active ingredient that can be combined with a carrier material to produce a single dosage form can vary depending upon the host or mode of administration to be treated. However, the specific dosage level for any particular patient depends on the specific compound used, age, weight, general state of health, sex, diet, time of administration, mode of administration, frequency of defecation, degree of drug combination, and the severity of the particular disease to be treated. Will be influenced. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and the skill and judgment of the normal clinician.

To achieve the object of the present invention, a therapeutically effective dose of a GSK3 inhibitor compound of the invention is about 0.1 to about 100 mg / kg / day, preferably about 1 to about 20 mg / kg / day, most preferably About 2 to about 10 mg / kg / day, which may be administered one or several times.

The compounds of the present invention can 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 monolamellar or multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Physiologically acceptable and metabolizable nontoxic lipids capable of forming liposomes can be used. The compositions of the present invention in liposome form may contain, in addition to the compounds of the present invention, stabilizers, preservatives, excipients and the like. Preferred lipids are phospholipids and phosphatidyl choline (lecithin), both natural and synthetic. Methods of forming liposomes are known in the art. See, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N. W., p. 33 et seq (1976).

The compounds of the present invention may be administered as the active agent alone, or may be used in combination with one or more other agents used to treat a disease. Examples of agents useful for combining with a compound of the present invention for the treatment of type 2 diabetes include insulin, troglitazone, rosiglitazone, pioglitazone, glipizide, metformin, sulfonylurea, acarbose and the like. Examples of agents useful for combining with a compound of the present invention for the treatment of Alzheimer's disease include donepezil, tacrine, and the like. Examples of agents useful for combining with a compound of the present invention for the treatment of bipolar disorder include lithium salts, valproate, carbamazepine, and the like. An example of a formulation useful for combining with a compound of the present invention for treating seizures is a tissue plasminogen activator.

When used with the addition of the active agent formulated with a compound of the present invention, the addition of surfactants generally by reference herein ^{[PHYSICIANS'DESK REFERENCE (PDR) 53 rd} Edition (1999)] or therapeutic amount of one of ordinary skill in the art given the It can be used in therapeutic amounts known to them.

Compounds of the invention and other therapeutically active agents may be administered in the recommended maximum clinical dose or in smaller amounts. The level of administration of the active compound in the compositions of the present invention may vary depending on the mode of administration, the severity of the disease and the patient's response to obtain the desired therapeutic response. The combination may be administered as a separate composition or as a single dosage form containing two agents. When administered in combination, the therapeutic agents may be formulated as separate compositions provided at the same time or at different times, or may be provided as a single composition.

One or more aspects described above of the present invention can be further understood in the following examples.

Example

Example  One

Characterization and Purification Methods

Compounds of the invention were characterized by high performance liquid chromatography (HPLC) using a Millennium Chromatography system from Waters, Milford, Mass., With a 2690 separation module. As an analytical column, Alltima C-18 reversible phase 4.6 x 250 mm from Alltech (Deerfield, Ill.) Was used. Gradient elution was generally used, starting with 5% acetonitrile / 95% water and treating with 100% acetonitrile over 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA). Compounds were detected at 220 nm or 254 nm with ultraviolet (UV) absorbance. HPLC solvents were either Burdick and Jackson (Muskegan, MI) or Fisher Scientific (Pittsburg, PA). In some cases, purity is measured by thin layer chromatography (TLC) using glass or plastic supported silica gel plates such as Baker-Flex Silica Gel 1B2-F flexible sheets. It was. TLC results were readily detected visually under ultraviolet light or using well known iodine vapors and various other staining techniques.

Mass spectrometry assays were performed on a Fisons VG Electrospray Mass Spectrometer. All masses were reported as the mass of the protonated parentions.

Nuclear magnetic resonance (NMR) analysis was performed with a Varian 300 MHz NMR (Varian: Palo Alto, CA). Spectral criteria were known chemical shifts of TMS or solvent. Some compound samples were handled at high temperatures (ie, 75 ° C.) to promote increased sample solubility.

The purity of some compounds of the invention was assayed by elemental analysis (Desert Analytics, Tucson, Arizona).

Melting points were measured with a Mel-Temp instrument from Laboratory Device (Holiston, Mass.).

Product separation was performed using Flash 40 chromatography system and KP-Sil, 60A (Biotage, Charlottesville, VA), Chromatotron radial Chromatography device (Harrison Research, Harrison Research, Palo Alto, CA). ) Or HPLC using a C-18 reversible phase column. Common solvents used were dichloromethane, methanol, ethyl acetate and triethyl amine.

Example 2

Solid phase synthesis of pyrimidine compounds (resin method A)

Step A: Knoevenagel Condensation

A suspension of benzaldehyde binding resin (lg, 0.52 mmol) in 8 ml of 1: 1 alcohol: dioxane was treated with 2.2 mole β-ketoester and 1.3 mmol amine such as piperidine. After the reaction mixture was shaken at room temperature for 20 minutes, the resin was filtered and washed with 4 x 10 ml dichloromethane (DCM).

Step B: Cyclization and Oxidation to the Pyrimidine Nucleus

The product from step A (100 mg, 0.052 mmol) was combined with 0.13 mmol NaHC0 ₃ and 0.26 mmol pyrazole carboxamidine hydrochloride in 1 ml N-methylpyrrolidinone. The reaction mixture was shaken at 70 ° C. for 24 hours. After cooling it, the reaction was washed with water, methanol, DMF, methylene chloride and ether and then dried. A small fraction of the resin showed that the desired dihydropyrimidine was present in high yield.

The dried resin was then taken up in THF and 1.1 equivalents of dicyanodichloroquinone (DDQ) was added. The resulting slurry was stirred for 0.5 h at which time the resin was washed with DMF, 10% Na ₂ HC0 ₃ , H ₂ O, dimethylformamide (DMF), methanol (MeOH), methylene chloride and ether and dried. A small fraction of the resin with trifluoroacetic acid / methylene chloride showed that pyrimidine was present in high yield.

Step C: Amine Substitution and Free from Solid Support

Pyrimidine (50 mg, 0.026 mmol) suspension in 0.75 ml NMP was treated with 1 mmol amine and 0.26 mmol acetic acid. The reaction mixture was shaken at 80 ° C. for 24 to 48 hours. After cooling, the resin was washed four times with methanol, DMF, and methylene chloride, respectively. The resin was then dried and 5% trifluoroacetic acid solution in methylene chloride was added. The resin was shaken for 2 hours, then filtered and washed three times with methylene chloride. The combined filtrates were concentrated and taken up in 1: 1 water / acetonitrile and lyophilized.

The following compounds of the invention were prepared according to Resin Method A using the ketoesters and amines specified in parentheses.

Ethyl 4- (4-carbamoylphenyl) -6-ethyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate) ( Prepared from ethyl 3-oxo-valorate and 2- (2-aminoethylamino) -5-nitropyridine: The compound is dehydrated with trifluoroacetic anhydride to give ethyl 4- (4-cyanophenyl) -6-ethyl- 2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxylate))

Ethyl 4- (4-carbamoylphenyl) -2-({2- [5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-pyridyl) pyrimidine-5-car Voxylate (prepared from ethyl 3- (4-pyridyl) -3-oxopropionate and 2- (2-aminoethylamino) -5-nitropyridine)

Ethyl 4- (4-carbamoylphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5- Carboxylate (prepared from ethyl 3- (4-nitrophenyl) -3-oxopropionate and 2- (2-aminoethylamino) -5-nitropyridine)

Example 3

Solid phase synthesis of pyrimidine compounds (resin method B)

Step 1: Sasrin resin (Bachem Biosciences, 5.0 g, slightly substituted 1.02 mmol / g) was shaken with triphenylphosphine dibromide in dry dichloromethane (60-70 ml) for 4 hours at room temperature. All solvents and glassware used to carry out this reaction were dried. The resin was washed with dichloromethane.

Step 2: The resin of step 1 was reacted with primary amine (0.5-1 M) in 1-methylpyrrolidone (NMP) at 70-80 ° C. for 3-5 hours to produce aminomethyl resin, amino Methyl resin was used as soon as it was produced. The resin was then washed thoroughly with dimethylsulfoxide (DMSO) (or DMF) and dichloromethane and then dried under vacuum.

Step 3: After drying, according to the method described in Example 10 (ie "Resin Method C"), provided that the cleavage of the product obtained from the resin was carried out under stronger acidic conditions, ie universally DCM 20-100% trifluoroacetic acid (TFA) in (eg, 60% TFA in DCM), the resin is benzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBop) ®, Nova Biochem, San Diego, Calif., Was used for overnight coupling with 4-acetylbenzoic acid.

Other types of resins having pendant CH ₂ 0H groups, such as Wang resin (Nova Biochem, San Diego, Calif.), Can be used to perform this method. It is also possible to load the primary amine on the solid support by other methods such as reductive amination of the solid support containing aldehydes.

Examples 4-9 describe the synthesis of the compounds of the present invention according to Resin Method B.

Example 4

N-{(3-bromophenyl) methyl] {4- [2-({3-[(5-nitro (2-pyridyl) amino] propyl} amino ) pyrimidin-4-yl] phenyl} carbox Synthesis of Voxamide

Step 1: A solution of 2-chloro-5-nitropyridine (3.16 g, 20 mmol) in dry acetylonitrile (40 ml) at room temperature dropwise in 1,3-diaminopropane (5.0 ml) in acetylonitrile (20 ml) To the solution. After 7.5 hours, a yellow solid precipitated out of the reaction mixture. The solvent was removed in vacuo and the residue was partitioned between 2.5 M aqueous sodium hydroxide solution and dichloromethane. The layers were separated and the aqueous portion extracted three times with dichloromethane. The combined organic layers were extracted again with saturated sodium chloride solution, then dried and concentrated in vacuo using a Buchi rotary evaporator model R-124 to give (3-aminopropyl) (5-nitro (2-pyridyl) as a yellow solid. )) Amine (2.55 g) was obtained. Amines (1.14 g, 6 mmol) and benzotriazole carboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and diisopropylethyl amine (DIEA) (1.05) in acetylonitrile (10 ml) at room temperature for 2 days. ml, 6 mmol). Dilution with ether gave amino- {3-[(5-nitro (2-pyridyl)) amino] propyl} carboxamidinium 4-methylbenzenesulfonate as a solid.

Step 2: Sasrin resin (10 g) was shaken with triphenylphosphine dibromide (4.5 g) in dry dichloromethane (ca. 80 ml) for 4 hours at room temperature. The resin was washed with dichloromethane and simply air dried. The air dried resin was separated into six equal parts. One portion was heated with a solution of 3-bromobenzylamine (8 mmol) in NMP (12 ml) at 70 ° C. for 4 hours. The resin was washed with DMF and dichloromethane and dried under vacuum at room temperature. The dried resin was shaken with PyBop® (3.12 g, 6 mmol), 4-acetylbenzoic acid (1.0 g, 6 mmol), and 4-methylmorpholine (12 mmol) solution in NMP (12 ml) overnight at room temperature. The resin was washed with DMF, DMSO and dichloromethane and simply air dried. The resin was then heated with N, N-dimethylformamide dimethylacetal (10 ml) at 95 ° C. for 9 hours. After cooling, the resin was washed with dichloromethane and dried under vacuum at room temperature. Thereafter, the resin (80 mg) was reacted with cesium carbonate (160 mg) in NMP (2 ml) and 100 mg of guadinin prepared in Step 1 overnight at 95 ° C., and then partitioned into 60% TFA in dichloromethane and {(3bromophenyl) methyl] {4- [2-({3-[(5-nitro (2-pyridyl) amino] propyl} amino) pyrimidin-4-yl] phenyl} carboxamide It was.

HPLC: 25.31 min (98% purity); MS: MH <+> = 562/564 (1 Br); C ₂₆ H ₂₄ N ₇ BrO ₃ = 561/563 g / mol.

Example 5

N-{(3-bromophenyl) methyl] {4- (2-({2-[(5-cyano (2-pyridyl) amino] ethyl} amino) pyrimidin -4-yl] phenyl} carbox Synthesis of Voxamide

Step 1: 6-chloronicotinnitrile (2.0 g) was treated with ethylenediamine (5 ml). The mixture was then heated at 50 ° C. for 22 hours. Excess was removed by rotary evaporation of ethylenediamine. The residue was partitioned between 2.5 M aqueous sodium hydroxide solution and dichloromethane. The aqueous layer was extracted four more times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried and concentrated in vacuo to afford 6-[(2-aminoethyl) amino] pyridine-3-carbonitrile as a tan liquid which became solid when left. The amine (0.97 g, 6 mmol) was shaken overnight with DIEA (1.05 ml, 6 mmol) and benzotriazolecarboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) in acetonitrile (10 ml). Ether was added to afford amino {2-[(5-cyano (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate as a white solid.

Step 2: Guadinin (120 mg) obtained from Step 1 was reacted with the resin prepared in Step 2 of Example 4 in the presence of cesium carbonate (160 mg) in NMP (2 ml) overnight at 90 ° C. Treatment of the resin with 60% TFA in dichloromethane gave the title compound.

HPLC: 23.70 min (98% purity)

MS: MH <+> 528/530 (1 Br) C ₂₆ H ₂₂ N ₇ BrO = 527/529 g / mole

Example 6

N-[(3-methoxyphenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} Carboxamide

Step 1: 2- (2-aminoethylamino) -5-nitropyridine (Aldrich Chemical Co., Milwaukee, Wisconsin) (1.08 g, 6 mol) was charged with acetonitrile (10 ml) and The mixture was shaken overnight at room temperature with DIEA (1.05 ml, 6 mmol) and benzotriazolecarboxamidinium 4-methylbenzenesulfonate (2.0 gm, 6 mmol) in DMF (3 ml). Ether was added to afford amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate as light orange crystals.

Step 2: Sasrin resin was prepared as described in Step 2 of Example 3. The resin (500 mg) was heated with a solution of 3-methoxybenzylamine (600 μl) in NMP (6 ml) at 70 ° C. for 4 hours. The resin was then washed with DMF and dichloromethane and washed with PyBop® (1.04 g, 2 mmol), 4-acetylbenzoic acid (0.33 g, 2 mmol), 4-methylmorpholine (4 mmol) in NMP (6 ml) overnight at room temperature. Shake with solution. A small amount of resin was treated with 20% TFA in dichloromethane to afford (4-acetylphenyl) -N-[(3-methoxyphenyl) methyl] carboxamide (HPLC: 23.94 min (97%) as an intermediate); MH ⁺ = 284 (as required)). The resin was then heated in DMFDMA (5 ml) at 95 ° C. for 7 hours.

After heating, the resin was washed with dichloromethane and then dried under vacuum. The dried resin (120 mg) was reacted with cesium carbonate (160 mg) in NMP (2 ml) overnight at 90 ° C. and 120 mg of guanidine prepared in step 1. Splitting with 20% TFA in dichloromethane gave the title compound.

HPLC: 22.32 min (85% purity)

MS: MH ⁺ = 500 C ₂₆ H ₂₅ N ₇ 0 ₄ = 499 g / mole

Example 7

Synthesis of (2-{[3- (4-nitroimidazolyl) propyl] amino} pyrimidin-4-yl) phenol

Step 1: 4-nitroimidazole (5.0 g, 44 mol) in DMF: THF (1: 1 (v / v), 40 ml) was treated with 60% NaH (2.2 g) at room temperature. When hydrogen evolution ceased, 3-bromopropylphthalimide (11.79 g, 44 mmol) was added and then heated at 70 ° C. overnight. The mixture was cooled, diluted with dichloromethane and carefully quenched with water. At this time, the solid product was precipitated to obtain 8.85 g of 2- [3- (4-nitroimidazolyl) propyl] isoindolin-1, 3-dione as a white solid. This solid was refluxed with methanol (60 ml) and anhydrous hydrazine (4 ml). The mixture was cooled to 4 ° C. and then filtered. The filtrate was concentrated to dryness and then partitioned between dichloromethane and 2.5M aqueous sodium hydroxide solution. The organic phase was washed with saturated sodium chloride solution, dried and concentrated in vacuo to yield 2.24 g of 3- (4-nitroimidazolyl) propylamine as an orange syrup. 1.18 g of amine was treated with DIEA (1.5 ml) and benzotriazolecarboxamidinium 4-methylbenzenesulfonate (2.2 g) in acetylonitrile (8 ml) with shaking overnight at room temperature. Ether was added to afford amino [3- (4-nitroimidazolyl) propyl] carboxamidinium 4-methylbenzenesulfonate as a beige solid.

Step 2: Sasrin resin (prepared according to Step 2 of Example 3) (2.5 g) was mixed with cesium carbonate (600 mg) and 4-hydroxyacetophenone (700 mg) in NMP (10 ml) for 24 hours at 80 ° C. Heated together. The resin was then washed with DMF, water, DMF and dichloromethane and dried under vacuum. The dried resin was then heated with DMFDMA (10 ml) overnight at 105 ° C. The resin was cooled down, filtered, washed with dichloromethane and dried under vacuum. Thereafter, the dried resin (100 mg) was treated with 100 mg of guanidine prepared in Step 1, 1,200 mg of cesium carbonate and 3 ml of NMP for 66 hours at 105 ° C. The resin was washed with DMSO, acetic acid, water, DMSO and dichloromethane, then shaken with 100% TFA for 1 hour and filtered. The filtrate was concentrated in vacuo and freeze dried to afford the title compound.

HPLC: 16.85 min (75% purity)

MS: MH ⁺ = 341 C ₁₆ H ₁₆ N ₆ 0 ₃ = 340 g / mol

Example 8

Synthesis of 4- [2- (2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -5-phenylpyrimidin-4-yl] phenol

0.9 g of bromomethyl sasrin resin (prepared according to step 2 of Example 3) with cesium carbonate (1.6 g) and benzyl 4-hydroxyphenyl ketone (1.06 g, 5 mmol) in NMP (8 ml) overnight at 80 ° C. Heated together. The resin was washed successively with DMF, water, DMF and dichloromethane and then dried under vacuum. The dried resin was heated with DMFDMA (8 ml) overnight at 100 ° C. After cooling, the resin was filtered off, washed with dichloromethane and dried under vacuum. Thereafter, the resin (75 mg) was subjected to 200 mg of cesium carbonate and amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidinium 4-methyl in NMP (2 ml) for 64 hours at 104 ° C. It was reacted with 100 mg of benzenesulfonate. The resin was then washed with DMSO, acetic acid, water, DMSO and dichloromethane. The resin was shaken with 100% TFA for 1 hour at room temperature. (1 h). The resin was filtered and concentrated in vacuo and then lyophilized to afford the title compound.

HPLC: 22.53 min (95% purity)

MS: MH ⁺ = 429 C ₂₃ H ₂₀ N ₆ 0 ₃ = 428 g / mol

Example 9

[(3-bromophenyl) methyl] ({4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin -4-yl] phenyl} sulfonyl Synthesis of Amine

Step 1: 4-acetylbenzenesulfonyl chloride in dichloromethane (10 ml) while shaking Sasrin resin (500 mg) (prepared according to step 1 of Example 3) substituted with m-bromobenzylamine for 0.5 hour at room temperature (1.1 g, 5 mmol) and DIEA (1.22 ml, 7 mmol). 4-dimethylaminopyridine (122 mg, 1 mmol) was added and shaken overnight at room temperature. The resin was washed with DMF and dichloromethane and then heated with DMFDMA (10 ml) at 95 ° C. overnight. The resin was washed with dichloromethane and dried under vacuum at room temperature.

Step 2: The resin prepared in step 1 (70 mg) was cesium carbonate (160 mg) and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidi in NMP (2 ml) overnight at 95 ° C. overnight. Treatment with nium 4-methylbenzenesulfonate (100 mg) The resin was washed successively with DMSO, acetic acid, water, DMSO, dichloromethane and then with 60% TFA in dichloromethane for 0.5 h at room temperature. Was filtered and the filtrate was concentrated in vacuo and then lyophilized to afford the title compound.

HPLC: 26.62 min (100% purity)

MS: MH ⁺ = 584/586 C ₂₄ H ₂₂ N ₇ BrO ₄ S = 583/585 g / mol (1 Br)

The following additional compounds were similarly synthesized according to Resin Method B by various uses of guanidine.

4- (2-{[2- (4-nitrophenyl) ethyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} benzamide

4- {2-[(4-pyridylmethyl) amino] pyrimidin-4-yl} benzamide

4- [2-({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzamide

4- (2-{[2- (pyrimidin-2-ylamino) ethyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(3-imidazol-5-ylethyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[2- (benzothiazol-2-ylamino) ethyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(2-{[5- (trifluoromethyl) -2-pyridyl] amino} ethyl) amino] pyrimidin-4-yl} benzamide

4- [2-({2-[(5-cyano-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzamide

4- {2-[(2-{[5- (aminothioxomethyl) -2-pyridyl] amino} ethyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[(3-bromophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- [2-({[4- (4-fluorophenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide

4- {2- [4-benzylpiperazinyl] pyrimidin-4-yl} benzamide

4- (2-{[(5-methylpyrazin-2-yl) methyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(3-imidazolylpropyl) amino] pyrimidin-4-yl} benzamide

4- {2-[(2,2-diphenylethyl) amino] pyrimidin-4-yl} benzamide

 4- [2-({[3- (trifluoromethyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide

4- (2-{[(3-nitrophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(naphthylmethyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[(4-bromophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(3,5-dichlorophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(3-methoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- [2-({[3- (3-methoxyphenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide

4- [2-({[3- (3-aminophenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide

4- {2-[({3- [3- (acetylamino) phenyl] phenyl} methyl) amino] pyrimidin-4-yl} benzamide

4- [2-({[4- (3-aminophenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide

4- (2-{[(3-chlorophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(2,4-dichlorophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(3-methylphenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(3,4-dimethoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- [2-({[4- (trifluoromethyl) phenyl] methyl} amino) pyrimidin-4-yl) benzamide

4- (2- {[(4-methoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(4-aminophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- [2-({[3, 5-bis (trifluoromethyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide

4- {2- [4- (2-methoxyphenyl) piperazinyl] pyrimidin-4-yl} benzamide

4- {2-[({3- [3- (trifluoromethyl) phenyl] phenyl} methyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[2- (3-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[2- (4-fluorophenyl) ethyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(3,4,5-trimethoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide

{4- [2-({2-[(4-amino-5-cyanopyrimidin-2-yl) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-[(3-bro Mophenyl) methyl] carboxamide

4- [2-({2-[(4-amino-5-cyanopyrimidin-2-yl) amino] ethyl} amino) pyrimidin-4-yl] benzamide

4- [2-({3-[(5-nitro-2-pyridyl) amino] propyl} amino) pyrimidin-4-yl] benzamide

4- (2-{[(4-cyanophenyl) methyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(2-phenylpropyl) amino] pyrimidin-4-yl} benzamide

4- {2-[(2-phenoxyethyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[2- (2,5-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[(2,6-dimethoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide

4-{[2- (2-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(4-phenylbutyl) amino] pyrimidin-4-yl} benzamide

4- {2-[(2- (2H-benzo [3,4-d] 1,3-dioxolen-5-yl) ethyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[2- (3-chlorophenyl) ethyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[2- (2,3-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(3-phenoxypropyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[3- (4-chlorophenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (4-methoxyphenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (3-methoxyphenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (3-bromophenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (2,4-dichlorophenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- [2-({3- [3- (trifluoromethyl) phenoxy] propyl} amino) pyrimidin-4-yl] benzamide

4- (2-{[3- (3-methylphenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (4-phenylimidazolyl) propyl] amino} pyrimidin- 4-yl) benzamide

4- (2-{[3- (5,6-dichlorobenzimidazolyl) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (3,4-dichlorophenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (5, 6-dimethylbenzimidazolyl) propyl] amino} pyrimidin-4-yl) benzamide

4-2-[(3- (6-quinolyloxy) propyl) amino] pyrimidin-4-yl} benzamide

4- {2-[(3-naphthyloxypropyl) amino] pyrimidin-4-yl} benzamide

4- (2-{[3- (3-phenylphenoxy) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (4-nitroimidazolyl) propyl] amino} pyrimidin-4-yl) benzamide

4- (2-{[3- (4, 5-dichloroimidazolyl) propyl] amino} pyrimidin-4-yl) benzamide

4- {2-[(3-benzimidazolylpropyl) amino] pyrimidin-4-yl} -2-chlorophenol

4- [2-({3- [4- (2,4-dichlorophenyl) imidazolyl] propyl} amino) pyrimidin-4-yl] benzamide

4- [2-({3- [4- (3-methoxyphenyl) imidazolyl] propyl} amino) pyrimidin-4-yl] benzamide

Example 10

Solid Phase Synthesis of Pyridine Compound (Resin Method C)

Link amide resin (Novabiochem, San Diego, Calif., Normally 0.46 mmol / g substitution) was deprotected with 20% v / v piperidine in DMF (about 60 ml) at room temperature for 0.5 hours. The resin was washed thoroughly with DMF and dichloromethane, then 4-acetylbenzoic acid (8 mmol), PyBOP® (8 mmol, Nova Biochem), 4-methylmorpholine (12 mmol) for 8.5 hours at room temperature on a wist shaker. And NMP (50 ml). The resin was washed with DMF and dichloromethane, air dried and separated into three portions. Each portion was treated with N, N-dimethylformamide dimethyl acetal (about 12 ml) while heating at 105 ° C. overnight (about 13 hours). The reaction was cooled and the resin washed with dichloromethane and then dried under vacuum at room temperature.

For the synthesis of pyrimidine, 100 mg of the dried resin was generally mixed with 200-300 mg of anhydrous cesium carbonate and 80-200 mg of the most suitable guanidine (most commonly 100 mg) as the tosylate salt and 2-3 ml of NMP. This mixture was heated at 90-105 ° C. for at least 12 hours. In many cases, the reaction was treated at this temperature for about 65 hours. The resin was cooled, filtered and washed with DMSO, glacial acetic acid, water, DMSO and finally dichloromethane. The product was removed by treating the resin with 95: 5 v / v dichloromethane / TFA for 0.5-1 hour at room temperature. The resin was filtered off, washed with dichloromethane and the filtrate was concentrated on a rotary evaporator. The quota was discarded by HPLC analysis and the remainder of the sample was lyophilized twice from the 1: 1 acetylonitrile: water solvent mixture to give pyrimidine as a fluffy solid.

Examples 11-16 describe methods for synthesizing the compounds of the present invention according to Resin Method C.

Example 11

Synthesis of 4- (2- {2- (2-pyridylamino) ethyl] amino, pyrimidin-4-yl) benzamide

Prepared from 2-chloropyridine and ethylenediamine according to the method described in 2- (2-aminoethylamino) pyridine (T. Mega et al, 1988, Bull. Chem. Soc. Japan 61: 4315). (6 mmol) was treated with benzotriazolecarboxamidinium 4-methylbenzenesulfonatesulfonate (2.0 g, 6 mmol) and DIEA (1.05 ml, 6 mmol) in anhydrous acetylonitrile (10 ml) for 65 hours. Then ether (about 10 ml) was added to this mixture. After 8 hours, the white solid amino [2- (2-pyridylamino) ethyl] carboxamidinium 4-methylbenzenesulfonate was filtered off and dried under vacuum. The resulting guanidine (200 mg) was reacted with 100 mg of resin (21 hours, 90 ° C.) according to the method described in Example 10 (Resin Method C) to give the title compound.

HPLC: 11.20 min (97% purity)

MS: MH ⁺ = 335 C ₁₈ H ₁₈ N ₆ 0 = 334 g / mol

Example 12

Synthesis of 4- (2-{[2- (2-quinolylamino) ethyl] amino} -pyrimidin-4-yl) benzamide

2-chloroquinoline (7.0 g) was heated with ethylenediamine (50 ml) at 120 ° C. under argon for 6 hours. Excess ethylenediamine was removed by rotary evaporation (oil pump). The residue was taken up in 2.5 M aqueous sodium hydroxide solution and extracted six times with dichloromethane. The combined organic layers were washed with a small amount of saturated aqueous NaCl solution, dried over Na ₂ SO ₄ and concentrated in vacuo. 0.55 g (3 mmol) of viscous product was stirred with benzotriazolecarboxamidinium 4-methylbenzenesulfonate (1.0 g, 3 mmol), DIEA (0.78 ml, 4.5 mmol) and acetylonitrile (8 ml) with shaking at room temperature overnight. Treated. Precipitation with ether gave amino [2- (2-quinolylamino) ethyl] carboxamidinium 4-methylbenzenesulfonate. The resulting guanidine (200 mg) was reacted with 100 mg of resin (21 hours, 90 ° C.) according to the method described in Example 10 (ie Resin Method C) to afford the title compound.

HPLC: 12.04 min (95% purity)

MS: MH ⁺ = 385 C ₂₂ H ₂₀ N ₆ 0 = 384 g / mol

Example 13

Synthesis of 4- [2-({2- [6-methoxy-2-pyridyl) amino] -ethyl} amino) pyrimidin-4-yl] benzamide

2-chloro-6-methoxypyridine (5.0 g) was heated with ethylenediamine (30 ml) overnight at 120 ° C. Excess ethylenediamine was removed by rotary evaporation. The residue was dissolved in a small amount of 2.5 M aqueous sodium hydroxide solution and extracted thoroughly with dichloromethane. The combined organic layers were washed with saturated sodium chloride, dried over sodium sulfate and concentrated in vacuo to give (2-aminoethyl) (6-methoxy (2-pyridyl) amine as an orange syrup. Was treated with DIEA (0.45 mmol) and benzotriazolecarboxamidinium 4-methylbenzenesulfonate (0.86 g) in acetylonitrile (6 ml) and stirred overnight at room temperature Precipitating with ether, guanidine, amino as oil -{2-[(6-methoxy (2-pyridyl)) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate was obtained 100 mg of resin according to Resin Method C was converted to guanidine (200 mg) in oil state. Reaction with (90 ° C., overnight) afforded the title compound.

HPLC: 11.84 min (85% purity)

MS: MH ⁺ = 365 C ₁₉ H ₂₀ N ₆ 0 ₂ = 364 g / mol

Example 14

Synthesis of 4- {2-[(3-benzimidazolylpropyl) amino] -pyrimidin-4-yl} benzamide

Benzimidazole (2.4 g, 20 mmol) in dry THF (40 ml) was treated with 60% NaH in oil (0.96 g) at room temperature. After the hydrogen evolution stopped, 3-bromopropylphthalimide (5.36 g, 20 mmol) was added and the mixture was heated at 80 ° C. overnight. The reaction was cooled, diluted with dichloromethane and water and then extracted twice with 5% aqueous potassium carbonate solution. The organic layer was dried over sodium sulfate and concentrated in vacuo to yield 4.1 g of a beige solid. This solid was dissolved in methanol (60 ml) and treated with anhydrous hydrazine (4.0 ml) and then refluxed for 4 hours. The mixture was cooled at 4 ° C. for several hours and then filtered. The filtrate was concentrated in vacuo. The residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide solution. The organic layer was washed with saturated sodium chloride solution, dried over sodium sulfate and concentrated in vacuo to yield 1.1 g of 3-benzimidazolpropyl amine as a pale pink oil. This amine (1.03 g, 6 mmol) was reacted with benzotriazolecarboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and DIEA (1.39 ml) in acetylonitrile (8 ml) overnight at room temperature to give amino (3 -Benzimidazolylpropyl) carboxamidinium 4-methylbenzenesulfonate was obtained, which was obtained as a beige solid after repeated precipitation with ether. Guanidine (100 mg) was reacted with 100 mg of resin (65 hours, 105 ° C.) according to the method described in Example 10 (ie Resin Method C) to afford the title compound.

HPLC: 12.12 min (95% purity)

MS: MH ⁺ = 373 C ₂₁ H ₂₀ N ₆ O = 372 g / mol

Example 15

Synthesis of 4- {2-[(3- (2-naphthyloxy) propyl) amino] pyrimidin-4-yl) benzamide

2-naphthol (2.9 g, 20 mmol) in dry THF (40 ml) was treated with 60% NaH suspension (0.96 g) at room temperature. After the hydrogen evolution stopped, 3-bromopropylphthalimide (5.36 g, 20 mmol) was added and the mixture was heated at 80 ° C overnight. The reaction was cooled and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted three times with ethyl acetate. The combined organic layers were extracted five times with 5% aqueous potassium carbonate solution, dried over sodium sulfate and concentrated in vacuo. The crude product (observed as single point in TLC) was taken up in methanol (60 ml), treated with anhydrous hydrazine (4 ml) and refluxed for 3.5 h. The mixture was cooled to 4 ° C. for several hours and then dried. The filtrate was concentrated to dryness and then partitioned between dichloromethane and 2.5M aqueous sodium hydroxide solution. The organic layer was washed with saturated sodium chloride solution, dried and concentrated in vacuo to yield 1.14 g of 3- (2-naphthyloxy) propyl amine as a beige solid. The amine (1.14 g, 5.7 mmol) was added to benzotriazolecarboxamidinium 4-methylbenzenesulfonate (1.89 g, 5.7 mmol) and DIEA (1.39) in acetylonitrile (8 ml) and DMF (2 ml) with shaking at room temperature overnight. ml). Precipitation with ether gave amino (3- (2-naphthyloxy) propyl) carboxamidinium 4-methylbenzenesulfonate as a solid of white crystals. This guanidine (100 mg) was reacted with resin (100 mg) according to the method described in Example 10 (ie Resin Method C) to afford the title compound.

HPLC: 22.52 minutes (95% purity)

MS: MH ⁺ = 399 C ₂₄ H ₂₂ N ₄ 0 ₂ = 398 g / mol

Example 16

Synthesis of N- (1-carbamoyl-2-phenylethyl) (4-2-{(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} phenyl) carboxamide

This example provides a modification of the resin method C in which the pyrimidine is linked to the α-amino resin residue.

Step 1: Link amide resin (1.5 g) was deprotected with 20% piperidine in DMF (1 x 0.5 h). The resin was washed with DMF and then stirred for 2 hours at room temperature with FMOC (L) -phenylalanine (5.0 mmol), 1-hydroxybenzotriazole (5.0 mmol) and diisopropylcarbodiimide (5.0) in DMF (10 ml). mmol). The resin was washed with DMF and then treated with 20% piperidine in DMF (1 × 30 min). The resin was washed with DMF and then treated with PyBop® (5 mmol), 4-methylmorpholine (8 mmol) and 4-acetylbenzoic acid (5 mmol) in NMP (10 ml). After 5 hours at room temperature, the negative ninhydrin test indicated completion of the reaction. The resin was washed with DMF and dichloromethane, air dried and heated with DMFDMA overnight at 110 ° C. The resin was then washed with dichloromethane and dried under vacuum at room temperature.

Step 2: The resin (150 mg) prepared in step 1 was subjected to amino (2- (2-pyridyl) ethyl) carboxamidinium 4-methylbenzenesulfonate (200 mg) and carbonic acid in NMP (2 ml) overnight at 85 ° C. Treatment with cesium (160 mg). The resin was washed with DMF and dichloromethane and then treated with 5% TFA in dichloromethane. The resin was filtered off, the filtrate was concentrated and lyophilized to afford the title compound.

HPLC: 15.08 min (95% purity)

MS: MH ⁺ = 467 C ₂₇ H ₂₆ N ₆ 0 ₂ = 466 g / mol

The following additional compounds were similarly synthesized according to Resin Method C by using various guanidines.

N-benzyl (4- {2-[(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} phenyl) carboxamide

Benzyl {[4- (2- {[2- (2-pyridylamino) ethyl] amino} pyrimidin-4-yl) phenyl] sulfonyl} amine

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-benzylcarboxamide]

 {4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N benzylcarboxamide

N-[(4-fluorophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Voxamide

N-[(3-bromophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} Carboxamide

N- (2-methoxyethyl) {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide

N- (naphthylmethyl) {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-{[3- (trifluoromethyl) Phenyl] methyl} carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (2-phenylethyl) carboxamide

N-[(4-methoxyphenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Voxamide

N-[(3-methoxyphenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Voxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (oxolane-2 -ylmethyl) car Voxamide

N-[(5-methylpyrazin-2-yl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] Phenyl} carboxamide

N- (2,2-diphenylethyl) {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4yl] phenyl} carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (4-piperidylmethyl) car Voxamide

N- [2- (2,4-dichlorophenyl) ethyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] Phenyl} carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (3-pyridylmethyl) carboxamide

 N- (3-imidazolylpropyl) {4- [2-({2-[(S-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (2 thienylmethyl) carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-[(3-nitrophenyl) methyl] car Voxamide

N-[(3-methylphenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-[(4- sulfamoylphenyl) methyl] Carboxamide

{4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-[(3-bromo Phenyl) methyl] carboxamide

N-[(3,5-dichlorophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} Carboxamide

N-[(3,4-difluorophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl Phenyl} carboxamide

N-[(4-bromophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Voxamide

N-[(2, 3-dimethoxyphenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl } Carboxamide

N-[(3-fluorophenyl) methyl] {4- [2- (12-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox amides

N-[(3-bromophenyl) methyl] {4- [2-({2-[(6-methoxy (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} Carboxamide

[4- (2- {[(3-bromophenyl) methyl] amino} pyrimidin-4-yl) phenyl] -N-[(3- methylphenyl) methyl] carboxamide

N-[(3-bromophenyl) methyl] {4- [2-({2-[(5-cyano (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} Carboxamide

 4- (2-{[(3- {3-[(methylamino) methyl] phenyl} phenyl) methyl] amino} pyrimidin-4-yl) benzamide

N-[(3-bromophenyl) methyl] (4- {2-[(3-imidazolylpropyl) amino] pyrimidin-4-yl} phenyl) carboxamide

N-[(3-bromophenyl) methyl] [4- {[2- (2-quinolylamino) ethyl] amino} pyrimidin-4-yl) phenyl] carboxamide

N-[(3-bromophenyl) methyl] {4- [2-({2-[(4-nitrophenyl) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide

N-[(3-bromophenyl) methyl] (4- {2-[(2-{[5- (trifluoromethyl) (2-pyridyl) amino} ethyl) amino] pyrimidin-4-yl } Phenyl) carboxamide

N-[(3-bromophenyl) methyl] [4- {[2- (pyrimidin-2-ylamino) ethyl] amino} pyrimidin-4-yl) phenyl] carboxamide

N-[(3-chlorophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox amides

N-[(3,4-dimethoxyphenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl } Carboxamide

N-[(3,4-dichlorophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} Carboxamide

[(3-bromophenyl) methyl] ({4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} sulfonyl ) Amine

N-[(3-iodophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox amides

[4- (2-{[2- (2,5-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) phenyl] -N-[(3-bromophenyl) methyl] carboxamide

N-[(3-bromophenyl) methyl] [4- (2-{[2- (3-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) phenyl] carboxamide

{4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (2-phenylcyclopropyl) carbox amides

3- [2-({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] phenol

4- [2-({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] phenol

4- {2-[(3-phenoxypropyl) amino] pyrimidin-4-yl} phenol

4- (2-{[3- (4-chlorophenoxy) propyl] amino} pyrimidin-4-yl) phenol

4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -5-phenylpyrimidin-4-yl] phenol

4- {2- [3-benzimidazolylpropyl) amino] pyrimidin-4-yl} phenol

4- {2-[(3-benzimidazolylpropyl) amino] pyrimidin-4-yl} -2-methoxyphenol

4- (2-{[3- (4-nitroimidazolyl) propyl] amino} pyrimidin-4-yl) phenol

4- (2-{[3- (2-aminobenzimidazolyl) propyl] amino} pyrimidin-4-yl) phenol

4- (2-{[3- (4, 5-dichloroimidazolyl) propyl] amino} pyrimidin-4-yl) phenol

Example 17

Solid phase synthesis of pyrimidine compounds (resin method D)

The primary amine was loaded onto the sardine resin as in Example 3 (ie Resin Method B). This amine resin was then added overnight to 2,4-dichloropyrimidine or ethyl 2,4 dichloropyrimidine-5-carboxylate (200 mg pyrimidine / 200 mg amine resin) and cesium carbonate (250 mg) in NMP (3 ml). Heating). The resin was washed with a suitable solvent (usually DMF or DMSO and dichloromethane) and then reacted with a second amine (eg, primary or secondary amine. The second amine substitution is typically carried out at high temperature in NMP, eg For example, it was performed for 48 hours at 120 to 130 ° C. The resin was washed again and treated with 100% TFA for 0.5 to 1 hour to obtain 2,4-diaminopyrimidine, which was often frozen from a mixture of acetonitrile and water. Obtained as a solid after drying.

Examples 18 and 19 describe the synthesis of the compounds of the present invention according to Resin Method D.

Example 18

Synthesis of [(3-chlorophenyl) methyl) [2-({2-[(5-nitro (2-pyridyl)) amino] -ethyl} amino) pyrimidin -4-yl] amine

The bromomethyl sasrin resin (prepared as in step 1 of Example 3, 0.9 g) was heated with 3-chlorobenzylamine (1 ml) in NMP (8 ml) at 80 ° C. for 1.5 hours and then at room temperature overnight. It was left. The resin was washed with DMF and dichloromethane and dried under vacuum. The dried resin (200 mg) was heated at 80 ° C. overnight with 250 mg of cesium carbonate and 2,4-dichloropyrimidine in NMP (3 ml) overnight. The resin was washed as before. Half of the resin was heated at 125 ° C. for 66 hours with 2- (2-aminoethylamino) -5-nitropyridine (180 mg, 1 mmol) in NMP (2 ml). The resin was washed as before and treated with 100% TFA for 0.5 hours. The resin was filtered and the filtrate was concentrated in vacuo and then lyophilized from acetylonitrile and water to give the title compound as a yellow solid.

HPLC: 23.46 min (82% purity)

MS: MH ⁺ = 400 C ₁₈ H ₁₈ ClN ₇ 0 ₂ = 399 g / mol

Example 19

Synthesis of ethyl-4- (3-cyanophenyl) methyl] amino}-2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxylate

Bromomethyl sasrin resin (prepared as in Step 1 of Example 3, 1.0 g) was reacted with 4-cyanobenzylamine (1.5 ml) in NMP (8 ml) at 80 ° C. for 4 hours. The resin was washed with DMF and dichloromethane and dried under vacuum at room temperature. The dried resin (400 mg) was cesium carbonate (400 mg) and ethyl 2,4-dichloropyrimidine-5-carboxylate in NMP (4 ml) overnight at 80 ° C. (VH Smith and BE ° C. stensten, J. Organic Chem., 20: 829 (1955)] (400 mg). The resin was washed and dried as before. The dried resin (200 mg) was then heated with 2- (2-aminoethylamino) -5-nitropyridine (180 mg, 1 mmol) in NMP (2 ml) at 104 ° C. for 21 hours. The resin was washed with DMSO, glacial acetic acid, water, DMSO, dichloromethane and treated with 100% TFA to afford the title compound.

HPLC: 25.27 min (100% purity)

MS: MH ⁺ = 463 C ₂₂ H ₂₂ N ₈ 0 ₄ = 462 g / mol

The following addition compounds were prepared according to Resin Method D using suitable amines.

(4-{[(3-bromophenyl) methyl] amino} pyrimidin-2-yl) {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

[(2, 4-dichlorophenyl) methyl] [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] amine

[(3-methylphenyl) methyl] [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] amine

 [(3,5-dichlorophenyl) methyl] (2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] amine

Ethyl 4-{[(3-bromophenyl) methyl] amino} -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

[2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzylamine

[(4-chlorophenyl) methyl] [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] amine

Ethyl 4- {[(2-chlorophenyl) methyl] amino} -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4-{[(4-cyanophenyl) methyl] amino} -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Example 20

Solid Phase Synthesis of Pyridine Compound (Resin Method E)

Amino resins (e.g., sasrin resin loaded with primary amines as described in Resin Methods B (Example 3) and D (Example 18)) at a temperature of about 25-50 ° C. from about 5 to about Reaction with cesium carbonate and 2,6-dichloro3-nitropyridine in NMP for 24 hours. The resin was then washed with DMF and dichloromethane and heated with primary amine in NMP overnight at 70-100 ° C. The resin was washed as described in Example 18 and the pyridine product was obtained by treating the resin with 20-100% TFA (preferably 80-100% TFA) for 0.5-1 hour.

Example 21 describes a method for synthesizing the compound of the present invention according to Resin Method E.

Example 21

Synthesis of {2-[(6-amino-5-nitro (2-pyridyl) amino] ethyl}-{5-nitro-6- [benzylamino] (2- pyridyl)} amine

Step 1: 2,6-dichloro-3-nitropyridine according to the method of 2-amino-6-chloro-3-nitropyridine (VW von Bebenberg, Chemiker-Zeitimg, 103: 387 (1979)). (2.65 g) was treated with ethylenediamine (5 ml) at room temperature. The temperature was gradually increased to 100 ° C. After 4 hours, excess ethylenediamine was removed by rotary evaporation. The residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide solution. The aqueous layer was further extracted three times with dichloromethane. The combined organic layers were concentrated in vacuo to afford (2-aminoethyl) (6-amino-5-nitro (2-pyridyl)) amine as a yellowish solid.

Step 2: The bromomethyl sasrin resin prepared according to Step 1 of Example 3 was heated with NMP (6 ml) of benzylamine (2 ml) at 70 ° C. for 4 hours. The resin was washed with DMF and dichloromethane and dried under vacuum. The dried resin (100 mg) was heated at 50 ° C. for 5.5 hours with cesium carbonate (100 mg) and 2,6-dichloro-3-nitropyridine (190 mg, 1 mmol) in NMP (2 ml). The resin was then washed with water, DMF and dichloromethane. The resin was air dried and then heated at 95 ° C. overnight with amine (90 mg) from Step 1 in NMP (2 ml). The resin was washed with DMSO, acetic acid, water, DMSO, dichloromethane and treated with 20% TFA to afford the title compound.

HPLC: 28.47 min (87% purity)

NMR: (300 MHz, 7/1 acetylonitrile-d ₃ / D ₂ O, 75 ° C .: 8.0 (2H, double overlap d), 7.2-7.4 (5H, Ph), 5.9 (2H, 2d overlap), 4.75 (s, 2H), 3.50-3.65 (m, 4H)

The following addition compounds were similarly prepared according to Resin Method E by using various pyridine and primary amines.

{2-[(5-nitro (2-pyridyl)) amino] ethyl} {5-nitro-6- [benzylamino] (2-pyridyl)} amine

6-{[2- ({5-nitro-6- [benzylamino] -2-pyridyl} amino) ethyl] amino} pyridine-3-carbonitrile

{6-[(2-methoxyethyl) amino] -5-nitro (2-pyridyl)} {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

(6-{[(2,4-dichlorophenyl) methyl] amino} -5-nitro (2-pyridyl)) {2-[(5-nitro (2-pyridyl))-amino] ethyl} amine.

Example 22

Synthesis of 4- [2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -5- [benzylamino] pyrimidin-4-yl ] benzenecarbonitrile (resin method F)

Benzylamine was reacted with bromomethyl sasrin resin to yield a benzylamine substituted resin as in Step 1 of Example 3. This resin (150 mg) was shaken with 4-cyanophenacylbromide (130 mg), DMF (2 ml) and 2,6-lutidine (200 μl) at room temperature for 6.5 hours. The resin was washed with DMF and dichloromethane and simply air dried. It was then heated at 80 ° C. overnight with DMFDMA (3 ml). The resin was then washed with DMF and dichloromethane and dried under vacuum. The dried resin was combined with cesium carbonate (160 mg) and amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg) in NMP (2 ml). Heated at 90 ° C. overnight. The resin was washed with DMF, water, DMF and dichloromethane and then treated with 95: 5 TFA: water to afford the title compound.

HPLC: 25.61 min (80% purity)

MS: MH ⁺ = 467 C ₂₅ H ₂₂ N ₈ 0 ₂ = 466 g / mol

Example 23

Solid phase synthesis of pyrimidine (C ₅  = Carboxyl) (resin method G)

Polystyrene Royal Resin (Novabiochem, 0.41 mmol / g, 2.2 g, 1.21 mmol) in toluene (22 ml), β-ketoester (Aldrich or Lancaster Chemical, 36.3 mmol) and dimethylaminopyridine (DMAP 12 mmol) was shaken at 90 ° C. for 16 h. The resin was filtered off, washed with DCM, DMF, DCM and dried.

A mixture of dried resin (100 mg, 0.055 mmol), aldehyde (0.55 mmol), piperidine (0.055 mmol), acetic acid (0.55 mmol) and 3A molecular sieve (product of Aldrich) in DMF (1.0 mL) was prepared. Shake at room temperature for hours. The resin was filtered off, washed with DMF and DCM and dried.

To the resulting mixture of resin (100 mg, 0.055 mmol) and NaHC0 ₃ (12 mg, 0.138 mmol) was added 0.4 M of appropriate guanidine in DMF (1.0 ml, 0.4 mmol). Then the mixture was shaken at 70 ° C. for 16 hours. The resin was then filtered off, washed with DMF, water, methanol, DMF, DCM and dried.

This resin was treated with 0.1 M DDQ in THF (1.1 ml, 0.11 mmol) at room temperature for 3 hours. The resin was filtered off, washed with DMF, saturated NaHC0 ₃ (aq), water, methanol, DMF, DCM and dried. The resin was treated with 95% TFA / water for 1 hour at room temperature, then filtered and washed with DCM. The filtrate and washes were combined and evaporated. The residue was dissolved in acetylonitrile / water (1: 1) and then lyophilized.

In all cases, the product pyrimidine exceeded 80% purity as determined by HLPC, MS and NMR analysis.

The following compounds are prepared using amino {2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-toluene sulfonate as guanidine source, and β-ketoester and aldehyde shown in parentheses. Prepared according to Method G:

6- (2-fluorophenyl) -2-({2- [5-nitro (2-pyridyl) amino] ethyl} amino) -4-phenylpyrimidine-5-carboxylic acid (ethyl 3- (4 -Fluorophenyl) -3-oxopropionate and benzaldehyde)

2-({2- [5-nitro (2-pyridyl) amino] ethyl} amino) -6- (4-nitrophenyl) -4-phenylpyridine-5-carboxylic acid (ethyl 3- (4-nitro Phenyl) -3-oxopropionate and benzaldehyde)

6-methyl-2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -4-phenylpyrimidine-5-carboxylic acid (ethylacetoacetate and benzaldehyde)

4,6-bis (4-nitrophenyl) -2-({2- [5-nitro (2-pyridyl) amino] ethyl} amino) pyridine-5-carboxylic acid (ethyl 3- (4-nitrophenyl ) -3-oxopropionate and 4-nitrobenzaldehyde)

2-({2- [5-nitro (2-pyridyl) amino] ethyl} amino) -6- (4-nitrophenyl) -4- (4-pyridyl) pyrimidine-5-carboxylic acid (ethyl 3- (4-nitrophenyl) -3-oxopropionate and 4 pyridylcarboxaldehyde)

4- (4-methoxyphenyl) -2-({2- [5-nitro (2-pyridyl) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid ( Ethyl 3- (4-nitrophenyl) -3-oxopropionate and 4-methoxybenzaldehyde)

4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid (Ethyl 3- (4-nitrophenyl) -3-oxopropionate and 4-cyanobenzaldehyde)

2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-nitrophenyl) pyrimidine-5-carboxylic acid (ethyl 3- (4-nitrophenyl ) -3-oxopropionate and formaldehyde)

4,6-bis (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxylic acid (ethyl 3- (4 -Cyanophenyl) -3-oxopropionate and 4-cyanobenzaldehyde)

 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -6- (3-nitrophenyl) -pyrimidine-5-carboxyl Acids (ethyl 3- (4-cyanophenyl) -3-oxopropionate and 3-nitrobenzaldehyde)

4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -6-phenylpyrimidine-5-carboxylic acid (ethyl 3- ( 4-cyanophenyl) -3-oxopropionate and benzaldehyde)

4- (3-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid (Ethyl 3- (4-nitrophenyl) -3-oxopropionate and 3-cyanobenzaldehyde)

4- (3-hydroxyphenyl) -2- ({2- (5-nitro (2-pyridyl) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid ( Ethyl 3- (4-nitrophenyl) -3-oxopropionate and 3-hydroxybenzaldehyde)

2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3-nitrophenyl) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid (Ethyl 3- (4-nitrophenyl) -3-oxopropionate and 3-nitrobenzaldehyde)

2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) -4- (4-quinolyl) -pyrimidine-5-carboxyl Acids (ethyl 3- (4-nitrophenyl) -3-oxopropionate and 4-quinolinecarboxaldehyde)

2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) -4- [4- (trifluoromethyl) -phenyl] pyrimidine -5-carboxylic acid (ethyl 3- (4-nitrophenyl) -3-oxopropionate and 4-trifluoromethylbenzaldehyde)

4- ({4-carboxyphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) -pyrimidine-5-car Acids (ethyl 3- (4-nitrophenyl) -3-oxopropionate and 4-carboxybenzaldehyde)

4-cyclohexyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid (ethyl 3- (4-nitrophenyl) -3-oxopropionate and cyclohexanecarboxaldehyde)

4- (4-cyanophenyl) -6- (4-fluorophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxyl Acids (ethyl 3- (4-cyanophenyl) -3-oxopropionate and 4-fluorophenylbenzaldehyde)

4- (4-cyanophenyl) -6- (3-furyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxylate (Ethyl 3- (4-cyanophenyl) -3-oxopropionate and 3-furylcarboxaldehyde)

Example 24

Solid phase synthesis of pyrimidine (C ₅  = Carboxyl, C ₄  Or C ₆  = H) (resin method G)

A suspension of resin (Nova Biochem, 0.51 mmol / g, 100 mg, 0.0 mmol) in DMF-dimethylacetal (1 ml) was shaken at room temperature for 17 hours. The resin was filtered off, washed with DCM and ether and dried.

To the resulting mixture of dry resin (100 mg, 0.055 mmol) and NaHC0 ₃ (12 n 0.138 mmol) was added 0.4 M of a suitable guanidine solution in DMF (1.0 ml, 0.4 mmol). The mixture was shaken at 70 ° C. for 16 hours. The resin was then filtered, washed successively with DMF, water, MeOH, DMF, DCM and dried. The resin was treated with 95% TFA / water for 1 hour at room temperature, then filtered and washed with DCM. The washes and filtrates were combined and evaporated. The residue was dissolved in acetylonitrile: water (1: 1 v / v) and lyophilized to give pyrimidine.

The following compounds were prepared according to the above method using N- (nitropyridin-6-yl) aminoethylguanidine and the appropriate β-ketoesters and aldehydes.

4-Methyl-2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxylic acid

2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -4- (4-nitrophenyl) pyrimidine-5-carboxylic acid

4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (3-nitrophenyl) pyrimidine-5-carboxyl mountain.

Example 25

Solution Phase Synthesis (Solution Method A)

Carbonyl containing compounds (e.g., β-keto esters, β-keto sulfones, β-ketonitriles, α-nitro ketones, etc.) are dissolved in a suitable organic solvent (typically THF) and somewhat excess (1.2-2 equivalents) Treated with DMFDMA. The mixture was heated at 60-80 ° C. for 3-15 hours, most commonly 3-5 hours. Thereafter, the reaction mixture was cooled. If carried out on a small scale (0.2 to lmmol), without removing some excess DMFDMA, the cooled mixture is prepared with guanidine (1 equivalent) and 1.2 equivalents in a suitable base (e.g. cesium carbonate or 1 ml ethanol). Sodium ethoxide) directly to the mixture.

The reaction was then heated at 70-80 ° C. for 12-24. At the end of the reaction, the glass bottle was cooled, poured into dichloromethane or ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was concentrated in vacuo and generally the product precipitated or crystallized by adding water to the acetonitrile or ethanol solution of the product. In some cases, chromatographic purification was performed by HPLC or radial chromatography of some preparations using silica gel plates eluted with a mixture of dichloromethane and methanol (Harrison Research, Palo Alto, Calif.). Larger scale reactions were carried out in round bottom flasks using typical organic chemical apparatus.

Examples 31,35-45, and 50-59 describe the synthesis of compounds of the present invention according to solution method A.

Example 26

Synthesis of ethyl 4- (4-cyanophenyl) -2-2- (2-quinolylamino) ethylamino} -pyrimidine-5-carboxylate

Ethyl 3- (4-cyanophenyl) 3-oxopropanoate (64 mg, 0.3 mmol) was heated with DMFDMA (50 μl) and dry THF (1 mL) at 70 ° C. for 3 hours. The cooled mixture was then amino [2- (2-quinolylamino) ethyl] carboxamidinium 4-methylbenzenesulfonate in ethanol (2 ml) containing 0.35 mmol sodium ethoxide (prepared according to Example 12). ) (120 mg, 0.3 mmol). The reaction was then heated at 80 ° C. overnight and then concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was taken up in acetonitrile. The product precipitated out with water and the precipitate was filtered off and dried to afford the title compound.

HPLC: 22.12 min (90% purity)

MS: MH ⁺ = 439 C ₂₅ H ₂₂ N ₆ 0 ₂ = 438 g / mol

Example 27

Ethyl 4- (6-morpholin-4-yl (3-pyridyl))-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine} -5- Synthesis of Carboxylate

Step 1: Ethyl 6-chloronicotinate (5.0 g) and morpholine (10 ml) were mixed and then heated to 100 ° C. After less than 5 minutes at this temperature, a thick paste was formed. Acetylonitrile (15 ml) was added and heated at 90 ° C. overnight. The mixture was cooled down, diluted with water and extracted with ethyl acetate. The organic layer was dried and concentrated in vacuo to yield ethyl 6-morpholin-4-ylpyridine-3-carboxylate as a white solid.

NMR (300 MHz, CDC1 ₃ : 8.80 (s, 1H), 8.05 (d, 1H), 6.60 (d, 1H), 4.35 (q, 2H), 3.80 (m, 4H), 3.65 (m, 4H), 1.35 (t, 3 H).

The solid was refluxed for 2 hours in a mixture of THF and aqueous potassium hydroxide solution. THF was removed under vacuum and the aqueous layer was extracted with ethyl acetate. The aqueous layer was acidified with acetic acid. A white solid precipitated out, which was washed with water and dried to give 6-morpholin-4-ylpyridine-3-carboxylic acid.

NMR (300 MHz, DMSO-d ₆ ) 8.65 (s, 1H), 7.95 (d, 1H), 6.85 (d, 1H), 3.70 (m, 4H), 3.60 (m, 4H)

Step 2: The acid described in step 1 was converted to β-keto ester as follows. Acid (5.6 g., 27 mmol) in dry THF (100 ml) was treated with oxalyl chloride (40 mmol) at room temperature followed by the addition of several drops of DMF. Thereafter, the mixture was refluxed for 2 hours. Potassium ethyl malonate (Aldrich Chemical Corporation, 9.2 g, 54 mmol) and anhydrous magnesium chloride (6.48 g) were mixed in dry acetylonitrile (100 ml). Triethylamine (6 ml) was then added and the mixture was stirred at rt for 4 h. After addition of 3 ml of triethylamine, acid chloride dissolved in 50 ml of dry acetylonitrile was added. After the mixture was stirred overnight at room temperature, the solvent was removed in vacuo. The residue was treated with toluene (about 200 ml), then sufficient 25% HC1 aqueous solution was added to completely dissolve the residue. The mixture was shaken and the organic and aqueous layers separated. The toluene layer was washed with water. The combined aqueous layers were then washed twice with toluene. The organic layer was discarded. The pH of the aqueous layer was adjusted to pH 7 by the addition of solid sodium carbonate. Then, the aqueous layer was extracted with toluene. The toluene layer was concentrated in vacuo to yield ethyl 3- (6-morpholin-4-yl) (3-pyridyl) -3-oxopropanoate as a yellow solid.

Step 3: The β-keto ester (83 mg, 0.3 mmol) from step 2 was heated with DMFDMA (50 μl) and dry THF (1 ml) at 70 ° C. for 3 hours. The cooled mixture is then amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate in ethanol (2 ml) containing 0.35 mmol of sodium ethoxide. (120 mg, 0.3 mmol), after which the reaction was heated overnight at 80 ° C. and then concentrated in vacuo, after which the organic phase was concentrated in vacuo and redissolved in acetonitrile. Was formed, filtered and dried to afford the title compound.

HPLC: 18.77 min (98%)

MS: MH ⁺ = 495 C ₂₃ H ₂₆ N ₈ O ₅ = 494 g / mol

Example 28

Synthesis of ethyl 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} -amino) -4- (4-cyano phenyl) pyrimidine-5-carboxylate

DMFDMA (50 μl) was added to a solution of ethyl 3- (4-cyanophenyl) -3-oxopropionate (63 mg, 0.3 mmol) in THF (1 ml). The solution was heated at 70 ° C. for 3 hours, followed by amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (123 mg, 0.3 mmol), ethanol ( 1 ml) and 1.0 M sodium ethoxide (0.35 ml) were added, the mixture was heated overnight at 80 ° C. The reaction was cooled, diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Concentrate and dissolve in acetylonitrile The product is precipitated with water to afford the title compound.

HPLC: 25.21 min

MS: MH ⁺ = 449 C ₂₁ H ₂₀ N ₈ 0 ₄ = 448 g / mol

NMR (DMSO-d ₆ ): 1.02 (t, 3H), 3.60 (m, 4H), 4.10 (q, 2H), 5.95 (d, 1H), 7.60 (d, 2H), 7.85 (d, 2H), 7.90 (d, 1 H), 8.80 (s, 1 H)

Example 29

Ethyl 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4- morpholin- 4 -ylphenyl) pyrimidine-5-carboxyl Rate Synthesis

DMFDMA (60 μL) was added to a solution of ethyl 3- (4-morpholinophenyl) -3-oxopropionate (70 mg, 0.3 mmol) in THF (1 mL). The solution was heated at 70 ° C. for 3 hours, followed by amino [2-[(6-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (123 mg, 0.3 mmol), ethanol ( 1 ml) and 1.0 M sodium ethoxide (0.35 ml) were added, the mixture was heated overnight at 80 ° C. The reaction was cooled, diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Concentrate and dissolve in acetylonitrile The product is precipitated with water to afford the title compound.

HPLC: 22.37 min (85% purity)

MS: MH ⁺ = 509 C ₂₄ H ₂₈ N ₈ 0 ₅ = 508 g / mol

NMR (DMSO-d ₆ ): 1.05 (t, 3H), 3.3 (m, 4H), 3.60 (m, 4H), 3.78 (m, 4H), 4.15 (q, 2H), 5.95 (d, 1H), 6.90 (d, 2H), 7.45 (d, 2H), 7.95 9d, 1H, 8.60 (s, 1H)

Example 30

Synthesis of ethyl 2- {2-[(6-amino-5-nitro (2-pyridyl) amino] ethyl} amino) 4- ( 2,4 - dichlorophenyl) pyrimidine-5-carboxylate

DMFDMA (70 μL) was added to a solution of ethyl 3- (2,4-dichlorophenyl) -3-oxopropionate (78 mg, 0.3 mmol) in THF (2 mL). The solution was heated at 70 ° C. for 3 hours and then amino [2-[(6-amino-5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (123 mg, 0.3 mmol ), Dry ethanol (1 ml) and 1.0 M sodium ethoxide (0.35 ml) were added, the mixture was heated overnight at 80 ° C. The reaction was cooled, diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo and dissolved in acetylonitrile The title compound was obtained after addition of water.

Example 31

Synthesis of ethyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine -5-carboxylate

DMFDMA (50 μl) was added to a solution of ethyl 3- (4-cyanophenylphenyl) -3-oxopropionate (65 mg, 0.3 mmol) in THF (1 mL). The solution was heated at 70 ° C. for 3 hours and then amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg, 0.3 mmol), dry ethanol (1 ml) and 1.0 M sodium ethoxide (0.35 ml) were added, the mixture was heated overnight at 80 ° C. The reaction was cooled, diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Concentrate under and dissolve in acetylonitrile The title compound is obtained after addition of water.

HPLC: 28.05 min (95% purity)

Example 32

Synthesis of 2-((2-((5-nitro (2-pyridyl) amino) ethyl) amino) -4- (4-cyanophenyl) -pyrimidine-5-carboxylate

Ethyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxylate in 1: 1 methanol / water To a suspension of 1.0 g (2.3 mmol) was added 1.5 mmol of sodium hydroxide and the solution was warmed to 60 ° C. for 45 minutes during which time the reaction became homogeneous. The pH was adjusted to 5.0, at which time the desired acid was precipitated from the solution The solids were collected and dried to give 2-((2-((5-nitro (2-pyridyl) amino) ethyl) amino) as a pale yellow powder. 890 mg (2.2 mmol, 98% yield) of 4- (4-cyanophenyl) pyrimidine-5-carboxylate was obtained.

Example 33

2- (dimethylamino) ethyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxylate synthesis

2-((2-((5-nitro (2-pyridyl) amino) ethyl) amino) -4- (4-cyanophenyl) -pyrimidine-5-carboxylate (300 mg, 0.74 mmol) Prepared as described in Example 32) in 5 ml of 2- (dimethylamino) ethanol at room temperature O-benzotriazole-N, N, N ', N'tetramethyluronium-hexafluoro-phosphate ( HBTU) (Advance Chem Tech, Louisville, Kentucky) was added to one portion and the mixture was stirred for 18 hours at room temperature. The resulting clear solution was poured onto an ice water mixture and thoroughly with ethyl acetate. The aqueous layer was extracted twice with ethyl acetate again, then the combined organic layers were dried over sodium sulfate and concentrated in vacuo. Desired compound 2- (dimethylamino) ethyl 2-((2) by HPLC and NMR assay -((5-nitro (2-pyridyl) amino) ethyl) amino) -4- (4-cyanophenyl) pyrimidine-5-car Butyl appeared to have formed in quantitative yield (> 95%).

By replacing the 2- (dimethylamino) ethanol set forth above with alcohols or amines, the following additional compounds of the present invention were similarly synthesized (alcohol or amines are shown in parentheses).

 t-butyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate (t-butyl alcohol )

Methyl 4- (4-cyanophenyl) -2-({2-[((5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate (methanol)

Butyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate (n-butanol)

Phenylmethyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate (benzyl alcohol)

N-butyl [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carboxamide (n -Butylamine)

[4- (4-cyanophenyl) -2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N-benzylcarboxamide ( Benzylamine)

 [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N, N dimethylcarboxamide (Dimethylamine)

N- (cyanomethyl) [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidin-5-yl] carbox Amide (aminoacetylonitrile)

N- (t-butyl) [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidin-5-yl] carbox Amide (t-butylamine)

N- [2- (dimethylamino) ethyl] [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5- General] carboxamide 38564 (2- (dimethylamino) ethyl amine)

[4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N- (2- hydroxy Ethyl) carboxamide (2-aminoethanol)

 4- [5- (morpholin-4-ylcarbonyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile (Morpholine)

[4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N methylcarboxamide (methyl Amines)

N- (2-aminoethyl) [4- (4-cyanophenyl) -2-({2-[(5-nitro (Z-pyridyl) amino] ethyl} amino) pyrimidin-5-yl] car Voxamide (ethylenediamine)

4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -5- (piperazinylcarbonyl) pyrimidine-4-] benzenecarbonitrile (piperazin)

4- (4-cyanophenyl) -2-({2- [5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidine-5-carboxamide (ammonia)

N- (carbamoylmethyl) [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] Carboxamides (glycineamides)

[4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N- (4- pyridyl Methyl) carboxamide ((4-pyridyl) methylamine)

2-hydroxyethyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate (ethylene glycol )

N- (1-carbamoyl-2-hydroxyethyl) [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) Pyrimidin-5-yl] carboxamide (serineamide)

Example 34

4- [5- (3-methyl (1,2,4-oxodiazol-5-yl))-2- {2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) Synthesis of Pyrimidin-4-yl] benzenecarbonitrile

Ethyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate (0.069 in THF (1 ml) to isobutyl chloroformate (13.4 μl, 0.14 mmol) was added to a mixture of mmol, prepared according to Example 31) and triethylamine (19.3 μl, 0.14 mmol). After stirring overnight at room temperature, suitable amidoximine (0.14 mmol) (prepared according to the reference CD Bedfore et al., J. Med. Chem. 20: 2174-2183 (1986)) is added and 70 ° C. The mixture was stirred for 6 h. After stirring for an additional 72 hours at room temperature, the reaction is filtered and the solids are washed successively with methanol and water and dried under vacuum to afford the desired oxadiazole, 4- [5- (3-methyl (1, 2,4- Oxadiazol-5-yl))-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile was obtained. The following addition compounds were prepared according to the above method by using the appropriate amidoximine:

4- [5- {3- [2- (dimethylamino) ethyl] (1,2,4-oxadiazol-5-yl) -2-({2-[(5-nitro (2-pyridyl) ) Amino] ethyl} amino) pyrimidin-4-yl)

(2-5- [2-({2-[(6-amino-5-nitro (2-pyridyl) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] (1, 2,4-oxadiazol-3-yl)} ethyl) dimethylamine

Example 35

Synthesis of ethyl 4- (4-morpholin-4-ylphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

DMFDMA (140 μL) was added to a solution of ethyl 3- (4-morpholinophenyl) -3-oxopropionate (193 mg, 0.7 mmol) in THF (1 mL). The solution was heated at 70 ° C. for 3 hours and then amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (280 mg, 0.7 mmol), ethanol ( 1 ml) and 1.0 M sodium ethoxide (0.82 ml) were added The mixture was heated overnight at 80 ° C. The reaction was cooled, diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Concentrate and dissolve in acetylonitrile The water is added to precipitate the product as an orange solid (126 mg) to afford the title compound.

HPLC 25.25 min (95% purity)

NMR (DMSO-d ₆ ): 1.15 (t, 3H), 3.20 (m, 4H), 3.60 (br. S, 4H), 3.78 (m, 4H), 4.05 (q, 2H), 6.59 (d, 1H ), 6.95 (d, 2H), 7.40 (d, 2H), 8.0 (m, 1H), 8.60 (s, 1H), 8. 90 (d, 1H)

MS: MH ⁺ = 494 C ₂₄ H ₂₇ N ₇ 0 ₅ = 493 g / mol

Example 36

Synthesis of ethyl 4-((4-imidazolylphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 3- (4-imidazol-1-yl) phenyl) -3-oxopropionate (73 mg, 0.3 mmol) in THF (1 ml) (see I. Sircar et al., J. Med. Chem., 28: 1405 (1985)] was added DMFDMA (50 μl). The solution was heated at 70 ° C. for 3 hours and then amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg, 0.3 mmol), ethanol ( 1 ml) and 1.0 M sodium ethoxide (0.35 ml) were added, the mixture was heated overnight at 80 ° C. The reaction was cooled, diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. After concentration and redissolution in acetylonitrile, water was added to precipitate the product of a yellow solid to afford the title compound.

HPLC: 18.50 min (95% purity)

MS: MH ⁺ = 475 C ₂₃ H ₂₂ N ₈ 0 ₄ = 474 g / mol

NMR (DMSO-d ₆ ): 1.05 (t, 3H), 3.62 (br. S, 4H), 4.10 (q, 2H), 6.58 (d, 1H), 7.15 (s, 1H), 7.60 (d, 2H ), 7.70 (d, 2H), 7.75 (s, 1H), 7.85 (br s, 1H), 7.9- 8.1 (m, 2H), 8.25 (s, 1H), 8.75 (s, 1H), 8.90 (s , 1H)

Example 37

Ethyl 2-([2- (5-nitro- (2-pyridyl)) amino] ethylamino) -4- (4- (1, 3-oxazol-5-yl) phenyl) pyrimidine-5-car Synthesis of Cyclate

Step 1: Methyl 6-formylbenzoate (Aldrich Chemical Corporation, St. Louis, Missouri) (5.0 g, 30.5 mmol), anhydrous potassium carbonate (4.55 g, 33 mmol) and p-toluenesulfonylmethyl isocyanide ( TOSMIC, Aldrich Chemical Corp.) (6.83 g, 30.5 mmol) was refluxed in methanol (100 ml) for 3.5 h. The mixture was then concentrated in vacuo until drying. The residue was dissolved in ethyl acetate, washed twice with water, dried and concentrated in vacuo to afford methyl 4- (1,3-oxazol-5-yl) benzoate as a beige solid (4.95 g).

(NMR (300 MHz, CD1 ₃ : 8. 10 (d, 2H), 7.98 (s, 1H), 7.75 (d, 2H), 7.48 (s, 1H), 3.94 (s, 3H)).

The ester was heated at reflux for 2 hours in a mixture of 1 M aqueous potassium hydroxide solution and 50 ml THF. THF was removed under vacuum and the solution was cooled and acidified with 50% HC1 to give 4- (1,3-oxazol-5-yl) benzoic acid as a white solid.

NMR (300 MHz, DMSO-d 6; 8.52 (s, 1 H), 8.05 (d, 2H), 7.82-7.9, m, 3H).

The dried acid was refluxed in purified thionyl chloride until all solids dissolved. Thionyl chloride was removed by rotary evaporation (using hexane). The crude acid chloride was simply dried under vacuum. On the other hand, dry acetylonitrile (150 ml) potassium ethyl malonate (11.1 g, 65 mmol) and anhydrous magnesium chloride (7.7 g, 81 mmol) were treated with triethylamine (5.15 ml, 37 mmol). After the mixture was stirred at room temperature for 3 hours, 1 ml of triethylamine was further added, followed by addition of the acid chloride solution prepared above in dry acetylonitrile (50 ml). The reaction was stirred at rt overnight. The mixture was concentrated in vacuo until drying and then partitioned between toluene and 0.25 M HC1 aqueous solution. The organic layer was washed with water, dried and concentrated to afford crude ethyl 3- (4- (1, 3-oxazol-5-yl) phenyl) -3-oxopropanoate. The crude product was purified by silica gel chromatography (hexane / ethyl acetate).

Step 2: DMFDMA (60 μl) was added to a solution of ethyl 3- (4- (1,3-oxazol-5-yl) phenyl) -3-oxopropionate (76 mg, 0.3 mmol) in THF (1 ml). Added. The solution was heated at 70 ° C. for 3 hours, followed by amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg, 0.3 mmol), ethanol ( 1 ml) and 1.0 M sodium ethoxide (0.35 ml) were added, the mixture was heated overnight at 80 ° C. The reaction was cooled, diluted with dichloromethane and washed with aqueous sodium bicarbonate solution. Concentrate and dissolve in acetylonitrile The product is precipitated with water to give the title compound as an orange solid.

HPLC: 26.75 min (90% purity)

NMR (DMSO-d ₆ ): 1.05 (t, 3H), 3.65 (br. S, 4H), 4.10 (q, 2H), 6.58 (d, 1H), 7.58 (d, 2H), 7.70 (s, 1H ), 7.75 (d, 2H), 7.82 (br. S, 1H), 7.95-8.10 (m, 2H), 8.40 (s, 1H), 8.75 (s, 1H), 8.85 (s, 1H)

Example 38

Synthesis of ethyl 4- (4- (2-furyl) phenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Step 1: Ethyl 4-iodobenzoate (2.76 g, 10 mmol) and 2-furylboric acid (Frontier Scientific, 1.12 g, 10 mmol) were added with 1,2-dimethoxyethane (20 ml) and 2M aqueous sodium carbonate solution. It was mixed with bis (triphenylphosphine) palladium dichloride (100 mg) in (20 ml). The mixture was bubbled with argon gas and then heated at 80 ° C. overnight under argon. The mixture was cooled down, diluted with ethyl acetate and washed with water. The organic layer was dried and concentrated in vacuo to afford crude solid ester. This material was taken up in a mixture of THF and 1M aqueous potassium hydroxide solution and refluxed for 2.5 hours. THF was filtered by rotary evaporation and the aqueous layer was acidified with acetic acid. After cooling to 4 ° C. 4- (2-furyl) benzoic acid precipitated as a brown solid (1.49 g).

(NMR (300 MHz, DMSO-d ₆ : 8. 10 (d, 2H), 7.90 (m, 3H), 7.24 (d, 1H), 6.75 (dd, 1H)).

Step 2: The acid described in step 1 was converted to acid chloride in a mixture of oxalyl chloride (1.3 ml), THF (20 ml) and several drops of DMF. After refluxing for 0.5 h, the solvent was removed in vacuo to afford the crude acid chloride. On the other hand, potassium ethyl malonate (2.7 g) was reacted with anhydrous magnesium chloride (1.9 g) and triethylamine (2.21 ml) in dry acetonitrile (50 ml) at room temperature for 3 hours. Triethylamine (6 ml) was added followed by a solution of acid chloride in acetonitrile. The mixture was stirred overnight at room temperature and then concentrated to dryness. The residue was partitioned between toluene and 10% aqueous HCl solution. The organic layer was washed with 10% HCl and water and dried to afford crude ethyl 3- (4- (2-furyl) phenyl) -3-oxopropanoate as a solid.

Step 3: The β-keto ester (76 mg, 0.3 mmol) from step 2 was heated with DMFDMA (60 μl) in dry THF (2 mL) at 70 ° C. for 4 h. This solution was then added to a mixture of amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg, 0.3 mmol) and cesium carbonate (160 mg). After addition, it was heated overnight at 80 ° C. to ethyl 4- (4- (2-furyl) phenyl) -2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidine- 5-carboxylate was obtained.

HPLC: 32.05 min (80% purity)

MS: MH ⁺ = 476 C ₂₄ H ₂₃ N ₆ O ₅ = 475 g / mol

Example 39

Synthesis of ethyl 4- (4-cyanophenyl) -2-({2-[(4-methyl-5-nitro (2-pyridyl)) amino] ethyl} amino ) pyrimidine-5-carboxylate

Step 1: 2-chloro-4-methyl-5-nitropyridine (2.0 g, 11.5 mmol) in acetylonitrile (10 ml) was added dropwise to ethylenediamine (2.5 ml) in acetylonitrile (10 ml). The mixture was stirred overnight at room temperature. The solvent was removed by rotary evaporation and the residue was partitioned between dichloromethane and 2.5M aqueous sodium hydroxide solution. The aqueous layer was extracted four more times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried and concentrated in vacuo to afford (2-aminoethyl) (4-methyl-5-nitro (2-pyridyl)) amine as an orange solid (1.74 g). .

Step 2: The amine (1.2 g, 6 mmol) from step 1 was subjected to benzotriazolecarboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and DIEA (1 .05 mL, 6 mmol) in dry acetylonitrile (10 mL). Shaken overnight at room temperature. Ether was added to precipitate amino {2-[(4-methyl-5-nitro (2-pyridyl)) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate as a yellow solid.

Step 3: Ethyl 3- (4-cyanophenyl) -3-oxopropanoate (64 mg, 0.3 mmol) in THF (1 ml) and DMFDMA (0.3 mmol) was heated at 70 ° C. for 3 hours. This solution was added to a mixture of guanidine (123 mg, 0.3 mmol) from step 2, 1.0 M sodium ethoxide in ethanol (0.35 ml) and ethanol (1 ml). The mixture was then heated at 80 ° C. overnight, cooled, diluted with dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo, redissolved in acetylonitrile and the product precipitated out with water.

HPLC: 27.63 min (85% purity)

MS: MH ⁺ = 448 C ₂₂ H ₂₁ N ₇ 0 ₄ = 447 g / mol

Example 40

Synthesis of 2-({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) -4-phenylpyrimidine-5- carbonitrile

3-oxo-3-phenylpropanenitrile (44 mg, 0.3 mmol) in THF (1 ml) and DMFDMA (50 μl) was heated at 70 ° C. for 3 hours. This solution was prepared in amino [2 [(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg, 0.3 mmol), 1.0 M sodium ethoxide in ethanol (0.35 ml) and To a mixture of dry ethanol (1 ml) and heated overnight at 80 ° C., then concentrated in vacuo, the residue was then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution The organic layer was concentrated in vacuo. The residue was taken up in acetylonitrile Water was added to give a precipitate which was filtered and dried to give the title compound.

HPLC: 13.87 min (95% purity)

Example 41

Synthesis of {2-[(5-nitro (2-pyridyl) amino] ethyl}-(5-nitro-4-phenylpyrimidin-2-yl) amine

2-nitro-1-phenylethan-1-one (50 mg, 0.3 mmol) in THF (1 ml) and DMFDMA (50 μl) was heated at 70 ° C. for 3 hours. The solution was diluted with 1.0 M sodium ethoxide in amino [2 [(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg, 0.3 mmol), ethanol (0.35 ml). And a mixture of dry ethanol (1 ml) and heated overnight at 80 ° C., then concentrated in vacuo, the residue was then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The residue was taken up in acetylonitrile Water was added to give a precipitate which was filtered and dried to give the title compound.

HPLC: 15.33 min (100% purity)

MS: MH ⁺ = 382 C ₁₇ H ₁₅ N ₇ 0 ₄ = 381 g / mol

Example 42

Synthesis of (5-nitro-4-phenylpyrimidin-2-yl) [2- (2-pyridylamine) ethyl] amine

2-nitro-1-phenylethan-1-one (50 mg, 0.3 mmol) in THF (1 ml) and DMFDMA (50 μl) was heated at 70 ° C. for 3 hours. The solution was diluted with amino [2 [(2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (105 mg, 0.3 mmol), 1.0 M sodium ethoxide in ethanol (0.35 ml) and dry ethanol (1 ml). ) Was heated to 80 ° C. overnight and then concentrated in vacuo. The residue was then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was taken up in acetylonitrile. Water was added to give a precipitate which was filtered and dried to give the title compound.

HPLC: 19.66 min (100% purity)

MS: MH ⁺ = 337 C ₁₇ H ₁₆ N ₆ O ₂ = 336 g / mol

Example 43

Synthesis of ethyl 4- (4-cyanophenyl) -2-[(2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-carboxylate

Step 1: 2-chloro-5- (trifluoromethyl) pyridine (5.0 g) was heated with ethylenediamine (20 ml) at 120 ° C. overnight. Excess ethylenediamine was removed by rotary evaporation and the residue was partitioned between dichloromethane and 2.5M aqueous sodium hydroxide solution. The aqueous layer was extracted four more times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried and concentrated in vacuo to afford (2-aminoethyl) (5- (trifluoromethyl) (2-pyridyl)) amine as an orange solid.

Step 2: The amine from step 1 (1.1 g, 5.36 mmol) was added benzotriazolecarboxamidinium 4-methylbenzenesulfonate (1.78 g, 5.36 mmol) and DIEA (0.93 ml, 5.36 in acetylonitrile (6 ml). mmol) at room temperature overnight. Ether was added to precipitate amino (2- {5- (trifluoromethyl) (2-pyridyl)) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate as a white solid.

Step 3: Ethyl 3- (4-cyanophenyl) -3-oxopropanoate (64 mg, 0.3 mmol) in THF (1 ml) and DMFDMA (50 μl) was heated at 70 ° C. for 4 hours. This solution was added to a mixture of guanidine (123 mg, 0.3 mmol) from step 2, 1.0 M sodium ethoxide in ethanol (0.35 ml) and dry ethanol (1 ml). The mixture was then heated at 80 ° C. overnight and then concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was taken up in acetonitrile. Water was added to give a precipitate which was filtered and dried to give the title compound.

HPLC: 24.46 min (85% purity)

MS: MH ⁺ = 457 C ₂₂ H ₁₉ N ₆ 0 ₂ F ₃ = 456 g / mol

Example 44

Synthesis of [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

Step 1: 2,4-dichlorophenacyl chloride (1.42 g, 6.4 mmol) and imidazole (1.18 g, 16 mmol) were heated in toluene (40 ml) at 75 ° C. for 2.25 h. The mixture was concentrated under vacuum to dryness. The residue was dissolved in dichloromethane, washed with 5% aqueous potassium carbonate solution and water, dried and concentrated in vacuo. The crude product was purified by passing through a pad of silica gel eluted with 5% methanol in dichloromethane to afford 1- (2,4-dichlorophenyl) -2-imidazolylethan-1-one as an orange oil. .

Step 2: The product from step 1 (95 mg) was heated with DMFDMA (2 ml) at 105 ° C. for 9 hours. The solvent is removed in vacuo, the residue is dissolved in dry THF (2 ml) and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzensulfonate (100 mg) , 0.3 mmol) and cesium carbonate (200 mg) The mixture was heated overnight at 80 ° C. and then concentrated in vacuo The residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. Concentrated in vacuo The product was purified by radiochromatography on silica gel.

HPLC: 22.48 min (96% purity)

MS: MH ⁺ = 471-473 (cluster, 2Cl) C ₂₀ H ₁₆ Cl ₂ N ₈ 0 ₂ = 471 g / mol

Example 45

Synthesis of 4- [2- ({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -5-imidazolylpyrimidin -4-yl] benzenecarbonitrile

Step 1: 4-cyanophenacyl bromide (0.72 g, 3.2 mmol) and imidazole (0.55 g, 8 mmol) were heated in toluene (20 ml) at 75 ° C. for 2.5 hours. The reaction mixture was dissolved in dichloromethane and washed with 5% aqueous potassium carbonate solution and water, dried and concentrated in vacuo to afford a pink solid (0.35 g). This method is described in Sakurai et al., 1996, Chem. Plaarm. Bull. 44: 1510, a variation of the method described.

Step 2: 1- (4-cyanophenyl) -2-imidazolylethan-1-one (prepared from Step 1, 63 mg, 0.3 mmol) was heated in DMFDMA (2 ml) at 105 ° C. for 9 hours. The solvent is removed in vacuo, the residue is dissolved in dry THF (2 ml) and amino [2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidinium 4-methylbenzene -Was added to a mixture of sulfonate (105 mg, 0.3 mmol) and cesium carbonate (200 mg). The mixture was heated at 80 ° C. overnight and then concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was crystallized from ethanol / ethanol to give yellow needles.

HPLC: 17.68 min (100% purity)

MS: MH ⁺ = 44 3 C ₂₁ H ₁₈ N ₁₀ 0 ₂ = 442 g / mol

Example 46

Synthesis of [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl) amino] ethyl} amine

1- (2,4-dichlorophenyl) -2-imidazol-2-ylethan-1-one (Macco et al., J Org. Chem., 20: 252 (1985), incorporated herein by reference). A solution of the appropriate acid chloride and 2-methylimidazole) and DMFDMA (10 ml / mmol of ketone) were stirred at reflux for 12 hours according to the established procedure. After concentrating this solution, the resulting solid was redissolved in DMF (10 ml / mmol). Cs ₂ CO ₃ ( ₃ mmol) and (2- (5-nitro (2-pyridyl) amino] ethyl) carboxamidinium 4-methylbenzenesulfonate (1.5 mmol) were added and the mixture was heated to 100 ° C. for 8 hours. The mixture was cooled, filtered and the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution The organic layer was concentrated to [4- (2,4-dichlorophenyl) -5-imide Dazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl) amino] ethyl} amine was obtained.

Example 47

[2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- imidazol-2-ylpyrimidin-2-yl] Synthesis of Amine

1- (2,4-dichlorophenyl) -2-imidazol-2-ylethan-1-one (Referred herein to Macco et al., J Org. Chem., 20: 252 (1985)) A solution of the appropriate acid chloride and 2-methylimidazole) and DMFDMA (10 ml / mmol of ketone) were stirred at reflux for 12 hours according to the established procedure. After concentrating this solution, the resulting solid was redissolved in DMF (10 ml / mmol). Cs ₂ CO ₃ ( ₃ mmol) and (2- (5-nitro (2-pyridyl) amino] ethyl) carboxamidinium 4-methylbenzenesulfonate (1.5 mmol) were added and the mixture was heated to 100 ° C. for 8 hours. The mixture was cooled, filtered and the filtrate diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution The organic layer was concentrated to [2-[(6-amino-5-nitro (2-). Pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine.

Example 48

Synthesis of 4- [5-imidazol-2-yl-2- ({2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl ] benzenecarbonitrile

Suitable acid chlorides according to the processes described in 4- (2-imidazol-2-ylacetyl) benzenecarbonitrile (Macco et al., J Org. Chem., 20: 252 (1985)) and A solution of 2-methylimidazole) and DMFDMA (10 ml / mmol of ketone) was stirred at reflux for 12 h. After concentrating this solution, the resulting solid was redissolved in DMF (10 ml / mmol). Cs ₂ CO ₃ ( ₃ mmol) and (2- (5-nitro (2-pyridyl) amino] ethyl) carboxamidinium 4-methylbenzenesulfonate (1.5 mmol) were added and the mixture was heated to 100 ° C. for 8 hours. The mixture was cooled, filtered and the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and the organic layer was concentrated to 4- [5-imidazol-2-yl-2- ( Synthesis of {2-[(5-nitro (2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile was obtained.

Example 49

4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -5-imidazol- 2-yl pyrimidin-4-yl] benzenecarbonitrile Synthesis of

Suitable acid chlorides according to the processes described in 4- (2-imidazol-2-ylacetyl) benzenecarbonitrile (Macco et al., J Org. Chem., 20: 252 (1985)) and A solution of 2-methylimidazole) and DMFDMA (10 ml / mmol of ketone) was stirred at reflux for 12 h. After concentrating this solution, the resulting solid was redissolved in DMF (10 ml / mmol). Cs ₂ CO ₃ ( ₃ mmol) and (2- (6-nitro (2-pyridyl) amino] ethyl) carboxamidinium 4-methylbenzenesulfonate (1.5 mmol) were added and the mixture was heated to 100 ° C. for 8 hours. The mixture was cooled, filtered and the filtrate was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and the organic layer was concentrated to 4- [2-({2-[(6-amino- Synthesis of 5-nitro (2-pyridyl)) amino] ethyl} amino) -5-imidazol-2-ylpyrimidin-4-yl] benzenecarbonitrile was obtained.

Example 50

Synthesis of ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl] amino) -4- (4-pyridyl) pyrimidine-5-carboxylate

This compound is ethyl 3-oxo-3- (4-pyridyl) propanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4- according to Solution Method A. Prepared from methylbenzenesulfonate.

HPLC: 17.78 min (90% purity)

NMR (300 MHz, 5/1 acetylonitrile-d ₃ / D ₂ 0): 8.85 (d, 1H), 8.82 (s, 1H), 8.80 (d, 2H), 8.01 (dd, 1H), 7.38 ( d, 2H), 6.43 (d, 1H), 4.10 (q, 2H), 3.60-3.80 (m, 4H), 1.06 (t, 3H).

Example 51

Synthesis of ethyl 4- (3-nitrophenyl) -2-({2- (2-pyridylamino) ethyl] amino) -4- (4-pyridyl) pyrimidine -5-carboxylate

This compound was prepared from ethyl 3-oxo-3- (3-nitrophenyl) propanoate and amino [2-[(2-pyridylamino) ethyl] carboxamidinium 4-methylbenzenesulfonate according to Solution Method A. Prepared.

HPLC: 21.25 min (90% purity)

MS: MH ⁺ = 409 C ₂₀ H ₁₉ N ₆ 0 ₄ = 408 g / mol

Example 52

Synthesis of ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl] amino) -4- [4- (trifluoromethoxy ) phenyl] pyrimidine-5-carboxylate

This compound is ethyl 3-oxo-3- (4-trifluoroethoxyphenyl) propanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxa according to solution method A. Prepared from midi 4-methylbenzenesulfonate.

HPLC: 22.50 min (91% purity)

MS: MH ⁺ = 493 C ₂₁ H ₁₉ N ₆ O ₅ F ₃ = 472 g / mol

Example 53

Synthesis of ethyl 4- (3,4-difluorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

This compound is ethyl 3-oxo-3- (3,4-difluorophenyl) propanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxa according to Solution Method A. Prepared from midi 4-methylbenzenesulfonate.

HPLC: 17.96 min (100% purity)

MS: MH ⁺ = 445 C ₂₀ H ₁₈ N ₆ 0 ₄ { ₂ = 444 g / mol

Example 54

Synthesis of ethyl 4- [4- (methylsulfonyl) phenyl] -2- (2-{(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

This compound is ethyl 3- (4-methylsulfonylphenyl) -3-oxopropanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium according to solution method A. Prepared from 4-methylbenzenesulfonate.

HPLC: 11.21 min (100% purity)

MS: MH ⁺ = 487 C ₂₁ H ₂₂ N ₆ O ₆ S = 486 g / mol

Example 55

Synthesis of ethyl 4- (4-methylthiophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

This compound was prepared according to solution method A, ethyl 3- (4-methylthiophenyl) -3-oxopropanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4 It was prepared from methylbenzenesulfonate.

HPLC: 17.26 min (92% purity)

MS: MH ⁺ = 455 C ₂₁ H ₂₂ N ₆ 0 ₄ S = 454 g / mol

Example 56

Synthesis of ethyl 4- (4- (dimethylamino) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino ) pyrimidine-5-carboxylate

This compound was prepared according to Solution Method A, ethyl 3- (4-dimethylaminophenyl) -3-oxopropanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4 It can be prepared from -methylbenzenesulfonate.

HPLC: 9.0 min (90% purity)

MS: MH ⁺ = 452 C ₂₂ H ₂₅ N ₇ 0 ₄ = 451 g / mol

Example 57

Synthesis of ethyl 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-cyanophenyl ) pyrimidine-5-carboxylate

This compound is ethyl 3- (4-cyanophenyl) -3-oxopropanoate and amino {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} according to solution method A. It can be prepared from carboxamidinium 4-methylbenzenesulfonate.

HPLC: 25.21 min (83% purity)

MS: MH ⁺ = 449 C ₂₁ H ₂₀ N ₈ 0 ₄ = 448 g / mol

Example 58

Synthesis of ethyl 4- (4-imidazolylphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

This compound is ethyl 3- [4- (1-imidazolyl) phenyl] -3-oxopropanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} according to Solution Method A. It can be prepared from carboxamidinium 4-methylbenzenesulfonate.

HPLC: 18.50 min (91% purity)

MS: MH ⁺ = 475 C ₂₃ H ₂₂ N ₈ 0 ₄ = 474 g / mol

Example 59

Synthesis of ethyl 4- (4-ethylphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

This compound was prepared according to Solution Method A, ethyl 3- (4-ethylphenyl) -3-oxopropanoate and amino [2-[(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4- It can be prepared from methylbenzenesulfonate.

HPLC: 32.45 min (95% purity)

MS: MH ⁺ = 437 C ₂₂ H ₂₄ N ₆ O ₄ = 436 g / mol

The following additional compounds can be prepared according to Solution Method A using suitable carbonyl containing compounds and guanidine.

Ethyl 4- (2-furyl) -2-[(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate

Ethyl 4- (3-trophenyl) -2-[(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate

Ethyl 4- (4-fluorophenyl) -2-[(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate

Ethyl 4- (4-methoxyphenyl) -2-[(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate

Ethyl 4- (4-cyanophenyl) -2-[(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate

2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-nitrophenyl) pyrimidine-5-carboxylic acid

Ethyl 4- (4-fluorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3-quinolyl) pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3-nitrophenyl) pyrimidine-5-carboxylate

Methyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3-pyridyl) pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-nitrophenyl) pyrimidine-5-carboxylate

Ethyl 4- [3, 5-bis (trifluoromethyl) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- [4- (trifluoromethyl) phenyl] pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- [3- (trifluoro methyl) phenyl] pyrimidine-5-carboxylate

Ethyl 4- (5-bromo (3-pyridyl))-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (2,4-difluorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (4-cyanophenyl) -2-{[2- (pyrimidin-2-ylamino) ethyleamino} pyrimidine-5-carboxylate

Ethyl 4- (4-methoxyphenyl) -2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (3-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (4-cyanophenyl) -2-({2-[(4-nitrophenyl) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (3-fluorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (3, 5-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

4- [5- (methylsulfonyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-sulfamoylphenyl) pyrimidine-5-carboxylate

Ethyl 4- (4-chlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (4-bromophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4-naphthyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-phenylphenyl) pyrimidine-5-carboxylate

Ethyl 4- (2H-benzo [3,4-d] 1, 3-dioxolen-5-yl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} -amino Pyrimidine-5-carboxylate

Ethyl 4- (4-butoxyphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

6-[(2-{[4- (4-cyanophenyl) -5- (ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxylic acid

t-butyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

t-butyl 6-[(2-{[4- (4-cyanophenyl) -5- (ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxylate.

Methyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Methyl 6-[(2-{[4- (4-cyanophenyl) -5- (ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxylate

Ethyl 4- (4-cyanophenyl) -2-[(2-{[5- (morpholin-4-ylcarbonyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-car Carboxylate

Ethyl 4- (4-cyanophenyl) -2-[(2-{[5- (N-ethylcarbamoyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-carboxylate

 4- [5-nitro-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzene carbonitrile

Ethyl 4- (4-cyanophenyl) -2-{[2-({5-nitro-6- [benzylamino] (2-pyridyl)} amino) ethyl] amino} pyrimidine-5-carboxylate

Ethyl 4- [4- (4-methylpiperazinyl) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-cyano (2-pyridyl)) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5-carboxylate

Ethyl 4- (4-cyanophenyl) -2-[(2-{[6- (methylamino) -5-nitro (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-carboxylate

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4- (1, 3-oxazol-5 yl) phenyl) pyrimidine-5- Carboxylate

Ethyl 2-({2-[(4-amino-5-nitropyrimidin-2-yl) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5-carboxylate

Ethyl 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4- (l, 3-oxazol-5-yl) phenyl) pyri Midine-5-carboxylate

Ethyl 4- [4- (methylethyl) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- [4- (t-butyl) phenyl] -2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (3,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (3,4-dimethoxyphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- [4- (diethylamino) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4,6-trichlorophenyl) pyrimidine-5-carboxylic acid

Ethyl 4- (4-methylphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (2-naphthyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 4- (3,4-dimethylphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate

Ethyl 2- {2-[(4-amino-5-cyanopyrimidin-2-yl) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5-carboxylate

4- (2-methoxyphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylic acid

Ethyl 4- (4-cyanophenyl) -2-{[2- (3-methoxyphenyl) ethyl] amino} pyrimidine-5-carboxylate

2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3,4-dichlorophenyl) pyrimidine-5-carbonitrile

4- (3,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carbonitrile

Ethyl 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4- (1, 2,4-triazol-4-yl) phenyl) pyrimidine- 5-carboxylate

2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5-carbonitrile

4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carbonitrile

2- {2-[(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5-carboxylic acid

Ethyl 2-({2-[(5-amino (2-pyridyl)) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5-carboxylate

Example 60

Solution Phase Synthesis (Solution Method B)

Ketones with CH ₂ or CH ₃ groups adjacent to the carbonyl group were heated in purified N, N-dimethylformamide dimethyl acetal (DMFDMA) at 90-110 ° C. for 5 to 24 hours, generally 8 to l4 hours. Excess DMFDMA was removed by rotary evaporation to afford the intermediate enaminoketone as an oil or a solid. This intermediate was crystallized if desired, but was generally used as crude in the next reaction step. Enaminoketones were dissolved in THF, ethanol, isopropanol or NMP for synthesis where a high reaction temperature is desired (about 1-2 ml solvent for 0.3-1 mmol of starting ketone).

The solution is then added to a mixture of suitable bases such as guanidine (1 equiv) and sodium ethoxide (cleanly prepared), cesium carbonate or powdered sodium hydroxide. Typical formulations are calcium carbonate in THF, sodium ethoxide in ethanol, sodium hydroxide in isopropanol or cesium carbonate in NMP, and other base and / or solvent combinations may be used. The reaction was then heated at 80-125 ° C. (depending on the boiling point of the solvent) for 12-66 hours.

Small scale (ie 0.2-1 mmol) reactions were performed in a screw cap vial. The vials were placed in pre-perforated antistatic aluminum blocks (Digi-Block, Laboratories, Holystone, Mass.) And shaken on a rotary shaker (Lab-Line Model G-2). The glass bottle was cooled and its contents poured into dichloromethane or ethyl acetate The organic layer was concentrated in vacuo and washed with saturated aqueous sodium bicarbonate solution The organic layer was concentrated in vacuo and generally acetonitrile or The product was precipitated or crystallized by the addition of water to the ethanol solution In some cases, the chromatographic purification was performed using silica gel plates on chromatron (Harrison Research, Palo Alto, CA) eluted with a mixture of dichloromethane and methanol. Performed by HPLC or radial chromatography of some preparations . Larger scale of the reaction was using the universal organic chemistry techniques carried out in a round bottom flask.

Examples 61-66 describe the synthesis of compounds prepared according to Solution Method B.

Example 61

Synthesis of [2- (2-pyridylamino) ethyl] (4- (3-pyridyl) pyrimidin-2-yl) amine

3-acetylpyridine (0.5 mmol) was heated with DMFDMA (300 μl) at 90 ° C. for 8.5 h. The solvent was removed by rotary evaporation. The residue is dissolved in isopropanol (2 ml) and in 170 mg (0.5 mmol) of amino [2- (2-pyridylamino) ethyl] carboxamidinium 4-methylbenzenesulfonate and powdered sodium hydroxide (70 mg). Added. After the mixture was heated at 85 ° C. overnight, the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was taken up in acetylonitrile. Water was added to give a precipitate which was filtered and dried to give the title compound.

HPLC: 9.9 min (100% purity)

NMR (300 MHz, 5/1 acetylonitrile-d ₃ / D ₂ 0, 75 ° C.): 9.20 (s, 1H), 8.65 (d, 1H), 8. 2-8. 4 (m, 2H), 7.94 (d, 1H), 7. 50 (dd, 1H), 7.38 (t, 1H), 7.10 (d, 1H), 6.50 (m, 2H), 3.70 (t, 2H) , 3.50 (t, 2H)

Example 62

Synthesis of (5-ethyl-4-phenylpyrimid-2-yl) [2- (2-pyridylamino) ethyl] amine

Butyrophenone (0.5 mmol) was heated with DMFDMA (300 μl) at 90 ° C. for 8.5 h. The solvent was removed by rotary evaporation. The residue is dissolved in isopropanol (2 ml) and in 170 mg (0.5 mmol) of amino [2- (2-pyridylamino) ethyl] carboxamidinium 4-methylbenzenesulfonate and powdered sodium hydroxide (70 mg). Added. After the mixture was heated at 90 ° C. overnight, the residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was taken up in acetylonitrile. Water was added to give a precipitate which was filtered and dried to give the title compound.

HPLC: 17.46 min (98% purity)

MS: MH ⁺ = 320 C ₁₈ H ₂₁ N ₅ = 319 g / mol

Example 63

Synthesis of [2- (2, 5-dimethoxyphenyl) ethyl] (4- (3-pyridyl) pyrimidin-2-yl) amine

Step 1: 2,5-dimethoxyphenethylamine (1.08 g, 6 mmol) was added benzotriazolecarboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) and DIEA (1.05) in dry acetylonitrile (10 ml). ml, 6 mmol) was shaken overnight at room temperature. Ether was added to precipitate amino [2- (2,5-dimethoxyphenyl) ethyl] carboxamidinium 4-methylbenzenesulfonate as a white solid.

Step 2: 3-acetylpyridine (37 mg, 0.3 mmol) was heated with DMFDMA (300 μl) at 100 ° C. for 8 hours. The solvent was removed by rotary evaporation and the residue was dissolved in dry THF (2 ml) and added to a mixture of cesium carbonate (160 mg) and 120 mg (0.3 mmol) of guanidine prepared in step 1. The mixture was then heated at 80 ° C. overnight and then concentrated in vacuo. The residue was taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was taken up in ethanol (2 ml). Water was added to give a precipitate which was filtered and dried to give the title compound.

HPLC: 18.03 min (100% purity)

MS: MH ⁺ = 337 C ₁₉ H ₂₀ N ₄ 0 ₂ = 336 g / mol

Example 64

Synthesis of [4- (4-morpholin-4-ylphenyl) pyrimidin-2-yl {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

4-morpholinoacetophenone (0.633 g, 2.5 mmol) was heated in 4 ml of DMFDMA at 100 ° C. for 9 hours. The mixture was concentrated to viscous oil by rotary evaporation. The oil was dissolved in isopropanol (10 ml), amino [2- (5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (1.0 g, 2.5 mmol) and powdered hydroxide Sodium (200 mg) was added The mixture was heated overnight at 80 ° C. The cooled mixture was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution The organic layer was concentrated in vacuo and dissolved in acetylonitrile. The precipitate was added to give a brown solid which was recrystallized from isopropanol to give the title compound.

M. P. 223-225 ° C. (decomposition)

Elemental analysis; C ₂₁ H ₂₃ N ₇ 0 ₃ . 0.7 H ₂ 0,

Theoretical: C 58.10 H 5.66 N 22.59

Found: C 58.02 H 5.30 N 22.39

HPLC: 20.85 min (100% purity)

MS: MH ⁺ = 422 mol (FW = 421)

NMR (DMSO-d ₆ ): 3.30 (m, 4H), 3.60 (m, 4H), 3.75 (m, 4H), 6.58 (d, 1H), 6.95 (m, 3H), 8.00 (d, 2H ), 8.10 (d, 1H), 8. 25 (d, 1H), 8.90 (s, 1H)

Example 65

Synthesis of [4- (2,4-dichlorophenyl) -5-ethylpyrimid-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

Step 1: 2, 4-dichlorobenzoyl chloride (4.5 g) and copper (I) iodide (200 mg) in dry THF (30 ml) were cooled to -20 ° C under argon. Thereafter, a solution of propyl magnesium chloride (2 M in ether, 11.0 ml) was added dropwise. After 10 minutes of addition, the cooling bath was removed and the mixture was stirred for 1 minute. Water was added carefully and then extracted with toluene. The toluene layer was washed with dilute HC1, water, saturated sodium bicarbonate solution, dried and concentrated in vacuo to afford 1- (2,4-dichlorophenyl) butan-1-one (4.0 g).

Step 2: The ketone from step 1 (108 mg, 0.5 mmol) was heated with DMFDMA (1.5 ml) at 95 ° C. overnight. The solvent is removed in vacuo and the residue is dissolved in dry ethanol (2 ml) and amino [2 [(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (200 mg) Was added to a mixture of 1.0 M sodium ethoxide (0.6 ml) and dry ethanol (2 ml) The mixture was heated at 85 ° C. overnight, then concentrated in vacuo, redissolved in dichloromethane and saturated aqueous sodium bicarbonate solution The organic layer was concentrated in vacuo The residue was purified by chromatography on silica gel using 10% methanol in dichloromethane Freeze drying from acetylonitrile / water to give the title compound as a solid. It was.

HPLC: 29.56 (85% purity)

MS: MH ⁺ = 433 C ₁₉ H ₁₈ N ₆ Cl ₂ 0 ₂ = 432 g / mol

Example 66

Synthesis of [4- (4-imidazolylphenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

4- (1-imidazolyl) acetophenone (57 mg, 0.3 mmol) was heated with DMFDMA (1 ml) at 105 ° C. for 8 hours. The solvent is removed in vacuo, the residue is dissolved in dry THF (2 ml) and amino [2 [(5-nitro (2-pyridyl) amino] ethyl} carboxamidinium 4-methylbenzenesulfonate (120 mg, 0.3 mmol) and cesium carbonate (200 mg), heated at 80 ° C. overnight, concentrated in vacuo, redissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate solution. The residue was purified by chromatography to give the title compound.

HPLC: 15.17 min (100% purity)

NMR (300 Mhz, DMSO-d ₆ ): 8.90 (s, 1H), 8.38 (d, 1H), 8.30 (s, 1H), 8.22 (d, 2H), 8.05 (d, 1H), 7.75 (d, 2H), 7.20 (s, 1H), 7.15 (d, 1H), 6.58 (d, 1H), 3.60 (m, 4H).

The following additional compounds were prepared analogously according to solution method B by various uses of ketones and guanidines:

(4-phenylpyrimidin-2-yl) (2- (2-pyridyl) ethyl) amine

4- {[2- (2-pyridylamino) ethyl] amino} pyrimidin-4-yl) benzenecarbonitrile

(4-phenylpyrimidin-2-yl) [2- (2-pyridylamino) ethyl] amine 4- {2-[(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} Benzenecarbonitrile

[4- (4-nitrophenyl) pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine [4- (4-imidazolylphenyl) pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine

[4- (3,4-difluorophenyl) pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine

[2- (2-pyridylamino) ethyl] {4- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amine

[4- (2,4-dichlorophenyl) pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine [4- (4-chlorophenyl) -5-methylpyrimidin-2-yl ]

[2- (2-pyridylamino) ethyl] amine [4- (4-methyl-l-phenylpyrazol-3-yl) pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] Amine

3- [2-({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile

[4- (2,4-dimethyl (1, 3-thiazol-5-yl)) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] -ethyl} amine

{2-[(5-nitro (2-pyridyl)) amino] ethyl} (4-pyrazin-2-ylpyrimidin-2-yl) amine [4-phenyl-5-benzylpyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine

4- [2-({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzenessulfonamide

{4- [4- (4, 5-dichloroimidazol-2-yl) phenyl] pyrimidin-2-yl}-{2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

4- (2- {[2- (2, 5-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzenecarbonitrile [2- (2, 5-dimethoxyphenyl) ethyl]

(4- (3-pyridyl) pyrimidin-2-yl) amine [4- (4-benzimidazolylphenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl) ) Amino] ethyl} amine

4- [5-imidazolyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzene carbonitrile

4- [2- ({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -5-imidazolylpyrimidin-4-yl] benzenecarbonitrile

[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amine

[4- (2,4-dimethylphenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine ethyl

4- [2-({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzoate

4- (2-{[3- (4-phenylimidazolyl) propyl] amino} pyrimidin-4-yl) benzenecarbonitrile (3-benzimidazolylpropyl) [4- (4-imidazolylphenyl ) Pyrimidin-2-yl] amine

N-14- [2- (12-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] phenyl} acetamide

Example 67

[5- (4- (fluorophenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl}] amine (solution method C)

Step 1: Dry DMF (22 ml) was cooled to 0 ° C. under argon. Phosphorus oxychloride (9.2 g) was added dropwise to the cooled DMF. The mixture was removed from the cooling bath and stirred continuously for 1 hour. Then 4-fluorophenylacetic acid (3.08 g, 20 mmol) was added as a solid and the mixture was heated at 85 ° C. for 6 hours. After the mixture was cooled to room temperature, it was poured into about 100 g of ice with stirring. Sodium perchlorate monohydrate (3.66 g) in water (10 ml) was added. The precipitated solid was filtered off, washed with water and dried under vacuum to afford [(2-E, Z) -3- (dimethylamino) -2- (4-fluorophenyl) prop-2-enylidene] dimethyl Ammonium perchlorate was obtained. This method is described in Chur et al., J; Org Chem., 60: 3750 (1995).

Step 2: The vinyl amidinium salt (100 mg, 0.3 mmol) obtained in step 1 was dried with ethanol (2 ml) and amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidi. Treatment with nium 4-methylbenzenesulfonate ((180 mg, 0.45 mmol). Then 0.45 ml of 1.0 M sodium ethoxide solution in ethanol were added and the mixture was shaken at room temperature for 0.5 h. Sodium ethoxide solution was added and then heated for 2 h at 70 ° C. The solvent was removed in vacuo The residue was partitioned between dichloromethane and water The organic layer was dried and concentrated in vacuo, then the resulting residue Water was dissolved in acetonitrile Water was added to the residue / acetonitrile mixture to afford the title compound as a precipitate of an orange solid.

HPLC: 18.49 min (80% purity)

NMR (300 MHz, DMSO-d ₆ : 8.90 (d, 1H), 8. 60 (s, 2H), 8.12 (dd, 1H), 7.65 (m, 2H), 7.24 (m, 2H), 6.60 (d , 1H), 3.58 (m, 4H)

Example 68

Synthesis of ethyl 4-[(2,4-dichlorophenyl) amino] -2- (2-[(5-nitro (2-pyridyl) amino] ethyl} amino ) pyrimidine-5-carboxylate (solution Method D)

Step 1: ethyl 2,4-dichloropyrimidine-5-carboxylate (0.49 g, 2 mmol), 2,4-dichloroaniline (0.33 g, 2 mmol) and DIEA (0.35 ml, 2 mmol) in acetylonitrile (6 ml) ) Was heated at 80 ° C. for 36 h. The mixture was cooled and 0.54 g of crystalline product ethyl 4 [(2,4-dichlorophenyl) amino] -2-chloropyrimidine-5-carboxylate was filtered off.

NMR (300 MHz, CDCl ₃ ): 8.90 (s, 1H), 8.44 (d, 1H), 7.45 (d, 1H), 7.32 (dd, 1H), 4.45 (q, 2H), 1.45 (t, 3H) ].

Step 2: The pyrimidine (69 mg, 0.2 mmol) from step 1 was converted to DIEA (100 1 L) and (2-aminoethyl) (5-nitro (2-pyridyl)) amine (36 mg, 0.2 mmol in NMP (3 ml). ) Was heated at 105 ° C. for 14 hours. The reaction was cooled, poured into water and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and concentrated in vacuo. The crude product was purified by chromatography on silica gel and then crystallized from a mixture of acetylonitrile, methanol and water to give colorless crystals.

HPLC: 30.32 min (> 95% purity)

MS: MH ⁺ = 492-494 (Cluster) C ₂₀ H ₁₉ N ₇ 0 ₄ Cl ₂ = 492 g / mol

Example 69

Synthesis of t-butyl 6-((2-{[4- (4-cyanophenyl) -5-ethoxycarbonyl) pyrimidin-2 yl] amino} ethyl) amino] pyridine-3-carboxylate

Step 1: Treatment of 6-chloro-pyridine-3-carboxylic acid (5.6 g, 36 mmol) with l, l'-carbonyldiimidazole (6.93 g, 42 mmol) in DMF (40 ml) at 40 ° C. for 1 hour. It was. Then t-butanol (9.5 ml, 0.11 mol) and 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) (5.38 ml, 36 mmol) were added and heating continued overnight. The mixture was cooled to rt and diluted with ether (300 ml). The mixture was extracted once with water. The aqueous layer was extracted twice with diroromethane again. The combined organic layers were washed with saturated aqueous citric acid solution, dried and concentrated in vacuo to give a colorless cream solid (7.07 g).

(NMR (300 MHz, CDC ₁₃ ): 8.92 (d, 1H), 8.20 (dd, 1H), 7.40 (d, 1H), 1.60 (s, 9H)).

t-butyl 6-chloropyridine-3-carboxylate was heated at 80 ° C. with ethylenediamine (20 ml) overnight. The solvent was removed in vacuo. The residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide solution. The aqueous layer was extracted three times with dichloromethane. The combined organic layers were washed with water, dried and concentrated in vacuo to afford t-butyl 6-[(2-aminoethyl) amino] pyridine-3-carboxylate.

NMR (300 MHz, CDC1 ₃ ): 8.70 (s, 1H), 7.95 (d, 1H), 6.40 (d, 1H), 3.42 (m, 2H), 2.96 (m, 2H), 1.70 (s, 9H)

Step 2: t-butyl 6-[(2-aminoethyl) amino] pyridine-3-carboxylate (1.42 g, 6 mmol), benzotriazolecarboxamidinium 4-methylbenzenesulfonate (2.0 g, 6 mmol) And DIEA (1.05 ml, 6 mmol) were shaken overnight in a mixture of dry acetylonitrile (10 ml) and DMF (2 ml). After adding ete, it was cooled at 4 ° C. for 4 days. The solid was filtered and dried under vacuum to afford t-butyl 6-{[(2- (amidinoammonium) ethyl] amino} pyridine-3carboxylate 4-methylbenzenesulfonate (1.87 g).

NMR (300 MHz, DMSO-d6: 8.55 (br s, 1H), 7.80 (d, 1H), 7.55 (d, 2H), 7.10 (d, 2H), 6.50 (d, 1H), 3.50 (m, 2H ), 3.30 (m, 2H), 2.30 (s, 3H), 1.52 (s, 9H).

Step 3: Ethyl 3- (4-cyanophenyl) -3-oxopropanoate (217 mg, 1.0 mmol) was heated with DMFDMA (200 μl) in dry THF (2 mL) at 70 ° C. for 5. 5 h. . In cooled solution t-butyl 6-{[(2- (amidinoammonium) ethyl] amino} pyridine-3-carboxylate 4-methylbenzenesulfonate (451 mg, 1.0 mmol), dry ethanol (4 ml) and ethanol (Mt 1.2 M) was added 1.0 M sodium ethoxyxide The mixture was heated overnight at 80 ° C. and the solvent was removed in vacuo The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The residue was dissolved in acetylonitrile Water was added to give the title compound (230 mg) as a solid.

HPLC: 25.90 min (80% purity)

MS: MH ⁺ 489 C ₂₆ H ₂₈ N ₆ 0 ₄ = 488 g / mol

Example 70

6- (2-{[4- (4-cyanophenyl) -5-ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino ] pyridine-3-carboxylic acid

t-butyl 6-[(2-{[[4- (4-cyanophenyl) -5-ethoxycarbonyl) pyrimidin-2yl] amino} ethyl) amino] pyridine-3-carboxylate (implemented 220 mg), prepared in Example 62, was shaken with 100% TFA for 1 hour at room temperature. TFA was removed under vacuum. The residue was dissolved in acetylonitrile and water was added. No precipitate formed at all. Several drops of concentrated ammonium hydroxide were added. This title compound was then obtained as a white solid (180 mg, after drying).

MS: MH ⁺ = 433 C ₂₂ H ₂₀ N ₆ O ₄ = 432 g / mol NMR (300 MHZ, DMSO-d6): 8.80 (s, 1 H), 8.58 (s, 1 H), 7.85 (d, 2H), 7.80 (m, 1H), 7.60 (d, 2H), 6.50 (d, 1H), 4.05 (q, 2H), 3.55 (m, 4H), 1.05 (t, 3H).

Example 71

Synthesis of Methyl 6-[(2- {[4- (4-cyanophenyl) -5-ethoxycarbonyl) pyrimidin-2yl] amino} ethyl) amino ] pyridine-3-carboxylate

Step 1: 6-[(2-{[4- (4-cyanophenyl) -5-ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxylic acid Prepared according to example 70, 120 mg) was dissolved in thionyl chloride (3 ml) and warmed at 50 ° C. for 0.5 h. The solvent was removed under vacuum to afford crude ethyl 2-({2-[(5- (chlorocarbonyl) (2-pyridyl)) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine- 5-carboxylate was obtained. This compound was dissolved in dichloromethane (4 ml).

Step 2: The acid chloride solution (1.0 ml) prepared in step 1 was treated with dry methanol (1 ml). After standing at room temperature for about 1 hour, the solvent was removed in vacuo to afford the title compound.

HPLC: 20.90 min (95% purity)

MS: MH ⁺ = 447 C ₂₃ H ₂₂ N ₆ 0 ₄ = 446 g / mol

Example 72

Ethyl 4- (4-cyanophenyl) -2-[(2- {[5- (morpholin-4-ylcarbonyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-car Synthesis of Cyclate

Ethyl 2-({2-[(5- (chlorocarbonyl) (2-pyridyl)) amino] ethyl} amino) -4- (4-cyano in dichloromethane prepared in step 1 of Example 71 Phenyl) pyrimidine-5-carboxylate (1.0 ml) was treated with morpholine (150 μl) in dichloromethane (1 ml) at room temperature. After 1 hour, the solvent was removed in vacuo to afford the title compound.

HPLC: 19.63 min (96% purity)

MS: MH <+> = 502 C ₂₆ H ₂₇ N ₇ 0 ₄ = 501 g / mol.

Example 73

Of ethyl 4- (4-cyanophenyl-2-{[2-({5-nitro-6] benzylamino] (2-pyridyl)} amino) ethyl] amino } pyrimidine-5-carboxylate synthesis

Step 1: 6-Chloro-3-nitro (2-pyridyl)) benzylamine was prepared according to the method described herein by von Bebenberg, Chemiker-Zeitung, 103: 387 (1979). The amine (1.8 g) was heated with ethylenediamine (5 ml) in acetylonitrile (15 ml) at 100 ° C. for 3.5 h. The solvent was removed in vacuo and the residue was partitioned between dichloromethane and 2.5 M aqueous sodium hydroxide solution. The aqueous layer was further extracted three times with dichloromethane. The combined organic layers were washed with saturated sodium chloride solution, dried and concentrated in vacuo to afford a yellow solid.

NMR (300 MHz, CDC1 ₃ ): 8.10 (d, 1H), 7.2-7.4 (m, 5H), 5.80 (s, 1H), 4.80 (AB q, 2H), 3.42 (m, 2H), 2.85 (m , 2H).

Step 2: The amine from step 1 (1.31 g) was treated with benzotriazolecarboxamidinium 4-methylbenzenesulfonate (1.52 g) and DIEA (800 μl) in acetylonitrile (15 ml) overnight at room temperature. The mixture was diluted with ether and then filtered to give guanidine, amino [2-({5-nitro-6- [benzylamino] (2-pyridyl)} amino) ethyl] -carboxamidinium 4-methylbenzenesulfonate Was obtained as a yellow solid.

NMR (300 MHz, DMSO-d ₆ ): 8. 02 (d, 1H), 7.72 (d, 2H), 7.30-7.40 (m, 5H), 7.10 (d, 2H), 6.00 (d, 1H), 4.78 (AB q, 2H), 3.50 (m, 2H), 3.30 (m, 2H), 2.25 (s, 3H).

Step 3: Ethyl 3- (4-cyanophenyl) -3-oxopropanoate (65 mg, 0.3 mmol) was heated with DMFDMA (60 μl) in THF (1 mL) at 70 ° C. for 3 hours. This solution was added to a mixture of guanidine (150 mg, 0.3 mmol), dry ethanol (1 ml) and 1.0 M sodium ethoxide in ethanol (0.35 ml) prepared in step 2. The solvent was removed in vacuo. The residue was partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic layer was concentrated in vacuo. The residue was dissolved in acetylonitrile, water was added to afford the title compound as a yellow solid.

HPLC: 34.06 min (98% purity)

MS: MH ⁺ = 539 C ₂₈ H ₂₆ N ₈ 0 ₄ = 538 g / mol

Example 74

Preparation of [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

1. Preparation of 1- (2,4-dichlorophenyl) -2-imidazol-2-ylethan-1-one

A solution of 2,4-dichlorobenzoyl chloride (9.75 M) in dichloromethane (75 ml) was diluted with 2-methyl in dichloromethane (500 ml) and N, N-diisopropylethylamine (Hunig's base) (136 ml). Stirring was added dropwise to the midazole (2) (0.49M) solution over 30 minutes [Reference: Macco, AA; Godefroi, E. F.; Drouen, J. J. M., J. Org. Chem. 1975, 40, 252-255]. The reaction mixture was cooled during the addition using an ice water bath. Thereafter, the reaction mixture was heated to reflux for 3.5 hours. A dark reddish black mixture formed. To dilute the dark heterogeneous reactant, additional dichloromethane (100-200 ml) was added as needed while the reaction was continued to stir. Upon cooling, dichloromethane (500 ml) was added and the solution transferred to a separating funnel. The organic layer was washed with distilled water (3 x 200 ml). Filtration or sinking for 15 minutes separated to form an emulsion. The wet organic layer is concentrated directly under reduced pressure and is not dried at this time. The solid product is then dried under vacuum for several hours.

To a dry solid (solid described above) was added (2: 1 v / v, 500-600 ml) glacial acetic acid and aqueous HC1 solution. Thereafter, the mixture was stirred at reflux for about 75 minutes. Acetic acid was removed via rotary evaporation. Distilled water (800 ml) and benzene (400 ml) were added to the solid residue and stirred vigorously for 15 minutes. The solid was filtered off and the filtrate was transferred to a separating funnel. After discarding the organic layer, the aqueous layer was washed with benzene (4 x 150 ml). The aqueous layer was transferred to a large beaker (4 L) and diluted with isopropyl ether (100 ml). Sodium bicarbonate was carefully added to the stirred mixture to make it basic (pH 7-8) to form a white solid. After further stirring for 2 hours, the desired solid was filtered off, washed with distilled water (3 x 60 ml), isopropyl ether (2 x 60 ml) and dried under vacuum overnight to give 1- (2,4-dichlorophenyl) -2 -Imidazol-2-ylethane-l-one was obtained in 56% yield.

2. Preparation of (2Z) -1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-imidazol-2-ylprop-2- en-l-one

A mixture of 1- (2,4-dichlorophenyl) -2-imidazol-2-ylethan-1-one (0.39 M) in N, N-dimethylformamide dimethyl acetal (DMFDMA) (150 ml) was added for 2.5 hours. Stir at 70-75 ° C. The DMFDMA was then removed under reduced pressure and dried under high pressure for several hours to give an orange yellow solid 4 in quantitative yield. The product (2Z) -1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-imidazol-2-ylprop-2-en-1-one was typically used without further purification.

3. Preparation of amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride

H-pyrazole-1-carboxamidine hydrochloride (0.47 M) and 2- (2-aminoethylamino) -5-nitropyridine (0.47 M) in acetylonitrile (500 ml) (purchased from Aldrich) or , Example {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine-2 -Yl] amine or Example 6- (2-{[4- (2,4-dichlorophenyl) -5 (4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) Amino] pyridine-3-carbonitrile) was reacted by reacting ethylene diamine with 2-chloro-5-nitropyridine over night (about 20 hours) at 70-80 ° C. Upon cooling, a yellow precipitate was collected by filtration. The yellow solid was washed thoroughly with acetylonitrile (3 x 100 ml), ethyl ether (3 x 100 ml) and dried under vacuum overnight to give amino {2-[(5 nitro (2-pyridyl)) in 87% yield. Amino) ethyl] carboxamidine, hydrochloride.

4. [4- (2,4-Dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2 -pyridyl)) amino] ethyl} amine Produce.

A solution of sodium ethoxide (0.59 M) dissolved in anhydrous ethanol (100 ml) was added to (2Z) -1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-imidazole- in anhydrous ethanol (260 ml). Stirring of 2-ylprop-2-en-1-one (0.23 M) and amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride (0.23 M) To the prepared mixture. The reaction was stirred at room temperature for 15 minutes and then at 75-80 ° C. for 2.5 hours. Upon cooling, a yellow precipitate was collected by filtration. The filtrate was stored for possible further isolation and retention of the product. The solid product was washed with anhydrous ethanol (3 x 50 ml), distilled water (3 x 50 ml), and ethyl ether (3 x 50 ml). The yellow solid was dried under vacuum overnight to give the final product [4- (2,4-dichlorophenyl) -5-imidazole-2-ylpyrimidin-2-yl] {2-[(5-nitro (5) in 52.7% yield. 2-pyridyl)) amino] ethyl} amine was obtained.

HPLC: 20.9 min (> 95% purity)

MS: MH ⁺ = 471 (C ₂₀ H ₁₆ Cl ₂ N ₈ 0 ₂ H = 471)

Example 75

{2- (4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- imidazol-2-ylpyrimidin-2-yl] amine Manufacture

{2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] The amine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyri), with the exceptions given below Dill)) amino] ethyl} amine (see Example 74).

1. Preparation of 2- (2-aminoethyl) amino-6-amino-5-nitropyridine

A mixture of 2-amino-6-chloro-3-nitropyridine (0.52 M) and ethylene diamine (40 ml) in acetylonitrile (70 ml) was stirred overnight (about 20 hours) at 75-80 ° C. under argon. Ethylene diamine was removed under reduced pressure. The remaining solution was basified with 1 M sodium hydroxide solution (50 ml). The aqueous solution was saturated with sodium chloride and extracted with a solution of 95% ethyl acetate and 5% methanol (3 x 150 ml) and a solution of 95% acetylonitrile and 5% methanol (3 x 150 ml). The organic extracts were combined and extracted with saturated sodium chloride solution (2 x 75 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The fine yellow solid was titrated with ether (2 x 25 ml) and dried under vacuum overnight to yield 2- (2-aminoethyl) amino-6-amino-5-nitropyridine in 99% yield.

2. Preparation of amino {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride

2- (2-aminoethyl) amino-6-amino-5-nitropyridine (0.44 M), 1Hpyrazole-1-carboxamidine hydrochloride (0.44 M) in acetylonitrile (75 ml) Stir at 75-80 ° C.). Upon cooling, a yellow precipitate was collected by filtration. The yellow solid was washed thoroughly with acetylonitrile (3 x 100 ml), ethyl ether (3 x 100 ml) and dried under vacuum overnight to give amino {2-[(6-amino-5-nitro (2) in 82% yield. -Pyridyl)) amino) ethyl] carboxamidine was obtained as HCl salt.

3. {2- [4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5 imidazol-2-ylpyrimidin-2-yl] Preparation of Amine.

A solution of sodium ethoxide (0.5 M) dissolved in anhydrous ethanol (8 ml) was added (2Z) -1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-imidazol-2-ylprop- 2-en-1-one (0.57 M) and amino {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride (0.57 M), and anhydrous ethanol (7 ml) was added to the mixture. The reaction was then stirred at 75-80 ° C. for 2.5 hours. Upon cooling, a yellow precipitate was collected by filtration. The filtrate was stored for possible further isolation and retention of the product. The solid product was washed with anhydrous ethanol (3 x 10 ml), distilled water (3 x 10 ml), and ethyl ether (3 x 10 ml). The yellow solid was dried under vacuum overnight to give the final product {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5 in 70% yield. -Imidazol-2-ylpyrimidin-2-yl] amine was obtained.

HPLC: 18. 7 min (> 95% purity)

MS: M + H = 486.2 (C ₂₀ H ₁₇ Cl ₂ N ₉ O ₂ + H = 486)

Example 76

Preparation of 6-[(2- {[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] pyridine -3-carbonitrile

1. Preparation of 4- (2-imidazolylacetyl) benzenecarbonitrile

A stirred solution of 4- (2-chloroacetyl) benzenecarbonitrile (0.5 M) and imidazole (1.5 M) in CH ₃ CN (200 ml) was heated at 60 ° C. for 14 hours. The solvent was removed from the product under reduced pressure. The residue was diluted with dichloromethane (250 ml) and water (100 ml) and the mixture was stirred for 30 minutes. After filtering out the solid impurities, the aqueous layer was separated and discarded. The organic layer was washed successively with water (60 ml), saturated aqueous NaHC0 ₃ solution (60 ml), water (60 ml), brine (60 ml), and dried over Na ₂ S0 ₄ . After filtration, it was concentrated under reduced pressure. The dark oil was dried under vacuum overnight to give 4- (2-imidazolylacetyl) benzenecarbonitrile in 90% yield.

2. Preparation of 4-[(2E) -3- (dimethylamino) -2-imidazolylprop-2-enoyl] benzene-carbonitrile

A mixture of 4- (2-imidazolylacetyl) benzenecarbonitrile (0.30 M) and N, N-dimethylformamide dimethyl acetal (DMFDMA) (80 ml) was stirred at 75 ° C. for 12 hours. The DMFDMA was then removed under reduced pressure and dried under high pressure for several hours to give 4-[(2E) -3- (dimethylamino) -2-imidazolylprop-2-enoyl] benzene as an orange yellow solid. Carbonitrile was obtained in quantitative yield. Enamineone product was typically used without further purification.

3. Preparation of amino {2-[(5-cyano (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride )

Amino {2-[(5-cyano (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride 6-[(2-{[4- (2,4-dichlorophenyl) -5- ( 4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile.

4. Preparation of 6- (2- (4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) -amino ] pyridine-3-carbonitrile

A solution of sodium ethoxide (0.66 M) dissolved in anhydrous ethanol (8 ml) was dissolved in 4-[(2E) -3- (dimethylamino) -2-imidazolylprop-2-enoyl] benzenecarbonitrile (0.33 M ), Amino {2-[(5-cyano (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride (0.33 M), and anhydrous ethanol (15 ml) were added to a stirred mixture. The reaction was then heated at 75-80 ° C. for 2.5 hours. On cooling, the reaction was diluted with ethyl acetate (400 ml), washed with saturated aqueous NaHCO ₃ (100 ml), distilled water (2 × 100 ml), brine (100 ml), dried over Na ₂ SO ₄ , filtered and concentrated. . The crude product was purified by flash chromatography on silica gel. The column was started with 1: 1 ethyl acetate and operated with hexanes, then ethyl acetate was used until all fast moving impurities were removed. The product was eluted with 1.5% methanol in ethyl ethyl acetate. The column was measured by TLC using 5% methanol in ethyl acetate as solvent system. Appropriate fractions were condensed. The off-white solid was dried under vacuum overnight to give 6-[(2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3carbonitrile Was obtained in 40% yield.

HPLC: 18.9 min (> 95% purity)

MS: MH ⁺ = 473.1 (C ₂₂ H ₁₇ N ₉ + H = 473)

Example 77

Preparation of (t-butoxy) -N- (2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) carboxamide

1. Preparation of N- (2-aminoethyl) (t-butoxy) carboxamide

T-butyl [(t-butyl) oxycarbonyloxy] formate (Boc ₂ O) (181 g, 830 mmol) in dichloromethane (1 L) was added to ethylene diamine (250 g, 4.16 mol) in dichloromethane (2.5 L) at room temperature. Was added slowly to the mechanically stirred solution of. After 24 hours, the reaction solution was washed with water (3x500ml), brine (500ml), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. Pure crude product N- (2-aminoethyl) (t-butoxy) carboxamide was obtained in 50% yield.

2. Preparation of N- [2- (amidinoamino) ethyl] (t-butoxy) carboxamide, hydrochloride

A portion of solid 1H-pyrazole-1-carboxamidine hydrochloride (91.10 g, 624 mmol)) was added to N- (2-aminoethyl) (t-butoxy) carboxamide in CH ₃ CN (1L) at 80 ° C. (100 g, 624 mmol) was added to the stirred solution. After 24 hours, the solvent of the reaction was removed under reduced pressure. The residue was washed with ether (3 x 100 ml) and dried in vacuo. Guanidine N- [2- (amidinoamino) ethyl] (t-butoxy) carboxamide, containing a small amount of pyrazole, was obtained in 100% yield. Guanidine was used without further purification.

3. Preparation of (t-butoxy) -N- (2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino } ethyl) carboxamide

4-[(2E) -3- (dimethylamino) -2-imidazolylprop-2-enoyl] benzenecarbonitrile (8.0 g, 30.0 mmol) in NMP (5 ml) was added to N- in NMP (15 ml). To a stirred mixture of [2- (amidinoamino) ethyl] (t-butoxy) carboxamide, hydrochloride (13.8 g, 45 mmol)) and Cs ₂ CO ₃ (11.72, 36.0 mmol). The reaction was heated to 100 ° C. for 48 hours. The reaction was analyzed by HPLC. After the analysis, the reaction was partitioned between water (50 ml) and dichloromethane (250 ml). The organic layer was separated, washed with water (2 × 50 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The product was purified by flash chromatography eluting with 10% methanol in dichloromethane. After the solvent was removed and dried in vacuo, 10.08 g of (t-butoxy) -N- (2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidine-2 as dark red glass was obtained -Yl] amino} ethyl) carboxamide was obtained in 83% yield.

Example 78

4- {5-imidazolyl-2-[(2- {[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino ] pyrimidin-4-yl} benzenecarbonitrile Produce

4- {5-imidazolyl-2-[(2- {[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyrimidin-4-yl} benzenecarbonitrile 6-[(2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile (60406 except as indicated in (See Example 76).

1. Preparation of N- (2-aminoethyl) (t-butoxy) carboxamide

A solution of t-butyl [(t-butyl) oxycarbonyloxy] phosphate (Boc ₂ O) (0.83 M) in dichloromethane (1 L) was added to ethylene diamine (1.66 M) in dichloromethane (2.5 L) at room temperature. Add slowly (3 hours). After 24 hours, the reaction solution was washed with water (3 x 500 ml), brine (500 ml), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. Pure N- (2aminoethyl) (t-butoxy) carboxamide was obtained in 50% yield.

2. Preparation of N- [2- (amidinoamino) ethyl] (t-butoxy) carboxamide, hydrochloride

A portion of solid lH-pyrazole-1-carboxamidine hydrochloride (91.10 g, 624 mmol)) was added to N- (2-aminoethyl) (t-butoxy) carboxamide in CH ₃ CN (1L) at 80 ° C. (0.62M) to a stirred solution. After 24 hours, the solvent was removed from the reaction under reduced pressure. The residue was titrated with ether (3 x 100 ml) and dried in vacuo. N- [2- (amidinoamino) ethyl] (t-butoxy) carboxamide, containing a small amount of pyrazole, was obtained in 100% yield. N- [2 (amidinoamino) ethyl] (t-butoxy) carboxamide, hydrochloride, was used without further purification. It was used without further purification.

3. Preparation of (t-butoxy) -N- (2- [[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2- yl] amino } ethyl) carboxamide

4-[(2E) -3- (dimethylamino) -2-imidazolylprop-2-enoyl] benzenecarbonitrile (6M) in NMP (5 ml) was replaced with N- [2- (in NMP (15 ml). Amidinoamino) ethyl] (t-butoxy) carboxamide, hydrochloride (3 M) and Cs ₂ CO ₃ (2.4) to a stirred solution. The reaction solution was heated to 100 ° C. for 48 hours. The reaction was analyzed by HPLC. After the analysis was completed, the reaction was partitioned between water (50 ml) and dichloromethane (250 ml). The organic layer was separated, washed with water (2x50ml), brine (50ml), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. The product was purified by flash chromatography eluting with 10% methanol in dichloromethane. After removing the solvent, it was dried under vacuum to give (t-butoxy) -N- (2- {[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl as dark red glassy matter. ] Amino} ethyl) carboxamide was obtained in 83% yield.

4. Preparation of 4- {2-[(2-aminoethyl) amino] -5-imidazolylpyrimidin-4-yl} benzenecarbonitrile

3M HCl aqueous solution (15-30 ml) was added to (t-butoxy) -N- (2-{[4- (4-cyanophenyl) -5 in CH ₃ CN (50 ml) at room temperature until the reaction became somewhat cloudy. Added to a stirred solution of imidazolylpyrimidin-2-yl] amino} ethyl) carboxamide (0.15M). After 16 h, the reaction was partitioned between dichloromethane (200 ml) and 1M HC1 (200 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (3 x 200 ml). The aqueous layer was carefully basified to pH 7-8 with solid NaHC0 ₃ . The solid was filtered off and dissolved in CH ₃ CN (100 ml). The organic solvent was washed with saturated aqueous NaHC0 ₃ solution (50 ml), brine (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated. The crude product was purified by flash chromatography on silica gel.

The column was eluted first with a 1: 1 dichloromethane / methanol mixture, then the product was eluted with a 5% TEA / 10% water / 85% methanol mixture. Appropriate fractions were condensed. The dark yellow glassy was dried under vacuum overnight to afford 4- {2-[(2-aminoethyl) amino] -5-imidazolylpyrimidin-4-yl} benzenecarbonitrile in 89% yield.

5. 4- {5-imidazolyl-2-[(2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyrimidin-4-yl} benzenecarboni Manufacture of tril

4- {2-[(2-aminoethyl) amino] -5-imidazolylpyrimidin-4-yl} benzene-carbonitrile (30 mg, 0.098 mmol), 2-chloro-5- in DMA (500 μl) A mixture of (trifluoromethyl) pyridine (18 mg, 0.098 mmol), and Hunig's base (70 μl, 0.4 mmol) was heated to 80 ° C. After stirring for 12 hours, the reaction solution was diluted with ethyl acetate (10 ml), extracted with saturated aqueous NaHC0 ₃ solution (2 x 5 ml), water (3 x 5 ml), brine (5 ml), and extracted with Na ₂ SO ₄ . Dried, filtered and concentrated. The product was purified by HPLC prepared using a reversible phase column and water / acetylonitrile gradient. Product 4- {5-imidazolyl-2-[(2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyrimidin-4-yl} benzenecarbonitrile Obtained as an off-white solid in 5% yield.

HPLC: 16.3 min (> 95% purity)

MS: M ⁺ H = 451. 2 (C ₂₂ H ₁₇ F ₃ N ₈ H = 451)

Example 79

Preparation of 4- {5-imidazolyl-2-[(2- {[(4-nitrophenyl) sulfonyl] amino} ethyl) amino] pyrimidin-4-yl} benzenecarbonitrile

4- {2-[(2-aminoethyl) amino] -5-imidazolylpyrimidin-4-yl} benzenecarbonitrile (30 mg, 0.098 mmol), chloro (4-nitrophenyl) in DMA (500 μl) A mixture of sulfone (22 mg, 0.1 mmol), and hunny base (70 μl, 0.4 mmol) was heated to 80 ° C. After stirring for 12 hours, the reaction solution was diluted with ethyl acetate (10 ml), extracted with saturated aqueous NaHC0 ₃ solution (2 x 5 ml), water (3 x 5 ml), brine (5 ml), and extracted with Na ₂ SO ₄ . Dried, filtered and concentrated. The product obtained was 27 mg (56%) of 4- {5-imidazolyl-2-[(2-{[(4-nitrophenyl) sulfonyl] amino} ethyl) amino] pyrimidin-4-yl} benzenecarbonitrile. Yield) and purity as determined by LCMS and HPLC was 90%.

Example 80

Preparation of N- (2- {4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) (3 nitrophenyl) carboxamide

4- {2-[(2-aminoethyl) amino] -5-imidazolylpyrimidin-4-yl} benzenecarbonitrile (30 mg, 0.098 mmol), 3-nitrobenzoic acid (17 mg, 0.1 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDC) (19 mg, 0.1 mmol), 1-hydroxybenzotriazole hydrate (HOBT) (14 mg, 0.1 mmol) , And a mixture of 4-dimethylaminopyridine (DMAP) (12 mg, 0.1 mmol) were stirred at room temperature. After 12 hours, the reaction solution was extracted with ethyl acetate (10 ml), extracted with saturated aqueous NaHC0 ₃ solution (2 x 5 ml), water (3 x 5 ml), brine (5 ml), dried over Na ₂ S0 ₄ , After filtration, it was concentrated. The product obtained was 32 mg (70%) of N- (2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) (3-nitrophenyl) carboxamide Yield) and the purity by LCMS and HPLC was about 95%.

Example 81

Preparation of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2 -pyridyl)) amino] ethyl} amine

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to ₂ mmol of phthalimide and ₂ mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature, followed by purification by titration with diethyl ether. 2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was obtained.

2. Preparation of 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} iso indolin-1,3-dione

 1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was heated to 80 ° C. for 6 hours in purified N, N-dimethylformamide dimethyl acetal It was. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} -isoindolin-1 , 3-dione was obtained.

3. 2- {N- [2- ({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- Preparation of 5-yl] carbamoyl} benzoic acid

1 mmol of 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} -isoindolin-1,3-dione, 1 mmol of amino {2-[( 6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 -(2,4-dichlorophenyl) pyrimidin-5-yl] carbamoyl} benzoic acid was obtained.

4. 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 dichlorophenyl) pyrimidin-5-yl] Preparation of Isoindolin-1,3-Dione

1 mmol of 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- 5-yl] carbamoyl} benzoic acid was heated to 120 ° C. in acetic acid for 4 hours and then concentrated in vacuo to give 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) Amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] isoindoline-1,3-dione was obtained.

Preparation of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2- pyridyl)) amino] ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl ] Isoindolin-1,3-dione and 20 mmol hydrazine were stirred in ethanol at 75 ° C. for 7 hours to [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained and the product was purified by column chromatography eluted with 5-10% methanol / methylene chloride.

HPLC: 5.704 min (100% purity)

MS: MH ⁺ = 435. One

Example 82

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-morpholin -4-ylpyrimidin-2-yl ] Preparation of Amine

1. Preparation of 1- (2,4-dichlorophenyl) -2-morpholin-4-ylethan-1-one

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to 10 mmol morpholine in DMF for 14 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 50% ethyl acetate and 50% hexanes to give 1- (2,4-dichlorophenyl) -2-morpholine-4 -Ylethan-1-one was obtained.

2. Preparation of (2E) -1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-morpholin-4-ylprop-2- en-l-one

1 mmol of 1- (2,4-dichlorophenyl) -2-morpholin-4-ylethan-1-one was heated to 80 ° C. in N, N-dimethylformamidedimethyl acetal for 6 hours. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give (2E) -1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-morpholin-4-ylprop-2- En-1-one was obtained.

3. 2- (6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) - 5-morpholin-4-yl-pyrimidin-2-yl; Preparation of Amine

1 mmol (2E) -1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-morpholin-4-ylprop-2-ene-1-one, 1 mmol amino {2- [ (6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and then purified by column chromatography eluted with 5-10% methanol / methylene chloride to give {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-morpholin-4-ylpyrimidin-2-yl] amine was obtained.

HPLC: 9.367 min (100% purity)

MS: MH ⁺ = 505

Example 83

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichloro phenyl) pyrimidin-5-yl] py Preparation of Ralidone-2,5-dione

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to ₂ mmol of phthalimide and ₂ mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature, followed by purification by titration with diethyl ether. 2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was obtained.

2. Preparation of doline-1,3-dione which is 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} iso

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was heated to 80 ° C. in purified N, N-dimethylformamidedimethylacetal for 6 hours It was. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give 2 {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} -isoindolin-1, 3-dione was obtained.

3. 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- Preparation of 5-yl] carbamoyl} benzoic acid

1 mmol of 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindoline-1,3-dione, 1 mmol of amino {2-[(6 -Amino-5-nitro (2-pyridyl))-amino] ethyl} carboxamidine, and 3 mmol of Cs ₂ CO were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] carbamoyl} benzoic acid was obtained.

4. 2- [2- ({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] Isoindolin-1,3-dione Preparation

1 mmol of 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- 5-yl] carbamoyl} benzoic acid was heated to 120 ° C. in acetic acid for 4 hours and then concentrated in vacuo to give 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)). ) Amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] isoindoline-1,3-dione was obtained.

5. Preparation of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl ] Isoindolin-1,3-dione and 20 mmol hydrazine were stirred in ethanol at 75 ° C. for 2 hours and then purified by column chromatography eluted with 5-10% methanol / methylene chloride [5-amino-4 -(2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

6. 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] Preparation of Pyrrolidone-2,5-dione

1 mmol of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, and 2 mmol succinic acid, 4 mmol HBTU, and 5 mmol N, N-diisopropylethylamine were added to the solution and stirred for 6 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give 1- [2-{{2-[(6-amino-5- Nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] pyrrolidone-2,5-dione.

HPLC: 8.917 min (100% purity)

MS: MH ⁺ = 517.1

Example 84

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-piperazinylpyrimidin -2-yl] amine

1. Preparation of t-butyl-4- [2- (2,4-dichlorophenyl) -2-oxoethyl] piperazinecarboxylate

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to 1.2 mmol of t-butyl piperazinecarboxylate and 1.2 mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 50% ethyl acetate and 50% hexane to give t-butyl 4- [2- (2,4-dichlorophenyl)- 2-oxoethyl] piperazinecarboxylate was obtained.

2. Preparation of t-butyl 4- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl } piperazinecarboxylate

1 mmol of t-butyl 4- [2- (2,4-dichlorophenyl) -2-oxoethyl] piperazinecarboxylate was heated to 80 ° C. for 6 hours in purified N, N-dimethylformamidedimethyl acetal. . For 6 hours. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give t-butyl 4- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} piperazincar Obtained the carboxylate.

3. t-butyl 4- [2- (2-{(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 (2,4-dichlorophenyl) pyrimidine-5- Production of Piperazinecarboxylate

1 mmol of t-butyl 4- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} piperazinecarboxylate, 1 mmol of amino {2-[(5- Nitro (2-pyridyl)) amino] -ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give t-butyl 4- [2- ({2-[(6-amino- 5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] piperazinecarboxylate.

4. {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl ) -5-piperazinylpyrimidin-2-yl] Preparation of Amine

1 mmol of t-butyl 4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 (2,4-dichlorophenyl) pyrimidine-5 -Yl] piperazinecarboxylate was heated to 60 ° C. in 3M HC1 in MeOH for 1 h and concentrated in vacuo to afford {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-piperazinylpyrimidin-2-yl] amine was obtained.

HPLC: 5.27 min (100% purity)

MS: MH ⁺ = 504. 2

Example 85

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-ethylphenyl) -5 imidazolylpyrimidin -2-yl] amine

1. Preparation of 2-bromo-1- (4-ethylphenyl) ethan-1-one

Under nitrogen, 20 mmol of l- (4-ethylphenyl) ethane-l-one, 1 ml of concentrated HC1, were mixed in 20 ml diethyl ether. To this solution was added dropwise a 20mmol Br ₂ solution in 20ml chloroform and left for 4 hours, then concentrated in vacuo to afford 2-bromo-1- (4-ethylphenyl) ethan-1-one.

2. Preparation of l- (4-ethylphenyl) -2-imidazolylethan-1-one

1 mmol of 2-bromo-1- (4-ethylphenyl) ethan-1-one in acetylonitrile was added dropwise to 5.5 mmol imidazole in acetylonitrile for 14 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 1- (4-ethylphenyl) -2-imidazolylethan-1-one.

3. Preparation of (2E) -3- (dimethylamino) -1- (4-ethylphenyl) -2-imidazolylprop-2-en-1-one

1 mmol of 1- (4-ethylphenyl) -2-imidazolylethan-1-one was heated to 80 ° C. for 6 hours in N, Ndimethylformamidedimethylacetal and concentrated in vacuo to give (2E) -3- ( Dimethylamino) -1- (4-ethylphenyl) -2-imidazolylprop-2-en-1-one was obtained.

4. Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-ethylphenyl) -5imidazolylpyrimidin-2-yl] amine

1 mmol (2E) -3- (dimethylamino) -l- (4-ethylphenyl) -2-imidazolylprop-2-ene-l-one, 1 mmol amino {2-[(6-amino- 5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give {2-[(6-amino-5-nitro (2-pyridyl) ) Amino] ethyl} [4- (4-ethylphenyl) -5-imidazolyl-pyrimidin-2-yl] amine.

HPLC: 7.733 min (100% purity)

MS: MH ⁺ = 446.2

Example 86

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4- pyridyl) pyrimidin-2-yl] Preparation of Amine

1- (2,4-dichlorophenyl) -2- (4-pyridyl) ethan-1-one was synthesized by the method described in Suzuki et al., "Facile dibenzoylation of picoline," J Hetercycl. Chem. 22 (6): 1487-9 (1985). 1 mmol of 1- (2,4-dichlorophenyl) -2- (4-pyridyl) ethan-1-one was heated to 80 ° C. for 6 hours in purified DMF-DMA. The reaction mixture was concentrated in vacuo and the residue was purified by titration with diethyl ether. Amino {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride (160 mg, 0.58 mmol, 1 equiv), enamineone (2E) -1- (2 , 4-dichlorophenyl) -3- (dimethylamino) -2- (4-pyridyl) prop-2-en-1-one (202 mg, 0.58 mmol) and Cs ₂ CO ₃ (246 mg, 1.3 equiv) Was dissolved in 5 ml DMF and heated at 95 ° C. for 6 h. The reaction mixture was concentrated in vacuo and extracted with ethyl acetate to afford the crude product, which was purified by column chromatography eluted with 10% methanol in methylene chloride and lyophilized to yield {2-[(6- Amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4-pyridyl) pyrimidin-2-yl] amine was obtained.

HPLC: 6.32 min (100%)

MS: MH + = 497

Example 87

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} {4- (2,4-dichlorophenyl) -5- [5- ( trifluoromethyl) (1, 2,3,4-tetraazolyl)] pyrimidin-2-yl} amine

Trifluoromethyl tetrazole was prepared according to a method known in the following literature [Tetrahedron Letters 38 (7): 1257-1260]. Tetrachlorosilane (5 mmol) and sodium azide (15 mmol) in trifluoromethyl acetamide (5 mmol) and dry acetylonitrile (10 ml) were refluxed and stirred to remove moisture. The reaction mixture was poured into sodium carbonate solution like ice and extracted with chloroform (3X20ml). The solvent was distilled off under reduced pressure to give trifluoromethyl tetrazole (MS: MH = 136.7) which was used without further purification. Trifluoromethyl tetrazole (lmmol), Cs ₂ CO ₃ (1.3 mmol) and 1- (2,4-dichlorophenyl) -2-chloroethan-1-one (lmmol) were refluxed in DMF (2 ml) overnight. . The reaction mixture was cooled down, concentrated in vacuo, extracted with ethyl acetate and dried over sodium sulfate. The extract was further purified by column chromatography on silica gel to give 1- (2,4-dichlorophenyl) -2 [5- (trifluoromethyl) (1, 2,3,4-tetraazolyl)] ethane-l -On was obtained. 1 mmol of 1- (2,4-dichlorophenyl) -2- [5- (trifluoromethyl) (1,2,3,4-tetraazolyl)] ethan-1-one in purified DMF-DMA Heated to 80 ° C. for hours. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether. 1 mmol of said enamine one, lmmol amino {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride and ₃ mmol Cs ₂ CO ₃ were dissolved in DMF and Heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and extracted with ethyl acetate and after evaporation of the solvent the residue was purified by column chromatography eluting with 5-10% methanol in methylene chloride, followed by lyophilization and {2-[(6-amino-5- Nitro (2-pyridyl)) amino] ethyl} {4- (2,4-dichlorophenyl) -5- [5- (trifluoromethyl) (1,2,3,4-tetraazolyl)] pyri Midin-2-yl} amine was obtained as a yellow powder.

MS: MH ⁺ = 556. 0,

HPLC: 10.77 min (98.3%)

Example 88

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4-methyl piperazinyl) pyrimidine-2- Preparation of Amine

1- (2,4-dichlorophenyl) -2-chloroethan-1-one (lmmol) and methylpiperazine (4 mmol) in 8 ml DMF were stirred at room temperature for 8 hours. The reaction mixture was concentrated in vacuo, extracted with ethyl acetate and the organic layer washed with water and dried over sodium sulfate. The residue was concentrated in vacuo and then purified by column chromatography eluting with 10% methanol in methylene chloride to give 1- (2,4-dichlorophenyl) -2- (4-methylpiperazinyl) ethan-1-one. Obtained. Ethanone was taken up in DMF-DMA and heated to 80 ° C. for 6 hours. After the reaction mixture was cooled down and concentrated in vacuo, the residue containing enamineone was purified by column chromatography. 1 mmol of enamineone obtained above, 1 mmol of amino {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride and ₃ mmol of Cs ₂ CO ₃ were converted to DMF. Suspended and heated to 90 ° C. for 14 h. The reaction mixture was cooled down and concentrated in vacuo. The residue was partitioned between water and acetate and the layers separated. The organic layer was dried over sodium sulphate and purified by chromatography on silica gel eluted with 5-10% methanol in methylene chloride after solvent removal, followed by freeze drying to {2-[(6-amino-5-nitro (2-pyridyl). )) Amino] ethyl} [4- (2, 4-dichlorophenyl) -5- (4-methylpiperazinyl) pyrimidin-2-yl] amine was obtained as a yellow powder.

LC RT 5.193 min (95.3%)

MS: MH ⁺ = 518. 2

Example 89

Preparation of [4- 4-dichlorophenyl) -5- (4-methylpiperazinyl) pyrimidin-2-yl] {2-[(5 nitro (2 -pyridyl)) amino] ethyl} amine

1- (2,4-dichlorophenyl) -2-chloroethan-1-one (lmmol) and methylpiperazine (4 mmol) in 8 ml DMF were stirred at room temperature for 8 hours. The reaction mixture was then concentrated in vacuo, extracted with ethyl acetate, the organic layer washed with water and dried over sodium sulfate. The residue was concentrated in vacuo and then purified by column chromatography eluted with 10% methanol in methylene chloride to give 1- (2,4-dichlorophenyl) -2- (4-methylpiperazinyl) ethan-1-one. Obtained. 1- (2,4-dichlorophenyl) 2- (4-methylpiperazinyl) ethan-1-one was heated to 80 ° C. for 6 hours in purified DMF-DMA. The reaction mixture was concentrated in vacuo and the residue obtained was purified by titration with diethyl ether to give enamineone. Obtained lmmol enamineone, lmmol amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride, and 1.3 mmol Cs ₂ CO ₃ were dissolved in DMF for 14 hours. Heated to 90 ° C.

The reaction mixture was cooled to rt and concentrated in vacuo. After addition of water, the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate. After evaporation of the solvent, the residue was purified by column chromatography eluting with 5-10% methanol in methylene chloride, followed by freeze drying of [4- (2,4-dichlorophenyl) -5- (4-methylpiperazinyl) pyridine. Midin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine was obtained as a yellow powder.

HPLC 5.933 min (> 95%)

MS: MH ⁺ = 503. One

Example 90

Preparation of 4- [6-imidazolyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl} benzenecarbonitrile

9.45 g (0.034 mol) of S-methylisourea nitrate, 13.57 g (0.062 mol) of ethyl 3- (4-cyano, according to the method of Weirenga (Hetercycles, 23: 1687 (1985)) Phenyl) -3-oxopropanoate and 8.0 g (0.142 mol) of potassium hydroxide were suspended in 40 ml water and the heterogeneous mixture was stirred for 18 hours. Thereafter, the mixture was filtered and the solid was washed with a sufficient amount of water. The solid was dried and recrystallized from 5% dimethylformamide / ethanol to give 2.47 g (34%) of 4- (2-amino-4-oxo-1, 3-oxazin-6-yl) benzenecarbonitrile as a colorless solid. Obtained as

44 ml DMF, 3.81 g (17.89 mmol) 4- (2-amino-4-oxo-1,3-oxazin-6-yl) benzenecarbonitrile and 8.57 g (53.63 mmol) N- (2-aminoethyl) (t-butoxy) carboxamide was heated to 50 ° C. for 3 hours. The reaction mixture was then concentrated in vacuo (0.5 mm Hg) and the resulting yellow solid was titrated with cold ethanol. The resulting suspension is filtered and the solid is washed with sufficient ethanol. Thus, 4.51 g (71%) of (t-butoxy) -N- (2-{[6- (4-cyanophenyl) -4-hydroxypyrimidin-2-yl] amino} as a white solid Ethyl) carboxamide was obtained.

4.01 g (11.2 mmol) of (t-butoxy) -N- (2-{[6- (4-cyanophenyl) -4-hydroxypyrimidin-2-yl] amino} ethyl) in 40 ml pyridine To an aqueous solution of carboxamide, 4.82 g (13.5 mmol) of N-phenyltrifluorosulfonamide, 4.03 g (12.4 mmol) of anhydrous cesium carbonate was added. The resulting suspension was stirred at rt for 18 h and then partitioned between ethyl acetate and water. The aqueous layer was extracted thoroughly with ethyl acetate and the combined organics were washed with 5% aqueous hydrochloric acid solution, water, and brine. After concentration was purified by chromatography (silica gel, ether, Rf = 0.40), and l.50 g of 2-({2-[(t-butoxy) carbonylamino] ethyl} amino) -6- (4-sia Nophenyl) pyrimidin-4-yl (trifluoromethyl) sulfonate was obtained as a gelatinous solid.

2-({2-[(t-butoxy) carbonylamino] ethyl} amino) -6- (4-cyanophenyl) pyrimidin-4-yl (trifluoromethyl) sulfonate (134 mg, 0.275 mmol ) Was dissolved in a 2M imidazole solution in N-methylpyrrolidinone and the resulting solution was heated to 90 ° C. for 18 hours. The solution was cooled, water was added, and the suspension was extracted thoroughly with ethyl acetate. The combined organic layers were concentrated to give a crude solid which was then purified by chromatography (silica gel, 0.5% ammonium hydroxide / 5% methanol / methylene chloride) to 66 mg of (t-butoxy) -N- (2- {[4 -(4-cyanophenyl) -6-imidazolyl-4-ylpyrimidin-2-yl] amino} ethyl) carboxamide was obtained as off-white solid.

Removal of the t-butoxy deprotection group was carried out in the following: (t-butoxy) -N- (2-{[4- (4-cyanophenyl) -6-imida, prepared as described above. Zolyl-4-ylpyrimidin-2-yl] amino} ethyl) carboxamide was dissolved in anhydrous trifluoroacetic acid (2 ml) and stirred at room temperature for 2 hours. The reaction mixture was concentrated to give 47.8 mg of 4- {2-[(2-aminoethyl) amino] -6-imidazolyl-4-ylpyrimidin-4-yl} benzene- as a trifluoroacetate salt (2x). Carbonnitrile was obtained.

4- {2-[(2-aminoethyl) amino] -6-imidazolyl-4-ylpyrimidin-4-yl} benzenecarbonitrile trifluoroacetate (48 mg, 0.074) prepared as described above mmol) was dissolved in 0.5 ml acetylonitrile and 2-chloro-5-nitropyridine (12 mg, 0.074 mmol) was added. The mixture was heated to 80 ° C. for 18 h and then concentrated. The residue was purified by chromatography (silica gel, 5% methanol / methylene chloride) to give 5.1 mg (15%) of 4- [6-imidazolyl-2-({2-[(5-nitro (2-pyri) Dill)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile was obtained as a pale yellow solid.

HPLC [Method AZ-S] 7.25 min (100%), 1 HNMR;

MS: (m + H) / z, 428.

Example 91

Preparation of 4- [6-morpholine-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl} benzenecarbonitrile

2-({2-[(t-butoxy) carbonylamino] ethyl} amino) -6- (4-cyanophenyl) pyrimidin-4-yl (trifluoromethyl) sulfonate (134 mg, 0.275 mmol ) Was dissolved in a 2M morpholine solution in acetonitrile and the resulting solution was heated to 90 ° C. for 18 hours. After cooling the solution, water was added and the suspension was extracted thoroughly with ethyl acetate. The combined organic layers were concentrated to give a crude solid which was then purified by chromatography (silica gel, 2% methanol / methylene chloride) to give 234 mg of (t-butoxy) -N- (2-{[4- (4- Cyanophenyl) -6-morpholin-4-ylpyrimidin-2-yl] amino} ethyl) carboxamide was obtained as off-white solid. Removal of the t-butoxy protecting group was carried out in the following manner: (t-butoxy) -N- (2-{[4- (4-cyanophenyl) -6-morpholin-4-yl, prepared above. Pyrimidin-2-yl] amino} ethyl) carboxamide was dissolved in anhydrous hydrogen chloride in dioxane (2 ml of 2M solution) and stirred at room temperature for 2 hours. After concentration 134 mg of 4- {2-[(2-aminoethyl) amino] -6imidazolyl-4-ylpyrimidin-4-yl} benzenecarbonitrile were obtained as a hydrochloride salt (2x).

4- {2-[(2-aminoethyl) amino] -6-morpholin-4-ylpyrimidin-4-yl} benzene-carbonitrile trifluoroacetate (50 mg, 0.14 mmol) prepared above was 0.25 Dissolved in ml acetylonitrile and 2-chloro-5-nitropyridine (22 mg, 0.074 mmol) was added. The mixture was heated to 80 ° C. for 18 h and then concentrated and the residue was purified by chromatography (silica gel, 5% methanol / methylene chloride) to give 5.1 mg (15%) of 4- [6-morpholine-2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile as a pale yellow solid.

HPLC [Method AZ-S] 7.20 min (100%), 1 HNMR;

MS: (m + H) / z, 447.

Example 92

Preparation of [5-benzotriazol-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

1- (2,4-dichlorophenyl) -2-chloroethan-1-one (10.0 g, 44.63 mmol), benzotriazole (10.6 g, 89.3 mmol) and triethylamine (9.0 g in 140 ml acetylonitrile , 89.3 mmol) was refluxed for 18 hours. Acetylonitrile was removed under vacuum and the residue was dissolved in ethyl acetate. Water was added and the aqueous layer was extracted twice with ethyl acetate. The combined organics were washed with brine, dried and concentrated to yield 13.2 g of a light brown solid. Recrystallization with ethyl acetate gave 4.8 g (35%) 2-benzotriazolyl-1- (2,4-dichlorophenyl) ethan-1-one as a colorless solid.

2-benzotriazolyl-1- (2,4-dichlorophenyl) ethan-1-one was dissolved in dimethylformamide dimethyl acetal (5 ml) and the solution was refluxed for 8 hours. 2-benzotriazolyl-1- (2,4-dichlorophenyl) -3- (dimethylamino) prop-2-ene-1- used as an air-sensitive red solid to evaporate the solvent without further purification in the next step On was obtained.

2-benzotriazolyl-1- (2,4-dichlorophenyl) -3- (dimethylamino) prop-2-en-1-one is dissolved in 64 ml N-methylpyrrolidinone and 6.82 g (20.9 mmol) ) Cesium carbonate and 4.19 g (16.12 mmol) of amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride were added. The resulting suspension was heated to 100 ° C. for 18 hours. Thereafter, the reaction mixture was cooled and partitioned between ethyl acetate and water. The aqueous layer was extracted with ethyl acetate and the combined organic layers were washed twice with water and once with brine. The combined organic layers were concentrated to give a yellow solid which was recrystallized from 5% ethyl acetate / methanol to 4.25 g (65%) of [5benzotriazol-4- (2,4-dichlorophenyl) pyrimidine-2- Il] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine was obtained as a pale yellow solid.

HPLC [Method AZ-S] 11.56 min (100%), 1 HNMR;

MS: (MH ⁺ ) / z, 522.

Example 93

Preparation of [4- (2,4-dichlorophenyl) -5-piperazinylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino ] ethyl} amine

1. Preparation of t-butyl 4- [2- (2,4-dichlorophenyl) -2-oxoethyl] piperazinecarboxylate

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to 1. mmol of t-butyl piperazinecarboxylate and 1.2 mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, purified by column chromatography eluted with 50% ethyl acetate and 50% hexanes to give t-butyl 4- [2- (2,4-dichlorophenyl) -2 -Oxoethyl] piperazinecarboxylate was obtained.

2. Preparation of t-butyl 4-2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl piperazinecarboxylate

1 mmol of t-butyl 4- [2- (2,4-dichlorophenyl) -2-oxoethyl] piperazinecarboxylate was heated to 80 ° C. for 6 hours in purified N, N-dimethylformamidedimethyl acetal. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give t-butyl 4- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} piperazincar Bixlate was obtained.

3. t-butyl 4-4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl Preparation of Piperazinecarboxylate

1 mmol of t-butyl 4- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} piperazinecarboxylate, 1 mmol of amino {2-[(5- Nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give t-butyl 4- [4- (2,4-dichlorophenyl) -2 -({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] piperazinecarboxylate was obtained.

4. Preparation of [4- (2,4-dichlorophenyl) -5-piperazinylpyrimidin-2-yl] {2-[(5-nitro (2- pyridyl)) amino] ethyl} amine

1 mmol of t-butyl 4- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] Piperazinecarboxylate was heated to 60 ° C. for 1 hour in 3M HC1 in MeOH and concentrated in vacuo to [4- (2,4-dichlorophenyl) -5-piperazinylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

HPLC: 7.683 min (100% purity)

MS: MH &lt; + &gt; = 489.1

Example 94

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl ) pyrimidin-5-yl] Preparation of -4-methylpiperazine-2,6-dione

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to ₂ mmol of phthalimide and ₂ mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature, followed by purification by titration with diethyl ether. 2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was obtained.

2. Preparation of 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl] iso indolin-1,3-dione

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was heated to 80 ° C. for 6 hours in N, N-dimethylformamide dimethyl acetal. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1, 3-dione was obtained.

3. 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- Preparation of 5-yl] carbamoyl} benzoic acid

1 mmol of 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindoline-1,3-dione, 1 mmol of amino {2-[(6 -Amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate and 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 ( 2,4-dichlorophenyl) pyrimidin-5-yl] carbamoyl} benzoic acid was obtained.

4. 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] Isoindolin-1,3-dione Preparation

1 mmol of 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine- 5-yl] carbamoyl} benzoic acid was heated to 120 ° C. in acetic acid for 4 hours and then concentrated in vacuo to give 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) Amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] isoindoline-1,3-dione was obtained.

5. Preparation of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl ] Isoindolin-1,3-dione and 20 mmol hydrazine were stirred in ethanol at 75 ° C. for 2 hours and purified by column chromatography eluted with 5-10% methanol / methylene chloride [5-amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

6. 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl ] -4-Methylpiperazine-2,6-dione

 1 mmol of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, 2 mmol Methylimino diacetic acid, 4 mmol HBTU, and 5 mmol N, N-diisopropylethylamine were added to the solution and stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] -4-methylpiperazin-2,6-dione was obtained.

HPLC: 7.560 min (99% purity)

MS: MH = 546.1

Example 95

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichloro phenyl) pyrimidin-5-yl]- Preparation of 3-morpholin-4-ylpyrrolidone-2,5-dione

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione

1 mmol of 2,4-dichlorophenacyl chloride of DMF was added dropwise to ₂ mmol of phthalimide and ₂ mmol of Cs ₂ CO ₃ in DMF at room temperature for 14 hours and then purified by diethyl ether to obtain 2- [2 -(2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1, 3-dione was obtained.

2. Preparation of doline-1,3-dione which is 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} iso

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was heated to 80 ° C. for 6 hours in N, N-dimethylformamidedimethylacetal. The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1, 3-dione was obtained.

3. 2- {N- [2-({2-{(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- Preparation of 5-yl] carbamoyl} benzoic acid

1 mmol of 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1,3-dione, 1 mmol of amino {2-[(6 -Amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] carbamoyl} benzoic acid was obtained.

4. 2- {2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl ] Isoindolin-1,3-dione Preparation

1 mmol of 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- 5-yl] carbamoyl} benzoic acid was heated to 120 ° C. in acetic acid for 4 hours and then concentrated in vacuo to give 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)). ) Amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] isoindoline-1,3-dione was obtained.

5. Preparation of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-{(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl ] Isoindolin-1,3-dione and 20 mmol hydrazine were stirred in ethanol at 75 ° C. for 2 hours. The reaction mixture was concentrated and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6 -Amino-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

6. 1- [2-(({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidine-5- Preparation of Japanese] -3-pyrroline-2,5-dione

1 mmol of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, and 2 mmol of maleic anhydride were stirred at room temperature for 4 hours. 2 mmol of HBTU, and 3 mmol of N, N-diisopropylethylamine were added to the solution and left at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate, and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give 1- [2-({2-[(6-amino-5-nitro ( 2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] -3-pyrroline-2,5-dione.

7. 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl ] -3-morpholin-4-ylpyrrolidone-2,5-dione

Clean fraction of 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4) in which a large amount of morpholine was concentrated in vacuo -Dichlorophenyl) pyrimidin-5-yl] -3-pyrroline-2,5-dione and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give 1- [2-({ 2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] -3-morpholin-4- Ilpyrrolidone-2,5-dione was obtained.

HPLC: 8. 133 min (100% purity)

MS: MH + = 602.2

Example 96

1- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -4-methyl Preparation of Piperazine-2,6-Dione

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to ₂ mmol phthalimide and ₂ mmol Cs ₂ CO ₃ in DMF at room temperature for 14 hours, followed by purification by titration with diethyl ether to give 2- [ 2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was obtained.

2. Preparation of 2-2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} iso indoline-1,3-dione

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was heated to 80 ° C. for 6 hours in purified N, N-dimethylformamidedimethylacetal. . The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1, 3-dione was obtained.

3. 2- {N- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl ] Carbamoyl} Preparation of Benzoic Acid

1 mmol 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} -isoindolin-1,3-dione, 1 mmol amino {2-[( 5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 2- {N- [4- (2,4-dichlorophenyl) -2- ({2 = [(5-nitro (2-pyridyl)) amino] Ethyl} amino) pyrimidin-5-yl] carbamoyl} benzoic acid.

4. 2- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethvl} -amino) pyrimidin-5-yl ] isoin Preparation of Dolin-1,3-Dione

1 mmol of 2- {N- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] Carbamoyl} benzoic acid was heated to 120 ° C. in acetic acid for 4 hours and then concentrated in vacuo to give 2- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2- Pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] isoindoline-1,3-dione was obtained.

5. Preparation of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl )) amino] ethyl} amine

1 mmol of 2- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] isoindolin -1,3-dione and 20 mmol hydrazine were stirred in ethanol at 75 ° C. for 2 hours and then purified by column chromatography eluted with 5-10% methanol / methylene chloride [5-amino-4- (2,4 -Dichlorophenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

6. l- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} -amino ) pyrimidin-5-yl]- Preparation of 4-methylpiperazine-2,6-dione

1 mmol of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 2 mmol methyliminodi Acetic acid, 4 mmol HBTU, and 5 mmol N, N-diisopropylethylamine were added to the solution and stirred at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluted with 5-10% methanol / methylene chloride to give 1- [4- (2,4-dichlorophenyl) -2-({ 2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -4-methylpiperazin-2, 6-dione was obtained.

HPLC: 12.850 min (100% purity)

MS: MH <+> 531.2

Example 97

l- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl] Preparation of 3- (dimethylamino) pyrrolidone-2,5-dione

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to ₂ mmol phthalimide and ₂ mmol Cs ₂ CO ₃ in DMF at room temperature for 14 hours, followed by titration with diethyl ether to purify 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was obtained.

2. Preparation of 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} iso indolin-1,3-dione

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was heated to 80 ° C. for 6 hours in purified N, N-dimethylformamide dimethyl acetal. . The reaction mixture was concentrated in vacuo and purified by titration with diethyl ether to give 2 {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1,3 -Dione was obtained.

3. 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine-5 -Yl] carbamoyl} benzoic acid

lmmol 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} -isoindoline-1,3-dione, lmmol amino {2-[( 6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and ₃ mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 ( 2,4-dichlorophenyl) pyrimidin-5-yl] carbamoyl} benzoic acid was obtained.

4. 2- [2- (2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl] Preparation of Isoindolin-1,3-Dione

1 mmol of 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine- 5-yl] carbamoyl} benzoic acid was heated to 120 ° C. in acetic acid for 4 hours and then concentrated in vacuo to give 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)). ) Amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] isoindoline-1,3-dione was obtained.

5. Preparation of [5-amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4 dichlorophenyl) pyrimidine-5- [5] Isoindolin-1, 3-dione and 20 mmol of hydrazine are stirred in ethanol at 75 ° C. for 2 hours and then by column chromatography eluting with 5-10% methanol / methylene chloride [5-amino-4 -(2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

6. 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] -3-Pyrroline-2, 5-Dione

1 mmol of [5-amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2 pyridyl)) amino] ethyl} amine, and 2 mmol of male anhydride was stirred at rt for 4 h. 2 mmol of HBTU, and 3 mmol of N, N-diisopropylethylamine were added to the solution and left at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was washed three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride to give 1- [2-({2-[(6-amino-5- Nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl] -3-pyrroline-2,5-dione was obtained.

7. 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino1ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] -3- (dimethylamino) pyrrolidine-2,5-dione

A large excess of dimethylamine was concentrated in vacuo to 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- ( 2, 4-dichlorophenyl) pyrimidin-5-yl] -3-pyrroline-2,5-dione.

HPLC: 5.215 min. (95% purity)

MS: MH ⁺ = 560.2

Example 98

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5 imidazolyl (2-pyridyl)] amine

1. Preparation of 1- (2,4-dichlorophenyl) -2-imidazolylethan-1-one

1- (2,4-dichlorophenyl) -2-chloroethan-1-one (0.95 M) and imidazole (2.68 M) stirred solution in CH ₃ CN (500 ml) was stirred at 75 ° C. for 14-16 hours. Heated. The product was freed of solvent under reduced pressure. The residue was diluted with dichloromethane (1 L) and water (400 ml) and the mixture was stirred for 30 minutes. After filtering off the solid impurities, the aqueous layer was removed and discarded. The organic layer was successively washed with water (300 ml), saturated aqueous NaHCO ₃ (300 ml), water (300 ml), brine (200 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The reddish black oil was dried in vacuo overnight to give 1- (2,4-dichlorophenyl) -2-imidazolylethan-1-one in 90% yield in 90% yield.

2. Preparation of ethyl 5- (2,4-dichlorophenyl) -4-imidazolyl-5-oxopentanoate

1- (2, 4-dichlorophenyl) -2-imidazolylethan-1-one (0.80 M) was heated to dissolve as needed in a stirred mixture of THF (250 ml) and anhydrous ethanol (250 ml). After cooling to room temperature, potassium hydroxide (0.20 M) was added and then ethyl acrylate (45.8 ml) was added dropwise over 10 minutes via an addition funnel. The exothermic reaction was cooled during the first 30 minutes using a room temperature water bath. After stirring for 14-16 hours, the reaction was dissolved in glacial acetic acid (10 ml) and concentrated under reduced pressure. The remaining dark reddish black slurry was dissolved in anhydrous ethanol (100 ml) and concentrated again under reduced pressure to yield ethyl 5- (2,4-dichlorophenyl) -4-imidazolyl-5-oxopentano in 108% yield. Eight (2) was obtained. The crude material is contaminated with potassium salt and used without further purification.

3. Preparation of 6- (2,4-dichlorophenyl) -5-imidazolyl-1, 3, 4-trihydropyridin-2-one

Ethyl 5- (2, 4-dichlorophenyl) -4-imidazolyl-5-oxopentanoate (0.51 M) is dissolved in glacial acetic acid (245 ml), toluene (135 ml), and anhydrous ethanol (405 ml) It was. Ammonium acetate (3.07 M) and flame dried 4mm powder molecular sieve (145 g) were added to the stirred solution. The resulting mixture was stirred under 90-95 ° C. argon for 44-46 hours. After 24 hours of heating, additional reagents were added, including ammonium acetate (0.51 M), acetic acid (41 ml), and flame dried 4x powder molecular sieve (24 g). Methanol (200 ml) was added with stirring for 15 minutes with cooling. The sieve was filtered and washed with methanol (2 x 150 ml). The filtrate was concentrated under reduced pressure. Dichloromethane (1.5 L) was added to the crude material. The organic layer was then washed with 5-10% sodium hydroxide solution (3 x 500 ml) until basic. The organic layer was then washed with distilled water (3 x 400 ml), saturated sodium chloride solution (300 ml), dried over sodium sulfate, filtered and concentrated under reduced pressure. The reddish orange solid was dried in vacuo to yield 102 g of crude product. A solution of 2% methanol in ethyl acetate (90-110 ml) was added to the crude product. The resulting solid was collected by filtration and washed with ethyl acetate (2 x 100 ml). The non-white solid was dried in vacuo to give 6- (2,4-dichlorophenyl) -5-imidazolyl-1, 3,4-trihydropyridin-2-one in 60% yield.

4. Preparation of 6- (2, 4-dichlorophenyl) -5-imidazolylhydropyridin-2-one

6- (2, 4-dichlorophenyl) -5-imidazolyl-1, 3,4-trihydropyridin-2-one (0.21 M), selenium (IV) oxide (0.63), and glacial acetic acid (400 ml) The mixture was stirred at 105-110 ° C. under argon for 10 hours. Acetic acid was removed under reduced pressure. Methanol (500 ml) was added. After mixing, the solution was filtered to remove selenium residues. To the methanol solution, lead (II) acetate trihydrate (99 g) and distilled water (50 ml) were added and stirred for 1 hour. The mixture was filtered through a celite plug (0.25-0.5 inch). The solution was concentrated under reduced pressure. The crude material was purified by silica gel column. The product eluted with ethyl acetate and slowly increased the gradient of methanol until reaching a final concentration of 8%. Appropriate fractions were concentrated under reduced pressure and dried in vacuo. The solid was further purified by trituration with small volumes of 1: 1 methanol and ethyl acetate. The non-white solid was dried in vacuo to give 6- (2,4-dichlorophenyl) -5imidazolylhydropyridin-2-one in 68% yield.

5. Preparation of [2- (2, 4-dichlorophenyl) -6-chloro-3-pyridyl] imidazole .

To dry solid 6- (2,4-dichlorophenyl) -5-imidazolylhydropyridin-2-one (2.40 M) is added N, N-dimethylacetamide (6 drops) followed by phosphorus oxychloride (20 ml) was added. The reaction mixture was stirred at 105-110 ° C. for 18-20 hours under argon. Phosphorus oxychloride was removed under reduced pressure. The crude product was taken up with dichloromethane (75 ml) and the solvent was removed in vacuo. The tacky solid was dried in vacuo to a free flowing solid at 3-4 hours to give [2- (2,4-dichlorophenyl) -6-chloro-3-pyridyl] imidazole in 167% yield. The crude material is used without further purification as a phosphorous residue.

6. Purification of (2-aminoethyl) [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] amine

The crude material, [2- (2, 4-dichlorophenyl) -6-chloro-3-pyridyl] imidazole, was cooled to -78 ° C with dry ice acetone under argon. Argon was poured all at once through the system in succession and ethylene diamine (200 ml) was added very carefully while monitoring the release of gas and heat. After the addition was completed, the reaction mixture was stirred for 5-6 hours at 105-110 ° C. under argon. While cooling, ethylene diamine was removed under reduced pressure and dried in vacuo for 2-3 hours. To the remaining material was added acetonitrile (100 ml) and saturated sodium bicarbonate solution (250-300 ml). To the stirred mixture was added sodium bicarbonate solid until the mixture was completely saturated. After 30 minutes, acetonitrile (300-350 ml) was added to the saturated aqueous solution. The mixture was stirred and the layers separated to give an aqueous and organic portion. The aqueous layer was extracted with acetonitrile (4 x 250 ml). The organic layers were combined and washed with saturated sodium chloride solution (100 ml), dried over sodium sulfate, filtered, concentrated and dried in vacuo. The residue was dissolved in methanol (70-90 ml). The mixture was filtered to remove residual salts and concentrated under reduced pressure. Dry the non-white solid in vacuo (97-aminoethyl) in 97% yield based on the initial amount of 6- (2,4-dichlorophenyl) -5-imidazolylhydropyridin-2-one used [ 6- (2, 4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] amine was obtained. The material contained a minimum amount of salt and was used without further purification.

7. {2-[(6-Amino-5-nitro (2-pyridyl)) amino1ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] amine Manufacture

(2-aminoethyl) [6- (2, 4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] amine (0.14 M), 6-chloro-3-nitro-2-pyridylamine ( 0.14 M), N, N-dimethylacetamide (40 ml), and a mixture of Hunig's base (2.5 ml) were stirred under argon at 85-90 ° C. for 12 hours. Ethylene diamine (3.8 ml) was added to remove unreacted chloropyridine and the mixture was stirred at 85-90 ° C. for an additional 0.75-1 hour. After cooling, the reaction was diluted with ethyl acetate (500-600 ml) and extracted with saturated sodium bicarbonate (4 x 200 ml), distilled water (3 x 150 ml), saturated sodium chloride (150 ml). The organic layer was temporarily dried (2-3 minutes) with sodium sulfate to avoid precipitation of the product. The organic layer was filtered, concentrated and dried in vacuo. To cause precipitation of the product, a minimum amount of methanol (3-5 ml) is added followed by the same volume of ethyl acetate. The mixture was aged for 2-3 hours. The solid was collected by filtration, washed with a minimum of 1: 1 methanol / ethyl acetate (5 ml) and finally with 100% ethyl acetate (2 × 10 ml). The yellow solid was dried in vacuo {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5-imidazolyl (2- Pyridyl)] amine was obtained in 61% yield.

HPLC: 19. 8 min (> 95% purity)

MS: M + H = 485 (C _2l H _l8 C _l2 N ₈ 0 ₂ ⁺ H = 485)

Example 99

6-[{(2- {4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino } ethyl) aminolpyridine-3 Preparation of Carbonnitrile

6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3- Carbonitrile is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl) with the exception noted below )) Amino] ethyl}-was prepared using the general method for amines.

1. Preparation of 1- (2,4-dichlorophenyl) -2- (4-methylimidazol-2-yl) ethane-1-one

A solution of 2,4-dichlorobenzoyl chloride (7.24 M) in dichloromethane (25 ml) was diluted with dichloromethane (75 ml) and N, N-diisopropylethylamine (Hunig's base) (34 ml) over 20 minutes. To the stirred solution of 2,4-dimethylimidazole (0.80M) in water was added dropwise.

The reaction mixture was cooled during the addition using a water bath. The reaction mixture was then heated to reflux for 5 hours. The response can be distinguished by a darker color. The product was freed of the solvent under reduced pressure and the resulting solid was dried under vacuum for 1 hour.

To the dry solid was added a solution of glacial acetic acid and aqueous concentrated HC1 (2: 1 v / v, 120 ml) (as described above). The mixture was then stirred at reflux for about 90 minutes. Acetic acid was removed via rotary evaporator. While cooling, distilled water (200 ml) and toluene (100 ml) were added to the solid residue, which was stirred vigorously for 30 minutes. The solid was filtered off, rinsed with 50 ml distilled water and discarded. The filtrate was transferred to a separating funnel. After discarding the organic layer, the aqueous layer was washed with toluene (2 × 100 ml). The aqueous layer was transferred to a large beaker (2 L) and diluted with isopropyl ether (50 ml). The stirred mixture was basified by careful addition of sodium bicarbonate (pH 7-8) which resulted in the formation of a sticky white solid. Dichloromethane (200 ml) was added and stirring continued for 10 minutes. The organic layer was separated and the aqueous layer was extracted again with dichloromethane (100 ml). The organic layers were combined and washed with saturated aqueous NaHC0 ₃ (100 ml), distilled water (100 ml), brine (100 ml), dried over Na ₂ S0 ₄ , filtered, concentrated and dried in vacuo in 46% yield. 1- (2, 4-dichlorophenyl) -2- (4-methylimidazol-2-yl) ethan-l-one was obtained.

2. Preparation of (2Z) -l- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (4-methylimidazol-2-yl) prop-2-en-1-one .

1- (2, 4-dichlorophenyl) -2- (4-methylimidazol-2-yl) ethan-1-one (0.33M) and N, N-dimethylformamide-dimethyl acetal (DMFDMA) (25 ml) was stirred at 70-75 ° C. for 2.5 h. DMFDMA was then removed under reduced pressure and dried for several hours under high pressure. A bright orange solid was obtained in quantitative yield. Enaminone product (2Z) -l- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (4-methylimidazol-2-yl) prop-2-en-1-one Was typically used without further purification.

3. Preparation of 6-[(2-aminoethyl) aminolpyridine-3-carbonitrile .

A mixture of 2-chloro-5-cyanopyridine (0.60 M) in acetonitrile (120 ml) and ethylene diamine (85 ml) was stirred overnight at 75-80 ° C. under argon (about 16 h). Ethylene diamine was removed under reduced pressure and dried in vacuo for 2-3 hours. The remaining solution was acidified with 1M sodium hydroxide solution (˜100 ml). The aqueous solution was saturated with sodium chloride and extracted with a solution of 95% ethyl acetate and 5% methanol (3 × 150 ml) and a solution of 95% acetonitrile and 5% methanol (3 × 150 ml). The organic extracts were combined and extracted with saturated sodium chloride solution (2 x 70 ml). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude white tan solid was triturated with ether (2 × 50 ml) and dried in vacuo overnight to give 78% yield of 6-[(2-aminoethyl) amino] pyridine-3-carbonitrile.

4. Preparation of amino {2-[(5-cyano (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride .

A mixture of 6-[(2-aminoethyl) amino] pyridine-3-carbonitrile (0.47 M), 1H-pyrazole-1-carboxamidine hydrochloride (0.47 M), and acetonitrile (120 ml) was added 75 Stir at -80 ° C for about 24 hours. While cooling, the precipitate was collected by filtration. The white solid was washed thoroughly with acetonitrile (2 x 100 ml), ethyl ether (3 x 100 ml) and dried overnight in vacuo to yield amino {2- [(5-cyano (2) as HC1 salt in 82% yield. -Pyridyl)) amino] ethyl} carboxamidine.

5. 6-[(2-{[4- (2,4-Dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) aminolpyridine- Preparation of 3-carbonitrile.

A solution of sodium ethoxide (0.58 M) dissolved in anhydrous ethanol (15 ml) was added (2Z) -l- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (4-methylimidazole -2-yl) prop-2-en-1-one (0.41 M), amino {2-[(5-cyano (2-pyridyl)) amino] ethyl} carboxamidine, hydrochloride (0.43 M ), And a stirred mixture of anhydrous ethanol (20 ml). The reaction was then heated to 75-80 ° C. for 2.5 hours. The reaction was diluted with ethyl acetate (400 ml) with cooling and washed with saturated aqueous NaHCO ₃ (100 ml), distilled water (2x100 ml), brine (100 ml), dried over Na ₂ S0 ₄ , filtered and concentrated. . The crude product (˜50% purity) was purified by flash chromatography on silica gel. The column was operated starting with 1: 1 ethyl acetate to hexanes and then ethyl acetate was used until all fast moving impurities were removed. The product was eluted with 1.5% methanol in ethyl acetate. The column is monitored by TLC as solvent system using 5% methanol in ethyl acetate. The product has UV activity in the long wavelength length region and "glows" blue on uncolored TLC plates. The appropriate portion was concentrated. The non-white solid was dried in vacuo overnight to give 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidine- in 28% yield. 2-yl] amino} ethyl) amino] pyridine-3-carbonitrile.

HPLC: 20.7 min (> 99% purity)

MS: M + H = 465. 3 (C ₂₂ H _l8 C _l2 N ₈ + H = 465)

Example 100

[5-((lE) -l-Aza-2-morpholin-4-ylprop-1-enyl) -4- (2,4-dichlorophenyl) pyrimidin -2- yll {2- [( Preparation of 6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyllisoindolin-1,3-dione

1 mmol of 2,4-dichlorophenacyl chloride in DMF was added dropwise to 2 mmol of phthalimide and 2 mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature and then purified by trituration with diethyl ether to give 2- [ 2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1, 3-dione was obtained.

Preparation of 2.2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylenel-2-oxoethyl} isoindolin- 1,3-dione

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1, 3-dione was heated to 80 ° C. in N, N-dimethylformamidedimethyl acetal for 6 hours. . The reaction mixture was concentrated in vacuo and triturated with diethyl ether to yield 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1,3- Dion was obtained.

3.2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidine-5- Production of carbamoyl} benzoic acid

1 mmol 2- {2- (2, 4-dichlorophenyl) -1- [(dimethylamino) methylene] -2-oxoethyl} isoindolin-1, 3-dione, 1 mmol amino {2- [ (6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and 3 mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 -(2, 4-dichlorophenyl) pyrimidin-5-yl] carbamoyl} benzoic acid.

4.2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, -4 dichlorophenyl) pyrimidin-5-yl Preparation of Isoindolin-1, 3-dione

1 mmol 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine -5-yl] carbamoyl} benzoic acid was heated in acetic acid at 120 ° C. for 4 hours and concentrated in vacuo to give 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino ] Ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] isoindolin-1, 3-dione was obtained.

5. [5-Amino-4- (2,4-dichlorophenyl) pyrimidin-2-yll {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine Produce

1 mmol of 2- [2- ({2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5- Isoindoline-1, 3-dione and 20 mmol of hydrazine were purified by column chromatography, stirred in ethanol at 75 ° C. for 2 hours, eluting with 5-10% methanol / methylene chloride, [5-amino- 4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

6.N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidine-5- Production of acetamide

1 mmol of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine and 1 mmol of acet anhydride was stirred in THF for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and eluted with 5-10% methanol / methylene chloride by N- [2-({2-[(6-amino-5-) by column chromatography. Nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] acetamide.

7. l- {{2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5- Preparation of Il Amino} Ethane-1-Tione

1 mmol of N- [2- ({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine-5- General] Acetamide and 2 mmol of Lawesson's reagent were stirred at 80 ° C. in 2 ml of DME and the reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride to give 1- {[2- ({2-[(6-amino-5 -Nitro (2-pyridyl))-amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] amino} ethane-1-thione.

8. [5-((lZ) -l-Aza-2-morpholin-4-ylprop-1-enyl) -4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2 Preparation of-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of 1-{[2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5 -Yl] amino} ethane-1-thione was heated to 90 ° C. in morpholine and purified by column chromatography eluting with 5-10% methanol / methylene chloride to give [5-((1Z) -1-aza-2- Morpholin-4-ylprop-1-enyl) -4- (2, 4-dichlorophenyl) pyrimidin-2yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino ] Ethyl} amine.

HPLC: 9.75 min. (100% purity)

MS: MH <+> 546. 3

Example 101

4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5 nitro (2-pyridyl)) amino] ethyl} Preparation of Amine

1. Preparation of 6-chloro-2-methoxy-3-nitro-pyridine

To a suspension of sodium hydride (684 mg, 28.49 mmol) in xylene (100 ml), methanol in xylene (30 ml) (0.98 ml, 25.9 mmol) was added under nitrogen. The mixture was stirred for 20 minutes. A solution of 2,6-dichloro-3-nitropyridine (5.0 g, 25.9 mmol) in xylene (100 ml) was added to the reaction mixture and stirred at rt overnight. Water (50 ml) was added and the organic layer was separated. The organics were washed with water (lX50ml) and brine (2X50ml), dried and concentrated in vacuo. The crude product was purified by flash chromatography (10: 1 methylene chloride and acetone) to afford the desired compound as a pale yellow solid (90%) 6-chloro-2-methoxy-3-nitro-pyridine as the only isomer. Provided.

2. [4- (2,4-Dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl} {2-[(6-methoxy-5-nitro (2-pyridyl)) Preparation of Amino] ethyl} amine

To a solution of [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-ylethyl amine (20 mg, 0.04 mmol) in DMF (lml), 2-methoxy-3 -Nitro-6-chloro-pyridine (8.3 mg, 0.04 mmol) and diisopropylethyl amine (31 μl, 0.018 mmol) were added. The reaction mixture was stirred for 12 h at 80 ° C. The crude mixture was concentrated in vacuo and column chromatographed to give a light yellow solid (10% methanol in methylene chloride) [4 (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine-2- Il] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

HPLC: 3.1 min (100% pure)

MS: MH <+> 501 C21H18Cl2N8O3 = 500 g / mol

Example 102

Preparation of [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(6-methoxy-5 nitro (2-pyridyl)) amino] ethyl} amine

 [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine from [4- (2,4-dichlorophenyl) -5-imidazol-1 ylpyrimidin-2-ylethylamine -2-yl] {2- [(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} prepared according to the above procedure for the preparation of amines.

HPLC: 3.2 min (100% pure)

MS: MH <+> 501 2C21H18Cl2N8O3 = 500 g / mol

Example 103

6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) aminol-3-nitropyridin-2-ol Produce

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl) amino] ethyl} The amine (7 mg, 0.01 mmol) was treated with hydrobromic acid (100-1) and acetic acid (100-1) and stirred overnight at 100 ° C. The mixture was concentrated in vacuo and lyophilized to give 6-[(2- { [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2yl] amino} ethyl) amino] -3-nitropyridin-2-ol as a dark brown solid.

HPLC: 2.7 min (100% pure)

MS: MH <+> = 487 C20H16Cl2N803 = 486 g / mol

Example 104

Preparation of 6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) aminol -3-nitropyridin-2-ol

6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] -3-nitropyridin-2-ol 6- [ In preparation for (2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -3-nitropyridin-2-ol Following the same procedure as described for [4- (2, 4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-yl] {2- [(6-methoxy-5-nitro (2 -Pyridyl) amino] ethyl} amine (7 mg, 0.01 mmol).

HPLC: 2.46 min (100% pure)

MS: MH <+> 487 C20H16C12N803 = 486 g / mol

Example 105

1- {6- (2- {4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino ] -3-pyridyl} ethan-1-one Manufacture

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } 1- {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) following the procedure described above for the preparation of amines) Amino] -3-pyridyl} ethan-1-one [4- (2,4-dichlorophenyl) -5-imidazol-1 ylpyrimidin-2-yl] ethylamine and 1- (6-chloro- 3-pyridyl) -ethanone (prepared as described in Tetrahedron 48: 9233 (1992)).

Example 106

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2- {5- (iminomethoxy methyl) (2-pyridyl) amino} ethyl) amine And 6-[(2- {4- (2,4-dichlorophenyl) 5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) aminolpyridine-3-carboxamide

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-cyano (2-pyridyl) amino] ethyl} amine (20 mg , 0.04 mmol) was treated with a saturated solution of methanol ammonia (lml) and ammonium chloride (lOmg) and stirred overnight at 60 ° C. The crude product was purified by column chromatography (10% methanol in methylene chloride) white powder As the title compound.

HPLC: 2.38 min (100% pure)

MS: MH <+> 484 C22H20C12N70 = 483 g / mol

HPLC: 1.94 min (100% pure)

MS: MH <+> 469 C22H20C12N70 = 468 g / mol

Example 107

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2 yl] amino} ethyl) amino] (3-pyridyl)} iminomethyl Preparation of hydroxylamine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] in aqueous ethanol (50-1 water in 500-1 ethanol) {2-[(5- A solution of cyano (2-pyridyl) amino] ethyl} amine (20 mg, 0.04 mmol) was converted to hydroxylamine hydrochloride (3.0 mg, 0.04 mmol) and diisopropylethyl amine (16 μl, 0.08 mmol). The reaction mixture was stirred under reflux overnight and concentrated in vacuo The residue was taken up with ethyl acetate, washed with brine and concentrated The crude mixture was subjected to column chromatography (10% methanol in methylene chloride). {6- [(2- {[4- (2, 4 Dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] (3-pyridyl)} iminomethyl Hydroxylamine was obtained.

HPLC: 2. 16 min (100% pure)

MS: MH <+> 484 C21H19OCl2N90 = 483 g / mol

Example 108

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2 yl] amino} ethyl) amino ] (3-pyridyl)} iminomethylhydroxyl Preparation of Amine

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) -amino] (3-pyridyl)} iminomethylhydrate Oxylamine was added to {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin2-yl] amino} ethyl} amino] (3-pyridyl)} Prepared from [4- (2, 4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-yl] ethylamine following the procedure described for the preparation of iminomethylhydroxylamine.

HPLC: 2.19 min (100% pure)

MS: MH <+> 484 C21H19OC12N90 = 483 g / mol

Example 109

Preparation of 6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) aminolpyridine-3-carboxamidine

[4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-cyano (2-pyridyl) amino in a saturated solution of methane ammonia ] A solution of ethyl} amine (20 mg, 0.04 mmol) was stirred for 48 h at 60 ° C. The product was purified from crude using reverse phase column chromatography to give 6-[(2-{[4- (2, 4 -Dichlorophenyl) -5imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxamidine.

HPLC: 2.14 min (100% pure)

MS: MH <+> 468 C21H19Cl2N9 = 467 g / mol

Example 110

Preparation of [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-yl] {2-[(4-cyano (2- pyridyl) amino] ethyl} amine

[4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-yl] {2-[(4-cyano (2-pyridyl) amino] ethyl} amine [4 -(2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine From [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] ethylamine and 2-chloro-4-cyanopyridine according to the procedure described above for the preparation of Prepared.

HPLC: 2.79 min (100% pure)

MS: MH <+> 451 C21H16C12N8 = 450 g / mol

Example 111

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yllamino} ethyl) amino] -3-nitro (2-pyridyl )} Preparation of Dimethylamine

1. Preparation of 6-chloro-2-dimethylamino-3-nitropyridine

2,6-dichloro-3-nitropyridine (1.9 g, 10mmole) and potassium carbonate (1.66 g, 12mmole) in 30 ml tetrahydrofuran were stirred at 0 ° C. for 5 minutes. A solution of dimethylamine / tetrahydrofuran (2M, 6ml, 12mmole) was added dropwise to the reaction mixture over 40 minutes. After 5 min stirring at 0 ° C., the mixture was warmed to rt and stirred overnight. The reaction mixture was filtered and the filtrate was collected and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 87% hexanes: 13% ethyl acetate to give 6-chloro-2-dimethylamino-3-nitropyridine (1.05 g).

HPLC: 11.18 min (90% pure)

MS: MH <+> 202.1 C7H8C1N302 = 201 g / mol

2. {6-[(2-{[4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2yl] amino} ethyl) amino] -3-nitro (2-pyri Dill)} preparation of dimethylamine

{6-[(2-{[4- (2,4-Dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) -amino] -3-nitro (2-pyri Dimethyl)} dimethylamine from [4- (2, 4-dichlorophenyl) -5imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-dimethylamino-3-nitropyridine [4 (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine It was prepared according to the procedure described above for the preparation of.

HPLC: 11.5 min (85% pure)

MS: MH <+> = 514. 2 C22H21Cl2N902 = 513g / mol

Example 112

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yllamino} ethyl) amino ] -3-nitro (2-pyridyl)} Preparation of Dimethylamine

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] 3-nitro (2-pyridyl)} dimethylamine [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(6-methoxy-5-nitro (2-pyridyl)) amino] Ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-dimethylamino- according to the procedure described above for the preparation of amines Prepared from 3-nitro pyridine.

HPLC: 11.6 min (85% pure)

MS: MH <+> = 514.3 C22H21C12N9O2 = 513 g / mol

Example 113

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[6 (methylamino) -5- nitro (2-pyridyl)] amino} Preparation of Ethyl) amine

1. Preparation of 6-chloro-2-methylamino-3-nitro-pyridine

6-Chloro-2-methylamino-3-nitro-pyridine was prepared according to the procedure described above for the preparation of 6-chloro-2-dimethylamino-3-nitropyridine by using a solution of methyl amine. The crude product was purified by flash chromatography, eluting 90% hexanes: 10% ethyl acetate at 16 (300 mg).

HPLC: 12.06 min (85% pure)

MS: MH <+> 188.1 C6H6C1N302 187 g / mol

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[6 (methylamino) -5- nitro (2-pyridyl) 1amino} Preparation of Ethyl) amine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[6- (methylamino) -5-nitro (2-pyridyl)] amino } Ethyl) amine from [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-ylethylamine and 6-chloro-2-methylamino-3-nitro-pyridine 4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} Prepared according to the procedure described above for the preparation of amines.

HPLC: 11 min (85% pure)

MS: MH <+> 500.3 C21H19C12N902 499 g / mol

Example 114

[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] (2- {6- (methylamino) -5-nitro (2-pyridyl) 1amino} ethyl) Preparation of Amine

[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] (2-{[6- (methylamino) -5-nitro (2-pyridyl)] amino} ethyl) The amine is [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl))- Amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-methyl according to the procedure described above for the preparation of amines Prepared from amino-3-nitro-pyridine.

HPLC: 11.3 min (85% pure)

MS: MH <+> 500.3 C21H19C12N902 499 g / mol

Example 115

2,6-dichloropyridine-3-carboxamide; And 2,6-dichloropyridine-3-carbonitrile ; And preparation of 6-chloro-2-methoxypyridine-3-carbonitrile

1. Preparation of 2, 6-dichloropyridine-3-carboxamide

A mixture of 2,6-dichloro-3-carboxypyridine (5.73 g, 30 mmole) and N-methylmorpholine (3.6 ml, 33 mmole) in dichloromethane (100 ml) was stirred in an ice bath for 5 minutes. Isopropyl chloroformate (4.28 ml, 33 mmole) was added to the reaction at 0 ° C. The reaction mixture was stirred for 30 minutes and then bubbled with pure ammonia gas for 2 minutes and stirred at room temperature overnight. The crude was concentrated under reduced pressure and sodium bisulfate (0.5 M, 35 ml) was added with stirring. The aqueous solution was extracted with ethyl acetate (3X 40ml). The organics were washed with water and brine and dried over sodium sulfate to give a yellow crude product (6.3 g, 50% pure).

Preparation of 2,6-dichloropyridine-3-carbonitrile

Trifluoroacet anhydride (4.23 ml, 30) in a mixture of 2,6-dichloro-3-acetamidopyridine (6.3 g, 55% pure) and pyridine (4.93 ml, 61 mmol) in dichloromethane (100 ml) mmole) was added. The reaction mixture was stirred at rt overnight and concentrated under reduced pressure. The crude product was purified by flash chromatography eluting with 85% hexanes: 15% ethyl acetate to give a pale yellow product (1.77 g, 90%).

HPLC: 10.26 min (90% pure)

MS: MH <+> 172.9 C6H2C12N2 171.9 g / mol

Preparation of 6-chloro-2-methoxypyridine-3-carbonitrile

6-chloro-2-methoxypyridine-3-carbonitrile from 2,6-dichloro pyridine-3-carboxamide according to the above procedure for the preparation of 6-chloro-2-methoxy-3-nitro-pyridine Prepared.

HPLC: 11.37 min (80% pure)

MS: MH <+> 169.1 C7H5C1N20 168 g / mol

Example 116

Preparation of 6-[(2- {4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2 yl] amino} ethyl) amino ] -2-methoxypyridine-3-carbonitrile

6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] -2 methoxypyridine-3-carbonitrile [4 -(2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine [4- (2,4-Dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and 6-chloro-2-methoxypyridine-3- according to the procedure described above for the preparation of Prepared from carbonitrile.

HPLC: 11.8 min (85% pure)

MS: MH <+> 481.2 C22H18C12N80 480 g / mol

Example 117

6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) aminol-2-methoxypyridine-3-carboni Manufacture of tril

6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -2-methoxypyridine-3-carboni Tril was obtained from [4- (2,4-dichlorophenyl) -5-imidazole 2-ylpyrimidin-2-ylethylamine and 6-chloro-2-methoxypyridine-3-carbonitrile [4- (2 For the preparation of 4 dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine It was prepared according to the above procedure.

HPLC: 11.37 min (80% pure)

MS: MH <+> 169.1 C7H5C1N20 168 g / mol

Example 118

N- {6- (2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) aminol-3-nitro-2- Preparation of Pyridyl} Acetamide

1. Preparation of N- (6-chloro-3-nitro-2-pyridyl) acetamide

To a suspension of sodium hydride (120 mg, 5 mmole) in tetrahydrofuran (10 ml), 2-amino-3-nitro-6-chloropyridine (870 mg, 5 mmole) in 20 ml tetrahydrofuran (20 ml) Solution was added. The reaction mixture was stirred at rt for 30 min. A solution of acet anhydride (377 μl, 6 mmole) in tetrahydrofuran (10 ml) was added and stirred overnight at room temperature. The reaction mixture was quenched with water and concentrated under reduced pressure. The crude product was dissolved in dichloromethane and washed with brine. The organic layer was dried over sodium sulfate and then concentrated in vacuo. The crude was purified by flash chromatography eluting with 78% hexanes: 22% ethyl acetate to give a yellow product (88 mg).

HPLC: 6.36 min and 9.78 min (88% pure)

MS: MH <+> 215.9 C7H6C1N303 215 g / mol

2. N- {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2 amino} ethyl) amino] -3-nitro-2- Preparation of Pyridyl} Acetamide

N- {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -3-nitro-2- Pyridyl} acetamide was obtained from [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl) )) Amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-ylethylamine and N- (6- Chloro-3-nitro-2-pyridyl) acetamide.

HPLC: 10.6 min (85% pure)

MS: MH <+> 528. 2 C22H19Cl2N903 527 g / mol

Example 119

N- {6-[(2- {4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) aminol-3-nitro-2-pyridyl} acet Preparation of Amides

N- {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] -3-nitro-2-pyridyl} Acetamide is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino ] -Ethyl} [4- (2,4-dichlorophenyl) -5 imidazol-1-ylpyrimidin-2-ylethylamine and N- (6-chloro-3-nitro) following the procedure described for the amine -2-pyridyl) acetamide.

HPLC: 10.8 min (85% pure)

MS: MH <+> 528.2 C22H19Cl2N903 527 g / mol

Example 120

{6- (2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -3-nitro (2-pyridyl) } (Methylsulfonyl) Amine Preparation

1.Preparation of (6-chloro-3-nitro (2-pyridyl)) (methylsulfonyl) amine

(6-Chloro-3-nitro (2-pyridyl)) (methylsulfonyl) amine was prepared according to the procedure described for the preparation of N- (6-chloro-3-nitro-2-pyridyl) acetamide. Prepared from -amino-3nitro-6-chloropyridine and methane sulfonyl chloride.

HPLC: 8.08 min (90% pure)

MS: MH <+> 251.9 C6H6C1N304S 251 g / mol

2. {6-[(2-{[4- (2,4-Dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -3-nitro (2 -Pyridyl)} (methylsulfonyl) amine preparation

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -3-nitro (2-pyridyl )} (Methylsulfonyl) amine to [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro ( 2-pyridyl)) amino] ethyl} amine [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-ylethylamine and ( 6-chloro-3-nitro (2-pyridyl)) (methylsulfonyl) amine.

HPLC: 10.8 min (85% pure)

MS: MH <+> 564 C21H19Cl2N904S 563 g / mol

Example 121

{6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino-3-nitro (2-pyridyl)} (methyl Sulfonyl) Preparation of Amines

[4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] 3 according to the procedures described for the preparation of amines -Nitro (2-pyridyl)} (methylsulfonyl) amine to [4- (2,4-dichlorophenyl) -5imidazol-1-ylpyrimidin-2-ylethylamine and (6-chloro-3 -Nitro (2-pyridyl)) (methylsulfonyl) amine.

HPLC: 11.1 min (85% pure)

MS: MH <+> 564 C21H19Cl2N904S 563 g / mol

Example 122

(2- {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -3-nitro (2 -Pyridyloxy)} ethyl) dimethylamine

1. Preparation of [2- (6-chloro-3-nitro (2-pyridyloxy)) ethyl] dimethylamine

[2- (6-Chloro-3-nitro (2-pyridyloxy)) ethyl] dimethylamine was prepared according to the procedure described above for the preparation of 6-chloro-2-methoxy-3-nitro-pyridine. Prepared from -dimethylaminoethanol.

HPLC: 4.9 min (65% pure)

MS: MH <+> 246.1 C9H12ClN303 245 g / mol

2. (2- {6-[(2-{[4- (2,4-Dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) aminol-3-nitro (2-Pyridyloxy)} Ethyl) Preparation of Dimethylamine

[4- (2 ,, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] Ethyl} (2-6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino according to the procedures described for the preparation of amines } Ethyl) amino] -3-nitro (2-pyridyloxy) ethyl) dimethylamine to [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-ylethylamine and Prepared from [2- (6-Chloro-3-nitro (2-pyridyloxy))-ethyl] dimethylamine.

HPLC: 8.5 min (85% pure)

MS: MH <+> 558. 3 C24H25Cl2N903 557.1 g / mol

Example 123

(2- {2-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] -3-nitro (2-pyridyl Oxy)} Ethyl) Preparation of Dimethylamine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } (2- {6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) according to the procedures described for the preparation of amines) Amino] -3-nitro (2-pyridyloxy) ethyl) dimethylamine with [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and [2- (6-chloro-3-nitro (2-pyridyloxy)) ethyl] from dimethylamine.

HPLC: 8.3 min (85% pure)

MS: MH <+> 558.3 C24H25Cl2N9O3 557.1 g / mol

Example 124

Preparation of (1Z) -1-Aza-2- (6-chloro (3-pyridyl))-1-methoxyprop-1-ene

To a solution of 5- (2-chloropyridinyl) oxime methyl ether (540 mg, 3.2 mmole) in acetonitrile (9 ml) was added ethylene diamine (2.8 ml, 42 mmole). The reaction mixture was stirred at 85 ° C. overnight and concentrated in vacuo. The crude product was dissolved in aqueous sodium hydroxide (1M, 15 ml) and extracted with a mixture of ethyl acetate and acetonitrile / methanol (10: 1). The organic extract was dried over sodium sulfate to give (lZ) -l-aza-2- (6-chloro (3-pyridyl))-l-methoxyprop-l-ene (547 mg, 75%) as a yellow oil. Got.

HPLC: 1.8 min (75% pure)

MS: MH <+> 195.1 C9H14N40 194.1 g / mol

Example 125

(2-{[5-((1Z) -2-aza-2-methoxy-1-methylvinyl) (2-pyridyl)] amino} ethyl) [4- (2,4- dichlorophenyl) -5 Preparation of -Imidazolylpyrimidin-2-yllamine

(2-{[5-((1Z) -2-aza-2-methoxy-1-methylvinyl) (2-pyridyl)] amino} ethyl) [4- (2, 4-dichlorophenyl) -5 -Imidazolylpyrimidin-2-yl] amine was prepared from guanidine. (This is from [2- (6-chloro-3-nitro (2-pyridyloxy)) ethyl] dimethylamine and the corresponding enamineminone Made).

HPLC: 9.3 min (85% pure)

MS: MH <+> 483.2 C22H20C12N80 482 g / mol

Example 126

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) aminolethyl} [4- (2,4-dichlorophenyl) -5- imidazolylpyrimidin-2-yllamine

 [4- (2,4-dichlorophenyl) -5-imidazol-2ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazolyl according to the procedures described for the preparation of amines Pyrimidin-2-yl] amine is substituted with [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-5-nitro-6-aminopyridine Prepared from.

HPLC [Method AZ-S], 6.15 min (100%)

MS (m + H / z), 486.

Example 127

Preparation of 6-[(2- {4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino ] pyridine-3-carbonitrile

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } 6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] pyridine- according to the procedures described for the preparation of amines. 3-carbonitrile was prepared from [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-ylethylamine and 2-chloro-5-cyanopyridine.

HPLC [method AZ-S], 5.94 min (100%);

MS (m + H / z), 451.

Example 128

[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-methyl (7a-hydro-1,2,4- triazolo [l, 5- a] pyrimidin-7-yl)) amino] ethyl} amine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-methyl (7a-hydro-1, 2,4triazol [1, 5-a] pyrimidin-7-yl)) amino] ethyl} amine to [4- (2, 4-dichlorophenyl) -5-imidazol-1-ylpyrimidine-2 Prepared from (1, 5-a) pyrimidine with -ylethylamine and 7-methyl-9-chloro-1,2,4triazol.

HPLC [method AZ-S], 5.80 min (70%);

MS (m + H / z), 481.

Example 129

Preparation of [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-trifluoromethyl (2-pyridyl)) aminolethyl} amine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-trifluoromethyl (2-pyri) according to the procedures described for the preparation of amines Dill)) amino] ethyl} amine from [4- (2, 4-dichlorophenyl) -5-imidazole-1-ylpyrimidin-2-ylethylamine and 2-chloro-5-trifluoromethylpyridine Prepared.

HPLC [method AZ-S], 7.62 min (60%);

MS (m + H / z), 494.

Example 130

4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (1, 3- thiazol-2-yl)) amino] ethyl} amine Produce

 [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } 4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (1, 3-thiazole-) according to the procedure described above for the preparation of amines 2-yl))-amino] ethyl} amine was added to [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin- 2-ylethylamine and 2-chloro-5-nitro- Prepared from thiazole.

HPLC [method AZ-S], 7.14 min (100%);

MS (m + H / z), 477.

Example 131

Preparation of [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(6-chloropyrimidin- 4-yl) amino] ethyl} amine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(6-chloropyrimidin-4-yl) following the procedure described for the preparation of the amine. Amino] ethyl} amine was prepared from [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin- 2-ylethylamine and 4,6-dichloropyrimidine.

HPLC [method AZ-S], 7.43 min (80%);

MS (m + H / z), 461.

Example 132

Preparation of [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(6-chlorobenzothiazo 1-2-yl) aminolethyl} amine

[4- (2,4-dichlorophenyl) -5-imidazol-2ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(6-chlorobenzothiazo 1-2 day) following the procedure described for the preparation of the amine. Amino] ethyl} amine was prepared from [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and 2,6-dichlorobenzothiazole.

HPLC [method AZ-S], 8.23 min (100%);

MS (m + H / z), 516.

Example 133

Preparation of [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(3-nitro (2-thienyl )) amino] ethyl} amine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl } [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(3-nitro (2-thienyl)) according to the procedure described for the preparation of amines Amino] ethyl} amine was prepared from [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-3-nitrothiophene.

HPLC [method AZ-S], 9.50 min (75%);

MS (m + H / z), 495.

Example 134

Preparation of 4-amino-2-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] pyrimidine-5-carbonitrile

[4- (2,4-dichlorophenyl) -5-imidazol-2ylpyrimidin-2-yl] {2-[(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} 4-amino- 2-[(2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino according to the procedures described for the preparation of amines ] Pyrimidine-5-carbonitrile is prepared by [4- (2,4-dichlorophenyl) -5-imidazol-1-ylpyrimidin-2-ylethylamine and 2-chloro-4-amino-5-cyano Prepared from pyrimidine.

HPLC [method AZ-S], 6.00 min (70%);

MS (m + H / z), 467.

Example 135

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) aminolethyl} [6- (2,4-dichlorophenyl) -5 nitro (2-pyridyl)] amine

1. Preparation of 2- (2,4-dichlorophenyl) -6-chloro-3-nitropyridine

1 mmol 2,6-dichloro-3-nitropyridine, 1.05 mmol of 2,4-dichlorobenzeneboronic acid, and 3 mmol of Na ₂ CO ₃ were dissolved in 1.5 ml THF and 0.5 ml water and purged with nitrogen. 0.05 mmol of [1, 1'-bis (diphenylphosphino) -ferrocene] dichloro-palladium (II) was added to the reaction and stirred for 14 hours under nitrogen at room temperature. The reaction mixture was concentrated and diluted with water and ethyl acetate in vacuo. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 10% ethyl acetate 90% hexanes to give 2- (2,4-dichlorophenyl) -6-chloro-3- Nitropyridine was obtained.

2. Preparation of (2-aminoethyl) (6-amino-5-nitro (2-pyridyl)) amine

1 mmol of 2-amino-6-chloro-3-nitropyridine and 15 mmol of 1,2-diaminoethane were stirred at reflux for 14 hours. The reaction mixture was concentrated in vacuo and 1.5 mmol of NaOH solution in water was added. This solution was extracted twice with 95% / 5% methylene chloride / methanol. The aqueous was then saturated with salt and extracted twice with 95% / 5% acetonitrile / methanol and then finally twice with 95% / 5% ethylacetate / methanol. All organic portions were combined and dried over sodium sulfate to give (2-aminoethyl) (6-amino-5-nitro (2-pyridyl)) amine.

3. Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5 nitro (2-pyridyl)] amine

1 mmol of 2- (2,4-dichlorophenyl) -6-chloro-3-nitropyridine at 80 ° C. for 2 hours at 2 mmol of (2-aminoethyl) (6-amino-5- in 2 ml of DMF. Nitro (2-pyridyl)) amine and 3 mmol of N, N-diisopropylethylamine were taken. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride to give {2-[(6-amino-5-nitro (2-pyridyl). )) Amino] ethyl} [6- (2, 4-dichlorophenyl) -5-nitro (2-pyridyl)] amine.

HPLC: 8.698 min. (100% purity)

MS: MH <+> 464.1

Example 136

6- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4 dichlorophenyl) pyrimidin-5-yl]- Preparation of 3-pyrrolino [3,4-b] pyridine-5,7-dione

1. Preparation of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1, 3-dione

1 mmol of 2, 4-dichlorophenacyl chloride in DMF was added dropwise to 2 mmol of phthalimide and 2 mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature and then purified by trituration with diethyl ether to give 2- [ 2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione was obtained.

Preparation of 2.2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylenel-2-oxoethyl} isoindolin- 1,3-dione

1 mmol of 2- [2- (2, 4-dichlorophenyl) -2-oxoethyl] isoindolin-1, 3-dione was heated to 80 ° C. for 6 hours in a straight N, N-dimethylformamide dimethyl acetal It was. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether to give 2- {2- (2,4-dichlorophenyl) -l-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1, 3-dione was obtained.

3.2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 dichlorophenyl) pyrimidin-5-yl l Carbamoyl} benzoic acid

1 mmol 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoindolin-1,3-dione, 1 mmol amino {2- [ (6-Amino-5-nitro (2-pyridyl)) amino 3 ethyl} -carboxamidine, and 3 mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate to give 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) 4- (2,4-dichlorophenyl) pyrimidin-5-yl] carbamoyl} benzoic acid.

4.2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl] Preparation of Isoindolin-1, 3-dione

1 mmol of 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine -5-yl] carbamoyl} benzoic acid was heated to 120 ° C. for 4 hours and then concentrated in vacuo in acetic acid to yield 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)). ) Amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] isoindolin-1, 3-dione.

5. Preparation of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine-5- [5] Isoindoline-1, 3-dione and 20 mmol of hydrazine were stirred in ethanol at 75 ° C. for 2 hours and then eluted with 5-10% methanol / methylene chloride by column chromatography [5-amino. -4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine was obtained.

6. 6- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] -3-pyrrolino [3, 4-b] pyridine-5, 7-dione

1 mmol of [5-amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, And 2 mmol of furano [3,4-b] pyridine-5,7-dione were stirred at room temperature for 4 hours. 2 mmol of HBTU, and 3 mmol of N, N-diisopropylethylamine were added to the solution and left at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and dried over, purified by column chromatography eluting with 5-10% methanol / methylene chloride to give 6- [2-({2-[(6- Amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) -pyrimidin-5-yl] -3-pyrrolino [3,4-b] Pyridine-5,7-dione was obtained.

HPLC: 7.829 min. (97.32% purity)

MS: MH &lt; + &gt; 566.0

Example 137

Preparation of [6- (2,4-dichlorophenyl) -5-imidazol-2-yl (2-pyridyl)] {2-[(5-nitro (2- pyridyl)) amino] ethyl} amine

1. Preparation of 1- (2, 4-dichlorophenyl) -2-imidazol-2-ylethan-1-one.

Preparation of the material 1- (2,4-dichlorophenyl) -2-imidazol-2-ylethan-1-one was carried out as described in [4- (2,4-dichlorophenyl) -5-imidazol-2ylpyrimidine- 2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine.

2. Preparation of 2- (2-aminoethylamino) -5-nitropyridine.

Preparation of the material 6-[(2-aminoethyl) amino] pyridine with various substitutions in pyridine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, Example 74, and analogs thereof.

3. Preparation of Methyl 2-phenylthiopropanoate

A solution of methyl-2-bromopropionate (6.13 M) in anhydrous ethanol (25 ml) was slowly added to a stirred solution of thiophenol (107 M), KOH (107 M) in anhydrous ethanol (90 ml) at room temperature. (˜1 h) was added. After 12 h, the reaction was filtered and the solvent was removed under reduced pressure. The resulting slurry was partitioned between water (150 ml) and ether (100 ml). The aqueous layer was extracted with ether (3 x 100 ml). The combined organic layers were washed with 1 M NaOH (2 × 50 ml), water (2 × 50 ml), brine (100 ml), dried over Mg ₂ SO ₄ , filtered and concentrated under reduced pressure. Drying in vacuo for 2-3 hours gave methyl 2-phenylthiopropanoate as a clean oil in 90% yield and> 99% purity. (Warren, S .; et. Al. J Chem. Soc. Perkin Trans. See similar procedure in 11986, 1939-1945.)

4. Preparation of Methyl 2- (phenylsulfinyl) propanoate.

A solution of mCPBA (57-86% active) in dry ether (200 ml, ˜0.25 g per ml) was stirred at 0 ° C. of methyl 2-phenylthiopropanoate (0.34 M) in dry ether (400 ml) To the prepared solution. The reaction was then subjected to TLC eluting with 10% ethyl acetate in hexanes. After all the starting material was consumed, the reaction was concentrated under reduced pressure. The residue was dissolved in ether (150 ml) and dichloromethane (400 ml). The organics were washed with 1 M Na ₂ S ₂ 0 ₃ (2 × 80 ml), saturated aqueous Na ₂ CO ₃ (4 × 100 ml), brine (100 ml) and dried over Na ₂ S0 ₄ . After removal of the volatile organics, methyl 2- (phenylsulfinyl) propanoate was obtained in 99% yield and 99% purity.

5. Preparation of Methyl 2-phenylthioprop-2-enoate.

A mixture of dichloromethane (800 ml), acet anhydride (20 ml), and methyl 2- (phenylsulfinyl) propanoate (0.17 M) in methanesulfonic acid (1.5 ml) was heated at 40 ° C. for 18 h. It was. The reaction was concentrated in a water bath maintained at a constant 35 ° C. under reduced pressure. The residue was partitioned between water (200 ml) and ether (100 ml). The aqueous layer was extracted with ether (3 x 50 ml). The combined organic layer was washed with water (50 ml), saturated aqueous Na ₂ CO ₃ (3 × 30 ml), brine (30 ml) and dried over MgSO ₄ . After filtration, the product was removed at <35 ° C. under reduced pressure. The product was purified through a short column of silica gel using 10% ethyl acetate in the hexane mixture as eluent. In concentration, methyl 2-phenylthioprop-2-enoate was isolated in 50% yield.

6. Preparation of methyl5- (2,4-dichlorophenyl) -4-imidazol-2-yl-5-oxo-2phenylthiopentanoate .

A solution of (1 M) tert-butoxide in tert-butanol (54.9 ml) was dissolved in dichloromethane (300 ml) and methanol (200 ml) at room temperature in 1- (2,4-dichlorophenyl) -2- To a stirred solution of imidazol-2-yletan-1-one (0.11 M) and methyl 2-phenylthioprop-2-enoate (0.14 M). The reaction developed to a dark color and was typically stirred under argon overnight (about 16 h). The reaction was monitored by TLC using 5% methanol in dichloromethane as solvent system. Further methyl 2-phenylthioprop-2-enoate was added as needed to consume all of the starting 1- (2,4-dichlorophenyl) -2-imidazol-2-ylethan-1-one. The reaction was quenched by addition of saturated aqueous NH ₄ C1 (-100 ml). The mixture was transferred to a separatory funnel and diluted with ethyl acetate (300 ml). The aqueous layer was removed and the organic layer was washed with saturated aqueous NH ₄ C1 (3 × 100 ml), brine (100 ml) and dried over Na ₂ SO ₄ . After filtration and evaporation, the residue was purified on silica gel by flash chromatography. The column was eluted starting with 100% dichloromethane to remove nonpolar methyl 2-phenylthioprop-2-enoate. The product was eluted with 3% methanol in dichloromethane.

After drying in vacuo overnight, methyl 5- (2, 4-dichlorophenyl) -4-imidazol-2-yl-5-oxo-2-phenylthiopentanoate was obtained in 71% yield as a deep red glass. A further 10% yield of the product could be obtained by sending the side product contaminated portion back to the second clarification by flash chromatography.

7.6- (2,4-Dichlorophenyl) -5-imidazol-2-yl-3-phenylthio-1,3,4-trihydropyridin -2-one.

The solution was prepared by heating the mixture to 90 ° C. to methyl 5- (2,4-dichlorophenyl) -4-imidazol-2-yl-5-oxo-2-phenylthiopentanoate (0.33 M), glacial acetic acid (21 ml ), Anhydrous ethanol (63 ml), toluene (21 ml). To the stirred solution, NH ₄ 0Ac (1.97 M) and 4A molecular sieve (15 g) were added. After 24 hours of heating, another portion of both NH ₄ 0Ac (1.97 M) and 4A molecular sieve (15 g) was added. After 48 hours, the reaction reached completion as determined by HPLC. The reaction was diluted with ethyl acetate (500 ml), filtered and washed with saturated aqueous NaHCO ₃ (4 × 250 ml) and brine (200 ml). The organic layer was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The residue was concentrated under reduced pressure in EtOAc. The residue was taken up in a minimum amount of EtOAc to precipitate the product. The remaining product was purified on silica gel by flash chromatography. The column was eluted using 100% ethyl acetate. After concentration, the product was dried in vacuo. Product 6- (2,4-dichlorophenyl) -5-imidazol-2-yl-3-phenylthio-1,3,4-trihydropyridin-2-one obtained from precipitation and chromatography was prepared from the tan solid 89 Obtained in% yield.

8. Preparation of 6- (2, 4-dichlorophenyl) -5-imidazol-2-ylhydropyridin-2-one.

Solution of 6- (2,4-dichlorophenyl) -5-imidazol-2-yl-3-phenylthio-1,3,4-trihydropyridin-2-one (0.17 M) in THF (40 ml) Dichloromethane (˜150 ml) was carefully added so as not to cause precipitation. A solution of mCPBA (2.85 g, ˜16.5 mmol; 65-85% active) in dichloromethane (50 mg per ml) is added dropwise to the stirred solution of phenylthiol at −20 ° C. After addition of approximately 1 equivalent of oxidant, the reaction was warmed to room temperature. Additional mCPBA is titrated into the reaction until all starting material disappears, as determined by TLC eluting in 5% MeOH in dichloromethane (product R _f is ˜0.1). When the reaction is near completion, the precipitate product begins to precipitate out of solution as rubber. Upon completion, the reaction is stirred for an additional 30 minutes. Triethylamine (4 ml; based on 2 eq. MCPBA) was added and added to the reaction to make the reaction completely clear for about 1 minute, followed by precipitation of nearly complete product as a non-white solid. The solid was filtered off and washed with dichloromethane (3 x 30 ml). The product was dried in vacuo to give 6- (2,4-dichlorophenyl) -5-imidazol-2-ylhydropyridin-2-one in 93% yield.

9. Preparation of 6- (2, 4-dichlorophenyl) -5-1-{(trifluoromethyl) sulfonyl] imidazol- 2 -yl} -2-pyridyl (trifluoromethyl) sulfonate.

Trifluoromethanesulfon anhydride (1.61 ml, 9.78 mmol) was added 6- (2,4-dichlorophenyl) -5-imidazol-2-ylhydropyridine- in pyridine (10 ml) at -10 ° C. 2-one (500 mg, 1.63 mmol) was added to the stirred suspension. After 30 minutes, the reaction was warmed to room temperature. Stirring was continued until all of the solid starting material was dissolved and reacted as determined by HPLC. The reaction is diluted with dichloromethane (500 ml) and washed sequentially with saturated aqueous NaHC0 ₃ (3 x 100 ml), water (2 x 100 ml), saturated aqueous NaHC0 ₃ (100 ml), brine, Na ₂ S0 ₄ Dried over, filtered and concentrated under reduced pressure. The residue was purified on a short column of silica gel eluting with 25% ethyl acetate in hexanes to remove the nonpolar product from the base material. After removing the solvent and drying in vacuo, the product 6- (2, 4 dichlorophenyl) -5- {1-[(trifluoromethyl) sulfonyl] imidazol-2-yl} -2-pyridyl (tri Fluoro-methyl) sulfonate was obtained in 95% yield as a slightly yellow clear glass weighing 874 mg.

10. Preparation of [6- (2,4-dichlorophenyl) -5-imidazol-2-yl (2-pyridyl) {2-((5-nitro (2- pyridyl)) amino] ethyl} amine .

(2-aminoethyl) (5-nitro (2-pyridyl)) amine (255 mg, 1.40 mmol) in N, N-dimethylacetamide (3 ml) containing dry powdered 4 ′ molecular sieve (50 mg) Suspension of dry powdered 6- (2,4-dichlorophenyl) -5- {1-[(trifluoromethyl) in N, N-dimethylacetamide (3 ml) containing 4 μg molecular sieves (50 mg) Sulfonyl] imidazole-2-yl} -2-pyridyl (trifluoromethyl) sulfonate (200 mg, 0.35 mmol) was added to the suspension. After stirring for 24 hours at 40 ° C., ethylenediamine (0.5 ml) and water (0.5 ml) were added to the reaction to hydrolyze one remaining triflate from the product. The reaction was stirred at 85 ° C. for 2 hours and left at room temperature for 12 hours. The reaction is then diluted with ethyl acetate (100 ml), filtered, extracted with saturated aqueous NaHCO ₃ (6 × 30 ml), brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. I was. Product [6- (2, 4-dichlorophenyl) -5-imidazol-2-yl (2-pyridyl)] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine (79859 ) Was obtained in 85% yield as a yellow glass weighing 143 mg.

HPLC: 22.1 min (> 95% purity)

MS: M + H = 470.2 ( C 2l H l7 Cl 2 N 7 0 2 + H = 470)

Example 138

[4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] methan-1-ol Produce

2.13 g (4.68 mmol) ethyl 4- (2, 4-dichlorophenyl) -2-({2-[(tert-butoxy) carbonylamino] ethyl} amino) pyrimidine-5-carboxyl in 10 mL THF To the stirred solution of the suspension of rate is added dropwise 25 mL of DIBAL-H (1 M in THF, 25.0 mmol) under nitrogen at room temperature. During this addition the suspension gradually turned into a uniform yellow solution. After 1 hour the resulting solution was heated to 70 ° C. for an additional 7 hours. The reaction was then cooled and the reaction was quenched by adding the salt of Rochelle. The resulting suspension was partitioned between methylene chloride and water. The aqueous layer was extracted twice with methylene chloride and the combined organic layers were washed with brine and dried over sodium sulfate.

Concentration gave 2.05 g of yellow foam. Chromatography on silica gel (110 g) using 5% methanol / ether as eluent gave 430 mg (22%) of N- (2-{[4- (2,4-dichlorophenyl)-as colorless foam. 5 (hydroxymethyl) pyrimidin-2-yl] amino} ethyl) (tert-butoxy) carboxamide.

HPLC [method AZ-S], 9.42 min (100%); MS (m + H / z), 413.

N- (2-{[4- (2,4-dichlorophenyl) -5- (hydroxymethyl) pyrimidin-2-yl] amino} ethyl) (tert-butoxy) carboxamide (372 mg, 0.90 mmol) was dissolved in 2 mL of anhydrous trifluoroacetic acid and stirred at room temperature for 2 hours. The solvent was evaporated to give trifluoroacetate salt, {2-[(2-aminoethyl) amino] -4- (2, 4-dichlorophenyl) pyrimidin-5-yl} methane-1-ol in quantitative yield. Got.

{2-[(2-aminoethyl) amino] -4- (2,4-dichlorophenyl) pyrimidin-5-yl} methan-1-ol was dissolved in 3 mL of anhydrous THF and 1.47 g (4.50 mmol) Anhydrous cesium carbonate was added. 2-Chloro-5-nitro-6-aminopyridine (143 mg, 0.9 mmol) was added in one portion and the yellow suspension was heated at 70 ° C. for 18 h. The reaction mixture was filtered, concentrated and the residue was chromatographed (silica gel, 5% methanol / methylene chloride) as a yellow solid [4- (2,4-dichlorophenyl) -2-({2-[(5- Nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] methane-1-ol, 216 mg (53%) were obtained.

HPLC [method AZ-S], 6.92 min (100%); MS (m + H / z), 450.

Example 139

Of [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) aminolethyl } amino) pyrimidin-5-yl] methan-1-ol Produce

 Example using 2-chloro-5-nitro-pyridine and {2-[(2- aminoethyl) amino] -4- (2, 4-dichlorophenyl) pyrimidin-5-yl} methane-1-ol Repeat the process of 140. Chromatography of the residue is a yellow solid (silica gel, 5% methanol / methylene chloride) 200 mg (51%) of [4- (2,4-dichlorophenyl) -2-({2- [(5-nitro ( 2-pyridyl)) amino] ethyl} amino) pyrimidin-5 yl] methane-l-ol.

HPLC [method AZ-S], 7.85 min (100%); MS (m + H / z), 435.

Example 140

[4- (2,4-dichlorophenyl) -5- (morpholin-4-ylmethyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} Preparation of Amine

100 mg of N- (2-{[4- (2,4-dichlorophenyl) -5 (hydroxymethyl) pyrimidin-2-yl] amino} ethyl) using the method of Swern, et al. tert-butoxy) carboxamide was dissolved in 1 mL of anhydrous methylene chloride and added to a solution of oxalyl chloride (30.7 μL, 0.363 mmol) and DMSO (51.6 μL, 0.726 mmol) and it was stirred at −78 ° C. for 15 minutes. Stirred. The resulting solution was stirred for an additional 30 minutes at which time 202 μL (1.45 mmol) triethyl amine was added. The resulting suspension was warmed to room temperature after 15 minutes and 1 mL of water was added and the layers separated.

The aqueous layer was extracted with methylene chloride and the combined organic layers were dried (sodium sulfate) and concentrated to N- (2-{[4- (2,4-dichlorophenyl) -5-formylpyrimidin-2-yl] Amino} ethyl) (tert-butoxy) carboxamide was obtained as a light yellow foam. This product proved to be air sensitive and was used without further manipulation.

HPLC [method AZ-S], 11. 41 min. (95%); MS (m + H / z), 411.

N- (2-{[4- (2,4-dichlorophenyl) -5-formylpyrimidin-2-yl] amino} ethyl) (tert-butoxy) carboxamide (50 mg, 0.121 mmol) Dissolved in 5 mL of THF, 242 μL of sodium cyanoborohydride (1M in THF) and 5 μL of glacial acetic acid were added and the mixture was heated to 70 ° C. for 18 hours. After slowly adding 1 mL of water to dissolve the excess reagent, the mixture was partitioned between ethyl acetate and saturated citric acid solution. The organic layer was discarded and the aqueous layer was carefully basified with sodium hydroxide to PH 9 and then extracted twice with ethyl acetate. The combined organic layers were dried (sodium sulfate), concentrated and purified by chromatography (silica gel, 10% methanol / methylene chloride) N- (2-{[4- (2,4-dichlorophenyl) -5 -(Morpholin-4-ylmethyl) pyrimidin-2-yl] amino} ethyl) (tert-butoxy) carboxamide, 30 mg (52%) was obtained.

HPLC [method AZ-S], 8.28 min (95%); MS (m + H / z), 482.

Using the state described in step 1.2 above, N- (2-{[4- (2,4-dichlorophenyl) 5- (morpholin-4-ylmethyl) pyrimidin-2-yl] amino} ethyl) Treatment of (tert-butoxy) carboxamide with anhydrous trifluoroacetic acid to give (2-aminoethyl) [4- (2,4-dichlorophenyl) -5- (morpholin-4-ylmethyl) pyrimidine- 2-yl] amine was obtained close to the quantitative yield.

HPLC [method AZ-S], 3.97 min (95%); MS (m + H / z), 382.

Using the conditions described in the previous examples, (2-aminoethyl) [4- (2,4-dichlorophenyl) -5- (morpholin-4-ylmethyl) pyrimidin-2-yl] amine and 9.7 [4- (2,4-Dichlorophenyl) -5- (morpholine-4-) according to chromatography with silica (0.061 mmol) 2-chloro-5-nitropyridine (silica gel, 5% methanol / methylene chloride) Ylmethyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine was obtained in 60% yield.

HPLC [method AZ-S], 7.43 min (100%); MS (m + H / z), 504.

Example 141

[4- (2,4-dichlorophenyl) -5- (morpholin-4-ylmethyl) pyrimidin-2-yl] {2- (5 nitro- 6-amino (2-pyridyl)) amino] Preparation of Ethyl} Amine

Using the conditions described in Example 139, (2-aminoethyl) [4- (2,4-dichlorophenyl) -5- (morpholin-4-ylmethyl) pyrimidin-2-yl] amine and 10.6 mg (0.061 mmol) of 2-chloro-5-nitro-6-aminopyridine is equivalent to 191 mg (60%) of [4- (2,4-dichlorophenyl) -5- (morpholin-4-ylmethyl) pyridine. Midin-2-yl] {2- [(5-nitro-6-amino (2 pyridyl)) amino] ethyl} amine was obtained after chromatography (silica gel, 5% methanol / methylene chloride) as a yellow solid.

HPLC [method AZ-S], 6.49 min (100%); MS (m + H / z), 519.

Example 142

[4- (2,4-dichlorophenyl) -5- (morpholin-4-ylmethyl) pyrimidin-2-yl} {2-[(5 nitro- 6-amino (2-pyridyl)) amino] Preparation of Ethyl} amine and Related Compounds

0.44 g (2.59 mmol) of 2,2,2-trifluoro-N- [2- (methylamino) ethyl] acetamide (Syn. Comm., 26: 3633-3636 (1996) in 5 mL anhydrous THF) Prepared) and 0.38 g (2.59 mmol) of 1-pyrazolocarboxamidine hydrochloride were stirred at room temperature for 3 hours. Concentration of this suspension gave a white solid which was obtained by 1 H NMR analysis with the desired guanidine, N- [2- (amidinomethylamino) ethyl] -2,2,2-trifluoroacetamide hydrochloride, and pyrazole. It was found to be composed. This was used without further purification in the next step.

A solution of 0.60 g (2.3 mmol) 2,4-dichloro-2- (1-imidazoyl) -ethan-1-one, 0.38 mL (2.82 mmol) dimethiformamide dimethylacetal and 5 mL THF was added for 2 hours. It was refluxed. Concentration gave 1- (2, 4-dichlorophenyl) -2- (1-imidazoyl) -3-dimethylaminoprop-2-en-l-one in quantitative yield as a light red solid. This solid is dissolved in 5 mL THF and 1.0 g (3.06 mmol) of anhydrous cesium carbonate and N- [2- (amidinomethylamino) ethyl] -2,2,2-trifluoroacetamide The residue containing was added and the resulting mixture was heated to 70 ° C. for 18 hours. After cooling, water was added and the resulting mixture was extracted with methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organics were washed with brine, dried and concentrated to give 1.56 g of brown oil. Chromatography (silica gel, 5% methanol / methylene chloride) gave 0.35 g of desired pyrimidine, N- (2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidine- as a brown solid. 2-yl] methylamino} ethyl) -2, 2,2-trifluoroacetamide.

HPLC [method AZ-S], 7.68 min (85%); MS (m + H / z), 459.

Pyrimidine, N- (2-{[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] methylamino} ethyl) -2,2,2-tri mentioned above Fluoroacetamide (114 mg, 0.25 mmol) was dissolved in 2 mL methanol and potassium hydroxide (40 mg, 1 mmol) was added. This suspension was stirred at room temperature for 1 hour. Water was added and the solution extracted with methylene chloride. The aqueous layer was extracted thoroughly with methylene chloride and the organic layers washed with brine, dried and concentrated to deprotected primary amine, (2-aminoethyl) [4- (2, 4-dichlorophenyl) -5imidazolylpyridine Midin-2-yl] methylamine was obtained in quantitative yield.

HPLC [method AZ-S], 4.43 min (90%); MS (m + H / z), 363.

Using the procedure described above in Example 139, (2-aminoethyl) [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] methylamine and 2-chloro-5- Reactant of nitropyridine was reacted to [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] methyl {2-[(5-nitro (2-pyridyl)) amino] ethyl } Amine (73174) was obtained.

HPLC [method AZ-S], 7.82 min (100%); MS (m + H / z), 485.

Using the procedure described above, (2-aminoethyl) [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] methylamine and 2-chloro-5-nitro-6- The reaction of amino-pyridine is reacted to [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2yl] methyl {2- [(5-nitro-6-amino (2-pyridyl) ) Amino] ethyl} amine.

HPLC [method AZ-S], 6.73 min (100%); MS (m + H / z), 500.

Using the procedure described above in Example 139, (2-aminoethyl) [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] methylamine and 2-chloro-5cya Nopyridine is reacted to [4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] methyl {2-[(5-cyano (2-pyridyl)) amino] ethyl} An amine was obtained.

HPLC [method AZ-S], 6.49 min (100%); MS (m + H / z), 465.

A solution of 0.60 g (2.3 mmol) 2,4-dichloro-2- (2-imidazoyl) -ethan-1-one, 0.38 mL (2.82 mmol) dimethiformamide dimethylacetal and 5 mL THF was added for 2 hours. It was refluxed. Concentration yielded 1- (2, 4-dichlorophenyl) -2- (2-imidazoyl) -3- (dimethylamino) prop-2-en-l-one in quantitative yield as a light red solid. . This solid was redissolved in 5 mL THF and 1.0 g (3.06 mmol) of anhydrous cesium carbonate and N- [2- (amidinomethylamino) ethyl] -2,2,2-trifluoroacetamide hydro Chloride (see above) was added and the resulting mixture was heated to 70 ° C. for 18 h. After cooling, water was added and the resulting mixture was extracted with methylene chloride. The aqueous layer was extracted with methylene chloride and the combined organic phases were washed with brine, dried and concentrated to give a brown oil. Chromatography (silica gel, 5% methanol / methylene chloride) gave 0.30 g of the desired pyrimidine, N- (2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-yl as brown solid. Pyrimidin-2-yl] methylamino} ethyl) -2, 2,2-trifluoroacetamide.

HPLC [method AZ-S], 7.25 min (100%); MS (m + H / z), 459.

Pyrimidine, N- (2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methylamino} ethyl) -2,2,2 -Trifluoroacetamide (114 mg, 0.25 mmol) was dissolved in 2 mL methanol and potassium hydroxide (40 mg, 1 mmol) was added. This suspension was stirred at room temperature for 1 hour. Water was added and extracted with solution methylene chloride. The aqueous layer was extracted thoroughly with methylene chloride and the organic layers were washed with brine, dried and concentrated to yield the deprotected primary amine, (2-aminoethyl) [4- (2, 4-dichlorophenyl) -5 in quantitative yield. -Imidazol-2-ylpyrimidin-2-yl] methylamine.

HPLC [method AZ-S], 3.92 min (100%); MS (m + H / z), 363.

Using the procedure described above in Example 139, (2-aminoethyl) [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methylamine and 2-chloro -5-cyanopyridine was reacted to [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] -methyl {2- [(5-cyano (2- Pyridyl)) amino] ethyl} amine.

HPLC- [method AZ-S], 5.98 min (100%); MS (m + H / z), 465.

Using the procedure described above in Example 139, (2-aminoethyl) [4 (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methylamine and 2-chloro- Reacting 5-nitropyridine to [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methyl {2-[(5-nitro (2-pyridyl)) Amino] ethyl} amine.

HPLC [method AZ-S], 7.31 min (100%); MS (m + H / z), 485.

Using the procedure described above in Example 139, (2-aminoethyl) [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methylamine and 2-chloro Reacting the reaction of -5-nitro-6-aminopyridine to [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] methyl {2-[(5-nitro -6-amino (2-pyridyl)) amino] ethyl} amine.

HPLC [method AZ-S], 5.85 min (100%); MS (m + H / z), 500.

Example 143

Preparation of {2-4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2- yloxylethyl } (5-nitro (2 pyridyl)) amine (76062) and related compounds

1.50 g (4.84 mmol) 1- (2, 4-dichlorophenyl) -2- (1-imidazoyl) -3- dimethylaminoprop-2-ene in 30 mL of N-methylpyrrolidinone (NMP) 1-one (prepared as described in step 3.1 above), 0.673 g (2.42 mmol) of S-methylisothiourea nitrate and 2.05 g (6.29 mmol) of suspension were heated to 80 ° C. for 2 hours. . Water was added and the mixture was extracted with ethyl acetate. The aqueous layer was further extracted with additional ethyl acetate. The combined organic layers were washed thoroughly with water, brine and dried over sodium sulfate. The residue was concentrated and chromatographed (silica gel, 2% methanol / methylene chloride) 800 mg (50%) of the desired pyrimidine, 4- (2, 4-dichlorophenyl) -5-imidazolyl-2-methyl Thiopyrimidine was calculated.

HPLC [method AZ-S], 7.40 min (100%); MS (m + H / z), 337.

4- (2, 4-dichlorophenyl) -5-imidazolyl-2-methylthiopyrimidine (219 mg, 0.65 mmol) was dissolved in 2 mL anhydrous methylene chloride and 590 mg (57-86%, 1.95 mmol) M-chloroperoxybenzoic acid was added at room temperature and stirred for 2 hours. Saturated sodium carbonate was added and the organic layer was separated and washed with 10% aqueous sodium sulfite. Drying (sodium sulfate) and concentration afforded 240 mg (100%) of 4- (2,4-dichlorophenyl) -5-imidazolyl-2- (methylsulfonyl) pyrimidine as a yellow solid which was further purified. It was used without.

HPLC [method AZ-S], 5.47 min (100%); MS (m + H / z), 369.

A stirred suspension of 1.58 g 2-chloro-5-nitropyridine (10.0 mmol) in 10 mL acetonitrile was added dropwise to 1.81 mL (30 mmol) ethanolamine at room temperature. After heating at 80 ° C. for 0.5 h, the reaction was cooled, water was added, followed by ether. This dibasic mixture was cooled at 5 ° C., leading to the formation of a yellow solid, which was collected and identified as 2- [(5-nitro-2-pyridyl) amino] ethan-1-ol.

HPLC [method AZ-S], 1.74 min (100%); MS (m + H / z), 184.

1.74 g 2-chloro-5-nitro-6-aminopyridine (10.0 mmol) was reacted with 1.81 mL (30 mmol) of ethanolamine at 80 ° C. The reaction mixture was cooled to result in the formation of a yellow solid, which was collected and identified as 2-[(6-amino-5-nitro-2-pyridyl) amino] ethan-l-ol.

HPLC [method AZ-S], 1.32 min (100%); MS (m + H / z), 199.

1.38 g 2-chloro-5-cyanopyridine (10.0 mmol) was reacted with 1.81 mL (30 mmol) of ethanolamine at 80 ° C. for 0.5 hour. The reaction is cooled and water is added followed by ether. This dibasic mixture was cooled at 5 ° C. resulting in the formation of a yellow solid which was collected and identified as 6-[(2-hydroxyethyl) amino] pyridine-3 carbonitrile.

HPLC [method AZ-S], 1.13 min (100%); MS (m + H / z), 164.

To a stirred solution of 37.2 mg (0.203 mmol) of 2- (5-nitro-2-aminopyridyl) ethanolamine in 1 mL anhydrous THF, 244 μL of 1M solution of sodium hexamethyldisilazide (1M in toluene, 0.244 mmol) was added. The solution was stirred for 1 hour and a solution of 4- (2,4-dichlorophenyl) -5-imidazolyl-2- (methylsulfonyl) pyrimidine in 1 mL anhydrous THF was added dropwise. After stirring for 4 hours, water was added and the reaction mixture was extracted thoroughly with ethyl acetate.

The combined organic phases were washed with brine, dried (sodium sulfate), concentrated and chromatographed (silica gel, 5% methanol / methylene chloride) as a yellow solid, 15.7 mg of {2- [4- (2,4- Dichlorophenyl) -5-imidazolylpyrimidin-2-yloxy] ethyl} (5-nitro (2-pyridyl)) amine (76062) was obtained.

HPLC [method AZ-S], 7.44 min (85%); MS (m + H / z), 472.

As described above, {2- [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yloxy] ethyl} (5-nitro-6-amino (2-pyridyl)) The amines (76063) were 4- (2, 4-dichlorophenyl) -5-imidazolyl-2- (methylsulfonyl) pyrimidine and 2- (5-nitro-6-amino-2- pyridyl) ethanolamine Synthesized using 24.3 mg of {2- [4- (2, 4-dichlorophenyl) -5 imidazolylpyrimidin-2-yloxy] ethyl} (5-nitro-6-amino ( 2-pyridyl)) amine was obtained.

HPLC [method AZ-S], 6.47 min (90%); MS (m + H / z), 487.

As described above, 4- (2, 4-dichloro-phenyl) -5-imidazolyl-2- (methylsulfonyl) pyrimidine and 6-[(2-hydroxyethyl) amino] -pyridine-3- {2- [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2 yloxy] ethyl} (5-cyano (2-pyridyl)) amine using carbonitrile (76064) Was synthesized to yield 27.6 mg of {2- [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yloxy] ethyl} (5-cyano (2-pyridyl) )) An amine was obtained.

HPLC [method AZ-S], 6.37 min (95%); MS (m + H / z), 452.

Example 144

[2- (dimethylamino) ethoxy] -N-4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) aminolethyl} amino) pyrimidine- Preparation of 5-yllcarboxamide

50 mg (0.12 mmol) of 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 in 2 mL of THF A solution of carboxylic acid, 26.2 compound (0.12 mmol, DPPA), 17.2 μL triethylamine (0.12 mmol) was heated to 75 ° C. for 24 h. After cooling, the solution was concentrated and the residue was chromatographed (silica, 5% methanol / methylene chloride) to 40.2 mg (68%) of the desired carbamate, [2 (dimethylamino) ethoxy] -N- [4 (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carboxamide as a colorless solid.

HPLC [method AZ-S], 6.23 min (100%); MS (m + H / z), 492.

Example 145

Preparation of Additional Compounds

The compounds described in detail below were synthesized using the following general procedure:

Step A. Alkylation

1 mmol of aryl substituted phenacyl chloride in DMF was added dropwise to 2 mmol of amine and 2 mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature. The reaction mixture was concentrated and diluted with water and ethyl acetate in vacuo. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by chromatography or trituration.

Step B. Enaminone Formation

1 mmol of substrate was heated to 80 ° C. for 6 hours in straight DMF-DMA. The product was concentrated and purified by trituration with diethyl ether in vacuo.

Step C. Pyrimidine Formation

lmmol substrate was dissolved in lmmol guanadine, and 3 mmol of C s ₂ CO ₃ in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated and diluted with water and ethyl acetate in vacuo. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by chromatography with 5-10% methanol in methylenechloride.

Step D. Cyclization with Imide

One mmol of the substrate was heated to 120 ° C. in acetic acid for 4 hours and then concentrated in vacuo and purified by column chromatography with 5-10% methanol in methylenechloride.

Step E. Splitting Phthalimides

1 mmol of substrate and 20 mmol of hydrazine were stirred at 75 ° C. in ethanol. Ethanol was removed from the reaction mixture in vacuo then methylene chloride was added to the solution and filtered. The filtrate was collected and concentrated in vacuo.

Step F. Acid Coupling

1 mmol of substrate, 2 mmol of carboxylic acid, 2 mmol of HBTU, and 3 mmol of diisopropylethyl amine were stirred in THF. The reaction mixture was concentrated and diluted with water and ethyl acetate in vacuo. The solution was extracted three times and dried with ethyl acetate, sodium sulfate, and purified by column chromatography with 5-10% methanol in methylenechloride.

Step G. Boc Deprotection

1 mmol of substrate was stirred in a mixture of 1 ml methylene chloride and 1 ml trifluoroacetic acid. For 30 minutes at 40 ° C. And concentrated in vacuo.

Step H. SnAr Tailpiece

1 mmol of substrate, 1.5 mmol of substituted 2-chloropyridine, and 4 mmol of diisopropylethyl amine were stirred for 14 h at 80 ° C. in 2 ml of DMF. The reaction mixture was concentrated and diluted with water and ethyl acetate in vacuo. The solution was extracted three times and dried with ethyl acetate, dried over sodium sulfate and purified by column chromatography with 5-10% methanol in methylenechloride.

Step I. Bromination

20 mmol of aryl substituted acetiphenone, 1 ml concentrated HC1, was mixed in 20 ml diethyl ether under 0 ° C. nitrogen. To this solution was added dropwise a solution of 20 mmol Br ₂ in 20 ml chloroform, left for 4 hours and then concentrated in vacuo.

Step J. SnAr in Ketones

1 mmol of 1- (4-fluorophenyl) -2-imidazolylethan-1-one, 0.3 mmol of amine, and 1 mmol of K ₂ CO ₃ were heated at 100 ° C. for 14 hours. The reaction mixture was poured onto ice, then filtered and the solid collected.

Step K. Anhydride Coupling

1 mmol of substrate and 1 mmol of anhydride were stirred in THF for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate: The solution was extracted three times and purified by column chromatography eluting with ethyl acetate, drying over sodium sulfate and eluting with 5-10% methanol / methylene chloride.

Step L. Suzuki Reaction

1 mmol of 2,6-dichloro-pyridine, 1.05 mmol of boronic acid, and 3 mmol of Na ₂ CO ₃ were dissolved in 1.5 ml THF and 0.5 ml water and purged with nitrogen. 0.05 mmol of [1, 1'-bis (diphenylphosphino) -ferrocene] dichloropalladium (II) was added to the reaction and stirred at room temperature under nitrogen for 14 hours. The reaction mixture was diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography with 10% ethyl acetate 90% hexane.

Step M. SnAr Reaction

1 mmol of substrate is taken at 80 ° C. for 2 hours with 2 mmol of amine and 3 mmol of diisopropylethyl amine in 2 ml of DMF. The reaction mixture was concentrated and diluted with water and ethyl acetate in vacuo. The reaction was extracted three times and dried with ethyl acetate, dried over sodium sulfate, and purified by column chromatography with 30% ethyl acetate 70% hexane.

Step N. Nitro Reduction

1 mmol of substrate was taken up with equal weight of 5% Pd-C with 20 mmol NaH ₄ and dissolved in THF. The reaction was stirred at reflux for 24 h and then filtered through celite and purified by column chromatography.

Step O. Ethanol Nitro Reduction

1 mmol of substrate was taken in equal weight 5% Pd-C and dissolved in ethanol. The reaction was placed in a Parr shaker for 6 hours under 35 PSI of hydrogen, then filtered through celite and purified by column chromatography.

Example 145-1

Preparation of [4- (2, 4-difluorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2 pyridyl)) amino] ethyl} amine

[4- (2,4-difluorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine was added to Step A, 1- (2,4difluorophenyl) -2-chloroethan-1-one and imidazole in step B and amino in step C {2-[(5-nitro (2-pyridyl)) amino] Ethyl} carboxamidine was used following the procedure described above.

HPLC: 7.150 min.

MS: MH <+> 439.1

Example 145-2

Preparation of [5-imidazolyl-4- (4-methylphenyl) pyrimidin-2-yl [{2-[(5-nitro (2 pyridyl)) amino] ethyl} amine

[5-imidazolyl-4- (4-methylphenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine according to the procedure described above according to step A, 2-bromo-1- (4methylphenyl) ethane-l-one and imidazole in step B and amino {2- [(5-nitro (2-pyridyl)) amino] ethyl} carboxamide in step C Made using midines.

HPLC: 7.333 min.

MS: MH ⁺ = 417. 2

Example 145-3

Preparation of [4- (2-chlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

[4- (2-chlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine was previously described via Step I. 1- (2-chlorophenyl) ethan-1-one and imidazole in step A, step B and amino {2-[(5-nitro (2-pyridyl)) amino] ethyl in step C according to the procedure } Made using carboxamidine.

HPLC: 7.233 min.

MS: MH <+> 437.1

Example 145-4

tert-butyl4- {4- [5-imidazolyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino ) pyrimidin-4-yl] phenyl} pipe Preparation of Ragincarboxylate

tert-butyl 4- {4- [5-imidazolyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} piperazine Step J using 2-bromo-1- (4-fluorophenyl) ethan-1-one and imidazole, tert-butyl piperazinecarboxylate in step A according to the procedure described above , Amino {2- [(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine in steps B and C.

HPLC: 9.670 min.

MS: MH ⁺ = 587. 2

Example 145-5

Preparation of {5-imidazolyl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} {2-[(5-nitro (2 pyridyl)) amino] ethyl} amine

{5-imidazolyl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine 1- [4- I (trifluoromethyl) phenyl] ethan-1-one using step I, A, B using imidazole, and amino {2-[(5-nitro (2-pyridyl)) amino] Ethyl} was made according to the procedure described above via C using carboxamidine.

HPLC: 8.533 min.

MS: MH <+> 471.2

Example 145-6

Preparation of [4- (4-ethylphenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2 pyridyl)) amino] ethyl} amine

[4- (4-ethylphenyl) -5-imidazolylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine 1- (4-ethylphenyl ) Step I using ethan-1-one, A, B using imidazole, and C using amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine Over the process described above.

HPLC: 8.267 min.

MS: MH <+> = 431. 2

Example 145-7

Preparation of [4- (3, 5-dichloro (2-thienyl))-5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2 pyridyl)) amino] ethyl} amine

[4- (3, 5-Dichloro (2-thienyl))-5-imidazolylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl))-amino] ethyl} amine Step I using 1- (3,5-dichloro-2-thienyl) ethan-1-one, A, B using imidazole, and amino {2-[(5-nitro (2-pyridyl) )) Amino] ethyl} carboxamidine was made according to the preceding procedures over C.

HPLC: 8.167 min.

MS: MH ⁺ = 477. One

Example 145-8

Preparation of [5-imidazolyl-4- (4-piperazinylphenyl) pyrimidin-2-yl] {2-[(5-nitro (2 pyridyl)) amino] ethyl} amine

[5-imidazolyl-4- (4-piperazinylphenyl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine 2-bromo- Step A using 1- (4-fluorophenyl) ethan-1-one and imidazole, J using tert-butyl piperazinecarboxylate, amino {2- [(5-nitro (2-pyridyl)) ) Amino] ethyl} carboxamidine prepared according to the process described previously over B, C, and G.

HPLC:

MS: MH <+> 487.3

Example 145-9

2- {N- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino ) pyrimidin-5-yl] car Bamoyl} benzoic acid

2- {N- [4- (2, 4-dichlorophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carba Moyl} Step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide with benzoic acid, amino {2- [(5-nitro (2-pyridyl)) amino ] Ethyl} carboxamidine was prepared according to the procedure described above over B, and C.

HPLC: 11.433 min.

MS: MH <+> 568.1

Example 145-10

Preparation of 5- [5-imidazolyl-2- (2-{(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin- 4-yl] thiophene-2-carbonitrile

5- [5-imidazolyl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] -thiophene-2-carbonitrile 5 Step I using acetylthiophene-2-carbonitrile, A, B using imidazole, and amino {2- [(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine It was prepared according to the procedure described above over C.

HPLC7.517 min.

MS: MH <+> 434.1

Example 145-11

Preparation of {5-imidazolyl-4- [4- (4-methylpiperazinyl) phenyl] pyrimidin-2-yl} {2-[(5 nitro (2-pyridyl)) amino] ethyl} amine

{5-imidazolyl-4- [4- (4-methylpiperazinyl) phenyl] pyrimidin-2-yl} {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine Step A using 2-bromo-I- (4-fluorophenyl) ethane-I-one and imidazole, J using B, methylpiperazine, and amino {2- [(5-nitro (2 -Pyridyl)) amino] ethyl} carboxamidine prepared according to the procedure described previously over C.

HPLC: 5.417 min.

MS: MH ⁺ = 501.3

Example 145-12

Preparation of [5-imidazolyl-4- (4-piperidylphenyl) pyrimidin-2-yl] {2-[(5-nitro (2- pyridyl)) amino] ethyl} amine

[5-imidazolyl-4- (4-piperidylphenyl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine 2-bromo- Step A using 1- (4-fluorophenyl) ethan-1-one and imidazole, J, B, and amino {2-[(5-nitro (2-pyridyl)) using piperidine Amino] ethyl} carboxamidine was prepared according to the procedure described above over C.

HPLC: 6.300 min.

MS: MH <+> 486. 2

Example 145-13

N- {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} -N- [4- (2,4-dichlorophenyl) 5- (3,5-dioxomorpholine -4-yl) pyrimidin-2-yl] acetamide

N- {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} -N- [4- (2,4-dichlorophenyl) -5- (3,5 dioxomorpholine -4-yl) pyrimidin-2-yl] acetamide using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide A, B, amino {2- [(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} C, D, E, and 1, 4-dioxane-2,6-dione and then excess acetic acid using carboxamidine It was prepared according to the procedure described above over K using hydride.

HPLC: 13.117 min.

MS: MH ⁺ = 575.1

Example 145-14

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- ( 2,4 dichlorophenyl) pyrimidin-5-yl] acet Preparation of Amides

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) -pyrimidin-5-yl] Steps A, B, amino {2-[(6-amino-5-nitro (2-) using acetamide as 1- (2, 4-dichlorophenyl) -2-chloroethan-1-one and phthalimide Pyridyl)) amino] ethyl} carboxamidine prepared according to the procedure described above over C, D, E, and K using acet anhydride.

HPLC: 10.200 min.

MS: MH ⁺ = 477.0

Example 145-15

4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 dichlorophenyl) pyrimidin-5-yl] mor Preparation of Pauline-3, 5-Dion

4- [2-({2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl)-pyrimidin-5-yl] Steps A, B, amino {2-[(6-amino-) using morpholine-3,5-dione as 1- (2, 4-dichlorophenyl) -2-chloroethan-1-one and phthalimide The procedure described above via C, D, E, 1, 4-dioxane-2,6-dione, and F using 5-nitro (2-pyridyl)) amino] -ethyl} carboxamidine It was prepared according to.

HPLC: 9.317 min.

MS: MH + = 533. 1

Example 145-16

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) aminolethyl, amino) -4- ( 2,4 dichlorophenyl) pyrimidin-5-yl] -2 Preparation of-(dimethylamino) acetamide

N- [2-({2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl]- Steps A, B, amino {2-[(6-amino-) using 2- (dimethylamino) acetamide as 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide Prepared according to the procedure described previously via C, D, E, and F using 2- (dimethylamino) acetic acid using 5-nitro (2-pyridyl)) amino] ethyl} carboxamidine.

HPLC: 6.567 min.

MS: MH <+> 520.2

Example 145-17

1- [2-({2- (6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 -dichlorophenyl) pyrimidin-5-yl]- Preparation of 3-pyrroline-2, 5-dione

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl]- Steps A, B, amino {2- [(6- using 3-pyrroline-2,5-dione as 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide Prepared according to the procedure described previously via C, D, E using K, and F using malic anhydride, using amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine.

HPLC: 10.083 min.

MS: MH <+> 515. One

Example 145-18

4- [4- (2,4-dichlorophenyl) -2-({2- [(5-nitro (2 pyridyl)) amino] ethyl} amino ) pyrimidin-5-yl] morpholine-3, Preparation of 5-dione

4- [4- (2, 4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] amino) pyrimidin5-yl] morpholine-3,5-dione Steps A, B, amino {2-[(5-nitro (2-pyridyl)) amino] using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide Ethyl} prepared via C, D, E, 1, K, and F using 1,4-dioxane-2,6-dione using carboxamidine, according to the procedure described above.

HPLC:

MS: MH ⁺ = 518.1

Example 145-19

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4 dichlorophenyl) pyrimidin-5-yl] -4 Of morpholin-4-ylbutanamide

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl]- Steps A, B, amino {2-[(6- using 4-morpholin-4-ylbutanamide as 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide Prepared according to the procedure described above via F using C, D, E, 4-chlorobutanoic acid using amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine. lmmol N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] -4bromobutanamide, 2 mmol of morpholine, 3 mmol diisopropylethyl amine, and 0.1 mmol of tetrabutylammonium iodide were stirred at room temperature for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography with 5-10% methanol in methylenechloride.

HPLC: 4.837 min.

MS: MH ⁺ = 590.2

Example 145-20

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 dichlorophenyl) pyrimidin-5-yl] pipe Razin-2, 6-Dion

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] pipe Steps A, B, amino {2-[(6-amino-5) using lazine-2, 6-dione as 1- (2, 4-dichlorophenyl) -2-chloroethane-l-one and phthalimide C, D, E, 2-[(tert-butoxy) -N- (carboxymethyl) carbonylamino] acetic acid using nitro (2-pyridyl)) amino] ethyl} carboxamidine , And G were prepared according to the procedure described above.

HPLC: 5.825 min.

MS: MH ⁺ = 532.2

Example 145-21

tert-butyl 4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 dichlorophenyl) pyrimidin-5-yl ] -3,5-dioxopiperazincarboxylate

tert-butyl 4- [2- {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5- Steps A, B, amino {2- using 1] (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide as the Japanese] -3,5-dioxopiperazincarboxylate C, D, E, and 2-[(tert-butoxy) -N- (carboxy-methyl) using [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine Carbonylamino] was prepared according to the procedure described above via F using acetic acid.

HPLC: 9.137 min.

MS: MH ⁺ = 632. 2

Example 145-22

tert-butyl 4- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino) ethyl} amino) pyrimidin-5-yl] -3 , Preparation of 5-dioxopiperazincarboxylate

tert-butyl 4- [4- (2, 4-dichlorophenyl) -2-({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -3 Step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide with, 5-dioxopiperazincarboxylate, amino {2-[(5-nitro ( 2-pyridyl)) amino] ethyl} B, C using carboxmidine, D, E, and F using 2-[(tert-butoxy) -N- (carboxymethyl) carbonylamino] acetic acid It was prepared according to the procedure described above over.

HPLC: 9.861 min.

MS: MH <+> 617.2

Example 145-23

1- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] piperazin-2, Preparation of 6-dione

1- [4- (2, 4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] piperazin-2, Step A using 6-dione as 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide, amino {2-[(5-nitro (2-pyridyl)) amino B, C, 2-[(tert-butoxy) -N- (carboxymethyl) carbonylamino] acetic acid using ethyl} carboxamidine The procedure described above via D, E, F, and G using acetic acid It was prepared according to.

HPLC: 6.554 min.

MS: MH ⁺ = 517.2

Example 145-24

tert-butyl 4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4-(2, 4-dichlorophenyl) pyrimidine-5- Preparation of Japanese] -2,6-dimethylpiperazinecarboxylate

tert-butyl 4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine-5- Japanese] -2,6-dimethylpiperazinecarboxylate was prepared as described above via step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and 2,6-dimethylpiperazine. It was prepared according to. 1 mmol of this product, l mmol of tert-butyl (tert-butoxycarbonyloxy) formate, and 2 mmol of triethylamine were stirred in methylene chloride for 4 hours at room temperature. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol in methylenechloride. This product was adapted for steps B and C using amino {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine.

HPLC: 10.96 min

MS: MH <+> 632.3

Example 145-25

tert-butyl 4- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino ) pyrimidin-5-yl]- Preparation of 2, 6-dimethylpiperazinecarboxylate

tert-butyl 4- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -2 , 6-Dimethylpiperazinecarboxylate was prepared according to the method described above via Step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and 2,6-dimethylpiperazine. . 1 mmol of this product, 1 mmol tert-butyl (tert-butoxycarbonyloxy) formate, and 2 mmol triethylamine were stirred in methylene chloride at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol in methylenechloride. This product was adapted for steps B and C using amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine.

HPLC: 11.713 min

MS: MH <+> = 617. 2

Example 145-26

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (3,5- dimethylpiperazinyl) pyrimidine- Preparation of 2-yl] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5- (3, 5-dimethylpiperazinyl) pyrimidine- 2-yl] Amine was prepared according to the method described above via Step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and 2,6-dimethylpiperazine. 1 mmol of this product, lmmol tert-butyl (tert-butoxycarbonyloxy) formate, and 2 mmol of triethylamine were stirred in methylene chloride at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol in methylenechloride. This product was adapted to steps B and C, and G using amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine.

HPLC: 5. 653 min

MS: MH <+> 532. 6

Example 145-27

[4- (2,4-dichlorophenyl) -5- (3, 5-dimethylpiperazinyl) pyrimidin-2-yl] {2-[(5 nitro (2-pyridyl)) amino] ethyl} amine Manufacture

[4- (2,4-dichlorophenyl) -5- (3,5-dimethylpiperazinyl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} The amine was prepared according to the method described above through step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and 2,6-dimethylpiperazine. Stir in 1 mmol of this product, lmmol tert-butyl (tertbutoxycarbonyloxy) formate, and 2 mmol of triethylaminemethylenechloride at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol in methylenechloride. This product was adapted to steps B and C, and G using amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine.

HPLC: 6.193 min

MS: MH <+> 157.6

Example 145-28

N- {4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) ami] ethyl} amino)

Preparation of Pyrimidin-5-yll-4-hydroxybutanamide

N- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -4-hydroxy Butanamide (74814) is prepared in step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide, amino {2-[(5-nitro (2-pyridyl)) Prepared according to the process described above via steps B, C, D, E, F using amino] ethyl} carboxamidine, and 4-bromobutanoic acid.

HPLC: 5.688 min

MS: MH <+> -506. 2

Example 145-29

[5-((lE) -1-Aza-2-pyrrolidinylprop-1-enyl) -4- (2,4-dichlorophenyl) pyrimidin-2-yl ] {2-[(6-amino Preparation of -5-nitro (2-pyridyl)) amino] ethyl} amine

[5- ((lE) -1-Aza-2-pyrrolidinylprop-1-enyl) -4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino -5-nitro (2-pyridyl)) amino] ethyl} amine is prepared by step A, amino {2- [using 1- (2,4-dichloro phenyl) -2-chloroethan-1-one and phthalimide. (6-Amino-5-nitro (2-pyridyl)) amino] ethyl} prepared via B, C, D, E, and K using acet anhydride according to the method described above. 1 mmol of N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ehtyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5 Sun] Acetamide and 2 mmol of Lawesson's reagent were stirred at 80 ° C. in 2 ml of DME. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride. 1 mmol of 1-{[2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine-5 -Yl] amino} ethane-1-thione was purified by column chromatography heated to 85 ° C. in pyrrolidine and eluted with 5-10% methanol / methylene chloride.

HPLC: 6.032 min

MS: MH <+> 530. 3

Example 145-30

{5-[(1E) -1-Aza-2- (cyclopropylamino) prop-1-enyl] -4- (2,4-dichlorophenyl) pyrimidin -2-yl} {2-[(6 Preparation of -amino-5-nitro (2-pyridyl)) amino] ethyl} amine

{5-[(lE) -l-Aza-2- (cyclopropylamino) prop-1-enyl] -4- (2,4-dichlorophenyl) pyrimidin-2-yl} {2-[(6 -Amino-5-nitro (2-pyridyl)) amino] ethyl} amine is prepared by step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide, amino {2 -[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} prepared according to the above-mentioned method via B, C, C, D, E, and K using acetic anhydride It was. 1 mmol of N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine-5- Sun] Acetamide and 2 mmol of Lawesson reagent were stirred at 80 ° C. in 2 ml of DME. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride. 1 mmol of 1-{[2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5 -Yl] amino} ethane-1-thione was purified by column chromatography heated to 40 ° C. in cyclopropylamine and eluted with 5-10% methanol / methylene chloride.

HPLC: 5.781 min

MS: MH <+> 516. 2

Example 145-31

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl ) pyrimidin-5-yl] Preparation of -3- (4-methylpiperazinyl) pyrrolidine-2,5-dione

1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl]- 3- (4-methylpiperazinyl) pyrrolidine-2,5-dione is A, amino {2 using 1- (2, 4-dichlorophenyl) -2-chloroethan-1-one and phthalimide Prepared according to the aforementioned method via B, C, D, E, K and F using-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine . Concentrated in vacuo 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 (2,4-dichlorophenyl) pyrimidine-5- An excess of morpholine was added to the clear portion of Il] -3-pyrroline-2,5-dione and purified by column chromatography eluting with 5-10% methanol / methylene chloride.

HPLC: 4.897 min

MS: MH <+> 546. 3

Example 145-32

Preparation of [6- (2,4-dichlorophenyl) -5-nitro (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

[6- (2,4-Dichlorophenyl) -5-nitro (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine is 2,6-dichloro-3 Prepared according to the process described above via step L using nitropyridine and 2,4-dichlorobenzeneboronic acid, and step M using (2-aminoethyl) (5-nitro (2-pyridyl)) amine.

HPLC: 9.598 min

MS: MH <+> 448.8

Example 145-33

N- [6-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -2- (2,4-dichloro phenyl) (3-pyridyl)]- Preparation of N-ethylacetamide

N- [6-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -2- (2, 4-dichlorophenyl) (3-pyridyl)]- N-ethylacetamide is obtained using step L using 2,6-dichloro-3-nitropyridine and 2,4-dichlorobenzeneboronic acid, M using N- (2-aminoethyl) (tert-butoxy) carboxamide , O, K using acetic anhydride, G using 6-chloro-3-nitro-2-pyridylamine, and H were prepared according to the aforementioned method.

HPLC: 6.223 min

MS: MH <+> 504. 2

Example 145-34

{5-[(6-Amino-5-nitro (2-pyridyl)) amino] -6- (2, 4-dichlorophenyl) (2 -pyridyl)} {2-[(6-amino-5- Preparation of Nitro (2-pyridyl)) amino] ethyl} amine

{5-[(6-Amino-5-nitro (2-pyridyl)) amino] -6- (2, 4-dichlorophenyl) (2-pyridyl)} {2- [(6- amino-5- Nitro (2-pyridyl)) amino] ethyl} amine was prepared using step L, N- (2-aminoethyl) (tert-butoxy) using 2,6-dichloro-3-nitropyridine and 2,4dichlorobenzeneboronic acid. ) Was prepared according to the method described above via M, N with carboxamide, H with 6chloro-3-nitro-2-pyridylamine, and G.

HPLC: 7.467 min

MS: MH &lt; + &gt; = 571. 0

Example 145-35

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5 (ethyl amino) (2-pyridyl)] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5- (ethylamino) (2-pyridyl)] amine L using 2,6-dichloro-3-nitropyridine and 2,4-dichlorobenzeneboronic acid, M using N- (2-aminoethyl) (tert-butoxy) carboxamide, 6-chloro-3- Prepared according to the method described above via O, G, and H using nitro-2-pyridylamine.

HPLC: 5.263 min

MS: MH &lt; + &gt;

Example 145-36

Preparation of [6- (2,4-dichlorophenyl) -3-nitro (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

[6- (2,4-Dichlorophenyl) -3-nitro (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine is 2,6-dichloro-3 According to the method described above via step L using nitropyridine and 2,4-dichlorobenzeneboronic acid collection hydrophobic product, and step M using (2-aminoethyl) (5-nitro (2-pyridyl)) amine Prepared.

HPLC: 12.003 min

MS: MH &lt; + &gt;

Example 145-37

Preparation of 2- (2,4-dichlorophenyl) -4-methyl-6-({2-[(5-nitro (2 pyridyl)) amino] ethyl} amino) pyridine -3-carbonitrile

2- (2,4-dichlorophenyl) -4-methyl-6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyridine-3-carbonitrile is 2,6- Through step L with dichloro-4-methylpyridine-3-carbonitrile and 2,4-dichlorobenzeneboronic acid, and step M with (2-aminoethyl) (5-nitro (2-pyridyl)) amine It was prepared according to the method described above.

HPLC: 12.183 min

MS: MH <+> 443.0

Example 145-38

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -3- nitro (2-pyridyl)] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -3-nitro (2-pyridyl)] amine is 2,6 Step L using dichloro-3-nitropyridine and 2,4-dichlorobenzeneboronic acid collection hydrophobic product, M, using N- (2-aminoethyl) (tert-butoxy) carboxamide, 6-chloro-3 Prepared according to the aforementioned method via G, and H with nitro-2-pyridylamine.

HPLC: 10.682 min

MS: MH <+> 464.0

Example 145-39

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (4-ethylphenyl) -5-nitro (2- pyridyl)] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (4-ethylphenyl) -5-nitro (2-pyridyl)] amine is 2,6-dichloro Step L with 3-nitropyridine and 4-ethylbenzeneboronic acid, M with N- (2aminoethyl) (tert-butoxy) carboxamide, 6-chloro-3-nitro-2-pyridylamine It was prepared according to the aforementioned method through G, and H using.

HPLC: 9.354 min

MS: MH <+> 424. 1

Example 145-40

N- {1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichloro phenyl) pyrimidine-5- Preparation of Japanese] -2,6-dioxo (3-piperidyl)} (tert-butoxy) carboxamide

N- {1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5- Ill] -2, 6-dioxo (3-piperidyl)} (tert-butoxy) carboxamides are 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide Step A using B, C, l-[(tert-butoxy) carbonylamino] propane-1, using amino {2- [(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine Prepared according to the aforementioned method via D, E, and F using 3-dicarboxylic acid.

HPLC: 9.152 min

MS: MH + = 646.4

Example 145-41

3-amino-1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4 dichlorophenyl) pyrimidine-5 Preparation of -yl] piperidine-2,6-dione

3-amino-1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino)-4- (2,4-dichlorophenyl) pyrimidine-5 -Yl] piperidine-2,6-dione was prepared using step A, amino {2-[(5-nitro) with 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide. B, C, l-[(tert-butoxy) carbonylamino] propane-1,3-dicarboxylic acid using (2-pyridyl)) amino] ethyl} carboxamidine, and It was prepared according to the aforementioned method through G.

HPLC: 5.247 min

MS: MH <+> -546. 3

Example 145-42

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl ) pyrimidin-5-yl] Preparation of 2-[(tert-butoxy) -N-methylcarbonylamino]

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl]- 2-[(tert-butoxy) -N-methylcarbonylamino] acetamide was prepared in step A using 1- (2,4-dichlorophenyl) -2chloroethane-l-one and phthalimide, amino {2 B, C, 2- [(tert-butoxy) -N-methylcarbonylamino] -acetic acid using-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine It was prepared according to the aforementioned method through D, E, and F used.

HPLC: 8.346 min

MS: MH + = 606.2

Example 145-43

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl ) pyrimidin-5-yl] Preparation of 2- (methylamino) acetamide

N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl]- 2- (methylamino) acetamide is prepared in step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide, amino {2-[(6-amino-5-nitro B, C, D, E and F, and G using 2-((tert-butoxy) -N-methylcarbonylamino] acetic acid using (2-pyridyl))-amino] ethyl} carboxamidine It was prepared according to the method described above.

HPLC: 4.716 min

MS: MH + = 506.1

Example 145-44

1- [6-({2-[(6-amino-5-nitro (2-pyridyl)) aminolethylTamino) -2- (4-ethylphenyl) -3 -pyridyllpyrrolidine- Preparation of 2, 5-dione

1- [6-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -2- (4-ethylphenyl) -3pyridyl] pyrrolidine-2 , 5-dione was obtained by step L using 2,6-dichloro-3-nitropyridine and 4-ethylbenzeneboronic acid, M using N- (2-aminoethyl) (tert-butoxy) carboxamide, ethane- Prepared according to the method described above via F using 1,2-dicarboxylic acid, G using 6-chloro-3-nitro-2-pyridylamine, and H.

HPLC: 6.072 min

MS: MH <+> 476.2

Example 145-45

2- {4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2 pyridyl)) amino] ethyl} amino) pyrimidin -5-yl] isoindolin-1 Of 3-, dione

2- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] isoindolin-1 , 3-dione is prepared by step A using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide, amino {2-[(5-nitro (2-pyridyl)) amino ] Ethyl} was prepared according to the method described above via B and C, and D using carboxamidine.

HPLC: 12.12 min

MS: MH <+> -549. 8

Example 145-46

2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) aminolethyl} amino) -4- (2,4-dichlorophenyl ) pyrimidin-5-yl] Preparation of 3-pyrrolino [3,4-c] pyridine-1,3-dione

2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl]- 3-pyrrolino [3,4-c] pyridine-1,3-dione is 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and 3-pyrrolino [3,4- c] Step A using pyridine-1, 3-dione, B and C using amino {2-[(6-amino-5-nitro (2 pyridyl)) amino] ethyl I carboxamidine, and D It was prepared according to the method described above.

HPLC: 9.85 min

MS: MH <+> 566. 1

Example 145-47

1-{[2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl ) pyrimidin-5-yl ] Amino} ethane-1-thione

1-{[2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] Amino} ethane-1-thione is A, amino {2-[(6-amino-5-nitro (2) using 1- (2,4-dichlorophenyl) -2-chloroethan-1-one and phthalimide -Pyridyl)) amino] ethyl} carboxamidine B, C, D, E, and K using acetic anhydride according to the method described above. 1 mmol of N- [2- ({2- [(6-amino-5 nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidin-5-yl Acetamide and 2 mmol of Lawesson's reagent were stirred at 80 ° C. in 2 ml of DME. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride.

HPLC: 11.63 min

MS: MH + = 493.1

Example 146

Preparation of 4- [5-imidazol-2-yl-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl ] benzenecarbonitrile

4- [5-imidazol-2-yl-2- (2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile is [4- ( 2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine using the general method Prepared from 4-cyanobenzoyl chloride.

HPLC: 21.9 min (> 95% purity)

MS: M + H = 428.1 (C ₂₁ H ₁₇ N ₉ O ₂ + H = 428)

Example 147

Preparation of 6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl} amino} pyridine-3-carbonitrile

6-[(2-{[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2pyridyl)) amino] ethyl} using the general method for amines Prepared from 2-chloro-5- (cyano) pyridine.

HPLC: 18.2 min (> 95% purity)

MS: M + H = 451. 1 (C _{2 l} H _l6 C _l2 N ₈ + H = 451)

Example 148

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- ( trifluoromethyl) (2-pyridyl)] amino} ethyl Preparation of Amine

[4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl ) Amine (71480) is [4- (2,4-dichlorophenyl) -5-imidazol-2ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl } Prepared from 2-chloro-5- (trifluoromethyl) pyridine using the general method for amines.

HPLC: 18.9 min (> 95% purity)

MS: M + H = 494.1 (C _2l H _l6 Cl ₂ F ₃ N ₇ + H = 494)

Example 149

[4- (2,4-dichlorophenyl) -5- (l-methylimidazol-2-yl) pyrimidin-2-yl] {2-[(5-nitro (2 -pyridyl)) amino] Preparation of Ethyl} amine

[4- (2,4-dichlorophenyl) -5- (l-methylimidazol-2-yl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] Ethyl} amine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} Prepared from 1,2-dimethylimidazole using the general method for amines.

HPLC: 21.9 min (> 95% purity)

MS: M + H = 485.1 ( C 2l H l8 Cl 2 N 8 0 2 + H = 485)

Example 150

{5-imidazol-2-yl-4-4- (trifluoromethyl) phenyl] pyrimidin-2-yl} {2-[(5-nitro (2- pyridyl)) amino] ethyl} amine Produce

{5-imidazol-2-yl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine Silver for [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from 4- (trifluoromethyl) benzoyl chloride using the general method.

HPLC: 22.0 min (> 95% purity)

MS: M + H = 471.2 ( C 2l H l7 F 3 N 8 0 2 + H = 471)

Example 151

6-{[2-({5-imidazol-2-yl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl } amino) ethyl] amino} pyridine-3-carbonitrile Produce

6- {[2-({5-imidazol-2-yl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} amino) ethyl] amino} pyridine-3-carbonitrile General for [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from 4- (trifluoromethyl) benzoyl chloride and 2-chloro-5- (cyano) pyridine using the method.

HPLC: 19.3 min (> 95% purity)

MS: M + H = 451.2 (C ₂₂ H ₁₇ F ₃ N ₈ + H = 451)

Example 152

{5-imidazol-2-yl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} (2-{[5- (trifluoromethyl ) (2-pyridyl) amino Preparation of Ethyl) amine

{5-imidazol-2-yl-4- [4- (trifluoromethyl) phenyl] pyrimidin-2-yl} (2- {[5- (trifluoro-methyl) (2-pyridyl) ] Amino} ethyl) amine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino ] Ethyl} prepared from 4- (trifluoromethyl) benzoyl chloride and 2-chloro-5- (trifluoromethyl) pyridine using the general method for amines.

HPLC: 20.0 min (> 95% purity)

MS: M + H = 494.2 (C ₂₂ H _l7 F ₆ N ₇ + H = 494)

Example 153

6-[(2-{[4- (2,4-dichlorophenyl) -5- (1-methylimidazol-2-yl) pyrimidin-2-yl ] amino} ethyl) amino] pyridine-3- Preparation of Carbon Nitrile

6-[(2-{[4- (2,4-dichlorophenyl) -5- (1-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3- Carbonitrile is [4- (2,4-dichlorophenyl) -5-imidazol-2-y] pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} Prepared from 1,2-dimethylimidazole and 2-chloro-5- (cyano) pyridine using the general method for amines.

HPLC: 19.0 min (> 95% purity)

MS: M + H = 465.1 ( C 22 H l8 Cl 2 N 8 + H = 465)

Example 154

[4- (2,4-dichlorophenyl) -5- (1-methylimidazol-2-yl) pyrimidin-2-yl] (2-{[5- ( trifluoromethyl) (2-pyri Dill)] amino} ethyl) amine

[4- (2,4-dichlorophenyl) -5- (1-methylimidazol-2-yl) pyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2-pyri Dill)] amino} ethyl) amine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl) Prepared from 1,2-dimethylimidazole and 2-chloro-5- (trifluoromethyl) pyridine using the general method for) amino] ethyl} amine.

HPLC: 20.0 min (> 95% purity)

MS: M + H = 508.1 (C ₂₂ H _l8 Cl ₂ F ₃ N ₇ + H = 508)

Example 155

Preparation of [4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2pyridyl)) amino] ethyl} amine

[4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine is [4 (2 , 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2pyridyl)) amino] ethyl} amine using the general method for Prepared from chlorobenzoyl chloride.

HPLC: 18.5 min (> 95% purity)

MS: M + H = 437.1 ( C 20 H l7 ClN 8 0 2 + H = 437)

Example 156

Preparation of 6-[(2-{[4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino ] pyridine-3-carbonitrile

6-[(2- {[4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] -pyridine-3-carbonitrile is [4- ( Using the general method for 2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from 2-chlorobenzoyl chloride and 2-chloro-5 (cyano) pyridine.

HPLC: 15.3 min (> 95% purity)

MS: M + H = 417.2 (C _2l H _l7 ClN ₈ + H = 417)

Example 157

[4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2- pyridyl)] amino} ethyl) amine Manufacture

[4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2pyridyl)] amino} ethyl) amine General method for [4- (2,4-dichlorophenyl) -5-imidazol2-yl pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Was prepared from 2-chlorobenzoyl chloride and 2-chloro-5 (trifluoromethyl) pyridine.

HPLC: 16.8 min (> 95% purity)

MS: M + H = 460.2 (C ₂₁ H ₁₇ ClF ₃ N ₇ + H = 460)

Example 158

[4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2 -pyridyl)) amino] ethyl} amine Manufacture

[4- (2-Chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2pyridyl)) amino] ethyl} amine General for [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from 2-chloro-4-fluorobenzoyl chloride using the method.

HPLC: 19.4 min (> 95% purity)

MS: M + H = 455. 1 (C ₂₀ H ₁₆ ClFN ₈ 0 ₂ + H = 455)

Example 159

{4- [4-fluoro-2- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} {2 [(5- nitro (2-pyridyl) amino] Preparation of Ethyl} amine

{4- [4-fluoro-2- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} {2-[(5-nitro (2-pyridyl)) Amino] ethyl} amine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] Prepared from 4-fluoro-2- (trifluoromethyl) benzoyl chloride using the general method for ethyl} amine.

HPLC: 21.0 min (> 95% purity)

MS: M + H = 489. 2 (C ₂₁ H ₁₆ F ₄ N ₈ 0 ₂ + H = 489)

Example 160

{4- [4-fluoro-2- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} {2 [(5- nitro (2-pyridyl)) amino ] Production of Ethyl} amine

{4- [4-fluoro-2- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} {2-[(5-nitro (2-pyridyl)) Amino] ethyl} amine is [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] Prepared from 4-fluoro-2- (trifluoromethyl) benzoyl chloride using the general method for ethyl} amine.

HPLC: 21.2 min (> 95% purity)

MS: M + H = 431.3 (C _{2 l} H _l6 F ₄ N ₈ 0 ₂ + H = 431)

Example 161

[4- (4-ethylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2- pyridyl) amino} ethyl) amine Produce

[4- (4-ethylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2- {[5- (trifluoromethyl) (2pyridyl)] amino} ethyl) General method for [4- (2,4-dichlorophenyl) -5-imidazol2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Was prepared from 4-ethylbenzoyl chloride and 2-chloro-5- (trifluoromethyl) pyridine.

HPLC: 19.4 min (> 95% purity)

MS: M + H = 454.3 (C ₂₃ H ₂₂ F ₃ N ₇ + H = 454)

Example 162

4- [2-fluoro-4- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} {2-((5- nitro (2-pyridyl)) amino ] Production of Ethyl} amine

{4- [2-fluoro-4- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} {2- [(5nitro (2-pyridyl)) amino ] Ethyl} amine is [4- (2, 4-dichlorophenyl) -5imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} Prepared from 2-fluoro-4- (trifluoromethyl) benzoyl chloride using the general method for amines.

HPLC: 22.2 min (> 95% purity)

MS: M + H = 489.2 (C _{2 l} H _l6 F ₄ N ₈ 0 ₂ + H = 489)

Example 163

6-[(2-{[4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) aminolpyridine-3-carbonitrile Produce

6- [(2- {[4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile General method for [4- (2,4-dichlorophenyl) -5-imidazol2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Was prepared from 2-chloro-4-fluorobenzoyl chloride and 2chloro-5- (cyano) pyridine.

HPLC: 16.3 min (> 95% purity)

MS: M + H = 435.2 (C _{2 l} H _l6 ClFN ₈ + H = 435)

Example 164

[4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl ) (2-pyridyl) amino Preparation of Ethyl) amine

[4- (2-Chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2- {[5- (trifluoromethyl) (2-pyridyl)] Amino} ethyl) amine is [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] Ethyl} was prepared from 2-chloro-4fluorobenzoyl chloride and 2-chloro-5- (trifluoromethyl) pyridine using the general method for amines.

HPLC: 17.7 min (> 95% purity)

MS: M + H = 478. 2 (C _{2 l} H _l6 ClF ₄ N ₇ + H = 478)

Example 165

6-{[2-({4- [4-fluoro-2- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2 yl} amino) ethyl] amino} pyridine-3 Preparation of Carbonnitrile

6-1 [2- (14- [4-fluoro-2- (trifluoromethyl) phenyl] -S-imidazol-2-ylpyrimidin-2-yl} amino) ethyl] amino} pyridine-3 -Carbonitrile is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2pyridyl)) amino] ethyl} amine Prepared from 4-fluoro-2 (trifluoromethyl) benzoyl chloride and 2-chloro-5- (cyano) pyridine using the general method for.

HPLC: 18.1 min (> 95% purity)

MS: M + H = 469.2 (C ₂₂ H _l6 F ₄ N ₈ + H = 469)

Example 165

{4- [4-fluoro-2- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} (2 {[5- (trifluoromethyl) (2- Preparation of Pyridyl)] amino} ethyl) amine

{4- [4-fluoro-2- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyridinin-2-yl} (2-{[5- (trifluoromethyl) (2 -Pyridyl)] amino} ethyl) amine is [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2pyridyl )) Amino] was prepared from 4-fluoro-2- (trifluoromethyl) benzoyl chloride and 2-chloro-5- (trifluoromethyl) pyridine using the general method for ethyl} amine.

HPLC: 18.8 min (> 95% purity)

MS: M + H = 512.2 (C ₂₂ H _l6 F ₇ N ₇ + H = 512)

Example 166

6-[(2- {4- (4-ethylphenyl) -5-imidazol-2-ylpyrimidin-2-yl ] amino} ethyl) amino] pyridine-3-carbonitrile

6-[(2-{[4- (4-ethylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile is [4- (2 , 4-dichlorophenyl) -5-imidazol-2ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} 4- Prepared from ethylbenzoyl chloride and 2-chloro-5- (cyano) pyridine.

HPLC: 17.9 min (> 95% purity)

MS: M + H = 411.2 (C ₂₃ H ₂₂ N ₈ + H = 411)

Example 167

Preparation of [4- (4-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2 pyridyl)) amino ] ethyl} amine

[4- (4-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine is [4 (2 , 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} using general method for amine 4 Prepared from -chlorobenzoyl chloride.

HPLC: 20.0 min (> 95% purity)

MS: M + H = 437.1 ( C 20 H l7 CIN 8 0 2 + H = 437)

Example 168

6-[(2-4- (4-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino]

Pyridine-3-carbonitrile

6-[(2-{[4- (4-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile is [4- (2 , 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} using the general method for amine 4 Prepared from -chlorobenzoyl chloride and 2-chloro-5- (cyano) pyridine.

HPLC: 17. 1 min (> 95% purity)

MS: M + H = 417.2 (C _2l H _l7 ClN ₈ + H = 417)

Example 169

Preparation of [4- (4-chloro-2-methylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2 -pyridyl)) amino] ethyl} amine

[4- (4-Chloro-2-methylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine is [4 General procedure for (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine From 4-chloro-2-methylbenzoyl chloride.

HPLC: 20.8 min (> 95% purity)

MS: M + H = 451.2 (C ₂₁ H ₁₉ ClN ₈ 0 ₂ + H = 451)

Example 170

[4- (4-chloro-2-methylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl ) (2-pyridyl)] amino} Preparation of Ethyl) amine

[4- (4-Chloro-2-methylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2- {[5- (trifluoromethyl) (2-pyridyl)] amino} Ethyl) amine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} Prepared from 4-chloro-2-methylbenzoyl chloride and 2-chloro-5- (trifluoromethyl) pyridine using the general method for amines.

HPLC: 19.2 min (> 95% purity)

MS: M + H = 474.2 (C ₂₂ H ₁₉ ClF ₃ N ₇ + H = 474)

Example 171

6-{[2-({4- [2-fluoro-4- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2 yl} amino) ethyl] amino} pyridine-3 Preparation of Carbonnitrile

6- [2-({4- [2-fluoro-4- (trifluoromethyl) phenyl] -5-imidazol-2-ylpyrimidin-2-yl} amino) ethyl] amino} pyridine-3 -Carbonitrile is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2pyridyl)) amino] ethyl} Prepared from 2-fluoro-4 (trifluoromethyl) benzoyl chloride and 2-chloro-5- (cyano) pyridine using the general method for amines.

HPLC: 19.7 min (> 95% purity)

MS: M + H = 469.3 (C ₂₂ H ₁₆ F ₄ N ₈ + H = 469)

Example 172

Preparation of [4- (2-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

[4- (2-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine is [4 ( 2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} using the general method for amines Prepared from 2-fluorobenzoyl chloride.

HPLC: 17.9 min (> 95% purity)

MS: M + H = 421.2 ( C 20 H l7 FN 8 0 2 + H = 421)

Example 173

Preparation of 6-[(2-{[4- (2-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine -3-carbonitrile

6- [(2-{[4- (2-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile is [4- ( 2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} using the general method for amines Prepared from 2-fluorobenzoyl chloride and 2-chloro-5 (cyano) pyridine.

HPLC: 14.7 min (> 95% purity)

MS: M + H = 401.2 (C ₂₁ H ₁₇ FN ₈ + H = 401)

Example 174

[4- (4-chloro-2-methoxyphenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2- pyridyl)) amino] ethyl} amine Manufacture

[4- (4-chloro-2-methoxyphenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- {(5-nitro (2-pyridyl)) amino] ethyl} amine Silver for [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from 4-chloro-2-methoxybenzoyl chloride using the general method.

HPLC: 19.9 min (> 95% purity)

MS: M + H = 467.3 ( C 21 H l9 ClN 8 0 3 + H = 467)

Example 175

Preparation of 6-[(2-{[4- (4-chloro-2-methoxyphenyl) -5-imidazol-2-ylpyrimidin-2 yl] amino} ethyl) amino] pyridine-3-carbonitrile

6-[(2- {[4- (4-chloro-2-methoxyphenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile General for [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from 4-chloro-2-methoxybenzoyl chloride and 2-chloro-5- (cyano) pyridine using the method.

HPLC: 16.9 min (> 95% purity)

MS: M + H = 447.3 (C ₂₂ H ₁₉ ClN ₈ O + H = 447)

Example 176

Preparation of 6-[(2-{[4- (4-chloro-2-methylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino ] pyridine-3-carbonitrile

6-[(2- {[4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) -amino] pyridine-3-carbonitrile Silver for [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from 4-chloro-2-methylbenzoyl chloride and 2-chloro-5- (cyano) pyridine using the general method.

HPLC: 17.9 min (> 95% purity)

MS: M + H = 430.8 (C ₂₂ H ₁₉ ClN ₈ + H = 430)

Example 177

[4- (4-Bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro

Preparation of (2-pyridyl)) amine

[4- (4-Bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine General for [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5nitro (2-pyridyl)) amino] ethyl} amine Prepared from 4-bromo-2-chlorolbenzoyl chloride using the method.

HPLC: 21.5 min (> 95% purity)

MS: M + H = 515.2 (C ₂₀ H _l6 BrClN ₈ 0 ₂ + H = 515)

Example 178

6-[(2-{[4- (4-bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino ] pyridine-3-carbonitrile Manufacture

6-[(2-{[4- (4-bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile General method for [4- (2,4-dichlorophenyl) -5-imidazol2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine Was prepared from 4-bromo-2-chlorobenzoyl chloride and 2-chloro-5- (cyano) pyridine.

HPLC: 17.7 min (> 95% purity)

MS: M + H = 495 (C ₂₁ H ₁₆ BrClN ₈ + H = 495)

Example 179

[4- (4-Bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2-{[5- (trifluoro methyl) (2-pyridyl)] Preparation of Amino} ethyl) amine

[4- (4-Bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] (2- {[5- (trifluoro-methyl) (2-pyridyl) ] Amino} ethyl) amine is [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) Amino] ethyl} prepared from 4-bromo-2-chlorobenzoyl chloride and 2-chloro-5- (trifluoromethyl) pyridine using the general method for amines.

HPLC: 19.7 min (> 95% purity)

MS: M + H = 538.2 (C ₂₁ H ₁₆ BrClF ₃ N ₇ + H = 538)

Example 180

4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -5-imidazol-2-ylpyrimidin -4-yl] benzenecarbonitrile Manufacture

4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -5-imidazol-2-ylpyrimidin-4-yl] benzenecarbonitrile Silver {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl Prepared from 4-cyanobenzoyl chloride using the general method for amines.

HPLC: 20.0 min (> 95% purity)

MS: M + H = 443.1 ( C 2l H l8 N l0 0 2 + H = 443)

Example 181

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} {5-imidazol-2-yl-4- [4- ( trifluoromethyl) phenyl] pyrimidine-2 Preparation of A-yl} amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} {5-imidazol-2-yl-4- [4- (trifluoromethyl) phenyl] pyrimidine-2 -Yl} amine is {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4 (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine- 2-yl] was prepared from 4- (trifluoromethyl) benzoyl chloride using the general method for amines.

HPLC: 20.2 min (> 95% purity)

MS: M + H = 486.2 (C ₂₁ H ₁₈ F ₃ N ₉ O ₂ + H = 486)

Example 182

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (1-methyl imidazol-2-yl) pyrimidine -2-yl] amine preparation

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (1-methylimidazol-2-yl) pyrid Midin-2-yl] amine is {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) 5-imidazol-2-yl Pyrimidin-2-yl] was prepared from 1,2-dimethylimidazole using the general method for amines.

HPLC: 19.6 min (> 95% purity)

MS: M + H = 500.2 (C ₂₁ H ₁₉ Cl ₂ N ₉ O ₂ + H = 500)

Example 183

Preparation of {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chlorophenyl) -5 imidazol-2 -ylpyrimidin-2-yl] amine

{2-[(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chlorophenyl) -5-imidazol-2-yl- pyrimidin-2-yl] amine Silver {2- [(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5imidazol-2-ylpyrimidin-2-yl] Prepared from 2-chlorobenzoyl chloride using the general method for amines.

HPLC: 16.4 min (> 95% purity)

MS: M + H = 452.7 (C ₂₀ H ₁₈ ClN ₉ O ₂ + H = 452)

Example 184

2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chloro-4-fluorophenyl) -5- imidazol-2-ylpyrimidine-2- Preparation of Amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyrimidine-2 -Yl] amine is {2- [(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine -2-yl] from 2-chloro-4-fluorobenzoyl chloride using the general method for amines.

HPLC: 17.3 min (> 95% purity)

MS: M + H = 470.2 (C ₂₀ H _l7 ClFN ₉ 0 ₂ + H = 470)

Example 185

2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} {4- [4-fluoro-2- (trifluoromethyl ) phenyl] -5-imidazol-2-yl Preparation of Pyrimidin-2-yl} amine

{2-[(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} {4- [4-fluoro-2- (trifluoromethyl) -phenyl] -5-imidazole-2 -Ylpyrimidin-2-yl} amine is {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5-imidazole -2-ylpyrimidin-2-yl] was prepared from 4-fluoro-2 (trifluoromethyl) benzoyl chloride using the general method for amines.

HPLC: 18.4 min (> 95% purity)

MS: M + H = 504.3 (C ₂₁ H ₁₇ F ₄ N ₉ O ₂ + H = 504)

Example 186

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chlorophenyl) -5-imidazol-2 -ylpyrimidin-2-yl] amine Produce

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine is {2- [(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] Prepared from 4-chlorobenzoyl chloride using the general method for amines.

HPLC: 18.0 min (> 95% purity)

MS: M + H = 452.2 ( C 20 H l8 C1N 9 O 2 + H = 452)

Example 187

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chloro-2-methylphenyl) -5- imidazol-2-ylpyrimidin-2-yl ] Preparation of Amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chloro-2-methylphenyl) -5-imidazol-2-ylpyrimidin-2-yl ] Amine is {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine-2 -Yl] from 4-chloro-2-methylbenzoyl chloride using the usual method for amines.

HPLC: 18.7 min (> 95% purity)

MS: M + H = 466.1 (C _{2 l} H ₂₀ ClN ₉ 0 ₂ + H = 466)

Example 188

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chloro-2-methoxyphenyl) -5- imidazol-2-ylpyrimidine- Preparation of 2-yl] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chloro-2-methoxyphenyl) -5-imidazol-2-ylpyrimidine-2 -Yl] amine is {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4 (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine- 2-yl] was prepared from 4-chloro-2-methoxybenzoyl chloride using the general method for amines.

HPLC: 17.8 min (> 95% purity)

MS: M + H = 482.1 (C _2l H ₂₀ ClN ₉ 0 ₃ + H = 482)

Example 189

{2-[(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-bromo-2-chlorophenyl) -5- imidazol-2-ylpyrimidine- Preparation of 2-yl] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chloro-2-methoxyphenyl) -5-imidazol-2-ylpyrimidine-2 -Yl] amine is {2-[(4-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5-imidazol-2-ylpyrimidine -2-yl] prepared from 4-bromo-2-chlorolbenzoyl chloride using the general method for amines.

HPLC: 19. 4 min (> 95% purity)

MS: M + H = 530 (C ₂₀ H ₁₇ BrClN ₉ 0 ₂ + H = 530)

Example 190

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-bromo-2-chlorophenyl) 5- (4-methylimidazol-2-yl Preparation of Pyrimidin-2-yl] amines

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-bromo-2-chlorophenyl) -5- (4-methylimidazole-2- Yl) pyrimidin-2-yl] amine is 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl ] Amino} ethyl) amino] prepared from 4-bromo-2-chlorolbenzoyl chloride and 2-amino-6-chloro-3-nitropyridine using the general method for pyridine-3carbonitrile.

HPLC: 19.4 min (> 95% purity)

MS: M + H = 544.1 ( C 2l H l9 BrClN 9 0 2 + H = 544)

Example 191

6-[(2-{[4- (4-bromo-2-chlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl ] amino} ethyl) amino] pyridine Preparation of 3-carbonitrile

6-[(2-{[4- (4-bromo-2-chlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2yl] amino} ethyl) amino] pyridine- 3-carbonitrile is 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) amino Prepared from 4-bromo-2-chlorobenzoyl chloride using the general method for pyridine-3-carbonitrile.

HPLC: 18.7 min (> 95% purity)

MS: M + H = 509.1 ( C 22 H l8 BrClN 8 + H = 509)

Example 192

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chloro-4- fluorophenyl) -5- (4-methylimidazole-2- I) Preparation of Pyrimidin-2-yl] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chloro-4-fluorophenyl) -5- (4-methylimidazole-2- I) pyrimidin-2-yl] amine is 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl ] Amino} ethyl) amino] prepared from 4-fluoro-2-chlorobenzoyl chloride and 2-amino-6-chloro-3-nitropyridine using the general method for pyridine-3-carbonitrile.

HPLC: 17.7 min (> 95% purity)

MS: M + H = 484. 3 (C ₂₁ H ₁₉ ClFN ₉ O ₂ + H = 484)

Example 193

6-[(2- [4- (2-chloro-4-fluorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino } ethyl) amino] pyridine Preparation of 3-carbonitrile

6- [(2-{[4- (2-chloro-4-fluorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) amino] pyridine 3-carbonitrile is 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) Amino] was prepared from 4-fluoro-2-chlorobenzoyl chloride using the general method for pyridine-3-carbonitrile.

HPLC: 16.7 min (> 95% purity)

MS: M + H = 449. 3 (C 22 H l8 CIFN 8 + H = 449)

Example 194

[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] {2-[(5-nitro (2 -pyridyl)) amino] Preparation of Ethyl} amine

[4- (2, 4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] Ethyl} amine is 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino} ethyl) amino] Prepared from 6-chloro-3-nitropyridine using the general method for pyridine-3-carbonitrile.

HPLC: 21.9 min (> 95% purity)

MS: M + H = 485.6 (C _2l H _l8 Cl ₂ N ₈ 0 ₂ + H = 485)

Example 195

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4 methyl imidazol-2-yl) pyrimidine- Preparation of 2-yl] amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyridine Midin-2-yl] amine is 6-[(2-{[4- (2, 4-dichlorophenyl) -5- (4-methylimidazol-2-yl) -pyrimidin-2-yl] amino } Ethyl) amino] was prepared from 2-amino-6-chloro-3-nitropyridine using the general method for pyridine-3-carbonitrile.

HPLC: 19.8 min (> 95% purity)

MS: M + H = 500.2 (C ₂₁ H ₁₉ Cl ₂ N ₉ O ₂ + H = 500)

Example 196

[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] (2-{[5- (trifluoromethyl ) (2-pyri Dill)] amino} ethyl) amine

[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2-pyri Dill)] amino} ethyl) amine is 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amino } Ethyl) amino] prepared from 2-chloro-5- (trifluoromethyl) pyridine using the general method for pyridine-3-carbonitrile.

HPLC: 20.0 min (> 95% purity)

MS: M + H = 508.1 (C ₂₂ H _l8 Cl ₂ F ₃ N ₇ + H = 508)

Example 197

Preparation of 4- [2-({2-[(6-chloropyrimidin-4-yl) amino] ethyl} amino) -5-imidazolylpyrimidin-4-yl ] benzenecarbonitrile

4- [2- ({2-[(6-chloropyrimidin-4-yl) amino] ethyl} amino) -5-imidazolylpyrimidin-4-yl] benzenecarbonitrile is 4- {5-imide 4, using the general method for dazolyl-2-[(2- {[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyrimidin4-yl} benzenecarbonitrile 4, Prepared from 6-dichloropyrimidine.

HPLC: 16.1 min (> 95% purity)

MS: M + H = 418.1 (C ₂₀ H _l6 ClN ₉ + H = 418)

Example 198

Preparation of 4-amino-2-[(2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino ] pyrimidine-5-carbonitrile

4-amino-2-[(2-{[4- (4-cyanophenyl) -5-imidazolylpyrimidin-2-yl] amino} ethyl) amino] pyrimidine-5-carbonitrile is 4- A general method for {5-imidazolyl-2-[(2-{[5- (trifluoromethyl) (2pyridyl)] amino} ethyl) amino] pyrimidin-4-yl} benzenecarbonitrile From 4-amino-2-chloropyrimidine-5-carbonitrile.

HPLC: 17.5 min (> 95% purity)

MS: M + H = 436.2 (C ₂₁ H ₁₇ N ₁₁ + H = 436)

Example 199

Of [6- (2,4-dichlorophenyl) -5- (4-methylimidazolyl) (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine Produce

[6- (2,4-Dichlorophenyl) -5- (4-methylimidazolyl) (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine For {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] amine Prepared from 4-methylimidazole (isolated using a silica gel column) and 2-chloro-5-nitropyridine using the general method.

HPLC: 22.8 min (> 95% purity)

MS: M + H = 484.2 (C ₂₂ H ₂₉ Cl ₂ N ₇ 0 ₂ + H = 484)

Example 200

[6- (2,4-dichlorophenyl) -5- (4-methylimidazolyl) (2-pyridyl)] (2-{[5- ( trifluoromethyl) (2-pyridyl) amino} Preparation of Ethyl) amine

[6- (2,4-Dichlorophenyl) -5- (4-methylimidazolyl) (2-pyridyl)] (2-{[5- (trifluoro-methyl) (2-pyridyl)] Amino} ethyl) amine is {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyri Dill)] from 4-methylimidazole (isolated using a silica gel column) and 2-chloro-5- (trifluoromethyl) pyridine using the general method for amines.

HPLC: 21.0 min (> 95% purity)

MS: M + H = 507 (C ₂₃ H ₁₉ Cl ₂ F ₃ N ₆ + H = 507)

Example 201

l- [2- (2,4-dichlorophenyl) -6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -3-pyridyl] hydropyridin -2-one Manufacture

1- [2- (2,4-dichlorophenyl) -6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -3pyridyl] hydropyridin-2-one For {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] amine Manufactured in the same manner as the method, with the following exceptions. 1- [2- (2, 4-dichlorophenyl) -2-oxoethyl] hydropyridin-2-one is dissolved in 2-hydroxypyridine with two equivalents of Hunig's base in acetonitrile. It was prepared by heating to 1- (2, 4 dichlorophenyl) -2-chloroethan-1-one. The reaction was heated at 65 ° C. for 18 hours and purified by silica gel column. In addition, 2-chloro-5-nitropyridine was used for the final step.

HPLC: X min (> 95% purity)

MS: M + H = X (C ₂₃ H _l8 Cl ₂ N ₆ 0 ₃ + H = X)

Example 202

1- [6-({2-[(6-amino-5-nitro (2 -pyridyl )) amino] ethyl} amino) -2- (2,4- dichlorophenyl ) -3-pyridyl] hydro Preparation of Pyridin-2-one

1- [6-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -2- (2, 4-dichlorophenyl) 3-pyridyl] hydropyridine- 2-one is {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2pyridyl)] Prepared according to the same method as for amines with the following exceptions. 1- [2- (2, 4-dichlorophenyl) -2-oxoethyljhydropyridin-2-one is heated until dissolved in 2-hydroxypyridine with 2 equivalents of Hunig base in acetonitrile and then dissolved Prepared by adding 1- (2,4-dichlorophenyl) -2-chloroethan-1-one. The reaction was heated at 65 ° C. for 18 hours and purified by silica gel column.

HPLC: X min (> 95% purity)

MS: M + H = X (C ₂₃ H _l9 Cl ₂ N ₇ 0 ₃ + H = X)

Example 203

Preparation of 6-[(2-{[6- (2,4-dichlorophenyl) -5- (2-oxohydropyridyl) -2-pyridyl] amino} ethyl) amino ] pyridine-3-carbonitrile

6- [(2-{[6- (2,4-dichlorophenyl) -5- (2-oxohydropyridyl) -2-pyridyl] amino} ethyl) amino] pyridine-3-carbonitrile is {2 -[(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] same as for amine Manufactured according to the method, with the following exceptions. 1- [2- (2,4-dichlorophenyl) -2-oxoethyl] hydropyridin-2-one was heated to dissolve 2-hydroxypyridine with 2 equivalents of Hunig base in acetonitrile until dissolved Prepared by adding 1- (2,4-dichlorophenyl) -2-chloroethan-1-one. The reaction was heated at 65 ° C. for 18 hours and purified by silica gel column. In addition, 2-chloro-5-cyanopyridine was used for the final step.

HPLC: X min (> 95% purity)

MS: M + H = X (C ₂₄ H ₁₈ Cl ₂ N ₆ O + H = X)

Example 204

Ethyl 6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2-phenylpyridine-3-

Preparation of Carboxylate

Ethyl 6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2-phenylpyridine-3-carboxylate is ethyl 3-oxo-3-phenylpropano as starting material. Prepared from DDQ in the ate and oxidation step. The final product was chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3-carboxylate with 2- (2-aminoethylamine) -5-nitropyridine in CH3CN and Hunig's base at 80 ° C. for 18 hours. Obtained directly from The process is based on the following formula: {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] It is similar to the regular method.

HPLC: 24.5 min (> 95% purity)

MS: M + H = 408.1 (C _{2 l} H ₂₁ N ₅ 0 ₄ + H = 408.1)

Example 205

Preparation of ethyl 2- (2,4-dichlorophenyl) -6- (2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyridine-3-carboxylate

Ethyl 2- (2,4-dichlorophenyl) -6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyridine-3-carboxylate is ethyl 3 as starting material. -(2,4-dichlorophenyl) -3-oxopropanoate (Ref. Wemple, J .; et. Al. Synthesis 1993 , 290-292.) And THF / ethanol as solvent in the first step (3: 1 ratio). Oxidation used DDQ. The final product was reacted from chloropyridine by reacting ethyl 6-chloro-2-phenylpyridine-3carboxylate with 2- (2-aminoethylamine) -5-nitropyridine in CH 3 CN and Hunig base at 120 ° C. for 18 hours. Obtained directly. The process is based on {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2pyridyl)] amine. It is similar to the general method.

HPLC: 31 minutes (> 95% purity)

MS: M + H = 476.1 (C ₂₁ H ₁₉ Cl ₂ N ₅ O ₄ + H = 476)

Example 206

Preparation of ethyl 2- (4-cyanophenyl) -6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyridine-3 -carboxylate

Ethyl 2- (4-cyanophenyl) -6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyridine-3carboxylate (62258) is ethyl 3 as starting material -(4-cyanophenyl) -3-oxopropanoate (Ref. Wemple, J .; et. Al. Synthesis 1993 , 290-292.) And THF / ethanol as solvent in the first step (1 : 5 ratio). Oxidation used DDQ in toluene. The final product was obtained directly by reacting ethyl 6-chloro-2phenylpyridine-3-carboxylate with 2- (2-aminoethylamine) -5-nitropyridine in DMA and Hunig's base at 120 ° C. for 18 hours. The process is based on {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2pyridyl)] amine It is similar to the general method.

HPLC: 26.8 min (> 95% purity)

MS: M + H = 433. 1 (C ₂₂ H ₂₀ N ₆ 0 ₄ + H = 433)

Example 207

4- [3-imidazolyl-6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2-pyridyl]

Preparation of Benzenecarbonitrile

4- [3-imidazolyl-6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2-pyridyl] benzenecarbonitrile is 4-cyanophenacyl bromide, CAN for oxidation (1: 1 acetic acid and water heated at 80 ° C. for 1 hour), and {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2 , 4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] was prepared from 2-chloro-5-nitropyridine using the general method for amines.

HPLC: 19.5 min (> 95% purity)

MS: M + H = 427.2 ( C 22 H l8 N 8 0 2 + H = 427)

Example 208

Preparation of ethyl 6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2- [4- (trifluoromethyl) phenyl] pyridine-3-carboxylate

Ethyl 6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2- [4- (trifluoromethyl) phenyl] pyridine-3-carboxylate is ethyl 3- Oxo-3- [4 (trifluoromethyl) phenyl] propanoate (Ref. Wemple, J .; et. Al. Synthesis 1993 , 290-292.) Was prepared as starting material. Oxidation was carried out using 4 equivalents of chlorotrimethicylline and 1 equivalent of bromine in dichloromethane. Ethyl 6-chloro-2- [4- (trifluoromethyl) phenyl] pyridine-3-carrine with 2- (2-aminoethylamine) -5-nitropyridine in DMA and Hunig's base for 72 hours at 70 ° C. Obtained directly by reacting a carboxylate. This method is based on {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] Similar to the general method for amines.

HPLC: 30.4 min (> 95% purity)

MS: M + H = 476.2 (C ₂₂ H ₂₀ F ₃ N ₅ 0 ₄ + H = 476)

Example 209

Preparation of ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2- [4- (trifluoromethyl) phenyl] pyridine -3-carboxylic acid

6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2- [4- (trifluoromethyl) phenyl] pyridine-3-carboxylic acid is {2-[(6 -Amino-5-nitro (2pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)]] ethyl prepared according to the general method for amine 6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -2- [4- (trifluoromethyl) phenyl] pyridine-3-carboxylate (71477) Prepared by digestion. Hydrolysis was performed by using a 1: 1 solution of water and concentrated hydrochloric acid and heating to 80 ° C. overnight.

HPLC: 24.0 min (> 95% purity)

MS: M + H = 448.1 (C ₂₀ H _l6 F ₃ N ₅ 0 ₄ + H = 448)

Example 210

Preparation of 2- (2,4-dichlorophenyl) -6-({2- (5-nitro (2-pyridyl)) amino} ethyl] amino) pyridine-3- carboxylic acid

2- (2,4-dichlorophenyl) -6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyridine-3-carboxylic acid is {2-[(6-amino- 5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)]] ethyl 2- prepared according to the general method for amines. (2, 4-dichlorophenyl) -6-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyridine-3-carboxylate (62257) was prepared by hydrolysis. Hydrolysis was performed by heating to 80 ° C. overnight using a 1: 1 solution of water and concentrated hydrochloric acid.

HPLC: 23.6 min (> 95% purity)

MS: M + H = 448.1 (C ₁₉ H ₁₅ Cl ₂ N ₅ O ₄ + H = 448)

Example 211

Preparation of [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine

[6- (2,4-Dichlorophenyl) -5-imidazolyl (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine is {2-[( 6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2pyridyl)] amine using conventional method 2 Prepared from -chloro-5- (nitro) pyridine.

HPLC: 22.9 minutes (> 95% purity)

MS: M + H = 470.1 (C _2l H _l7 Cl ₂ N ₇ 0 ₂ + H = 470)

Example 212

6-[(2-{[6- (2,4-dichlorophenyl) -5-imidazolyl-2 pyridyl] amino} ethyl) amino]

Preparation of Pyridine-3-carbonitrile

6-[(2-{[6- (2, 4-dichlorophenyl) -5-imidazolyl-2-pyridyl] amino} ethyl) amino] pyridine-3-carbonitrile is {2-[(6- Amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) 5-imidazolyl (2-pyridyl)] 2-chloro using the general method for amines Prepared from pyridine-5-carbonitrile.

HPLC: 18.8 min (> 95% purity)

MS: M + H = 450 (C ₂₂ H ₁₇ Cl ₂ N ₇ + H = 450)

Example 213

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5- (4-methyl imidazolyl) (2-pyridyl Production of Amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5- (4-methyl-imidazolyl) (2-pyri Dill)] amine is {2-[(6-amino-5-nitro (2pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-imidazolyl (2-pyridyl) ] Prepared from 4-methylimidazole (isosomes separated using a silica gel column) using the general method for amines.

HPLC: 21.5 min (> 95% purity)

MS: M + H = 499.3 (C ₂₂ H ₂₀ Cl ₂ N ₈ 0 ₂ + H = 499)

Example 214

6-[(2-{[6- (2,4-dichlorophenyl) -5- (4-methylimidazolyl) -2-pyridyl] amino} ethyl)

Preparation of Amino] pyridine-3-carbonitrile

6-[(2-{[6- (2,4-dichlorophenyl) -5- (4-methylimidazolyl) -2-pyridyl] amino} ethyl) amino] pyridine-3-carbonitrile is {2 -[(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5-imidazolyl (2-pyridyl)]] General method for amines Was prepared from 4-methylimidazole (isosomes separated using a silica gel column) and 2-chloropyridine-5-carbonitrile.

HPLC: 20.7 min (> 95% purity)

MS: M + H = 464.2 (C ₂₃ H _l9 Cl ₂ N ₇ + H = 464)

Example 215

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5 -imidazol-2-yl (2-pyridyl)] Preparation of Amine

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5-imidazol2-yl (2-pyridyl)] amine Silver for [6- (2, 4-dichlorophenyl) -5-imidazol-2-yl (2-pyridyl)] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from (2-aminoethyl) (6-amino-5-nitro (2-pyridyl)) amine using the general method.

HPLC: 20.1 min (> 95% purity)

MS: M + H = 485.4 (C _2l H _l8 Cl ₂ N ₈ 0 ₂ + H = 485)

Example 216

[6- (2,4-dichlorophenyl) -5-imidazol-2-yl (2-pyridyl)] (2-{[5- (trifluoromethyl) (2- pyridyl)] amino} ethyl Preparation of Amine

[6- (2,4-Dichlorophenyl) -5-imidazol-2-yl (2-pyridyl)] (2- {[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl ) Amine is [6- (2, 4-dichlorophenyl) -5-imidazol-2-yl (2pyridyl)] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine Prepared from (2-aminoethyl) [5- (trifluoromethyl) (2-pyridyl)] amine using the general method for the above.

HPLC: 20.3 min (> 95% purity)

MS: M + H = 493.3 (C ₂₂ H _l7 Cl ₂ F ₃ N ₆ + H = 493)

Example 217

Preparation of 6-[(2-{[6- (2,4-dichlorophenyl) -5-imidazol-2-yl-2-pyridyl] amino} ethyl) amino] pyridine -3-carbonitrile

6-[(2-{[6- (2,4-dichlorophenyl) -5-imidazol-2-yl-2-pyridyl] amino} ethyl) amino] pyridine-3-carbonitrile is [6- ( 2,4-dichlorophenyl) -5-imidazol-2-yl (2-pyridyl)] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine using the general method Prepared from 6-[(2-aminoethyl) amino] pyridine-3-carbonitrile.

HPLC: 18.9 min (> 95% purity)

MS: M + H = 450.4 (C ₂₂ H _l7 Cl ₂ N ₇ + H = 450)

Example 218

Preparation of 1- (2, 4-dichlorophenyl) -2-pyrazolylethan-1-one

To a solution of 2 ', 4'-dichlorophenacyl chloride (2.0 g, 8.9 mmol) and anhydrous MeCN (50 mL) at 23 ° C. was added pyrazole (3.1 g, 44.8 mmol). The resulting solution was heated at 80 ° C. for 5 hours and then cooled to 23 ° C. MeCN was removed under reduced pressure and CH ₂ C1 ₂ (50 mL) was added. The resulting solution was washed with H ₂ 0 (2 × 15 mL) and the organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The resulting residue was purified on silica gel (40% EtOAc / hexanes) to give a light yellow solid.

m / z 256 (MH +)

Example 219

Preparation of 1- (2,4-dichlorophenyl) -2- (4-methylimidazolyl) ethan-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -2-pyrazolylethan-1-one, except 4-methylimidazole (3.7 g, 44.8 mmol) was used instead of pyrazole. The crude residue was purified on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give a light yellow solid.

m / z 270 (MH &lt; + &gt;).

Example 220

Preparation of 1- (2,4-dichlorophenyl) -2- (2,4-dimethylimidazol) ethan-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -2-pyrazolylethan-1-one, except 2,4-dimethylimidazole (4.3 g, 44.8 mmol) instead of pyrazole. It was. The crude residue was purified on silica gel (5% MeOH / CH ₂ Cl ₂ ) to give a light yellow solid.

m / z 284 (MH +)

Example 221

Preparation of 1- [2- (2,4-dichlorophenyl) -2-oxoethyl] hydropyridin-2-one

To a solution of 2 ', 4'-dichlorophenacyl chloride (1 .0 g, 4.5 mmol) and anhydrous MeCN (20 mL) at 23 ° C., polystyrene-linked 1,5,7-triazabicyclo [4. 4.0] Dec-5-ene (2.6 g, 6.7 mmol) and 2-hydroxypyridine (428 mg, 4.5 mmol) were added and the resulting mixture was shaken at 23 ° C. for 20 h. The mixture was filtered and the resin washed with MeCN (10 mL). MeCN was removed under reduced pressure and the resulting residue was purified on silica gel (5% MeOH / CH ₂ C1 ₂ ) to give a light yellow solid.

m / z 283 (MH +)

Example 222

Preparation of 2-benzimidazolyl-I- (2,4-dichlorophenyl) ethan-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -2-pyrazolylethan-1-one, except benzimidazole (5.3 g, 44.8 mmol) was used instead of pyrazole. The crude residue was purified on silica gel (50% EtOAc / hexanes) to give a light yellow solid.

m / z 306 (MH +)

Example 223

Preparation of 1- (2,4-dichlorophenyl) -2- (2-methylimidazolyl) ethan-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -2-pyrazolylethan-1-one, except 2-methylimidazolee (3.7 g, 44.8 mmol) was used instead of pyrazole. . The crude residue was purified on silica gel (5% MeOH / CH ₂ C1 ₂ ) to give a light yellow solid.

m / z 270 (MH +)

Example 224

Preparation of 1- (2,4-dichlorophenyl) -2- (4-phenylimidazolyl) ethan-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -2-pyrazolylethan-1-one, except 4-phenylimidazole e (6.5 g, 44.8 mmol) was used instead of pyrazole. . The crude residue was purified on silica gel (50% EtOAc / hexanes) to give a light yellow solid.

m / z 332 (MH +)

Example 225

Preparation of 1- (2,4-dichlorophenyl) -2-imidazolylethan-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -2-pyrazolylethan-1-one, except imidazole (3.1 g, 44.8 mmol) was used instead of pyrazole. The crude residue was purified on silica gel (5% MeOH / CH ₂ C1 ₂ ) to give a light yellow solid.

m / z 256 (MH +)

Example 226

Preparation of 1- [2- (2,4-dichlorophenyl) -2-oxoethyl] -5-chlorohydropyridin-2-one

Prepared using the same method as 1- [2- (2,4-dichlorophenyl) -2-oxoethyl] hydropyridin-2-one, with the exception of 5-chloro-2-hydroxypyridine instead of 2-hydroxypyridine. (583 mg, 4.5 mmol) was used. The crude residue was purified on silica gel (5% MeOH / CH ₂ C1 ₂ ) to give a light yellow solid.

 m / z 317 (MH +)

Example 227

Preparation of 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-pyrazolylprop-2-en-1-one

A solution of 1- (2,4-dichlorophenyl) -2-pyrazolylethan-1-one (I, 1.0 g, 3.9 mmol) and dimethylformamide dimethyl acetal (10 mL, 75 mmol) at 100 ° C. for 2 hours Heated during. The resulting reddish brown solution was concentrated under reduced pressure to give a dark reddish brown oil which was used without further purification.

m / z 311 (MH +)

Example 228

Preparation of 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (4-methylimidazolyl) prop-2-en-l-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-pyrazolylprop-2-en-1-one except 1- (2,4-dichloro Phenyl) -2- (4-methylimidazolyl) ethan1-one (II, 1.0 g, 3.7 mmol) was used. The crude residue was used without further purification.

m / z 325 (MH &lt; + &gt;)

Example 229

Preparation of 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2,4-dimethylimidazolyl) prop-2-en-1- one

Prepared using the same method as 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-pyrazolylprop-2-en-1-one except 1- (2,4-dichloro Phenyl) -2- (2, 4-dimethylimidazol) ethan-l-one (III, 1.0 g, 3.5 mmol) was used. The crude residue was used without further purification.

m / z 339 (MH +)

Example 230

Preparation of 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2-oxohydropyridyl) prop-2-en-l- one

1- [2- (2,4-dichlorophenyl) -2-oxoethyl] hydropyridin-2-one (IV, 1.0 g, 3.5 mmol), anhydrous THF (25 mL) and dimethylformamidedimethyl acetal (10 mL , 75 mmol) was heated at 75 ° C. for 2.5 h. The resulting thick solution was concentrated under reduced pressure and the oily residue was used without further purification.

m / z 338 (MH +)

Example 231

Preparation of 2-benzimidazolyl-1- (2,4-dichlorophenyl) -3- (dimethylamino) prop-2-en-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2pyrazolylprop-2-en-1-one, except 2-benzimidazolyl-1- (2,4-dichlorophenyl) ethan-1-one (V, 1.0 g, 3.3 mmol) was used. The crude residue was used without further purification.

m / z 361 (MH +)

Example 232

Preparation of 1- (2, 4-dichlorophenyl) -3- (dimethylamino) -2- (2-methylimidazolyl) prop-2-en-l-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-pyrazolylprop-2-en-1-one except 1- (2,4-dichloro Phenyl) -2- (2-methylimidazolyl) ethan1-one (VI, 1.0 g, 3.7 mmol) was used. The crude residue was used without further purification.

m / z 325 (MH &lt; + &gt;)

Example 233

Preparation of 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (4-phenylimidazolyl) prop-2-en-l-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2-oxohydropyridyl) prop-2-en-1-one except 1- (2, 4-dichlorophenyl) -2- (4-phenyl-imidazolyl) ethane-l-one (VII, 1.0 g, 3.0 mmol) was used. The crude residue was used without further purification.

m / z 387 (MH &lt; + &gt;)

MS:

Example 234

Preparation of 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2-imidazolylprop-2-en-1-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2-oxohydropyridyl) prop-2-en-1-one, except 1- (2, 4-dichlorophenyl) -2-imidazolylethan-1-one (VIII, 1.0 g, 3.9 mmol) was used. The crude residue was used without further purification.

m / z 311 (MH +)

Example 235

Preparation of 1- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) -methylene] -2-oxoethyl} -5-chlorohydro pyridin-2-one

Prepared using the same method as 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2-oxohydropyridyl) prop-2-en-l-one, except 1- [2- (2, 4-dichlorophenyl) -2-oxoethyl] -5-chlorohydropyridin-2-one (IX, 1.0 g, 3.2 mmol) was used. The crude residue was used without further purification.

m / z 372 (MH +)

Example 236

Preparation of [4- (2,4-dichlorophenyl) -5-pyrazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine dihydrochloride

1- (2, 4-dichlorophenyl) -3- (dimethylamino) -2-pyrazolylprop-2-en-1-one (X, 400 mg, 1.3 mmol) and EtOH (10 mL) at 23 ° C. To a solution of amino {2-[(5-nitro (2pyridyl)) amino] ethyl} -carboxamidine hydrochloride (365 mg, 1.4 mmol) was added followed by NaOEt (1.6 mL, 1.6 mmol) in EtOH. Was added and the resulting solution was heated at 90 ° C. for 16 h. EtOH was removed under reduced pressure and the resulting residue was purified on silica gel (1-5% MeOH / CH ₂ C1 ₂ ) to give a yellow solid dissolved in MeCN / 0.5M HC1 (3 mL, 1: 1) and then frozen And lyophilization to give a yellow solid.

m / z 472 (MH +)

Example 237

[4- (2,4-dichlorophenyl) -5- (4-methylimidazolyl) pyrimidin-2-yl] {2-[(5-nitro (2- pyridyl)) amino] ethyl} amine di Preparation of Hydrochloride

[4- (2,4-dichlorophenyl) -5pyrazolylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} using the same method as amine dihydrochloride 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (4-methylimidazolyl) prop-2-en-1-one (XI, 421 mg, 1.3 mmol) was used.

m / z 486 (MH +)

Example 238

[4- (2,4-dichlorophenyl) -5- (2,4-dimethylimidazolyl) pyrimidin-2-yl] {2-[(5 nitro (2 -pyridyl)) amino] ethyl} amine Preparation of Dihydrochloride

Prepared using the same method as XIX except 1- (2,4-dichlorophenyl) -3 (dimethylamino) -2- (2,4-dimethylimidazolyl) -prop-2-ene-1- Warm (XII, 439 mg, 1.3 mmol) was used.

m / z 500 (MH +)

Example 239

1- [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin -5-yl] hydropyridine -2 Preparation of -on Hydrochloride

[4- (2,4-Dichlorophenyl) -5pyrazolylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine dihydrochloride using the same method 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2-oxohydropyridyl) prop-2-ene-1-one (438 mg, 1.3 mmol) Silver was used and the crude product was purified by recrystallization (CH ₂ C1 ₂ / Et20 / hexanes).

m / z 499 (MH +)

Example 240

Preparation of [5-benzimidazolyl-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine dihydrochloride

[4- (2,4-dichlorophenyl) -5pyrazolylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine dihydrochloride using the same method Except for 2-benzimidazolyl-1- (2, 4-dichlorophenyl) -3- (dimethylamino) prop-2-en-1-one (XIV, 468 mg, 1.3 mmol) The crude product was purified by recrystallization (CH ₂ Cl ₂ / Et20 / hexanes).

m / z 522 (MH &lt; + &gt;)

Example 241

[4- (2,4-dichlorophenyl) -5- (2-methylimidazolyl) pyrimidin-2-yl] {2-[(5-nitro (2- pyridyl)) amino] ethyl} amine di Preparation of Hydrochloride

[4- (2,4-dichlorophenyl) -5pyrazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino) ethyl} amine dihydrochloride using the same method 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2-methylimidazolyl) prop-2-ene-1-one (XV, 421 mg, 1.3 mmol) was used.

m / z 486 (MH +)

Example 242

2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (2- methylimidazolyl) pyrimidin-2-yl ] Preparation of Amine Dihydrochloride

[4- (2,4-dichlorophenyl) -5pyrazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine dihydrochloride using the same method 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2-methylimidazolyl) prop-2-ene-1 source (XV, 421 mg, 1.3 mmol) ) And amino {2-[(6-amino-5-nitro (2pyridyl)) amino] ethyl} carboxamidine hydrochloride (386 mg, 1.4 mmol) were used.

m / z 501 (MH +)

Example 243

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4-dichlorophenyl) -5- (4 phenyl imidazolyl) pyrimidin-2-yl ] Preparation of Amine Dihydrochloride

[4- (2,4-dichlorophenyl) -5pyrazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} using the same method as the amine dihydrochloride 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (4-phenylimidazolyl) prop-2-ene-1-one (502 mg, 1.3 mmol) And amino {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride (386 mg, 1.4 mmol) and the crude product was silica gel (5% MeOH / Purified on CH ₂ CI ₂ ).

m / z 563 (MH +)

Example 244

2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} (4- (2, 4-dichlorophenyl) -5 (2,4- dimethylimidazolyl) pyrimidine-2- Preparation of Amine Dihydrochloride

[4- (2,4-dichlorophenyl) -5-pyrazolylpyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine dihydrochloride 1- (2,4-dichlorophenyl) -3- (dimethylamino) -2- (2,4-dimethylimidazolyl) -prop-2-en-l-one (439 mg) , 1.3 mmol) and amino {2-[(6-amino-5-nitro (2pyridyl)) amino] ethyl} carboxamidine hydrochloride (386 mg, 1.4 mmol) and the crude product was reversed-phase HPLC (95 Purified from H ₂ 0: MeCN at 5: 5 to H ₂ 0: MeCN gradient at 5:95).

m / z 515 (MH +)

Example 245

Preparation of Polymer-linked N-BOC-Ethylenediamine

To a suspension of Merrifield resin (30 g, 21 mmol) and NMP (200 mL) was added 4-hydroxy-2-methoxybenzaldehyde (6.4 g, 42 mmol) and K ₂ CO ₃ (8.7 g, 63 mmol). . The resulting mixture was heated for 16 h with shaking at 120 ° C. The resulting light brown mixture was filtered and the resin washed with H ₂ O, NMP and CH ₂ CI ₂ . The resin was dried under vacuum at 40 ° C. for 12 hours.

To a suspension of resin-bound aldehyde (30 g, 21 mmol) and (MeO) ₃ CH (200 mL) was added N-BOC-ethylenediamine (6.7 mL, 42 mmol). The resulting mixture was shaken at 23 ° C. for 12 h, then filtered and washed with CH ₂ Cl ₂ . Resin-bound imine, slightly moistened with CH ₂ Cl _2, was used immediately.

Borane-pyridine complex (6.8 mL, 67 mmol) was added to a suspension of resin-bound imine (30 g, 21 mmol) and MeOH / CH ₂ Cl ₂ / HOAc (200 mL, 2: 2: 1). The resulting mixture was shaken at 23 ° C. for 12 h, then filtered and washed with NMP and CH ₂ Cl ₂ . The resin was dried under vacuum at 30 ° C. for 12 hours to obtain polymer-bonded N-BOC-ethylenediamine.

Example 246

Preparation of polymer-bonded (2aminoethyl) (5-nitro (2-pyridyl)) amine

2-chloro-5-nitropyridine (16.6 g, 105) in a suspension of polymer-bound N-BOC-ethylenediamine (30 g, 21 mmol), NMP (200 mL) and iPr2NEt (18.3 mL, 105 mmol) at 23 ° C. mmol) was added. The resulting mixture was heated for 12 h with shaking at 120 ° C., then filtered and washed with NMP, H ₂ O and CH ₂ Cl ₂ .

To a resin-bound, N-BOC-protected amine was added a solution of 2,6-lutidine and CH ₂ C1 ₂ (100 mL, 150 mmol), followed by TMSOTf and CH ₂ C1 ₂ (100 mL, 100 mmol). Solution was added. The resulting mixture was shaken at 23 ° C. for 3 hours, then filtered and washed with MeOH, Et 3 N and CH ₂ Cl ₂ . The resin was naturally dried to give a polymer-bonded (2-aminoethyl) (5-nitro (2-pyridyl)) amine.

Naturally dried resin (10 mg) was suspended in 80% TFA / CH ₂ C1 ₂ (1 mL) for 1 hour, filtered, washed with CH ₂ Cl ₂ (1 mL) and concentrated under air stream to a light yellow color. A residue was obtained.

m / z 183 (MH +)

Example 247

Polymer-bonded {2-[(5-nitro (2-pyridyl)) amino] ethyl} [(2-nitrophenyl)

Preparation of Sulfonylamine

Of resin-bonded (2-aminoethyl) (5-nitro (2-pyridyl)) amine (30 g, 21 mmol), CH ₂ Cl ₂ (250 mL) and iPr ₂ NEt (18.3 mL, 105 mmol) at 23 ° C. To the suspension was added 2-nitrobenzenesulfonyl chloride (23.3 g, 105 mmol). The resulting mixture was shaken at 23 ° C. for 6 hours, filtered, washed with NMP, H 2 O and CH 2 Cl 2 and air dried to yield polymer-bonded {2-[(5-nitro (2-pyridyl)) amino] ethyl} [ (2-nitrophenyl) sulfonyl] amine was obtained.

Naturally dried resin (10 mg) was suspended in 80% TFA / CH ₂ C1 ₂ (1 mL) for 1 hour, filtered, washed with CH ₂ Cl ₂ (1 mL) and concentrated under air stream to a light yellow color. A residue was obtained.

m / z 368 (MH +)

Example 248

Preparation of polymer-linked [2- (dimethylamino) ethyl] {2-[(5-nitro (2 pyridyl)) amino] ethyl} [(2- nitrophenyl) sulfonyl] amine

DIAD (6.6 mL, 42 mmol) was added to a solution of Ph ₃ P (11 g, 42 mmol) and CH ₂ C1 ₂ (20 mL) at 23 ° C. and the resulting yellow solution was maintained at 23 ° C. for 30 minutes. To this solution was added 2- (dimethylamino) -ethanol (4.2 mL, 42 mmol) and the resulting solution was kept at 23 ° C. for 5 minutes, followed by resin bonding {2- [(5-nitro (2-pyridyl)) Amino] ethyl} [(2-nitrophenyl) sulfonyl] amine (3.0 g, 2.1 mmol) and CH ₂ C1 ₂ (30 mL) were added to a solution. The resulting mixture was shaken at 23 ° C. for 12 h, filtered, washed with NMP, H ₂ O and CH ₂ C1 ₂ and naturally dried to afford polymer-bonded [2 (dimethylamino) ethyl] {2-[(5 -Nitro (2-pyridyl)) amino] ethyl} [(2-nitrophenyl) sulfonyl] amine.

Naturally dried resin (10 mg) was suspended in 80% TFA / CH ₂ C1 ₂ (1 mL) for 1 hour, filtered, washed with CH ₂ Cl ₂ (1 mL) and concentrated under air stream to a light yellow color. A residue was obtained.

m / z 439 (MH +)

Example 249

Polymer-bonded dimethyl [2-({2-[(5-nitro (2-pyridyl))

Preparation of Amino] ethyl} amino) ethyl] amine

Resin-bonded [2- (dimethylamino) ethyl] {2-[(5-nitro (2-pyridyl))-amino] ethyl} [(2-nitrophenyl) sulfonyl] amine at 23 ° C. (3.0 g, 2.1 mmol) and DMF (30 mL) were added H ₂ 0 (2 drops), K ₂ CO ₃ (2.9 g, 21 mmol) and PhSH (2.2 mL, 21 mmol). The resulting mixture was shaken at 23 ° C. for 12 h, filtered, washed with NMP, H ₂ O and CH ₂ C1 ₂ and dried to polymer-bonded dimethyl [2-({2-[(5-nitro (2- Pyridyl)) amino] ethyl} amino) ethyl] amine.

Naturally dried resin (10 mg) was suspended in 80% TFA / CH ₂ C1 ₂ (1 mL) for 1 hour, filtered, washed with CH ₂ Cl ₂ (1 mL) and concentrated under air stream to a light yellow color. A residue was obtained.

m / z 254 (MH +)

Example 250

Preparation of polymer-bonded amino [2- (dimethylamino) ethyl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride

Polymer-bonded dimethyl [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) ethyl] amine (3.0 g, 2.1 mmol), NMP (30 mL) and iPr2NEt at 23 ° C. To a suspension of (3.7 mL, 21 mmol) was added 1 H -pyrazole-1-carboxamidine hydrochloride (3.1 g, 21 mmol). The resulting mixture was heated at 90 ° C. for 18 hours, filtered, washed with NMP, H ₂ O and CH ₂ C1 ₂ and naturally dried to afford polymer-bonded amino [2- (dimethylamino) ethyl] {2- [( 5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride was obtained.

Naturally dried resin (10 mg) was suspended in 80% TFA / CH ₂ C1 ₂ (1 mL) for 1 hour, filtered, washed with CH ₂ Cl ₂ (1 mL) and concentrated under air stream to a light yellow color. A residue was obtained.

m / z 296 (MH +)

Example 251

[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] [2- (dimethylamino) -ethyl] {2-[(5-nitro (2-pyridyl)) amino ] Ethyl} amine trihydrochloride

Resin-bonded amino [2- (dimethylamino) ethyl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} -carboxamidine hydrochloride at 23 ° C. (3.0 g, 2.1 mmol) and NMP To a suspension of (30 mL) 7-methyl-1,5,7-triazabicyclo [4.4.0] deck-5-ene (1.5 mL, 10.5 mmol) and 1- (2, 4-dichlorophenyl) -3 -(Dimethylamino) -2-imidazolylprop-2-en-1-one (XVII, 1.3 g, 4.2 mmol) was added. The resulting mixture is heated at 120 ° C. for 20 hours, filtered, washed with NMP, H ₂ O and CH ₂ Cl ₂ and air dried to give resin-bonded [4- (2, 4-dichlorophenyl) -5imide Zolylpyrimidin-2-yl] [2- (dimethylamino) -ethyl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine trihydrochloride was obtained.

The resin was suspended in 80% TFA / CH ₂ C1 ₂ (30 mL) and shaken at 23 ° C. for 1.5 h, then filtered and concentrated under a stream of air. Resulting crude material is dissolved in a reverse phase HPLC (95: 5: 95 in a MeCN H ₂ 0 of: 5 in H ₂ 0: MeCN gradient) to give the material a number of times and was MeCN / 0.5M HC1 (1 3 mL , 1) It was then frozen and lyophilized to give a yellow solid.

m / z 543 (MH +)

Example 252

Preparation of polymer-linked {2-[(5-nitro (2-pyridyl)) amino] ethyl} [(2-nitrophenyl) sulfonyl (2 -pyrrolidinylethyl) amine

Polymer-bonded [2- (dimethylamino) ethyl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} [(2-nitrophenyl) sulfonyl] prepared using the same method as amine, The exception was 1- (2-hydroxy-ethyl) pyrrolidine (4.9 mL, 42 mmol).

m / z 465 (MH +)

Example  253

Preparation of polymer-bonded (5-nitro (2-pyridyl)) {2-[(2-pyrrolidinylethyl) amino] ethyl} amine

Polymer-bonded dimethyl [2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) ethyl] amine, using the same method as amines with the exception of resin-linked {2-[(5 -Nitro (2-pyridyl)) amino] ethyl} [(2-nitrophenyl) sulfonyl] (2-pyrrolidinylethyl) amine was used.

m / z 280 (MH +)

Example 254

Preparation of polymer-linked amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} (2-pyrrolidinylethyl) carboximidine hydrochloride

Polymer-bonded amino [2- (dimethylamino) ethyl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} prepared using the same method as carboxamidine hydrochloride, with the exception of resin-bonded (5-nitro (2-pyridyl)) {2 [(2-pyrrolidinylethyl) amino] ethyl} amine was used.

m / z 322 (MH +)

Example 255

(4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2-[(5-nitro (2 pyridyl)) amino] ethyl} (2-pyrrolidinylethyl) Preparation of Amine Trihydrochloride

[4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] [2- (dimethylamino) -ethyl] {2-[(5-nitro (2-pyridyl)) amino Prepared using the same method as ethyl} amine trihydrochloride, with the exception of resin-bonded amino {2-[(5-nitro (2-pyridyl)) amino] ethyl} (2-pyrrolidinylethyl) carboxa Midine hydrochloride was used.

m / z 569 (MH +)

Example 256

Polymer-bonded (2-morpholin-4-ylethyl) {2-[(5-nitro (2-pyridyl)) amino] ethyl}

Preparation of [(2-nitrophenyl) sulfonyl] amine

Polymer-bonded [2- (dimethylamino) ethyl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} [(2-nitrophenyl) sulfonyl] prepared using the same method as amine, Exception was used 4- (2-hydroxyethyl) morpholine (5.1 mL, 42 mmol).

m / z 481 (MH +)

Example 257

Preparation of Polymer Bond 2-[(2-morpholin-4-ylethyl) amino] ethyl} (5-nitro (2-pyridyl)) amine

Polymer-bonded dimethyl [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) ethyl] amine, using the same method as amines except resin-bonded (2-morpholine -4-ylethyl) {2-[(5-nitro (2-pyridyl)) amino] ethyl} [(2-nitrophenyl) sulfonyl] amine was used.

m / z 296 (MH +)

Example 258

Preparation of polymer-bonded amino {2-morpholin-4-ylethyl) {2-[(5-nitro (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride

Polymer-bonded amino [2- (dimethyl-amino) ethyl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} prepared using the same method as carboxamidine hydrochloride, except resin- A bond {2-[(2-morpholin-4-ylethyl) amino] ethyl} (5-nitro (2-pyridyl)) amine was used.

m / z 338 (MH +)

Example 259

[4- (2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] (2-morpholin-4 ylethyl) {2-[(5-nitro (2-pyridyl)) amino ] Ethyl} Preparation of Amine Trihydrochloride

[4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] [2- (dimethylamino) -ethyl] {2-[(5-nitro (2-pyridyl)) amino ] Ethyl} prepared using the same method as amine trihydrochloride with the exception of resin-bonded amino {2-morpholin-4-ylethyl) {2- [(5-nitro (2-pyridyl)) amino] ethyl } Carboxamidine hydrochloride was used.

m / z 585 (MH +)

Example 260

6-[(2-{[4- (2,4-dichlorophenyl) -5- (5-chloro-2-oxohydropyridyl) pyrimidine-2

Preparation of -yl] amino} ethyl) amino] pyridine-3-carbonitrile hydrochloride

1- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) -methylene] -2-oxoethyl} -5-chlorohydropyridin-2-one at 23 ° C. (XVIII, 482 mg, 1.3 mmol) and DMF (10 mL) were added amino {2-[(5-cyano (2-pyridyl)) amino] ethyl} carboxamidine hydrochloride (337 mg, 1.4 mmol) followed by Cs ₂ C0 ₃ (652 mg, 2.0 mmol) was added and the resulting mixture was heated at 100 ° C. for 16 h. The DMF was removed under reduced pressure and the resulting residue was purified by recrystallization (CH ₂ C1 ₂ / Et20 / hexanes) to give a yellow solid dissolved in MeCN / 0.5M HCl (3 mL, 1: 1), then frozen and frozen Drying gave a yellow solid.

m / z 513 (MH +)

Example 261

Ethyl 6- {2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4-phenylpyridine-3-

Preparation of Carboxylate

1. Preparation of diethyl (2Z) -3-phenylpent-2-ene-1,5-dioate.

A solution of iodinebenzene (1.08 ml, 9.67 mmol) in DMA (5 ml) was diluted with diethylglutaconate (2 g, 10.74 mmol), Pd (OAc) 2 (250 mg) in DMA (5 ml) at 115 ° C. under argon. , 1.07 mmol), NaOAc (880 mg, 10.74 mmol) was added dropwise. After heating at 130 ° C. for 8 hours, the reaction was cooled, diluted with CH 2 C 12 (60 ml) and washed with water (4 × 10 ml). The organic layer was washed with saturated aqueous NaHC0 ₃ (20 ml), brine (20 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The dark oil was purified by column chromatography using CH ₂ C1 ₂ as eluent. The product oil was dried overnight in vacuo to afford diethyl (2Z) -3-phenylpent-2-ene-1, 5-dioate in 28% yield.

2. Preparation of diethyl (3E) -2- (hydroxymethylene) -3-phenylpent-3-ene-1, 5-dioate .

A stirred mixture of NaH (158.4 mg, 6.6 mmol) and ethyl formate (1.07 ml, 13.2 mmol) in Et 2 O (5 ml) was refluxed under argon for 15 minutes. Diethyl (2Z) -3-phenylpent-2-ene-1,5-dioate in Et 2 O (5 ml) was added dropwise to the solution over 5 minutes at room temperature. The reaction was refluxed for 12 hours. Diluting the non-uniform quality of the yellow mixture to Et2O (100 ml), washed with saturated NH ₄ C1 (40 ml), half saturated NH ₄ C1 (40 ml), the function (20 ml) to the next, Na ₂ S0 ₄ Dried, filtered and concentrated under reduced pressure. The product diethyl (3E) -2- (hydroxymethylene) -3-phenylpent-3-ene-1, 5-dioate was obtained in 97% yield and could be used without further purification.

3. Preparation of ethyl 6-oxo-4-phenylhydropyridine-3-carboxylate.

A solution of diethyl (3E) -2- (hydroxymethylene) -3-phenylpent-3-ene-1,5-dioate (0.62 g, 2.13 mmol) was added to glacial acetic acid (1 ml), toluene (1 ml). And in anhydrous ethanol (3 ml). Ammonium acetate (0.07 g, 9.08 mmol) and flame dried 4x powder molecular sieve (0.4 g) were added to the stirred solution. The reaction mixture was stirred at 90-95 ° C. for 44-46 hours. After heating for 24 hours, additional reagents were added, including ammonium acetate (0.07 g, 9.08 mmol), acetic acid (1 ml), and flame dried 4mm powder molecular sieve (0.4 g). EtOAc (80 ml) was added with stirring for 15 minutes while cooling. The sieve was filtered off and washed with EtOAc (2 × 10 ml). The filtrate was concentrated under reduced pressure. To the crude was added EtOAc (100 ml). The organic layer was then washed with distilled water (2 x 30 ml), saturated aqueous NaHC0 ₃ (30 ml) solution, water (30 ml), brine (30 ml), dried over Na ₂ S0 ₄ , filtered and concentrated under reduced pressure. . The oil was purified by column chromatography using 5% MeOH in CH ₂ C1 ₂ as eluent. The product oil was dried in vacuo overnight to afford ethyl 6-oxo-4-phenylhydropyridine-3-carboxylate in 72% yield.

4. Preparation of ethyl 6-chloro-4-phenylpyridine-3-carboxylate.

To anhydrous ethyl 6-oxo-4-phenylhydropyridine-3-carboxylate (141 mg, 0.58 mmol) is added phosphorus oxychloride (10 ml) followed by N, N dimethylacetamide (1 drop). It was. The reaction mixture was stirred at 100 ° C. for 12 h under argon. Phosphorus oxychloride was removed under reduced pressure. The crude product was taken up in ditlo methane (2 × 25 ml) and the solvent was removed under vacuum. The glass was dried in vacuo for 3-4 hours to give ethyl 6-chloro-4-phenylpyridine-3-carboxylate in 97% yield. The crude material was contaminated with phosphorus residues and used without further purification.

5. Preparation of ethyl 6- (2-[(5-nitro (2-pyridyl)) aminolethyl] amino) -4-phenylpyridine-3 -carboxylate

The crude, ethyl 6-chloro-4-phenylpyridine-3-carboxylate (140 mg, 0.56 mmol), (2-aminoethyl) (5-nitro (2-pyridyl)) amine (408 mg, 2.24 mmol), Hunig's base (390 ul), and DMA (2 ml) were mixed under argon with stirring at 70-75 ° C. for 48 hours. After the reaction, TLC and HPLC were performed. When judged to terminate, the reaction was diluted with EtOAc (100 ml) and washed with saturated aqueous NaHCO ₃ solution (5 × 30 ml), brine (30 ml), dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. . The yellow solid was purified by column chromatography using 5% MeOH in CH ₂ Cl ₂ as eluent. The product was dried overnight in vacuo to afford ethyl 6-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4-phenylpyridine-3-carboxylate in 70% yield. Got it.

HPLC: 3.52 min (> 95% purity) (HP-1 method)

MS: M + H = 408.2 (C _{2 l} H _{2 l} N ₅ 0 ₄ + H = 408)

Example 262

[5-((1E) -1-Aza-2-morpholin-4-ylprop-1-enyl) -4- (2, 4-dichlorophenyl) pyrimidin-2-yl] 2-[(6 Preparation of -amino-5-nitro (2-pyridyl)) amino] ethyl} amine

A. 2- [2- (2, 4-dichlorophenyl) -2-oxoethyl] isoindolin-1,3-dione

1 mmol of 2, 4-dichlorophenacyl chloride in DMF was added dropwise to 2 mmol of phthalimide and 2 mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature, then the reaction mixture was concentrated in vacuo to water and ethyl acetate. Diluted. The ethyl acetate layer was concentrated and then purified by trituration with diethyl ester.

B. 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoin doline-1,3dione

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindolin-1, 3-dione was heated to 80 ° C. for 6 hours in N, N-dimethylformamidedimethylacetal. . The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ester.

C. 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine- 5-yl] carbamoyl} benzoic acid

1 mmol 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} -isoindolin-1,3-dione, 1 mmol amino {2- [(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and 3 mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate.

D. 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl Isoindolin-1,3-dione

1 mmol of 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine -5-yl] carbamoyl} benzoic acid was heated to 120 ° C. in glacial acetic acid and concentrated in vacuo.

E. {5-Amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5- Isoindoline-1,3-dione and 20 mmol of hydrazine were purified by column chromatography, stirred in ethanol at 75 ° C. for 2 hours and eluted with 5-10% methanol / methylene chloride.

F. N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl Acetamide

1 mmol of [5-amino-4- (2,4-dichlorophenyl) pyrimidin-2-yl] {2- [(6-amino-5-nitro (2pyridyl)) amino] ethyl} amine and 1 mmol acetic anhydride was stirred in THF at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride.

G. 1-{[2- (2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl ] Amino} ethane-1-thione

1 mmol of N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5- Sun] Acetamide and 2 mmol of Lawesson's reagent were stirred at 80 ° C. in 2 ml of DME. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride.

H. [5-((lZ) -l-Aza-2-morpholin-4-ylprop-1-enyl) -4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of l-{[2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5 -Yl] amino} ethane-1-thione was heated by morpholine to 90 ° C. and purified by column chromatography eluting with 5-10% methanol / methylene chloride.

HPLC: 9.75 min (100% purity)

MS: MH <+> -546. 3

Example 263

{2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4-dichlorophenyl) -5-

Preparation of Nitro (2-pyridyl)] amine

A. 2- (2,4-dichlorophenyl) -6-chloro-3-nitropyridine

1 mmol of 2,6-dichloro-3-nitropyridine, 1.05 mmol of 2,4-dichlorobenzeneboronic acid, and 3 mmol of Na ₂ CO ₃ were dissolved in 1.5 ml THF and 0.5 ml water and purged with nitrogen. 0.05 mmol of [l, l'-Bis (diphenylphosphino) -ferroken] dichloropalladium (II) was added to the reaction and stirred at room temperature under nitrogen for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was washed three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 10% ethyl acetate / 90% hexane.

B. (2-aminoethyl) (6-amino-5-nitro (2-pyridyl)) amine

1 mmol of 2-amino-6-chloro-3-nitropyridine and 15 mmol of 1,2-diaminoethane were stirred at reflux for 14 hours. The reaction mixture was concentrated in vacuo and 1.5 mmol of NaOH solution in water was added. This solution was extracted twice with 95% / 5% methylene chloride / methanol. The aqueous solution was then extracted twice with 95% / 5% acetonitrile / methanol and finally extracted twice with 95% / 5% ethyl acetate / methanol. All organic portions were combined and dried over sodium sulfate.

C. {2-[(6-Amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2,4- dichlorophenyl ) -5-nitro (2-pyridyl)] amine

1 mmol of 2- (2,4-dichlorophenyl) -6-chloro-3-nitropyridine at 80 ° C. for 2 hours at 2 mmol of (2-aminoethyl) (6-amino-5- in 2 ml of DMF. Nitro (2-pyridyl)) amine and 3 mmol of N, N-diisopropylethylamine. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride.

HPLC: 8.698 min (100% purity)

MS: MH &lt; + &gt; 464. 1

Example 264

6- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl ) pyrimidin-5-yl] -3-pyrrolino [3,4-b] pyridine-5,7-dione

A. 2- [2- (2, 4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione

1 mmo of 2,4-dichlorophenacyl chloride in DMF was added dropwise to 2 mmol of phthalimide and 2 mmol of Cs ₂ CO ₃ in DMF for 14 hours at room temperature, then the reaction mixture was concentrated in vacuo and water and ethyl acetate Diluted with. The ethyl acetate layer was concentrated and then triturated with diethyl ether to purify.

B. Dolin-1,3dione 2- {2- (2,4-dichlorophenyl) -1-[(dimethylamino) methylene] -2-oxoethyl} isoin

1 mmol of 2- [2- (2,4-dichlorophenyl) -2-oxoethyl] isoindoline-1,3-dione was heated to 80 ° C. in pure N, N-dimethylformamidedimethylacetal for 6 hours. It was. The reaction mixture was concentrated in vacuo and purified by trituration with diethyl ether.

C. 2- {N- [2- (2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4-dichlorophenyl) pyrimidine-5 -Yl] carbamoyl} benzoic acid

1 mmol 2- {2- (2, 4-dichlorophenyl) -1- [(dimethylamino) methylene] -2-oxoethyl} isoindolin-1, 3-dione, 1 mmol amino {2- [ (6-amino-5-nitro (2-pyridyl)) amino] ethyl} carboxamidine, and 3 mmol of Cs ₂ CO ₃ were dissolved in DMF and heated to 90 ° C. for 14 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate and dried over sodium sulfate.

D. 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2,4- dichlorophenyl) pyrimidin-5-yl Isoindolin-1, 3-dione

1 mmol 2- {N- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine -5-day] carbamoyl} benzoic acid was heated in glacial acetic acid to 120 ° C. for 4 hours and then concentrated in vacuo.

E. [5-Amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] 2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine

1 mmol of 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5- Isoindolin-1, 3-dione and 20 mmol of hydrazine were purified by ethanol at 75 ° C. for 2 hours and then purified by column chromatography eluting with 5-10% methanol / methylene chloride.

F. 6- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4- dichlorophenyl) pyrimidin-5-yl ] -3-pyrrolino [3, 4-b] pyridine-5, 7-dione

1 mmol of [5-amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, And 2 mmol of furano [3,4-b] pyridine-5,7-dione were stirred at room temperature for 4 hours. 2 mmol of HBTU and 3 mmol of N, N-diisopropylethylamine were added to the solution and left at room temperature for 6 hours. The reaction mixture was concentrated in vacuo and diluted with water and ethyl acetate. The solution was extracted three times with ethyl acetate, dried over sodium sulfate and purified by column chromatography eluting with 5-10% methanol / methylene chloride.

HPLC: 7.829 min (97.32% purity)

MS: MH &lt; + &gt; 566.0

Example 265

Screening for GSK3 Inhibitory Activity Using Cell-Free Assays

The pyrimidine and pyridine compounds of the invention were dissolved in DMSO and then tested for inhibition of human GSK3β (nucleotide sequence for human GSK3β is represented by Accession Number L33801 in GenBank). For example, GSK3β is described in Hughes et al., Eur. J. Biochem., 203: 305-11 (1992).

300 ul of substrate buffer (30 mM Tris-HCl, 10 mM MgCl 2, 2 mM DTT, 3 pg / ml GSK3β and 0.5 uM biotinylated prephosphorylated SGSG-linked CREB peptide (Chiron Technologies PTY Ltd., Clayton, Australia) An aliquot of) was dispensed into the wells of a 96 well polypropylene microtiter plate. Add 3.5 μl / well of DMSO containing known kinase inhibitor used as each compound or staurosporin (positive control or negative control (ie DMSO only)) to be assayed and mix thoroughly. The reaction was started by adding 1 μM unlabeled ATP and 1-2 × 10 ⁷ cpm γ ³³ P-labeled ATP and allowed to proceed for about 3 hours at room temperature.

During the reaction, streptavidin-encoding Labsystems “Combiplate 8” capture plates (Labsystems, Helsinki, Finl and) were incubated with 300 wells / μl of PBS containing 1% bovine serum albumin for at least 1 hour at room temperature. Blocked. The blocking solution was then removed by aspiration and the capture plate was filled with 100 μl / well of stop reagent (50 μM ATP / 20 mM EDTA).

At the end of the 3 hour enzymatic reaction, 100 μl aliquots of each of the three reaction mixtures were transferred to three wells (three capture plates per well) containing the stop solution and the contents of the wells mixed well. After 1 hour at room temperature, the wells of the capture plate were emptied by aspiration and washed five times with PBS and 12 channel Coming 430474 ELISA plate cleaner. Finally, 200 μl of Microscint-20 scintillation liquid was added to each well of the plate. The plate was coated with a plate sealant and then left to shaker for 30 minutes. Each capture plate was counted on a Packard TopCount Scintillation Counter (Meridian, Connecticut) and the results shown as a function of compound concentration.

Compounds of the invention were screened for inhibitory activity against GSK3 according to this assay. The following compounds have an IC of 10 μM or less for GSK3 in this cell-free assay ₅₀ Indicated: (4-phenylpyrimidin-2-yl) (2- (2-pyridyl) ethyl) amine, (4-phenylpyrimidin-2-yl) [2- (2-pyridylamino) ethyl] amine, [2- (2-pyridylamino) ethyl] (4- (3-pyridyl) pyrimidin-2-yl) amine, 4- {2-[(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} benzenecarbonitrile, 4- {2-[(4-pyridylmethyl) amino] pyrimidin-4 yl} benzamide, 4- {2-[(3-imidazol-5-ylethyl) amino] pyrimidin-4-yl} benzamide, 4- (2-{[2- (2-pyridylamino) ethyl] amino} pyrimidin-4-yl) benzenecarbonitrile, 4-methyl-2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylic acid, 4- (2- {[(3-methylphenyl) -methyl] amino} pyrimidin-4-yl) benzamide, 4- (2-{[(4-aminophenyl) methyl] amino} pyrimidin-4-yl) benzamide, (5-ethyl-4-phenylpyrimidin-2-yl) [2- (2-pyridylamino) ethyl] amine, 4- (2-{[(5-methylpyrazin-2-yl) methyl] amino} pyrimidin-4-yl) benzamide, 4- {2- [(3-phenoxypropyl) amino] pyrimidin-4-yl} phenol, 4- {2- [(3-imidazolylpropyl) amino] pyrimidin-4-yl} benzamide, [4- (3, 4-difluorophenyl) pyrimidin-2-yl] [2- (2-pyridylamino) -ethyl] amine, 4- (2- {[(4-cyanophenyl) methyl] amino} pyrimidin-4-yl) benzamide, 4- {2-[(2-phenoxyethyl) amino] pyrimidin-4-yl} benzamide, 4- (2-{[(3-methoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide, 4- (2-{[(4-methoxyphenyl) methyl] amino} pyrimidin-4yl) benzamide, 4- (2- {[2- (4-fluorophenyl) ethyl] amino} pyrimidin-4-yl) benzamide, [2- (2, 5dimethoxyphenyl) ethyl] (4- (3-pyridyl) pyrimidin-2-yl) amine, [4- (4-nitrophenyl) pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine, {2- [(5-nitro (2-pyridyl)) amino] ethyl} (4-pyrazin-2-ylpyrimidin-2-yl) amine, Ethyl 4- (2-furyl) -2-[(2- (2-pyridyl) ethyl) amino] pyrimidine-5carboxylate, 4- (2- {[(3-chlorophenyl) methyl] amino} pyrimidin-4-yl) benzamide, [4- (4-chlorophenyl) -5-methylpyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine, 4- {2- [(3-benzimidazolylpropyl) amino] pyrimidin-4-yl} phenol, 4- {2- [(4-phenylbutyl) amino]-pyrimidin-4-yl} benzamide, 4- (2- {[2- (3-methoxyphenyl) ethyl] amino} pyrimidin-4-yl)-benzamide, 4- {2-[(3-phenoxypropyl) amino] pyrimidin-4-yl} benzamide, 4- (2-{[(3-nitrophenyl) methyl] amino} pyrimidin-4-yl) benzamide, 4- [2- ({2- [(5-nitro-2-pyridyl) -amino] ethyl3 amino) pyrimidin-4-yl] phenol, 3- [2-({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] phenol, 4- (2- {[2- (3-chlorophenyl) ethyl] amino} pyrimidin-4yl) benzamide, 4- {2-[(naphthylmethyl) amino] pyrimidin-4-yl} benzamide, [5- (4-fluoro-phenyl) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 4- (2-{[3- (4-chlorophenoxy) propyl] amino} pyrimidin-4-yl) phenol, [4- (4-imidazolylphenyl) pyrimidin-2-yl] [2 (2-pyridylamino) ethyl] amine, 4- (2-{[3- (2-aminobenzimidazolyl) propyl] amino} pyrimidin4-yl) phenol, 4- (2-{[2- (2, 5-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzenecarbonitrile, [4- (2, 4-dichlorophenyl) pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine, 3- [2- ({2-[(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile, 4- (2-{[3 (3-methylphenoxy) propyl] amino} pyrimidin-4-yl) benzamide, 4- {2- [(2- (2H-benzo [3, 4d] 1, 3-dioxolen-5-yl) ethyl) amino] pyrimidin-4-yl} benzamide, 4- (2- {[2- (4-nitrophenyl) ethyl] amino} pyrimidin-4-yl) benzamide, 4- (2-{[(2, 6-dimethoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide, 4- (2-{[(3, 4-dimethoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide, [2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4yl] benzylamine, Ethyl 4- (4-fluorophenyl) -2- [(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate, [4- (2, 4-dimethyl (1, 3-thiazol-5-yl)) pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, [4- (4-Methyl-l-phenylpyrazol-3-yl) pyrimidin-2-yl] [2- (2-pyridyl-amino) ethyl] amine, 4- [2-({[3- (trifluoromethyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide, 4- [2-({[4- (trifluoromethyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide, 4 (2-1 [(3, 5-dichlorophenyl) methyl] amino} pyrimidin-4-yl) benzamide, 4- {2- [4-benzylpiperazinyl] pyrimidin-4-yl} benzamide, 4- (2-{[(2, 4-dichlorophenyl) methylamino} pyrimidin-4-yl) benzamide, Ethyl 4- (4-cyanophenyl) -2-[(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate, [2- (2-pyridylamino) ethyl] {4- [4- (trifluoromethoxy) phenyl] pyrimidin-2-yl} amine, {6-[(2-methoxyethyl) amino] -t-nitro (2-pyridyl)} {2-[(5nitro (2-pyridyl)) amino] ethyl} amine, 4- (2- {[3- (3-methoxyphenoxy) propyl] amino} pyrimidin-4-yl) benzamide, Ethyl 4- (4-methoxyphenyl) -2- [(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate, [(3-methylphenyl) methyl] [2- ({2- [(5-nitro- (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] amine, 4- (2-{[3- (4-phenylimidazolyl) propyl] amino} pyrimidin-4-yl) benzenecarbonitrile, 4- {2- [(3-benzimidazolylpropyl) -amino] pyrimidin-4-yl} -2-chlorophenol, 4- [2- (13- [4- (2, 4-dichlorophenyl) imidazolyl] propyl} amino) pyrimidin-4-yl] benzamide, 4- [2-({3- [4- (3-methoxyphenyl) imidazolyl] propyl} amino) pyrimidin-4-yl] benzamide, (3-benzimidazolylpropyl) [4- (4-imidazolyl-phenyl) pyrimidin-2-yl] amine, N- {4- [2- ({2- [(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] phenyl} acetamide, 4- (2-{[3- (4-chlorophenoxy) propyl] amino} pyrimidin-4yl) benzamide, 4- (2-{[(4-bromophenyl) methyl] amino} pyrimidin-4-yl) benzamide, 4- [2- ({[4- (4-fluorophenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide, 4- (2-{[(3 bromophenyl) methyl] amino} pyrimidin-4-yl) benzamide, 6-{[2-({5-nitro-6- [benzylamino] 2-pyridyl} amino) ethyl] amino} pyridine-3-carbonitrile, Ethyl 4- (4-cyanophenyl) -2-{[2- (pyrimidin-2-ylamino) ethyl] amino} pyrimidine-5-carboxylate, 4- {2- [4- (2-methoxyphenyl) piperazinyl] pyrimidin-4-yl} benzamide, 4- (2-{[2- (benzothiazol-2-ylamino) ethyl] amino} pyrimidin-4-yl) benzamide, Ethyl 4- (3-nitrophenyl) -2- [(2- (2-pyridyl) ethyl) amino] pyrimidine-5-carboxylate, 6-methyl-2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) 4-phenylpyrimidine-5-carboxylic acid, 4- {2-[(2, 2-diphenylethyl) amino] pyrimidin-4-yl} benzamide, 4- (2-{[(3, 4, 5-trimethoxyphenyl) methyl] amino} pyrimidin-4-yl) benzamide, Methyl 2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3-pyridyl) pyrimidine-5-carboxylate, 4- [2-({[3- (3-aminophenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide, 4- [2-({[4- (3-aminophenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide, 4- {2- [(3- (2-naphthyloxy) propyl) amino] pyrimidin-4-yl} benzamide, 4- {2-[(3- (6-quinolyloxy) propyl) amino] pyrimidin-4-yl} benzamide, [(3-chlorophenyl) methyl] [2-({2-[(5-nitro (2-pyridyl))-amino] ethyl} amino) pyrimidin-4-yl] amine, [(4-chlorophenyl) methyl] [2- ({2- [(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] amine, Ethyl 4- (4-cyanophenyl) -2- {[2- (3-methoxyphenyl) ethyl] amino} pyrimidine-5-carboxylate, Ethyl 2- ({2- [(5-amino (2pyridyl)) amino) ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5-carboxylate, 4- [5-nitro-2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile, Ethyl 4 [2- ({2- [(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzoate, Ethyl 4- (3-nitrophenyl) -2-{[2- (2-pyridylamino) ethyl] amino} pyrimidine-5-carboxylate, N-benzyl (4 {2-[(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} phenyl) carboxamide, {2- [(5-nitro (2-pyridyl)) amino] ethyl} {5-nitro-6- [benzylamino] (2-pyridyl)} amine, 4- (2-methoxyphenyl) -2-({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylic acid, 4- [2-({[3- (3methoxyphenyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide, 4- [2- ({2- [(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzenesulfonamide, 4- (2-{[3- (2, 4-dichlorophenoxy) propyl] amino} pyrimidin-4-yl) benzamide, 4- (2- {[3- (3, 4-dichlorophenoxy) -propyl] amino} pyrimidin-4-yl) benzamide, 4- (2- {[3- (3-phenylphenoxy) propyl] amino} pyrimidin-4-yl) benzamide, 4- (2-{[(3- {3-[(methylamino) methyl] phenyl} phenyl) methyl] amino} pyrimidin-4-yl) benzamide, Ethyl 4- (3-fluorophenyl) -2-({2-[(5nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, [4-phenyl-5-benzyl-pyrimidin-2-yl] [2- (2-pyridylamino) ethyl] amine, 4- (2-{[3- (3-bromophenoxy) propyl] amino} pyrimidin-4-yl) benzamide, 4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -5phenylpyrimidin-4-yl] phenol, 4- (2, 4-dichlorophenyl) -2- (12- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carbonitrile, 4- (3, 4-dichlorophenyl) -2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidine-5-carbonitrile, 6-[(2-{[4- (4-cyanophenyl) -5 (ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxylic acid, Ethyl 4- (3-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, [(3, 5-dichlorophenyl) methyl] [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4yl] amine, [(2, 4-dichlorophenyl) methyl] [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino)-pyrimidin-4-yl] amine, Ethyl 4- (4-carbamoylphenyl) -6-ethyl-2-{[2- (2-pyridylamino) ethyl] amino} pyrimidine-S-carboxylate, Ethyl 4- (4-carbamoylphenyl) -6-ethyl-2-{[2- (pyrimidin-2- ylamino) ethyl] amino} pyrimidine-5-carboxylate, Ethyl 4- (3, 4-dimethylphenyl) -2-({2-[(5nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, N- (2-methoxyethyl) {4- [2 ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, 4- {2 [({3- [3- (acetylamino) phenyl] phenyl} methyl) amino] pyrimidin-4-yl} benzamide, Ethyl 4- (4-cyanophenyl) -2- [2- (2-quinolylamino) ethyl] amino} pyrimidine-5-carboxylate, 4- [2-({[3, 5-bis (trifluoromethyl) phenyl] methyl} amino) pyrimidin-4-yl] benzamide, Ethyl 4- (2, 4difluorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, (4- {[(3-bromophenyl) methyl] amino} pyrimidin-2-yl) {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3, 4-dichlorophenyl) pyrimidine-5-carbonitrile, Methyl 6-[(2-{[4- (4-cyanophenyl) -5- (ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxylate, 4- {2- [({3- [3- (trifluoromethyl) phenyl] phenyl} methyl) amino] pyrimidin-4-yl} benzamide, [4- (4-benzimidazolylphenyl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, Ethyl 2 (12- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3-nitrophenyl) pyrimidine-S-carboxylate, Ethyl 4-naphthyl-2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, Ethyl 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3-quinolyl) pyrimidine-5- carboxylate, Ethyl 4- (4-cyanophenyl) -2-[(2-{[5- (N-ethylcarbamoyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-carboxylate , Benzyl {[4- (2-{[2- (2-pyridylamino) ethyl] amino} pyrimidin-4-yl) phenyl] sulfonyl} amine, Ethyl 4- (4-cyanophenyl) -2-[(2- {[6- (methylamino) -5-nitro (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-carboxylate , {4- [2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (oxolan-2-ylmethyl) carb Replica, N- (1-carbamoyl-2-phenylethyl) [4-methyl-2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carbox Replica, N- (1-carbamoyl-2-phenyl-ethyl) (4- {2-[(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} phenyl) carboxamide, Ethyl 4- (3, 4 dimethoxyphenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 carboxylate, {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -Nbenzylcarboxamide, {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4yl] phenyl} -N- (3-pyridylmethyl) carboxamide, {4- [4- (4, 5-dichloroimidazol-2-yl) phenyl] pyrimidin-2-yl} {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, Ethyl 4- (4-butoxyphenyl) -2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, Ethyl 4- {[(2-chlorophenyl) methyl] amino} -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 carboxylate, 6- (2-fluorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4-phenyl-pyrimidine-5-carboxylic acid, {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (2-thienylmethyl) carboxamide , Ethyl 2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) -4- [3- (trifluoromethyl) phenyl] pyrimidine-5-carboxylate, Ethyl 4- (3, 4-dichlorophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 carboxylate, Ethyl 4- (3, 5-dichlorophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4yl] phenyl} -N- (4-piperidylmethyl) carboxamide , (6-{[(2, 4-dichlorophenyl) methyl] amino} 5-nitro (2-pyridyl)) {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, Ethyl 4- (4carbamoylphenyl) -6-ethyl-2- ({2- [(3-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 carboxylate, Ethyl 4- [4- (diethylamino) phenyl] -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (2-phenylethyl) carboxamide, N- [(3-methylphenyl) methyl] {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide , 2-({2 [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4, 6-trichlorophenyl) pyrimidine-5-carboxylic acid, Ethyl 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-phenylphenyl) pyrimidine- 5-carboxylate, {4- [2- ({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4 yl] phenyl} -N-benzylcarboxamide, N- [(5-methylpyrazin-2-yl) methyl] {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl } Carboxamide, N-[(3-fluorophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Replica, Ethyl 2-({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-sulfamoyl-phenyl) pyrimidine-5-carboxylate, N- [(4-fluorophenyl) methyl] {4- [2- ({2- [(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox mid, [4- (2-{[(3-bromophenyl) methyl] amino} pyrimidin-4-yl) phenyl] -N-[(3-methylphenyl) methyl] carboxamide, Ethyl 4- (5-bromo (3-pyridyl))-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5carboxylate, N- (3-imidazolylpropyl) {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide , tert-butyl 6-[(2-{[4- (4-cyanophenyl) -5 (ethoxycarbonyl) pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carboxylate, N-[(3bromophenyl) methyl] (4- {2- [(3-imidazolylpropyl) amino] pyrimidin-4-yl} phenyl) -carboxamide, Ethyl 4- [(2, 4-dichlorophenyl) amino] -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, Ethyl 4- (4-carbamoylphenyl) -6-ethyl-2- ({3- [(5-nitro (2-pyridyl)) amino] propyl} amino) pyrimidine-5-carboxylate, {4- [2- ({2- [(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- (2-phenylcyclopropyl) carboxamide, N- [(4-methoxyphenyl) methyl] {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Replica, 2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) -4-phenylpyrimidine-5-carboxylic acid, 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) -4- (4-pyridyl) pyrimidine-5-carboxylic acid, Ethyl 4- (4-carbamoylphenyl) -6-ethyl-2- [(2- {[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-5- Carboxylate, Ethyl 4- (4-cyanophenyl) -2- [(2- {[5- (morpholin-4- ylcarbonyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-5-car Cyclate, N- [(3-chlorophenyl) methyl] {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxa mid, N- [(3, 4-difluorophenyl) methyl] {4- [2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] carboxamide, Ethyl 4- [4- (4-methylpiperazinyl) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5carboxylate, 4-cyclohexyl-2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4 nitrophenyl) pyrimidine-5-carboxylic acid, {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- [(3-nitrophenyl)-methyl] carbox Replica, Ethyl 4- [(3-bromophenyl) methyl] amino} -2- ({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, N- [(3-bromophenyl) methyl] [4- (2- {[2- (3-methoxyphenyl) ethyl] amino} pyrimidin-4-yl) phenyl] carboxamide, N- (naphthyl-methyl) {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, 4- (3-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid, N- [(3, 4-dimethoxyphenyl) methyl] {4- [2- ({2- [(5- nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, N-[(2, 3 dimethoxyphenyl) methyl] {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, 4- (4-methoxyphenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl}-amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid , N- [(3-bromophenyl) methyl] {4- [2- ({2-[(6-methoxy (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} Carboxamide, {4 [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-{[3- (trifluoromethyl) phenyl Methyl} carboxamide, N-[(3, 5-dichlorophenyl) methyl] {4- [2-({2 [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, N-[(3, 4-dichlorophenyl) methyl {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4yl] phenyl} carboxamide, Ethyl 4- (4-cyanophenyl) -2- {[2- ({5-nitro-6- [benzylamino] (2pyridyl)} amino) ethyl] amino} pyrimidine-5-carboxylate, Ethyl 4- [3, 5-bis (trifluoromethyl) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, 4, 6bis (4-nitrophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylic acid, [4- (2-{[2- (2, 5-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) phenyl] -N-[(3-bromophenyl) methyl] carboxamide, 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (3- nitrophenyl) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid, N- [(3-bromophenyl) -methyls {4- [2-({2-[(4-nitrophenyl) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, N- [(3-bromophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin4-yl] phenyl} carboxa mid, N-[(4-bromophenyl) methyl] {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Replica, {4- [2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N-[(4-sulfamoylphenyl) methyl] Carboxamide, N- [2- (2, 4-dichlorophenyl) ethyl] {4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl}-amino) pyrimidin-4-yl] phenyl} carboxamide, N- [(3-bromophenyl) methyl] [4- (2- {[2- (2- quinolylamino) ethyl] amino} pyrimidin-4-yl) phenyl] carboxamide, 2- ({2- [(5-nitro (2 pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) -4- (4-quinolyl) pyrimidine-5-carboxylic acid, N- (2, 2-diphenylethyl) {4- [2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, N- [(3-bromophenyl) methyl] {4- [2-({3-[(5-nitro (2-pyridyl)) amino] propyl} amino) pyrimidin-4-yl] phenyl} carbox Replica, {4- [2-({2-[(6-amino-5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- [(3-bromophenyl ) Methyl] carboxamide, 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) -4- [4- (trifluoromethyl) phenyl] pyrimidine- 5-carboxylic acid, N- [(3-bromophenyl) methyl] (4- {2- [(2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyrimidine-4- Phenyl) carboxamide, [(3-bromophenyl) methyl] ({4- [2-({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} sulfonyl ) Amines, And N-[(3-iodophenyl) methyl] {4- [2-({2-[(5nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carbox Replica, 1- [2- {[2- ({6- amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -4- (2, 4-dichlorophenyl) 5-pyrimidinyl] -2-piperazinone, 1- [2-{[2- ({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -4- (2, 4-dichlorophenyl) -5-pyrimidinyl] -4-ethyl-3-methyl-2-piperazinone, 1- {[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl2-piperazinone, 1- [2-{[2-({6-amino5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -4- (2, 4-dichlorophenyl) -5 pyrimidinyl] -4-methyl-2-piperazinone, 6- [(2- {[6- (2, 4-dichlorophenyl) -5- (4-methyl-2-oxo-1-piperazinyl) -2-pyridinyl] amino} ethyl) amino] nicotinonitrile, 1- [6-{[2- ({6-amino-5 [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (4-ethylphenyl) -3-pyridine Diyl] -4-methyl-2-piperazinone, 6-[(2-{[6- (4-ethylphenyl) -5- (4-methyl-2-oxo-1-piperazinyl) -2-pyridinyl] amino} ethyl) amino] nicotinonitrile, 6- ({2- [[6- (4-ethylphenyl) -5- (4-methyl-2-oxo1-piperazinyl) -2-pyridinyl] (methyl) amino] ethyl} amino) nicotino Nitrile, 6-[(2-{[4- (2, 4-dichlorophenyl) -5- (4-methyl-2-oxo-1-piperazinyl) -2-pyrimidinyl] amino} ethyl) amino] nicotinonitrile, 1- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-difluorophenyl) 3--pyridinyl] -4-methyl-2-piperazinone, 4- [6-{[2- ({6-amino5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -3- (4-methyl-2-oxo-1 Piperazinyl) -2-pyridinyl] benzonitrile, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-isopropyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4- dichlorophenyl) -3-pyridinyl] -4-ethyl-2-piperazinone, 1- {6- {[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- [2- (trifluoromethyl) Phenyl] 3-pyridinyl} -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2pyridinyl} amino) ethyl] amino} -2- (2-bromophenyl) -3- Pyridinyl] -4-methyl-2-piperazinone, 1- {[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) propyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) propyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) -1-methylethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6 {[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) -1-methylethyl] amino} -2 (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- {[2-({6-amino-5 [hydroxy (oxy) amino] -2-pyridinyl} amino) -1, 1-dimethylethyl] amino} -2- (2, 4-dichloro-phenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] [2- (1-pyrrolidinyl) ethyl] amino} -2- (2, 4-dichlorophenyl) 3-pyridinyl] -4-methyl-2-piperazinone, 1- [6- [3-({6-amino-5- [hydroxy (oxy) amino] -2pyridinyl} amino) propyl] -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-[[2- ({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] (methyl) amino] -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6- [2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethoxy] -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} oxy) -ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxido) amino] -2-pyridinyl} amino) ethyl] [2- (4-morpholinyl) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -2-piperazinone, 1- [6- [2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-cyclopropyl-2-piperazinone, 1 [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-cyclohexyl-2-piperazinone, 1- [6- {[2- ({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (4-bromophenyl) -3 -Pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} -amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -3, 4-dimethyl-2-piperazinone, 1 (2- (2, 4-dichlorophenyl) -6-{[2-({5- [hydroxy (oxy) amino] -6-methoxy-2-pyridinyl} amino) -ethyl] amino} -3-pyridinyl)- 4-methyl-2-piperazinone, 1- (2- (2, 4-dichlorophenyl) -6-{[2-({5 [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -3-pyridinyl) -4-methyl-2-pipe Lazinon, 4- [6- {[2- ({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl]-amino} -3- (4-methyl-2-oxo -1-piperazinyl) -2-pyridinyl] benzamide, 2- [6-{[2-({6-amino-5 [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] hexyhydropyrrolo [1, 2-a] pyrazine-3 (4H) -one, 1- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4- (methylsulfonyl) -2-piperazinone, 4-acetyl-1- [6- {[2- ({6-amino-5- [hydroxy (oxydo) amino] 2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -2-piperazinone, 2- [6 {{6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4dichloro ~ phenyl) -3-pyridinyl] hexahydropyrrolo [1, 2-a] pyrazine-3 (4H) -one, 2- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) 3-pyridinyl] hexahydropyrrolo [1, 2-a] pyrazine-3 (4H) -one, 2- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] hexahydropyrrolo [1, 2-a] pyrazine-1 (2H) -one, 2- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] 2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] hexahydropyrrolo [1, 2-a] pyrazine-1 (2H) -one, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} -amino) ethyl] amino} -2- (2, 4-difluorophenyl) -3-pyridinyl] -4-ethyl-2-piperazinone, 4- [6-{[2- ({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -3- (4-ethyl-2-oxo- 1-piperazinyl) -2-pyridinyl] benzonitrile, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2pyridinyl} amino) propyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4-ethyl-2-piperazinone, 1- (6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2-phenyl-3-pyridinyl)- 4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy- (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (4-chlorophenyl) -3 -Pyridinyl] -4-methyl- 2-piperazinone, 3-amino-1- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} -amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -2-piperidinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (3-chlorophenyl) -3- Pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenoxy) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] -amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -4- (2, 2, 2-trifluoroethyl) -2-piperazinone, 4- [6 {[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3-pyridinyl] -3-morpholine source, 1- {6- [2- (6-amino-5-nitro-pyridin-2-ylamino) ethylamino]-[2, 3 '] bipyridinyl-3-yl} -4-methyl-piperazin-2-one, 1- [6- {[2- ({6-amino-5 [hydroxy (oxy) amino] -2-pyridinyl} amino) ethyl] amino} -2- (2, 4-dichlorophenyl) -3pyridinyl] -2-piperidinone, 1- [6- {[2- ({6-amino-5- [hydroxy (oxy) amino] -2-pyridinyl} -amino) ethyl] amino} -2- (4-chloro-2-methylphenyl ) -3-pyridinyl] -4-methyl-2-piperazinone, 1- [6-{[2-({6-amino-5- [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (4methoxyphenyl) -3- Pyridinyl] -4-methyl-2-piperazinone, And 1- [6-{[2-({6-amino-5 [hydroxy (oxydo) amino] -2-pyridinyl} amino) ethyl] amino} -2- (3-furyl) -3-pyrid Diyl] -4-methyl-2-piperazinone.

The following compounds showed IC ₅₀ of 1 M or less for GSK3 in this cell-free assay: 4- {2-[(2- (2-pyridyl) ethyl) amino] pyrimidin-4-yl} benzamide, 4- {2-[(2phenylpropyl) amino] pyrimidin-4-yl} benzamide, 4- (2-{[2- (2-pyridylamino) ethyl] amino} pyrimidin-4-yl) Benzamide, 4- (2-{[2- (pyrimidin-2-ylamino) ethyl] amino} pyrimidin4-yl) benzamide, (5-nitro-4-phenylpyrimidin-2-yl) [ 2- (2-pyridylamino) ethyl] amine, 4- (2- {[3- (4-nitroimidazolyl) propyl] amino} pyrimidin-4-yl) phenol, 4- {[2- ( 2-methoxyphenyl) -ethyl] amino} pyrimidin-4-yl) benzamide, 4- [2- ({2- [(5-cyano-2-pyridyl) amino] ethyl} amino) pyrimidine -4-yl] benzamide, 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4phenylpyrimidine-5-carbonitrile, 4- [2-({ 2-[(6-methoxy-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benz Mid, 4- (2-{[3- (4,5-dichloroimidazolyl) propyl] amino} pyrimidin-4yl) phenol, 4- (2- {[3- (4-nitroimidazolyl) Propyl] amino} pyrimidin-4-yl) benzamide, 4- {2- [(3 benzimidazolylpropyl) amino] pyrimidin-4-yl} benzamide, 4- [2- ({2- [ (4-amino-5-cyano-pyrimidin-2-yl) amino] ethyl} amino) pyrimidin-4-yl] benzamide, 4- {2- [(3-benzimidazolylpropyl) amino] Pyrimidin-4-yl} -2-methoxyphenol, 4- (2-{[2- (2,5dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzamide, 4- (2- {[2- (2, 3-dimethoxyphenyl) ethyl] amino} pyrimidin-4-yl) benzamide, 4- (2-{[3- (4-methoxyphenoxy) propyl] amino} pyrimidine -4-yl) benzamide, 4- [2- ({2- [(5-nitro-2-pyridyl) amino] ethyl} amino) pyrimidin-4-yl] benzamide, {2-j (5 -Nitro (2-pyridyl)) amino] ethyl} (5-nitro-4-phenylpyrimidin-2-yl) amine, 4- (2- { [2- (2-quinolylamino) ethyl] amino} pyrimidin-4-yl) benzamide, 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl )) Amino] ethyl} amino) pyrimidine-5carbonitrile, 4- (2- {[3- (4, 5-dichloroimidazolyl) propyl] amino} pyrimidin-4-yl) benzamide, 4 { 2-[(2-{[5- (aminothioxomethyl) -2-pyridyl] amino} ethyl) amino] pyrimidin-4-yl} benzamide, 4- [2-({3-[(5 -Nitro-2-pyridyl) amino] propyl} amino) pyrimidin-4-yl] benzamide, 4- (2-{[3- (4phenylimidazolyl) propyl] amino} pyrimidin-4-yl ) Benzamide, 4- {2- [(3-naphthyloxypropyl) -amino] pyrimidin-4-yl} benzamide, 4- (2-{[3- (5, 6-dimethylbenzimidazolyl ) -Propyl] amino} pyrimidin-4-yl) benzamide, [4- (4-imidazolylphenyl) pyrimidin-2-yl] {2-[(5nitro (2-pyridyl)) amino] Ethyl} amine, 4- {2-[(2-{[5- (trifluoromethyl) -2-pyridyl] amino} ethyl) amino] Rimidin-4-yl} benzamide, 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-car Copyamide, 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylic acid, 2-({2- [(6-Amino-5-nitro (2pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5-carboxylic acid, ethyl 2 ({2-[(5-nitro (2-pyridyl)) amino] ethyl] amino) -4- (2-pyridyl) pyrimidine-5-carboxylate, ethyl 2- ({2-[(5-cyano (2-pyridyl)) ) Amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5carboxylate, 4- [2-({3- [3- (trifluoromethyl) phenoxy] propyl} amino) Pyrimidin-4-yl] benzamide, [4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino)-pyrimidine-5 -Yl] -N-methylcarboxamide, methyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} ah Mino) pyrimidin-5-carboxylate, [4- (4-morpholin-4-ylphenyl) -pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] Ethyl} amine, ethyl 4- (4-methylphenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, {2- [ (6-amino-5nitro (2-pyridyl)) amino] ethyl} {5-nitro-6- [benzylamino] (2-pyridyl)} amine, 2-({2-[(5-nitro- (2-pyridyl)) amino] ethyl} amino) -4- (4-nitrophenyl) pyrimidine-5-carboxylic acid, ethyl 4- (4- fluorophenyl) -2-({2-[(5- Nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, 4 [5-imidazolyl-2- ({2- [(5-nitro (2-pyridyl)) amino ] Ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile, 4- [5-imidazol-2-yl-2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} Amino) pyrimidin4-yl] benzenecarbonitrile, ethyl 2- ({2-[(4-amino-5-cyanopyrimidin-2-yl) Amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidin-5-carboxylate, [4- (2,4-dimethylphenyl) -5-imidazolylpyrimidin-2-yl] { 2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 (2,4-dichlorophenyl) pyrimidine-5carbonitrile, ethyl 4- (4-cyanophenyl) -2- ({2-[(4-nitrophenyl) amino] ethyl} amino) pyrimidine-5 -Carboxylate, [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N, N-dimethylcarboxamide, ethyl 4- (4-cyanophenyl) -2- ({2- [(5- nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate , [4- (2, 4-dichlorophenyl) -5-ethylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, ethyl 4- (4- Ethylphenyl) -2- (12-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxy Silates, ethyl 4- (4-methoxyphenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, 4- [ 5- (methylsulfonyl) -2- (12- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile, 4- (2-{[3 -(5, 6-dichlorobenzimidazolyl) propyl] amino} pyrimidin-4-yl) benzamide, 4- [2- ({2- [(6-amino-5-nitro (2-pyridyl) ) Amino] ethyl} amino) -5-imidazolylpyrimidin-4-yl] benzenecarbonitrile, 4- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino ] Ethyl} amino) -5-imidazol-2-ylpyrimidin-4-yl] benzenecarbonitrile, N- (cyanomethyl) [4- (4-cyanophenyl) -2- ({2- [ (5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carboxamide, 4- [5- (3-methyl (1, 2,4-oxadiazole-5- Yl))-2- ([2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarboni Reyl, ethyl 4- (4-chlorophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, ethyl 4- (3 , 4-difluorophenyl) -2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, N- (2aminoethyl) [ 4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin5-yl] carboxamide, ethyl 4- (4- Cyanophenyl) -2-({2-[(4-methyl-5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, ethyl 2- {2-[(6 -Amino-5-nitro (2pyridyl)) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5-carboxylate, [4- (4-cyanophenyl) -2- ({2- ((5- Nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N- (2-hydroxyethyl) carboxamide, 2-hydroxyethyl 4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimi -5-carboxylate, ethyl 2-({2- [(4-amino-5-nitropyrimidin-2-yl) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine- 5-carboxylate, ethyl 4- [4- (methylethyl) phenyl] -2-({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 carboxylate , Ethyl 4- [4- (dimethylamino) phenyl] -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, ethyl 4- (2H-benzo [3, 4-d] 1,3-dioxolen-5-yl) -2-({2-[(5nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 -Carboxylate, ethyl 2- ({2- [(5-nitro (2pyridyl)) amino] ethyl} amino) -4- (4-nitrophenyl) pyrimidine-5-carboxylate, ethyl 4- (4-methylthiophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5carboxylate, ethyl 4- (4-cyanophenyl) -2-[(2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amino] pyri Din-5-carboxylate, ethyl 4- (2-naphthyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] -ethyl} amino) pyrimidine-5-carboxyl Late, N-butyl [4- (4-cyanophenyl) -2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carboxamide, N- (tert-butyl) [4- (4-cyano-phenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] Carboxamide, ethyl 4- (4-orbamoylphenyl) -2- ({2- [(5-cyano (2-pyridyl)) amino] ethyl} amino) -6-ethyl- pyrimidine-5- Carboxylate, tert-butyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, N- (carbamoylmethyl) [4- (2-cyanophenyl) -2-({2 [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carbox Copymid, ethyl 4- (4-cyanophenyl) -6-ethyl-2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyri Dine-5-carboxylate, butyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5carboxylate , Ethyl 4-1 [(4-cyanophenyl) methyl] amino} -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate , Ethyl 4-{[(3-cyanophenyl) methyl] amino} -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate , Ethyl 4- [4- (tert-butyl) phenyl] -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, 4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -5- [benzylamino] pyrimidin-4-yl] benzenecarbonitrile, [4- (2, 4 -Dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl))-amino) ethyl} amine, [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] Methyl} amine, 4- (4-cyanophenyl) -6- (3-furyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 -Carboxylic acid, 4- [2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -5- (piperazinylcarbonyl) pyrimidin-4-yl] benzenecarbonitrile , Ethyl 4- (4- imidazolylphenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 carboxylate, 4- [5- (Morpholin-4-ylcarbonyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile, ethyl 4- ( 4- (2-furyl) phenyl) -2- ({2- [(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, ethyl 2- ({2- [ (5-nitro (2pyridyl)) amino] ethyl} amino) -4- (4- (1, 3-oxazol-5-yl) phenyl) pyrimidine-5-carboxylate, ethyl 2- ( {2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4- (1, 2,4-triazol-4-yl) phenyl) pyri Dean5-carboxylate, N- [2- (dimethylamino) ethyl] [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl } Amino) pyrimidin-5-yl] carboxamide, 2- (dimethylamino) ethyl 4- (4-cyano-phenyl) -2- ({2- [(5-nitro (2-pyridyl)) Amino] ethyl} amino) pyrimidine-5-carboxylate, ethyl 2 ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- [4- (trifluoromethyl ) Phenyl] pyrimidine-5carboxylate, ethyl 4- (2, 4-dichlorophenyl) -2- ({2- [(5-nitro (2-pyridyl)) aminoethyl} amino) pyrimidine-5 -Carboxylate, ethyl 4- (sol (1H-1, 2,3,4-tetrazol-5-yl) phenyl) -2-({2-[(5-nitro (2-pyridyl)) amino ] Ethyl} amino) pyrimidine-5-carboxylate, ethyl 4- (4-carbamoylphenyl) -6-ethyl-2- {2-[(5-nitro (2-pyridyl)) amino] ethyl } Amino) pyrimidine-5-carboxylate, 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-py Dill)) amino] ethyl} amino) -6-phenylpyrimidine-5carboxylic acid, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4- Dichlorophenyl) -5imidazolylpyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl ) -5-imidazol-2-ylpyrimidin-2-yl] amine, ethyl 4- (4-bromophenyl) -2-({2-[(5nitro (2-pyridyl)) amino] ethyl } Amino) pyrimidine-5-carboxylate, ethyl 4- [4- (methylsulfonyl) phenyl] -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) Pyrimidine-5-carboxylate, ethyl 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4- (1, 3-oxa Sol-5yl) phenyl) pyrimidine-5-carboxylate, N- [2- (dimethylamino) ethyl] [4- (4-cyanophenyl) -2- ({2-[(5-nitro ( 2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] -N-methylcarboxyamide, N (1-carbamoyl-2-hydroxyethyl) [4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] carboxamide, 3- (dimethyl Amino) propyl 4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, ethyl 2- ( {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidine-5-carboxylate, 2- (dimethylamino ) Ethyl 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-cyanophenyl) pyrimidine-5-carboxylate, [ 2- (dimethylamino) ethoxy] -N- [4- (4-cyanophenyl) -2- ({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine- 5-yl] carboxamide, ethyl 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -4- [4 (trifluoromethoxy) phenyl] pyrimidine-5 -Carboxylate, ethyl 4- (4-morpholin-4-ylphenyl) -2- (12- [(5-nitro (2- Ridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, [4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl } Amino) pyrimidin-5-yl] -N-benzyl-carboxamide, ethyl 4- (6-morpholin-4-yl (3-pyridyl))-2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, [4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) ) Amino] ethyl} amino) pyrimidin-5-yl] -N- (4-pyridylmethyl) carboxamide, phenylmethyl 4- (4- cyanophenyl) -2- ({2- [(5- Nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, 4 (4-cyanophenyl) -6- (4-fluorophenyl) -2- ({2- [( 5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylic acid, N-[(3-methoxyphenyl) methyl] {4- [2-({2-[(5-nitro (2pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] phenyl} carboxamide, 4- [5- {3- [2- (dimethylamino) Tyl] (1, 2, 4-oxadiazol-5-yl)}-2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-4-yl] Benzenecarbonitrile, N-[(3-bromophenyl) methyl] [4- (2- {[2- (pyrimidin-2-ylamino) ethyl] amino} pyrimidin-4-yl) phenyl] carboxa Mid, 4- (dimethyl-amino) butyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine5-carboxyl , 4,6-bis (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylic acid, ethyl 2- ( {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (4-morpholin-4-ylphenyl) pyrimidine-5-carboxylate, 4- (3-hydroxyphenyl)-2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid, 2- Morpholin-4-ylethyl 4- (4-cyanophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimi Din-5-carboxylate, 4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl ) Pyrimidine-5-carboxylic acid, 4- (4-cyanophenyl) -2- (12- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (3-nitrophenyl) Pyrimidine-5-carboxylic acid, N- [(3-bromophenyl) methyl] {4- [2- ({2- [(5-cyano (2-pyridyl)) amino] ethyl} amino) pyzolmidine -4-yl] phenyl} carboxamide, ethyl 4- (4-carbamoylphenyl) -2- ({2- [(5-nitro- (2-pyridyl)) amino] ethyl})-6- (4-pyridyl) pyrimidine-5-carboxylate, 2- (dimethylamino) ethyl 2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino ) -4- (2,4-dichloro-phenyl) pyrimidine-5-carboxylate, 2- [bis (2-hydroxyethyl) amino] ethyl4- (4-cyanophenyl) -2 ({2 -[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5-carboxylate, {4- [2- ({2- [(4- Mino-5-cyanopyrimidin-2-yl) amino] ethyl} amino) pyrimidin-4-yl] phenyl} -N- [(3-bromo-phenyl) methyl] carboxamide, 4- (4 -Carboxyphenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylic acid, 2-hydroxy- 3-morpholin-4-ylpropyl 4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine-5 carboxylate , Ethyl 4- (4-cyanophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) -6- (4- nitrophenyl) pyrimidine-5- Carboxylate, (2- {5- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) Pyrimidin-5-yl] (1, 2,4-oxadiazol-3-yl)} ethyl) dimethylamine, ethyl 4- (4-carbamoylphenyl) -2- ({2- [(5- Nitro (2-pyridyl)) amino] ethyl} amino) -6- (4-nitrophenyl) pyrimidine-5-carboxylate, [4- (4-di Midazolylphenyl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino) ethyl} amine, 4- [5-imidazolyl-2- ({2- [(5 -Nitro (2-pyridyl))-amino] ethyl} amino) pyrimidin-4-yl] benzenecarbonitrile, 4- [2-({2-[(6-amino-5-nitro (2pyridyl) ) Amino] ethyl} amino) -5-imidazolylpyrimidin-4-yl] benzenecarbonitrile, [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2 -[(5-nitro (2-pyridyl)) amino] ethyl} amine, 4- [2- ({2- [(5-nitro-2-pyridyl) amino] ethyl} amino) -7a-hydro- 1, 2,4-triazolo [1, 5-a] pyrimidin-7yl] benzenecarbonitrile, {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4 -(2,4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] amine, [4- (2,4-dichlorophenyl) -5-imidazol-2-yl- pyrimidin-2- Yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, 6-[(2-{[4- (2,4-dichlorophenyl) 5-imidazolylpyrimidine-2 -Yl] amino} ethyl) amino] pyridine-3-carbonitrile, [5-benzotriazolyl-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2- [(5-nitro (2 -Pyridyl)) amino] ethyl} amine, [2-({2 [(6-amino-5-nitromin-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyri Midin-5yl] methane-l-ol, [4- (2,4-dichlorophenyl) -2-({2-[(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidine- 5-ylgmethane-1-ol, 2- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4 (2,4-dichlorophenyl ) Pyrimidin-5-yl] isoindolin-1,3-dione, [5-amino-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5 -Nitro (2-pyridyl)) amino] ethyl} amine, {2 [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5 -Morpholin-4-ylpyrimidin-2-yl] amine, {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} {4- (2, 4-dichlorophenyl) -5- [5- (t Fluoromethyl) (1, 2,3,4-tetrazolyl)] pyrimidin-2-yl} amine, 1- [2- ({2-[(6-amino-5-nitro (2-pyridyl) ) Amino] ethyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] pyrrolidine-2, 5-dione, [4- (2,4-dichlorophenyl) -5-pyra Zolylpyrimidin-2-yl] {2-[(5-nitro (2pyridyl)) amino] ethyl} amine, [4- (2, 4-dichlorophenyl) -5- (4-methylimidazolyl) Pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, [4- (2, 4-dichlorophenyl) -5- (2, 4 dimethyl imidazolyl ) Pyrimidin-2-yl] {2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 6-[(2-{[4 (2,4-dichlorophenyl) -5-imi Dazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3carbonitrile, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4 (2,4-dichlorophenyl) -5 (morpholin-4-ylmethyl) pyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] Ethyl} [4- (2,4-dichloro Phenyl) -5-piperazinylpyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2pyridyl)) amino] ethyl} [4- (4-ethylphenyl) -5 -Imidazolylpyrimidin-2-yl] amine, 1- [4- (2, 4-dichlorophenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino ) Pyrimidin-5-yl]-hydropyridin-2-one, [5-benzimidazolyl-4- (2, 4-dichlorophenyl) pyrimidin-2-yl] {2- [(5-nitro- (2-pyridyl)) amino] ethyl} amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5- Imidazolylpyrimidin-2-yl] methylamine, {2- [(6-amino-5-nitro (2pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5- ( 4-pyridyl) pyrimidinyl-2-yl] amine, {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl)- 5- (4-methylpiperazinyl) -pyrimidin-2-yl] amine, [4- (2,4-dichlorophenyl) -5- (2-methylimidazolyl) pyrimidin-2-yl] { 2 [(5-Knit (2-pyridyl)) amino] ethyl} amine, {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4 (2,4-dichlorophenyl) -5- ( 2-methylimidazolyl) pyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichlorophenyl) -5- (4-phenylimidazolyl) pyrimidin-2 yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4- Dichlorophenyl) -5- (2,4-dimethylimidazolyl) pyrimidin-2-yl] amine, [4- (2,4-dichlorophenyl) -5-imidazol-2 ylpyrimidin-2-yl] (2-{[5- (trifluoromethyl) (2-pyridyl)] amino} ethyl) amine, [4- (2, 4 dichlorophenyl) -5-piperazinylpyrimidin-2-yl] {2- [(5-Nitro (2-pyridyl)) amino] ethyl} amine, [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] [2- (dimethyl Amino) ethyl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, 1- [2- ({2-[(6-amino-5-nitro (2-pyridyl)) Amino] Tyl} amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] -4-methylpiperazin-2,6-dione, [4- (2, 4- dichlorophenyl) -5- ( l-methylimidazol-2-yl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, 1- [2- ({2-[( 6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4-dichloro-phenyl) pyrimidin-5-yl] -3-morpholin-4-ylpyrrolidine -2, 5-dione, 1- [4- (2, 4-dichlorophenyl) 2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl ] -4-methylpiperazin-2, 6 dione, 1- [2-({2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4 dichlorophenyl) pyrimidin-5-yl] -3- (dimethylamino) pyrrolidine-2, 5-dione, {5-imidazol-2 yl-4- [4- (trifluoromethyl) phenyl] Pyrimidin-2-yl} {2-[(5-nitro (2 pyridyl)) amino] ethyl} amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2,4 Dichlorophenyl) -5- (1-methyl is Midazol-2-yl) pyrimidin-2-yl] amine, [4- (2, 4-dichlorophenyl) 5- (4-methylpiperazinyl) pyrimidin-2-yl] {2- [(5 -Nitro (2-pyridyl)) amino] ethyl} amine, [4- (2, 4 dichlorophenyl) -5- (morpholin-4-ylmethyl) pyrimidin-2-yl] {2- [(5 -Nitro (2pyridyl)) amino] ethyl} amine, [4- (2, 4-dichlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl3 amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2, 4-dichloro Phenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl] amine, {2- [(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [ 4- (2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine, [4- (2-chloro-4-fluorophenyl) -5-imidazol-2-ylpyri Midin-2-yl] {2- [(5-nitro (2 pyridyl)) amino] ethyl} amine, [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] {2- [(5 nitro (2-pyridyl)) Mino] ethyl} (2-pyrrolidinylethyl) amine, [4- (2, 4-dichlorophenyl) -5-imidazolylpyrimidin-2-yl] (2-morpholin-4-ylethyl) { 2- [(5-nitro (2 pyridyl)) amino] ethyl] amine, 6-[(2-{[4- (2,4-dichlorophenyl) -5- (4-methylimidazol-2yl ) Pyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile, {2- [(6-amino-5-nitro (2 pyridyl)) amino] ethyl} [4- (2-chloro -4-fluorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine, [4- (4-ethylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-Nitro (2 pyridyl)) amino] ethyl} amine, [5-((1E) -1-aza-2-morpholin-4-ylprop-1-enyl) -4- (2,4 dichlorophenyl) pyrimidin-2-yl] {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} amine, N- [4- (2,4-dichloro Phenyl) -2- ({2- [(5-nitro (2-pyridyl)) amino] ethyl} amino) pyrimidin-5-yl] acetamide, [4- (2, 4-dichlorophenyl) -5 Imidazol-2-ylpi Rimidin-2-yl] {2- [(6-methoxy-5-nitro (2-pyridyl)) amino] ethyl} amine, 6-[(2- {[4- (2, 4-dichlorophenyl ) -5-imidazolylpyrimidin-2-yl] methylamino} ethyl) amino] pyridine-3-carbonitrile, 6- [(2- {[4- (2, 4-dichlorophenyl) -5-imide Dazol-2-ylpyrimidin-2-yl] methylamino} ethyl) amino] pyridine-3-carbonitrile, [4- (2, 4-dichlorophenyl) -5-imidazol-2-ylpyrimidine-2 -Yl] methyl-2-[(5-nitro (2-pyridyl)) amino] ethyl} amine, 6-[(2- {[4- (2-chloro-4-fluorophenyl) -5-im Dazol-2-ylpyrimidin-2-yl] amino} ethyl) amino] pyridine-3-carbonitrile, [4- (4-chlorophenyl) -5-imidazol-2 ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-chloro -2-methylphenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- ( 4- Lomo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] amine, 6-[(2- {4- (4-bromo2-chlorophenyl) -5-imidazole- 2-ylpyrimidin-2yl] amino} ethyl) amino] pyridine-3-carbonitrile, 6- [2-({2-[(6-amino-5-nitro (2pyridyl)) amino] ethyl} Amino) -4- (2, 4-dichlorophenyl) pyrimidin-5-yl] -3-pyrrolino [3,4b] pyridine-5, 7-dione, N- [2- ({2-[( 6-amino-5-nitro (2-pyridyl)) amino] ethyl} amino) -4- (2, 4- dichlorophenyl) pyrimidin-5-yl] -2- (methylamino) acetamide, {2 -[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (4-bromo-2-chlorophenyl) -5- (4-methylimidazol-2-yl) Pyrimidin-2yl] amine, 6- [(2- {[4- (4-bromo-2-chlorophenyl) -5- (4-methylimidazol-2-yl) pyrimidin-2-yl ] Amino} ethyl) amino] pyridine-3-carbonitrile, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [4- (2-chloro-4-fluorophenyl ) -5- (4-methylimide Dazol-2-yl) pyrimidin-2-yl] amine, 6-[(2- {[4- (2,4-dichlorophenyl) -5- (5-chloro-2-oxohydropyridyl) pyrimidine -2-yl] amino} ethyl) amino] pyridine-3-carbonitrile, [6- (2, 4-dichlorophenyl) -5-imidazolyl (2-pyridyl)] {2- [(5-nitro (2-pyridyl)) amino] ethyl} amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5- Imidazolyl (2-pyridyl)] amine, 6- [(2- {[6- (2, 4-dichlorophenyl) -5imidazolyl-2-pyridyl] amino} ethyl) amino] pyridine-3 -Carbonitrile, {2-[(6-amino-5-nitro (2pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5-nitro (2-pyridyl)] amine, {2-[(6-amino-5-nitro (2-pyridyl)) amino] ethyl} [6- (2, 4-dichlorophenyl) -5- (4-methylimidazolyl) (2pyridyl) ] Amine, 6-[(2-{[6- (2, 4-dichlorophenyl) -5- (4-methylimidazolyl) -2-pyridyl] -amino} ethyl) amino] pyridine-3-carboni T Aryl, and [4- (4-bromo-2-chlorophenyl) -5-imidazol-2-ylpyrimidin-2-yl] {2- [(5-nitro (2-pyridyl)) amino] Ethyl} amine.

Thus, these results demonstrate that the compounds of the present invention exhibit inhibitory activity against GSK3.

Example 266

Screening for GSK3 Inhibitory Activity Using Cell-Based Glucogen Synthetase Assay

CHO-HIRC cells are maintained in 10 cm tissue culture plates containing Han's F12 medium / 10% dialysate fetal serum. Cells from confluent 10 cm plates were harvested and dispensed into 6 wells of 6-well tissue culture plates to a final volume of 2 ml of medium. Cells were allowed to grow for 24 hours at 37 ° C. Cells were then washed three times in Hans F12 medium without fetal bovine serum and finally placed at 37 ° C. for 24 hours in 2 ml serum free medium.

At the end of this time, 20 μl of compound dissolved in DMSO is added to each well and incubated at 37 ° C. After 20 minutes the medium is removed and the cells are washed once with PBS at room temperature and then quickly frozen in liquid nitrogen to a plate state. The cells are then thawed on ice in the presence of 140 μl of lysis buffer solution per well (50 mM Tris pH 7.8; 1 mM EDTA, 100 mM NaF, 25 llg / ml leupetin, 1 mM DTT, 1 mM PMSF). . The cells are scraped from the plate and placed in Eppendorf tubes on dry ice and frozen. The cell lysate is then thawed and re-frozen on dry ice.

After recommissioning, the cell lysate is centrifuged at 14,000 g for 15 minutes. The supernatant is then removed and stored on ice. Each supernatant (45 μl) was added to 45 μl of reaction buffer (65 mM Tris pH 7.8; 26 mM EDTA, 32.5 mM KF, 9.3 mM UDP-glucose; 11 mg / ml glycogen; 500 nCi / ml 14C-UDP-glucose) Add another 45 μl to 45 μl reaction buffer / 20 mM glucose-6-phosphate. The reaction is incubated at 30 ° C. for 30 minutes and then spotted on 2 cm ² 31ET chromatography paper (Whatman). The filter paper is washed twice in 66% ethanol for 20 minutes, briefly rinsed with acetone and dried at room temperature for 1 hour.

Filter paper is added to 5 ml of liquid scintillation and counted in a liquid scintillation counter. The percentage of total glycogen synthase active in any lysate is expressed as 100 × (cpm-glucose-6-phosphate) / (cpm + glucose-6-phosphate). This value was measured in duplicate for five different compound concentrations and DMSO alone, and then the values were plotted in logarithm of the concentration. The concentration of compound stimulating glycogen synthase activity at 50% of maximum level was determined by matching the sigmoidal curve to the data shown. The maximum level is defined as the level at which the glycogen synthase activity tends to be asymptotic when the concentration of the test compound substantially increases beyond the EC ₅₀ .

Example 267

Screening for Inhibition of Tau Protein Phosphorylation

A. Transient Transfection of COS Cells with GSK3 Expression Plasmid and Tau Expression Plasmid Constructs

COS cells are maintained in a T25 tissue culture flask containing high glucose MEM medium / 5% fetal bovine serum. The cells from the confluent T25 flasks are harvested and seeded with 80,000 cells / well in a final volume of 2 ml / well medium in Coming 6-well tissue culture plates. The cells are allowed to grow for 48 hours at 37 ° C. The cells are then washed twice with Opti-MEM without fetal bovine serum, and finally the cells are left in 1 ml Opti-MEM.

Polynucleotides encoding tau protein were subcloned into plasmid pSG5 under the initial SV40 promoter to generate tau expression plasmids. Cloning of cDNA encoding tau protein is described in Goedert et al., EMBO Journal, 8 (2): 393-399 (1989), which is incorporated herein by reference. GSK3 expression plasmids are prepared by subcloning polynucleotides encoding GSK3β into pCG, which are described as ApEVRF derivatives by Giese et al., Genes & Development, 9: 995-1008 (1995) and Matthias et al., Nucleic Acid Research, 17: 6418 (1989), both of which are incorporated herein by reference.

The following solutions are prepared in 1.5 ml Eppendorf tubes: Solution A: For each transfection, 2 μg of DNA (tau expression plasmid) and 0.7 μg of DNA (GSK3 expression plasmid) are added in 100 μl Opti-MEM. Dilution into (Gibco BRL); Solution B: For each transfection, 8 μl Lipofectamine reagent is diluted into 100 μl Opti-MEM. The two solutions are combined, gently mixed, and incubated at room temperature for 45 minutes to form the DNA-liposomal complex. For each transfection, 0.8 ml of Opti-MEM is added to the tube containing the complex. Mix the dilution solution gently and spread over rinsed cells. Cells are incubated with complex DNA / lipopeptamine for 6 hours at 37 ° C. in a CO 2 incubator. After incubation, 1 ml of growth medium (high glucose MEM) with 20% FBS is added to each well and incubated overnight at 37 ° C. After 18 hours from the start of transfection, the medium is replaced with fresh complete medium and the cells are allowed to grow at 37 ° C. for another 48 hours.

B. Tau Phosphorylation Inhibition Assay

Two hours before harvesting, 2 μl of test compound (GSK3 inhibitor) dissolved in DMSO is added to each well and incubated at 37 ° C. After 2 hours the medium is removed and the cells are quickly frozen on dry plates with dry ice and stored at -70 ° C. 200 μl of cell lysis buffer (1% Triton ^® X-100,20 mM Tris pH 7.5,137 mM NaCl, 15% glycerol, 25 μg / ml leupetin, 1 μg ml pepstacin-A, 1 μM PMSF, Thaw cells on ice with 21 μg / ml aprotinin, 50 mM NaF, 50 mM p-glycerophosphate, 15 mM sodium pyrophosphate, 1 mM sodium orthovanadate. Centrifuge the contents of each well at 14,000 g at 4 ° C. for 5 minutes and transfer the supernatant to a clear tube. At this time, the cell lysate may be stored at -20 ° C.

C. ELISA for Detection of Phosphorylated Tau in Cytolysates

Immulon 4 Strips (Dynatech) is coated with monoclonal anti-phosphorylated tau (AT8, Polymedco, Inc.) at a concentration of 5 μg / ml in PBS containing 100 μl / well Ca ++ and Mg ++. After overnight incubation at 4 ° C., the strips were washed twice with wash buffer (PBS containing 0.05% Tween® 20) and PBS containing 1% BSA, 5% normal mouse serum and 0.05% Tween® 20 1 hour at room temperature. The strips are washed five times with wash buffer. Cell lysates (100 μl) diluted 1:10 with PBS containing 1% BSA, 0.1% NaN ₃ are added to each well and incubated for 1 hour at room temperature. After washing, 100 μl of 0.5 μg / ml biotinylated monoclonal anti- (non-phosphorylated) tau (HT7, Polymedco, Inc.) in PBS-BSA is added to each well. The strips are washed five times and HRP-conjugated streptavidin is added, then incubated for 30 minutes at room temperature and washed extensively with wash buffer. TMB substrate (Pierce) is used for color development and the reaction is stopped by addition of an equal volume of 0.8 M sulfuric acid. Strips are read on an ELISA plate reader using a 450 nm filter. The concentration of compounds that inhibit tau phosphorylation at 50% of the maximum level (ie IC ₅₀ ) was determined by matching the sigmoidal curves to the data shown.

Example 268

Protects primary hippocampal cells from glutamate-promoting toxicity

Screening of GSK3 Inhibitors

Hippocampus was excised from rats 18-19 days of embryo. Tissues were collected in Hibernate ™ medium (Gibco BRL) and chopped into approximately lmm pieces. Tissues were isolated using Papain dissociation system (Worthington Biochemical Corporation). After isolation, cells were resuspended in serum-free medium consisting of Neurobasal ™ (Gibco BRL), 2% B27 additive (GibcoBRL), L-glutamine and antibiotics. Cells were plated at a concentration of 7.5 × 10 ⁴ cells / dish in 35 mm tissue culture dishes coated with poly-L-lysine. After 10-14 days at 37 ° C. with 5% C02 cells were rinsed and nourished with fresh medium. The next day representative compounds of the invention were added to the culture medium at a final concentration between 1 nM and 100 μM. Conditional medium was removed from the cells 4-8 hours after compound addition and stored at 37 ° C. Cultures were rinsed twice with HEPES-buffered balanced salt solution (HBSS) containing 10 μM glycine. Grabb and Choi, J. Neuroscience 19 : 1657-62 (1999). The culture was then exposed to 200 uM glutamic acid in the same HBSS for 5 minutes at room temperature. After exposure, the culture was rinsed three times with buffer and then returned to the original conditioned medium containing the compound. After 20 to 24 hours from glutamic acid exposure, the cultures were rinsed with HBSS and exposed to Trypan Blue for 10 minutes. This dye is absorbed into dead cells. The cultures were rinsed and then fixed in 4% paraformaldehyde for 30 minutes. Live and dead (blue nucleus) giant neurons were counted and photographed with a phase contrast microscope (at least 200 cells from each culture). Using this method, it was shown that the compounds of the present invention can significantly reduce the ability of glutamine to induce neuronal cell death.

Example 269

Evaluation of Efficacy in Diabetic Rodents

(Glucose intolerance test)

Compound preparations for oral administration:

Test compound was prepared in 1% carboxymethylcellulose / 0. Typically formulated for oral nutrition as a solution in water or suspension in 1% tween-80 (both purchased from Sigma Chem., MO). Some initial compounds were formulated as solutions in 15% Captisol (converted cyclodextrin, CyDex Co., IL) following a method common to those below. In aqueous solution, the dried and lyophilized test compound powder is dissolved in distilled water and mixed well by vortexing and sonication. If necessary, the test solution is adjusted to pH with 1 N NaOH or 1 N HC1 and finally distilled filtered through a syringe with a 0.2 micron cellulose acetate membrane (Millipore Co., MA). For oral suspension, the test compound powder is mixed with a fresh suspension of 1% carboxymethylcellulose / 0.1% tween-80, the pH is adjusted as needed as described above, the particle size is equalized and <10 microns in size. It was vortexed until it became.

Diabetic Mouse Glucose Tolerance Test:

Obese db / db (female C57B1Ks / J) mice, 8 weeks old, were obtained from Jackson Labs (Bar Harbor, ME) and used for efficacy testing 1 to 2 weeks later. On the morning of the test, food was removed early in the morning (7-8 hours prior to the administration of glucose pills). Apply local anesthesia at the end of the tail (EMLA creme, Astra Pharm., MA) and take 50-100 μl of blood sample from a piece of tail tip containing 5ul 500U / ml sodium heparin (Elkins-Sinn, NJ). The plasma was separated after collection in an Eppendorf tube. Samples were taken at various intervals of 6-8 hours in total during the day. Mice were randomized into treatment groups and tested once again 4.5 hours prior to glucose administration and 0.5 hours prior to administration of 0.2 ml 50% dextrose (Abbott Lab., IL) via oral nutrition (oGTT) or intraperitoneal injection. One oral dose (0.2 ml volume) was administered. About 2 hours after glucose administration the final blood sample was taken and the animals were fed again.

Regulation of basal glycemia and insulinemia:

Test compounds were typically administered orally to db / db mice (see above) or ZDF rats (Genetic Models, Inc .; Indianapolis, Ind.) In a single, multiple, or multiple dose regimen. ZDF rats were obtained at 8 weeks of age and used for efficacy testing 1 to 2 weeks later. Food was removed about 30 days prior to dosing and a single pill of the test compound (dose ranging from 1 to 8 mg / ml) was administered. Blood was then collected at points 1-6 as described above over 2-3 hours. After taking a blood sample, animals were fed into cages.

Primary endpoint:

Glucose and insulin levels are measured from plasma and / or blood samples. Glucose levels are measured from whole blood with a One-Touch Glucometer (Lifescan Co., CA) and from plasma with a Bekman glucose analyzer. Glucose results typically reflect blood levels for mice and plasma levels for rat studies. Measurement of insulin levels is via ELISA (Crystal Chem. Co., IL) according to the manufacturer's protocol.

Quantify the results:

Efficacy is expressed as mg / dL glucose or ng / ml insulin or area under the curve for plasma glucose (taken above 100 mg / dL normal blood glucose baseline) and insulin (taken above 1 ng / mL normal insulin baseline) It was expressed as (AUC). Typically, when expressed as AUC, the results are eventually expressed as reduced AUC ([(excipient control AUC-test group AUC) / excipient control AUC X 100]). This expression provides a single quantitative representation of the magnitude of improved glucose treatment and / or reduced basal hyperglycemia or insulin retention compared to the placebo control.

result:

Representative compounds of the present invention exhibit good efficacy in vitro and exhibit high bioavailability and tissue penetration in vivo when formulated with captisol and administered subcutaneously to mice (30 mg / kg). Significant reduction in basal hyperglycemia just prior to the glucose tolerance test, and significantly improved glucose treatment after glucose secondary challenge was observed. When the glucose response was quantified by measuring the area under the blood glucose curve (AUC) from -16 min to +120 min, a 45-50% reduction in AUC was observed compared to the control. This is equivalent to the efficacy obtained with Troglitazone (orally taken at least several days at 60 or 100 mg / kg / day). Also important is the observation that insulin levels in treated animals were kept lower than control mice.

While the preferred embodiments of the invention have been illustrated and described, it will be apparent that various changes are possible without departing from the spirit and scope of the invention.

Claims (5)

A compound having the formula (I) or a pharmaceutically acceptable amount thereof, in an amount effective to modulate glycogen synthase kinase 3 activity in a human or animal subject when administered to a human or animal subject, together with a pharmaceutically acceptable carrier: A composition comprising a possible salt. (Formula 1)

Where: W is carbon or nitrogen; A is pyridyl, which may be optionally substituted with one or more substituents independently selected from nitro, amino, cyano and (C1-C10) alkoxy; R ₁ , R ₂ , R ' ₂ , R ₃ , R' ₃ and R ₄ are independently selected from the group consisting of hydrogen and (C 1 -C 10) alkyl; R ₅ and R ₇ are hydrogen; Phenyl which may be optionally substituted with one or more substituents independently selected from nitro, cyano, halo, (C1-C10) alkyl and (C1-C10) alkoxy; Independently selected from the group consisting of 3-pyridyl and 3-furyl; R ₆ is a monoketopiperazinyl group having the formula:

Wherein R ₁₅ and R ₁₆ are independently selected from the group consisting of hydrogen, (C1-C10) alkyl, halo (C1-C10) alkyl, cyclopropyl and cyclohexyl; Or R ₁₆ together with R ₁₅ can form a pyrrolidine ring; o is an integer from 1 to 6. A compound having the formula (4), or a pharmaceutically acceptable thereof, in an amount effective to modulate glycogen synthase kinase 3 activity in a human or animal subject when administered to a human or animal subject, together with a pharmaceutically acceptable carrier: A composition comprising a possible salt. (Formula 4)

R ₁ , R ₂ , R ₃ , and R ₄ are independently selected from the group consisting of hydrogen and (C 1 -C 10) alkyl; R ₅ is hydrogen; Phenyl which may be optionally substituted with one or more substituents independently selected from nitro, cyano, halo, (C1-C10) alkyl and (C1-C10) alkoxy; 3-pyridyl and 3-furyl; R ₆ is a monoketopiperazinyl group having the structure:

Wherein R ₁₅ and R ₁₆ are independently selected from the group consisting of hydrogen, (C1-C10) alkyl, halo (C1-C10) alkyl, cyclopropyl and cyclohexyl; Or R ₁₆ together with R ₁₅ can form a pyrrolidine ring; o is an integer from 1 to 6; R ₈ and R ₉ are independently selected from the group consisting of hydrogen, nitro, amino and cyano; R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₄ are independently selected from the group consisting of hydrogen, nitro, cyano, halo, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy. A compound having the formula (5) or a pharmaceutically acceptable amount thereof, in an amount effective to modulate glycogen synthase kinase 3 activity in a human or animal subject when administered to a human or animal subject, together with a pharmaceutically acceptable carrier: A composition comprising a possible salt. (Formula 5)

Where: R ₁ , R ₂ , R ₃ and R ₄ are independently selected from the group consisting of hydrogen and (C 1 -C 10) alkyl; R ₅ is hydrogen; Phenyl which may be optionally substituted with one or more substituents independently selected from nitro, cyano, halo, (C1-C10) alkyl and (C1-C10) alkoxy; 3-pyridyl and 3-furyl; R ₆ is a monoketopiperazinyl group having the structure:

Wherein R ₁₅ and R ₁₆ are independently selected from the group consisting of hydrogen, (C1-C10) alkyl, halo (C1-C10) alkyl, cyclopropyl and cyclohexyl; Or R ₁₆ together with R ₁₅ can form a pyrrolidone ring; o is an integer from 1 to 6; R ₈ and R ₉ are independently selected from the group consisting of hydrogen, nitro, amino and cyano; R ₁₀ , R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₄ are independently selected from the group consisting of hydrogen, nitro, cyano, halo, (C 1 -C 10) alkyl and (C 1 -C 10) alkoxy; R ₁₇ is hydrogen, nitro, cyano, amino, (C1-C10) alkyl, halo, halo (C1-C10) alkyl, (C1-C10) alkyloxycarbonyl, aminocarbonyl, (C1-C10) alkylsul Is selected from the group consisting of fonyl and phenylsulfonyl. A combination formulation of a compound according to any one of claims 1 to 3 and at least one further active agent for use in treating a glycogen synthase kinase 3-mediated disease in a human or animal subject. 5. The combined agent of claim 4, wherein the glycogen synthase kinase 3-mediated disease is diabetes and the additional active agent is selected from the group consisting of insulin, troglitazone, rosiglitazone, pioglitazone, glipizide and metformin.