BG65128B1 - Substituted pyramidine compounds and their application - Google Patents

Abstract

The new compounds are effective for prevention and treatment of diseases running with mediation of TNF-alpha, IL-beta, IL-6 and/or IL-8 for reducing pains and in diabetes. The invention relates to new compounds, to their analogues, promedicamentous forms and pharmaceutically acceptable salts, pharmaceutical compositions and to methods for prevention and treatment, as well as to processes for the preparation of their compounds and to intermediate products.

Description

Technical field

The invention relates to substituted pyrimidine compounds and their pharmaceutically acceptable salts, to pharmaceutical compositions and to the use of these compounds for the preparation of a medicament for the prevention and treatment of diseases resulting from TNF-alpha, IL-1 beta and / or IL- 6 and / or IL-8 and other suffering such as pain and diabetes.

BACKGROUND OF THE INVENTION

The application is a derivative of US provisional application Serial Number 60 / 032,128, filed December 5, 1996, of US provisional application Ser. No. 60 / 050,950, filed June 13, 1997, and U.S. Patent Application No. 08 / 976,054, filed November 21, 1997, which applications are incorporated herein by reference in their entirety. The invention encompasses a new class of compounds useful in the treatment of mild diseases, such as those mediated by TNF-alpha, IL1beta, IL-6 and / or IL-8 and other suffering, such as pain and diabetes. In particular, the compounds of the invention are useful for the preparation of a medicament for the prevention and treatment of diseases or inflammatory processes.

Interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) are pro-inflammatory cytokines secreted by various cells, including monocytes and macrophages, in response to many inflammatory stimulants (eg, lipopolysaccharide - LPS ) or extracellular stress (eg osmotic shock or peroxide).

Increased concentrations of TNF-alpha and / or IL-1 above baseline levels are involved in the induction or intensification of a number of disease states, including rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute and chronic myelogenous leukemia, beta cells; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammation of the intestine; adult respiratory failure syndrome (ARDS); psoriasis; Croon's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle atrophy; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption; protective reactions against organ transplantation; ischemic reperfusion injury; atherosclerosis; brain injury; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; high fever and myalgia for infection, HIV-

I, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses (incl. HSV-1, HSV-2), and herpes zoster, are also activated by TNF-alpha.

TNF-alpha has been reported to play a role in head trauma, stroke and ischemia. For example, in animal models of head trauma (rats), the content of TNF-alpha is increased in the injured hemisphere (Shohami et al.,

J. Cereb. Blood Metab. 14, 615 (1994). In a rat model of ischemia disease in which the middle cerebral artery is obstructed, the concentration of TNF-alpha mRNA factors by TNF-alpha is increased (Feurstein et al., Neurosci. Lett. 164, 125 (1993)). The administration of TNF-alpha by introduction into the rat cerebral cortex has been reported to result in significant neutrophil accumulation in the capillaries and adherence of small blood vessels. TNF-alpha promotes the infiltration of other cytokines (IL-1 beta, IL6) as well as chemokines that promote infiltration of the neotrophil in the infarction region (Feurstein, Stroke 25, 1481 (1994)), and TNF has also been reported. -alpha plays a role in type II diabetes (Endocrinol. 130,43-52,1994; and Enfocrinol. 136, 1474-1481, 1995).

TNF-alpha appears to play a role in validating the lifecycle of certain viruses and the disease states associated with them. For example, TNF-alpha secreted by monocytes induces increased concentrations of HIV expression in a chronically infected clone of cell T (Clouse et al., J. Immunol. 142, 431 (1989)). Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discuss the role of TNF-alpha in HIV-related conditions in cachexia and muscle breakdown.

TNF-alpha is a forward in the cascade of inflammatory cytokine processes. As a result, increased concentrations of TNF-alpha can lead to elevated levels of other inflammatory or pro-inflammatory cytokines, such as IL-1, IL-6 and IL8, found to mediate and accelerate many conditions including rheumatoid arthritis, osteoarthritis, rheumatoid spondylitis; arthritis due to gout; inflammation of the intestine; adult respiratory failure syndrome (ARDS); psoriasis; Croon's disease; ulcerative colitis; anaphylaxis; muscle atrophy; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; ischemic reperfusion suffering; atherosclerosis; brain injury; multiple sclerosis; sepsis; septic shock; and toxic shock syndrome. IL-1 also affects viruses sensitive to TNFalpha inhibition, e.g. HIV-1, HIV-2, HIV-3.

TNF-alpha and IL-1 appear to play a role in pancreatic beta-cell breakdown and in diabetes. Pancreatic beta cells produce insulin, which helps regulate blood homeostasis. Pancreatic beta-cell alteration often accompanies type I diabetes. Functional disorders of pancreatic beta-cells can occur in patients with type II diabetes. Type II diabetes is characterized by functional insulin resistance. In addition, type II diabetes is also often accompanied by increased blood glucagon concentrations and increased rates of liver sugar production. Glucagon is a regulatory hormone that attenuates the inhibition of insulin-induced hepatic glucogenesis. Glucagon receptors have been identified in the liver, kidney, and adipose tissues. Therefore, glucagon antagonists are useful for reducing blood sugar (WO 1997/016442, incorporated herein by reference in its entirety). It is believed that by counteracting glucagon receptors, the insulin response in the liver will be improved, thereby reducing glucogenesis and reducing the rate of liver sugar production.

In animal models of rheumatoid arthritis, repeated injection of IL-1 into the joints of animals results in an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol. Immunopathol. 55, 382 (1990)). In studies using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than TNFalpha (Firestem, Am. J. Pathol. 140, 1309 (1992)). Neutrophil, lymphocyte and monocyte emigration is observed at local injection sites. This emigration is attributed to the induction of chemokines (eg, IL-8) and the regulation of adhesion molecules (Dinerello, Eur. Cytokine Netw. 5, 517-531 (1994)).

IL-1 also appears to play a role in promoting the life cycle of some viruses. For example, increased expression of HIV in chronically infected cytokine-induced macrophage lines has been associated with a simultaneous and selective increase in IL-1 production (Folks et al., J. Immunol. 136, 40 (1986)). Beutler et al. (J. Immunol. 135, 3969 (1985)) discuss the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308, 553 (1983)) discuss the role of IL-1 in muscle atrophy.

In rheumatoid arthritis, both IL-1 and TNF-alpha cause synoviocytes and chondrocytes to produce collagenase and neutral proteases, leading to tissue destruction in diseased joints. In one model of arthritis (collagen-induced arthritis (CIA) arthritis in rats and mice), intra-articular administration of TNF-alpha before or after induction of CIA results in accelerated arthritis and a more severe course of the disease (Brahn et al., Lymphokine Cytokine Res. 11,253 (1992); and Cooper, Clin. Exp. Immunol. 898, 244 (1992).

IL-8 has been found to be involved in exacerbation and / or in the induction of many disease states (in which massive neutrophil infiltration at sites of inflammation or injury (eg ischemia) is due to IL-8 involvement its chemotactic nature), including but not limited to: asthma, bowel inflammation, psoriasis, respiratory failure syndrome in the elderly; cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the effect of chemotaxis on neutrophils, IL-8 also has the ability to activate neutrophils. Thus, a decrease in the concentration of IL-8 could lead to a decrease in neutrophil infiltration.

Several approaches have been taken to block the effects of TNF-alpha. One involves the use of soluble TNF-alpha receptors (eg, TNFR-55 or TNFR-75) that demonstrate efficacy in animal 5 models of TNF-mediated disease. A second approach to neutralize TNF-alpha, using TNF-alpha-specific monoclonal antibodies, cA2, demonstrates an improvement in the number of 10 joints in Phase II human treatment for rheumatoid arthritis (Feldmann et al., Immunological Reviews , pp. 195-223 (1995)). These approaches block the effects of TNF-alpha and IL-1 either by protein sequestration or by 15 receptor antagonism.

Bennet et al. (J. Med. Chem. 21,623 (1978)) synthesize a number of pyrimidines of the general formula:

wherein, inter alia, R _a 'is 2-, 3- or 4-pyridyl, R _a ² is H, methyl or phenyl, and R _a ³ is H, a 25 amino group. They report that none of these compounds tested for excipient-induced rat edema showed a level of activity sufficient to warrant further study and that additional testing confirmed that the compounds showed a sequence from false positives to a carrageenan-induced model of edema.

Ife et al. (Bioorg. Med. Chem. Lett. 5, 543 (1995)) report that another pyrimidine (R _a '= 2- 35 methylphenyl, R _a ² = 2-pyridyl and Ra ³ = η-propyl, where RJ, Ra ² and R _a ³ are radicals in structural formula I (above) having several times lower H ⁺ / K ⁺ -ATPase inhibitory activity than that associated with 4- (2-pyridyl) compounds ) -5-Phenylthiazole.

WO 1997/003388 describes substituted pyrimidine compounds that are useful in the treatment of cytokine-related diseases. 45

Brief description of the invention

The present invention relates to a new class of compounds useful for the prevention and treatment of diseases and other suffering, such as diabetes and pain, which involve TNF-alpha, IL-16era, IL-6 and / or IL-8. In particular, the compounds of the invention are useful for the prevention and treatment of diseases or conditions affecting inflammation. Accordingly, the invention also relates to pharmaceutical compositions composed of compounds and to the use of these compounds for the preparation of a medicament for the prevention and treatment of diseases mediated by TNFalpha, IL-16eTa, IL-6 and / or IL- 8, such as inflammation, pain and diabetes, using compounds and compositions of the invention as well as intermediates and processes useful for the preparation of the compounds of the invention.

The compounds of the invention are represented by the following general structural formula:

wherein R ¹ , R ² , R ¹¹ and R ¹² are defined below.

The aforementioned text summarizes certain aspects of the invention and is not intended or intended to be limiting text to the invention in any way. All patents and other publications cited herein are hereby incorporated by reference in their entirety.

SUMMARY OF THE INVENTION

In accordance with the present invention, compounds of the general formula r _{2 are provided}

(I) or pharmaceutically acceptable salts thereof, in which the formula each of the radicals R ₍ and R ₂ may be an independent chain type-N-Y, as long as (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each chain -Ζ-Y- should be 0-3, preferably 0-2, and more preferably 0-1;

(2) the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 and Rj is 0-4; preferably 0-3, more preferably 0-2; and preferably 0-1;

preferably, It may be a hydrogen radical, a C 1 -C ₄ alkyl radical, halo, hydroxy, C 1 -C ₄ alkoxy, a C 1 -C ₂ haloalkoxy radical of 1-3 halo radicals, a thiol, C 1 -C ₄ alkylthio , aminosulfonyl, C 1 -C, alkylaminosulfonyl, di (C 1 -C ₄ alkyl) aminosulfonyl, amino, C 1 -C ₄ alkylamino, di-C 1 -C 4, alkyl) amino, C 1 -C 3 alkanoylamino, (C-Q , alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino or C 1 -C ₂ haloalkyl group of 1-3 halo radicals;

more preferably, R ₂ is a radical of: hydrogen, C 1 -C ₄ alkyl, halo, hydroxy, C 1 -C 5 alkoxy, trifluoromethoxy, thiol, C 1 -C ₄ alkylthio, amino, C 1 -C ₄ alkylamino, a di- (C 1 -C ₄ alkyl) trifluoromethoxy, amino, methylamino, dimethylamino, acetylamino or trifluoromethyl group;

most preferably, R ₂ is a hydrogen or hydroxy radical;

wherein each Z can be independently:

(1) chemical bond;

(2) alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 radicals, from an amino group, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo group, and (b) radicals; from a heterocyclyl, aryl or heteroaryl group optionally substituted by 1-3 radicals such as amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl;

(3) a heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl;

preferably, each Z may be independently:

(1) chemical bond;

(2) C ₍ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl radical optionally substituted by 1-3 amino groups, C ₍ -C ₄ alkylamino, di-C 1 -C 6 alkyl) amino, C ₁ -C ₆ alkanoylamino, (C ₁ -C ₄ alkoxy) carbonylamino, C ₃ -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio or halo groups, and (b) 1-2 radicals from heterocyclyl, aryl or heteroaryl groups optionally substituted by 1-3 radicals of an amino group, C ₁ -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C ₃ -C ₄ alkoxy, C 1 -C ₄ alkylthio, halo, C 1 -C ₄ alkyl l or C-C, haloalkyl groups of 13 halo radicals;

(3) heterocyclyl radical optionally substituted by 1-3 amino radicals, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C ₁ -C ₄ alkylsulfonylamino, hydroxy, Cj-C ₄ alkoxy, S.-S. alkylthio, C.-C. an alkyl or C 1 -C haloalkyl group of 1-3 halo radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C ₄ alkylamino, di- (C ₅ -C ₄ alkyl) amino, C ₃ -C ₃ alkanoylamino, (C 1 -C) ₄ alkoxy) carbonylamino, C ₁ -C ₄ alkylsulfonylamino, hydroxyl, C 1 -C ₄ alkoxy, C ₁ -C ₄ alkylthio, cyano, halo, C 1 -C ₄ alkyl or a C ₁ -C ₄ haloalkyl group of 1-3 halo radicals;

more preferably, each Z may be independently (1) a chemical bond;

(2) C 1 -C ₈ alkyl-, C ₂ -C ₈ alkenyl- or C ₂ -C ₈ alkynyl radical optionally substituted by 1-3 amino groups, C 1 -C ₄ alkylamino, di- (C] - C ₄ alkyl) amino, C 1 -C ₃ alkanoylamino, (C ₁ -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxyl, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl group optionally substituted by 1-3 radicals of amino, Cj-C ₄ alkylamino, di- (C] _-C4 alkyl) amino, C _t -C ₅ alkanoylamino, (C , -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, halo, C 1 -C ₄ alkyl or C ₍ -C ₄ haloalkyl groups of 1-3 halo radicals;

(3) heterocyclyl radical optionally substituted by 1-2 radicals of amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C-C ₄ alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxyl, C 1 -C alkoxy, C 1 -C. alkylthio, C.-C. an alkyl or C 1 -C ₁ haloalkyl group of 1-3 halo radicals; or (4) aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C ^ C alkylamino, di- (C ₁ -C ₄ alkyl) amino, C] -C ₅ alkanoylamino, (C-C alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C 1 -C ₆ alkyl or C 1 -C ₄ haloalkyl group of 1-3 halo radicals;

more preferably, each Z may be independently (1) a chemical bond;

(2) C _t -C ₈ alkyl or C ₂ -C ₈ alkenyl radical optionally substituted by 1-3 radicals of amino, C _D C ₄ alkylamino, di _{((C 4} alkyl) amino] - C 1-6 alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxyl, C ₁ -C ₄ alkoxy, C 1 -C ₄ alkylthio or halo, and (b) 1-2 radicals heterocyclyl, arylene or heteroarylene optionally substituted by 1- 3 radicals of amino, C 1 -C 6 alkylamino, di- (C ₁ -C ₄ alkyl) amino, C 1 -C 6 alkanoylamino, (C ₄ -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C alkoxy, C 1 -C ₄ alkylthio, halo, a C 1 -C ₄ alkyl or a C 1 -C ₄ haloalkyl group of 1-3 halo radicals;

(3) a heterocyclyl radical optionally substituted by 1-2 radicals of an amino group, di- (C 1 -C ₄ alkyl) amino, (C 1 -C 6 alkoxy) carbonylamino, hydroxyl, C 1 -C alkoxy, C 1 -C alkylthio, or C1-C6 alkyl radicals; or (4) aryl or heteroaryl radical optionally substituted by 1-3 radicals of an amino group, C1-C6 alkylamino, di- (C1-C6 alkyl) amino, C1-C6 alkanoylamino, (C1-C4 alkoxy) carbonylamino, C _t- C ₄ alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C 1 -C alkyl or C 1 -C ₂ haloalkyl group of 1-3 halo radicals;

more preferably, each Z may be independently (1) a chemical bond;

(2) C 1 -C ₄ alkyl-, C ₂ -C ₅ alkenyl radical optionally substituted by 1-3 radicals of an amino group, flH- (C 1 -C ₂ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C 3 alkoxy) ) carbonylamino, hydroxy, C 1 -C ₂ alkoxy, C 1 -C ₂ alkylthio or halo radical, and (b) 1-2 radicals of a heterocyclyl, aryl or heteroaryl group optionally substituted with 1-3 amino radicals, C 1 -C alkylamino , di- (C 1 -C ₂ alkyl) amino, C 1 -C ₃ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, halo, C 1 -C an alkyl group or trifluoromethyl radical;

(3) heterocyclyl radical optionally substituted by 1-2 radicals of amino, di- (C ₁ -C ₂ alkyl) amino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₂ alkoxy, C ₍ - C ₂ alkylthio, C 1 -C 6 alkyl radicals, or (4) arylene or heteroaryl radical optionally substituted by 1-3 radicals of amino, di (C 1 -C ₆ alkyl) amino, C 1 -C ₅ alkanoylamino, (C-C alkoxy) carbonylamino, hydroxy, C 1 -C ₂ alkoxy, C 1 -C ₂ alkylthio, cyano, halo, C 1 -C 6 alkyl or trifluoromethyl radicals;

more preferably, each Z may be independently (1) a chemical bond;

(2) C ₁ -C ₆ alkyl, C ₂ -C ₅ alkenyl radical optionally substituted by 1-3 amino radicals, di (C 1 -C ₂ alkyl) amino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₂ alkoxy, C ₁ -C alkylthio or halo groups, and (b) 1-2 radicals of an aryl or heteroaryl group optionally substituted with 1-2 radicals of amino, di- (C 1 -C ₂ alkyl) amino , acetamido, (C ₁ -C ₄ alkoxy) carbonylamino, hydroxy, C-C ₂ alkoxy, C _t -C ₂ alkylthio, halo, C-C alkyl or trifluoromethyl radicals;

(3) aryl- or heteroaryl-radical optionally substituted by 1-3 radicals of amino, di- (C ₁ -C ₂ alkyl) amino, acetamido, C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C alkoxy, C- W alkylthio, cyano, halo, _C-C4 alkyl or trifluoromethyl radicals;

more preferably, each Z may be independently (1) a chemical bond;

(2) C-C alkyl radical optionally substituted by 1-2 radicals of amino, di- (C -C ₂ alkyl) amino, _(C-C4 alkoxy) carbonylamino, hydroxy, C _t -C ₂ alkoxy, W-W alkylthio, halo or aryl or heteroaryl radical optionally substituted by 1-2 radicals of hydroxy, C _d -C ₂ alkoxy, C-C alkylthio, halo, C-C alkyl or trifluoromethyl; and most preferably, each Z may be independently (1) a chemical bond; or (2) C1-C6 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or haloradicals;

each Y may be independently (1) a hydrogen radical;

(2) halo or nitro radical;

(3) the radicals -C (O) -R, _O or -C (NR ₅ ) NR ₁ R ₃ ;

(4) radical, -OR _21, -OC (O) -R _21, -O-C (O) -NR ₅ R ₂₁ or OC (O) -NR, ₂ -

S (O) ₂ -R ₂₀ ;

(5) radical -SR ₂₁ -S (O) -R ₂₀ , -S (O) ₂ -R ₂₀ , -SiOj-NRjR ,,, -S (O) ₂ -NR ₂₂ -C (O) -R ₂₁ ,

-S (O) ₂ -NR ₂₂ -C (O) -OR ₂₀ or -S (O) ₂ -NR ₂₂ C (O) -NR ₅ R ₂₁ ; or (6) the radical -NR ₅ R ₂₁ , -NR ₂₂ -C (O) -R ₂₁ , -NR ₂₂ -C (O) -OR ₂₀ , -NR ₂₂ -C (O) -NR ₅ R ₂₁ , - nr ₂₂ C (NR ₅ ) -NR ₅ R ₂₁ , -NR ₂₂ -S (O) ₂ -R ₂₀ or -NR 4 -SCO), NRA, preferably, each Y may be independently (1) a hydrogen radical;

(2) halo radical;

(3) the radicals -C (O) -R ₂₀ or -C (NR ₅ ) MUC;

(4) the radical-OR ₂₁ , -OC (O) -R ₂₁ , -O-C (O) NRA ,;

(5) the radical -SR ₂₁ , -S (O) -R ₂₀ , -S (O) ₂ -R ₂₀ , -S (O) ₂ -NR ₅ R ₂₁ , or (6) the radical -NR ₅ R ₂₁ , -NR ₂₂ -C (O) -R ₂₁ , -NR ₂₂ -C (O) -OR ₂₀ , -NR ₂₂ -C (O) -NR ₅ R ₂₁ , -NR ₂₂ C (NR _s ) -NR ₅ R ₂₁ , -NR ^ -SCO) ^ or -NR ^ -SCO), NRA, more preferably, any Y may be:

(1) a hydrogen radical;

(2) the radical -C (O) -R ₂₀ ;

(3) the radical -OR _2I , -SR ₂₁ , -S (O) -R ₂₀ , or -S (O) ₂ -R ₂₀ -S (O) ₂ -NR _with R ₂₁ , or (4) the radical -NR ₅ R ₂₁ , -NR ₂₂ -C (O) -R ₂₁ , -NR ₂₂ -C (O) -OR ₂₀ , -nr ₂₂ -c (O) -nr ₅ r ₂₁ , -nr ₂₂ S (O) ₂ -R ₂₀ or -NR ₂₂ -S (O) ₂ -NR ₅ R ₂₁ ;

more preferably, each Y can be:

(1) a hydrogen radical;

(2) the radical -C (O) -R ₂₀ ;

(3) the radical -OR _2I , -SR ₂₎ , -S (O) -R ₂₀ , or -S (O) ₂ -R ₂₀ , -SCOVNRjR ,,, or (4) the radical -NR ₅ R ₂₁ , - NR ₂₂ -C (O) -R ₂₁ , -NR ₂₂ -S (O) ₂ -OR ₂₀ ;

more preferably, each Y can be:

(1) -C (O) -R ₂₀ radical;

(2) the radical -OR _{2 |} , -SR ,,, -S (O) -R ₂₀ , -S (O) ₂ Rj ₀ , or S (O) ₂ -NR ₅ R _2I , or (3) the radical -NR ₅ R ₂₁ , -NR ₂₂ -C (O) -R ₂₁ , -NR ₂₂ -S (O) ₂ -OR ₂₀ ;

most preferably, each Y may be independently one radical, such as -OR ₂₁ , -SR ₂₁ or -NR ₅ R ₂₎ ;

wherein each R _s may be independently:

(1) hydrogen radicals;

(2) alkyl-, alkenyl- or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, -SO ₃ H or halo; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl, or cycloalkylalkyl radicals optionally substituted by 1-3 radicals of the amino, alkylamino, dialkylamino, hydroxy, alkyloxy, alkyl or alkyl group, ;

preferably, each R _s may be independently:

(1) hydrogen radicals;

(2) C 1 -C 4 alkyl, C 1 -C alkenyl or C-C alkynyl radicals optionally substituted by 1-3 radicals of amino, C 1 -C alkylamino, di- (C 1 -C 6 alkyl) amino, hydroxy, C-C ₄ alkoxy, C 1 -C ₆ alkylthio, -SO ₃ H, or (3) aryl, heteroaryl, aryl-C 1 -C 4 alkyl, heteroaryl-C 1 -C 6 alkyl, heterocyclyl, heterocyclyl-C 1 -C 8 alkyl, C 1 -C cycloalkyl or C- C 1 -cycloalkyl-C 1 -C 6 alkyl radicals optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, C -C 1 alkyl or C 1 -C haloalkyl radicals of 1-3 halo radicals;

more preferably, each R ₅ may be independently:

(1) hydrogen radicals;

(2) C 1 -C ₄ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl radicals optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di- (C 1 -C 6) alkyl amino radicals , hydroxy, C-C alkoxy, C] -C ₄ alkylthio, -SO ₃ H, or halo groups; or (3) aryl, heteroaryl, aryl-C 1 -C ₄ alkyl, heteroaryl-C 1 -C ₄ alkyl, heterocyclyl, heterocyclyl-C 1 -C ₄ alkyl, C ₁ -C cycloalkyl or C ₃ -C ₈ cycloalkyl-C] - C ₄ alkyl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkyl or C 1 -C ₄ haloalkyl of 1-3 halo radicals;

more preferably, each R ₅ may be independently:

(1) hydrogen radicals;

(2) C 1 -C ₄ alkyl, C ₂ -C ₃ alkenyl or C ₂ -C ₅ alkynyl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, hydroxy, C 1 -C ₄ alkoxy radicals, C ] -C ₄ alkylthio, -SO ₃ H, or halo groups; or (3) phenyl-C 1 -C ₂ -alkyl, heteroaryl-C ₁ -C ₂ alkyl, heterocyclyl-C ₁ -C ₂ -alkyl, or C -C ₆ -cycloalkyl-C 1 -C ₂ -alkyl radicals optionally substituted by 1-3 radicals of amino, di- (C 1 -C ₄ alkyl) amino, hydroxy, C 1 -C ₆ alkoxy, C 1 -C alkylthio , C 1 -C ₄ alkyl or C 1 -C ₂ haloalkyl of 1-3 halo radicals;

more preferably, each R ₅ may be independently:

(1) a hydrogen radical;

(2) C 1 -C ₄ alkyl radical optionally substituted by 1-3 amino radicals, di- (C 1 -C ₂ alkyl) amino, hydroxy, C 1 -C ₂ alkoxy, C ₃ -C ₂ alkylthio, or halo group; or (3) phenyl-C 1 -C-alkyl, heteroaryl-C 1 -C ₂ alkyl, heterocyclyl-C ₁ -C ₂ -alkyl, C ₃ -C ₆ cycloalkyl-C-C ₂ -alkyl radicals optionally substituted with 1-3 radicals of amino, di- (C 1 -C ₄ alkyl) amino, hydroxy, C 1 -C ₂ -alkoxy,

C] -C ₂ alkylthio, methoxy, methylthio, Cj-C alkyl or trifluoromethyl radicals;

more preferably, each R ₅ may be independently:

(1) a hydrogen radical;

(2) a C 1 -C ₄ alkyl radical optionally substituted with 1-3 haladical; or (3) phenyl-C 1 -C ₂ alkyl or heteroaryl-C 1 -C 6 alkyl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy;

methylthio, methyl or trifluoromethyl radicals; more preferably, each R ₅ may be independently hydrogen or C 1 -C 4 alkyl radical and, most preferably, each R ₅ may be a hydrogen radical;

in which the formula each R ₂₀ can be independently (1) an alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of an amino group, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N (alkoxycarbonyl) -N- (alkyl) amino , aminocarbonyl, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl , para kilsulfonylamino, alkanoyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, alkyl or haloalkyl;

or (2) a heterocyclyl radical optionally substituted by 1-3 radicals of an amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl;

or (3) aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano or halo, halo, halo, halo ;

preferably, each R ₂₀ may be independently alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, C 1 -C alkanoyl , hydroxy, C 1 -C alkoxy,

C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halo, C 1 -C 4 alkyl or C 1 -C haloalkyl groups of 1-3 halo radicals;

(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, C ^ C alkylamino, di- (C] _-C4 alkyl) amino, N-C alkanoylamino, (C-C alkoxy) carbonylamino, alkylsulfonylamino , hydroxy, C 1 -C alkoxy,

S.-S. alkylthio, C.-C. alkyl or C-C, haloalkyl group of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino CjS _4, flH- (Cj-C ₄ alkyl) amino, Cj-C ₅ alkanoylamino, (C _{(-C 4} alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, (C 1 -C ₄ alkoxy) carbonyl, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, azido-, C 1 -C ₄ alkyl or C ₍ -C ₄ haloalkyl group of 1-3 halo radicals;

more preferably, each may be independently (1) C 1 -C 8 alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl radicals optionally substituted by 1-3 radicals of amino, C 1 -C ₄ alkylamino , di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkoxy) carbonyl-L-C 1 -C 4 alkyl) amino, aminocarbonylamino, C 1 - C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halo or arylC 1 -C ₄ alkoxy, aryl-C] -C ₄ alkylthio, aryl-C [-C ₄ alkylsulfonyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl or heteroaryl radicals, amesteni by 1-3 radicals of amino, C] _-C4 alkylamino, di- (C] _-C4 alkyl) amino, Cj-Cj alkanoylamino, (Cj-C ₄ alkoxy) carbonylamino, Cj-C alkylsulfonylamino, , -C ₅ alkanoyl, hydroxy, C 1 -C ₄ alkoxy, C ₍ -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halo-, C 1 -C ₄ alkyl or C 1 -C ₄ haloalkyl groups of 1-3 halo radicals;

(2) heterocyclyl radicals optionally substituted by 1-3 radicals of amino, C ₁ -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₄ alkanoylamino, (C 1 -C ₄ alkoxy) ) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkyl or a C 1 -C ₄ haloalkyl group of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C, - With alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, (C 1 -C ₄ alkoxy) carbonyl, hydroxy, C ₁ -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, azido-, C 1 -C ₄ alkyl or C] -C ₄ haloalkyl group of 1-3 halo radicals;

more preferably, each R ₂₀ may be independently (1) C 1 -C ₈ alkyl, or C ₂ -C ₅ alkenylra dicals, optionally substituted by 1-3 radicals of amino, C 1 -C ₄ alkylamino, di - (C ₁ -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, N - ((C 1 -C ₄ alkoxy) carbonyl) N- (C 1 -C ₄ alkyl) amino , aminocarbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, halo or aryl-C 1 -C ₄ alkoxy, aryl-C ] -C ₄ alkylthio, aryl-C 1 -C ₄ alkylsulfonyl, C ₃ -C ₈ cycloalkyl, heterocyclyl, aryl, or heteroaryl radicals substituted by boron with 1-3 radicals of amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C 6 alkanoylamino, (C ₃ -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, C , -C ₅ alkanoyl, hydroxy, C 1 -C ₄ alkoxy, alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halo, C 1 -C 6 alkyl or C 1 -C ₂ haloalkyl groups of 1-3 halo radicals;

(2) heterocyclyl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino radicals , C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkyl or C 1 -C ₄ haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, C ₁ -C ₄ alkylamino, di-C 1 -C 4, alkyl) amino, C 1 -C ₄ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, (C 1 -C ₄ alkoxy) carbonyl, hydroxy, C ₁ -C ₄ alkoxy, O, -O, alkylthio, cyano, halo, azido-, O, -O ₄ alkyl or C 1 -C ₂ haloalkyl group of 1-3 halo radicals;

more preferably, each R ₂₀ may be independently (1) C 1 -C ₈ alkyl, or C ₂ -C ₅ alkenyl radicals optionally substituted by 1-3 radicals of amino, C 1 -C ₄ alkylamino, di - (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (O, -O ₄ alkoxy) carbonylamino, N- (C 1 -C ₄ alkoxy) carbonyl) -N (O-O ₄ alkyl) amino, aminocarbonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halo or aryl-C 1 -C ₄ alkoxy, aryl-C, - C ₄ alkylthio, arylC, -C ₄ alkylsulfonyl, C ₃ -C ₆ cycloalkyl, heterocyclyl, aryl, or heteroaryl radicals optionally substituted by 1-3 amine radicals o, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, alkylsulfonylamino, C 1 -C ₅ alkanoyl, hydroxy,

S.-S. alkoxy, C.-C. alkylthio, halo, C 1 -C 10 alkyl 14 or C 1 -C ₂ haloalkyl groups of 1-3 halo radicals;

(2) heterocyclyl radicals optionally substituted by 1-2 radicals of amino, di- (C 1 -C ₄ alkyl) amino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C ₁ -C ₄ alkoxy, C] -C ₄ alkylthio, C 1 -C ₄ alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, acetamido, (C ₁ -C ₄ alkoxy) carbonylamino, C ₁ -C ₄ alkylsulfonylamino, (C 1 -C ₄ alkoxy) carbonyl, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, azido-, C 1 -C ₄ alkyl or trifluoromethyl radicals;

more preferably, each R ₂₀ may be independently (1) C 1 -C 8 alkyl radicals, or C ₂ -C ₅ alkenyl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C) radicals , -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, N- (C 1 -C ₄ alkoxy) carbonyl) -N- (C ₁ -C ₄ alkyl) amino, aminocarbonylamino , hydroxy, C ₁ -C ₄ alkoxy, C _t -C ₄ alkylthio, C ₁ -C ₄ alkylsulfinyl, C-C ^ alkylsulfonyl, halo or aryl-C-C-alkoxy, aryl C _t -C ₄ alkoxy, aryl C _x -C ₄ alkylthio, aryl-Cj-C ₄ alkylsulfonyl, C ₃ -C ₆ cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, di- (C] _-C4 alkyl) amino, C] -C ₅ aalkanoilamino, (C ₄ -C ₄ alkoxy) carbonylamino, Cj-C ₄ alkylsulfonylamino, hydroxy, C] - C ₄ alkoxy, C 1 -C ₄ alkylthio, halo, C 1 -C ₄ alkyl or C 1 -C ₂ haloalkyl of 1-3 halo radicals;

(2) heterocyclyl radical optionally substituted by 1-2 radicals of hydroxy or C _t -C ₄ alkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;

more preferably, each R ₂₀ may be independently (1) C 1 -C 8 alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t-butoxycarbonylamino, N- (t-butoxy) carbonyl) -N - (methyl) amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C ₅ -C ₆ cycloalkyl, heterocyclyl, phenyl, or heteroaryl radicals optionally substituted by 1 to 2 radicals dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl, or trifluoromethyl radicals;

(2) heterocyclyl radical, (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;

more preferably, each R ₁₀ may be independently (1) C 1 -C ₆ alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, t-butoxycarbonylamino, N- (t-butoxy) carbonyl) -Y1- (methyl) amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C ₅ -C ₆ cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;

(2) heterocyclyl radical, or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;

most preferably any R ₂₀ may be independently (1) C 1 -C ₆ alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxy or phenyl or heteroaryl radicals optionally substituted by 1 -2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;

(2) heterocyclyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals;

each radical R _2] may be independently a hydrogen radical or R ₂₀ ;

each radical R ₂₂ may be independently (1) a hydrogen radical;

(2) an alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkylsulfonyl, alkoxy, alkylsulfonyl, alkoxy cyano, halo, alkyl, or haloalkyl; or (3) heterocyclyl, aryl, or heteroaryl radicals optionally substituted by 1-3 radicals, such as amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfinyl, alkylsulfinyl, or haloalkyl; as long as Z is a chemical bond and Y is -NR 1 -C (O) -NH ₂ , then R ₂₂ is not an optionally substituted aryl radical;

preferably, each radical R ₂₂ may be independently (1) a hydrogen radical;

(2) C 1 -C ₄ alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 radicals of an amino group, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) ) amino, Cj-Cg alkanoylamino, (Ο ₃ -Ο ₄ alkoxycarbonylamino, Cj-C alkylsulfonylamino, hydroxy, Cj-C ₄ alkoxy, C, -C ₄ alkylthio Cj-C ₄ alkylsulfinyl, Cj-C ₄ alkylsulfonyl, cyano, halo , C 1 -C ₄ alkyl or C 1 -C ₄ haloalkyl radical of 1-3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- ( C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) si) carbonylamino, C 1 -C ₄ alkylsulfonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C ₃ -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, cyano, halo, C 1 -, halo C ₄ alkyl or C _t -C ₄ haloalkyl of 1-3 halo radicals; provided that when Z is a chemical bond and Y is -NR ₂₂ -C (O) -NH _2, then R ₂₂ can not be an optionally substituted aryl radical;

more preferably, each radical R ₂₂ may be independently (1) a hydrogen radical; or (2) Cj-Cj alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, di- (C ₁ -C ₂ alkyl) amino, Cj-C _s alkanoylamino , (C 1 -C ₄ alkoxycarbonylamino, hydroxy, C ₃ -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C 1 -C ₄ alkyl, or C 1 -C ₂ haloalkyl of 1-3 halo radicals;

more preferably, each R ₂₂ radical may be independently hydrogen or a C 1 -C ₄ alkyl radical;

and most preferably, each radical R ₂₂ may be independently hydrogen or methyl radical;

The radicals R, ₁ and R ₁₂ may be, each independently, an aryl or heteroaryl radical optionally substituted by 1-3 radicals of the radicals (1) R ₃₀ (2) halo or cyano radicals;

(3) -C (O) -R ₃₀ , -C (O) -OR ₂₉ , -C (O) -NR ₃₁ R ₃₂ or -C (NR ₃₁ ) -NR ₃₁ R ₃₂ (4) radicals -OR ₂₉ , -OC (O) -R ₂₉ , -OCCOJ-NR 4 R 7 or -OC (O) -NR ₃₃ -S (O) ₂ -R ₃₀ ;

(5) the radicals -SR ₂₉ , -S (O) -R ₃₀ , -SCO ^ -R ^, -S (O) ₂ -NR ₃₁ R ₃₂ , -S (O) ₂ -NR ₃₃ -C (O) -R ₃₀ , -S (O) ₂ NR ₃₃ -C (O) -OR ₃₀ , or -SiO ^ -NR ^ -CtOLNR ^, or (6) radicals -NR ₃₁ R ₃₂ , -NR ₃₃ -C (O ) -R ₂₉ , -NR ₃₃ -C (O) -OR ₃₀ , -NR ₃₃ -C (O) -NR ₃₁ R ₃₂ , -NR ₃₃ C (NR ₃₁ ) -NR ₃₁ R ₃₂ , -NR ₃₃ -S (O) ₂ -R ₃₀ or -NR ₃₃ SCO 4 -NR 4;

as long as it is valid that (1) R _n is anything but 4-pyridyl, 4-pyrimidyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted with 1-2 substituents, and that (2 ) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted individually in R _H and R ₁₂ is 0-1;

preferably, R _H and R ₁₂ may each independently be an aryl or heteroaryl radical optionally substituted by 1-2 radicals of (1) R ₃₀ (2) halo or cyano radicals;

(3) -C (O) -R ₃₀ , -C (O) -OR ₂₉ , -C (O) -NR ₃₁ R ₃₂ or -C (NR _3I ) -NR _3] R ₃₂ (4) radicals - OR ₂₉ , -OC (O) -R ₂₉ , -OC (O) -NR ₃₁ R ₃₂ or -OC (O) -NR ₃₃ - S (O) ₂ -R ₃₀ ;

(5) radicals -SR ₂₉ , -S (O) -R ₃₀ , -S (O) ₂ -R ₃₀ , -S (O) ₂ -NR ₃₁ R ₃₂ , -S (O) ₂ -NR ₃₃ -C (O) -R ₃₀ , -S (O) ₂ NR ₃₃ -C (O) -OR ₃₀ , or -S (O) ₂ -NR ₃₃ -C (O) -NR ₃₁ R ₃₂ , or (6) radicals -NR ₃₁ R ₃₂ , -NR ₃₃ -C (O) -R ₂₉ , -NR ₃₃ -C (O) -OR ₃₀ , -NR ₃₃ -C (O) -NR ₃₁ R ₃₂ , -NR ₃₃ C (NR ₃₁ ) -NR ₃ , R ₃₂ , -NR ₃₃ -S (O) ₂ -R ₃₀ or -NR ₃₃ SCO-NR ^ as long as (1) R _n is anything but 4- pyridyl, 4-pyrimidyl, 4-quinolyl or 6-isoquinolyl radical optionally substituted with 1-2 substituents, as well as (2) the total number of aryl, heteroaryl, cycloalkyl, and heterocyclyl radicals substituted individually in C 1 and R _{] 2} is 0-1;

with greater preference, the radicals Rj _t and _{R) 2,} each can be independently aryl or heteroaryl radical optionally substituted by 1-2 radicals of

d) R ₃₀ (2) halo or cyano radicals;

(3) -C (O) -R ₃₀ , -C (O) -OR ₂₉ , -C (O) -NR ₃₁ R ₃₂ or -C (NR ₃₁ ) -NR ₃₁ R ₃₂ (4) radicals -OR ₂₉ , -SR ₂₉ , -S (O) -R ₃₀ , -S (O) ₂ -R ₃₀ , -S (O) ₂ -NR ₃₁ R ₃₂ , NR ₃₁ R ₃₂ , -NR ₃₃ -C (O) R ₂₉ HnH-NR ₃₃ -C (O) -OR ₃₀ , more preferably, R _H is an aryl radical, while R ₁₂ is a heteroaryl radical, wherein the aryl and heteroaryl radical is optionally substituted by 1-2 radicals, such as (1) R ₃₀ (2) halo or cyano radicals;

(3) -C (O) -R ₃₀ , -C (O) -OR ₂₉ , -C (O) -NR ₃₁ R ₃₂ or -C (NR ₃₁ ) -NR ₃₁ R ₃₂ or, (4) radicals -OR ₂₉ , -SR ₂₉ , -5 (O) -R ₃₀ , -s (O) ₂ -r ₃₀ , -S (O) ₂ -NR ₃₁ R ₃₂ , -nr ₃₁ r ₃₂ , -NR ₃₃ -C (O) ^ 29 ', more preferably, R _n is an aryl radical, while R ₁₂ is a heteroaryl radical, the aryl and heteroaryl radical being optionally substituted by 1-2 radicals, such as (1) R ₃₀ (2) halo - or cyano radicals; or (3) -C (O) -NR ₃₁ R ₃₂ , -OR ₂₉ , -SR ₂₉ , -S (O) -R ₃₀ , -S (O) ₂ -R ₃₀ , -S (O) ₂ - NR ₃₁ R ₃₂ , nr ₃₁ r ₃₂ , -NR ₃₃ -C (O) -R ₂₉ , more preferably, R _n is an aryl radical optionally substituted by 1-2 radicals, such as (DRao;

(2) halo or cyano radicals; or (3) the radicals -C (O) -NR ₃₁ R ₃₂ , -OR ₂₉ , -SR ₂₉ , -s (O) -r ₃₀ , - s (O) ₂ -r ₃₀ , -s (O) ₂ - nr ₃₁ r ₃₂ , nr ₃₁ r ₃₂ , -NR ₃₃ -C (O) -R ₂₉ ;

more preferably, R _n is an aryl radical optionally substituted by 1-2 radicals such as amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals;

more preferably R _n is an unsubstituted phenyl or naphthyl radical or phenyl radical, substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methylcarbonyl or methylcarbonyl, methylcarbonyl or methylcarbonyl, methylcarbonyl or methylcarbonyl radicals;

and most preferably, R _H is an unsubstituted phenyl radical or phenyl radical substituted with 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl, or trifluoromethyl radicals;

more preferably, the radical R ₁₂ is a heteroaryl radical optionally substituted by 1-2 radicals, such as (ί) R ₃₀ ;

(2) halo or cyano radicals; or (3) the radicals -C (O) -NR ₃₎ R ₃₂ , -OR ₂₉ , -SR ₂₉ , NR ₃₁ R ₃₂ , -NR ₃₃ -C (O) -R ₂₉ ;

more preferably, R ₁₂ is a heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals;

more preferably R ₁₂ is 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-pyrimidinyl, optionally substituted by a radical such as amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl, or trifluoromethyl radicals ;

and most preferably, R ₁₂ is a 4-pyridyl radical substituted with amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals;

wherein each R ₃₀ may be independently (1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of the radicals NR ₃₁ R ₃₁ , -OC (O) ₂ -R ₂₃ , hydroxy, alkoxy, alkylthio, alkylsulfinyl , alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkyl sulfonyl, heterocyclyl, aryl, or heteroaryl radicals optionally substituted by , alkylsulfonyl, cyano, halo, alkyl or haloalkyl;

(2) heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyanoalkyl, cyanoalkyl; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;

preferably each R ₃₀ may be independently (1) C 1 -C ₄ alkyd, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl radicals optionally substituted by 1-3 radicals of NR ₃₁ R _3] , -OC (O) ₂ -R ₂₃ , hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, cyano, halo or aryl-C 1 -C * alkoxy, aryl-C 1 -C 4 alkylthio, aryl-C 1 -C 4 alkylsulfonyl, heterocyclyl, aryl, or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 6 alkylamino, di- (C 1 -C ₄₎ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C j-C ₄ alkylsulfinyl, Cj-C ₄ alkylsulfonyl, cyano, halo, C _t -C ₄ alkyl or C] _-C4 haloalkyl of 1-3 halo radicals;

(2) heterocyclyl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C ₁ -C ₄ alkyl) amino, C _t -C ₅ alkanoylamino, (C _f -C ₄ alkoxy) radicals ) carbonylamino, Cj-C ₄ alkylsulfonylamino, hydroxy, C ₁ -C ₄ alkoxy, Cj-C ₄ alkylthio, cyano, Cj-C ₄ alkyl or C] _-C4 haloalkyl of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C] - C ₄ alkoxy) carbonylamino, Cj-C ₄ alkylsulfonylamino, hydroxy, C] _-C4 alkoxy, Cj-C ₄ alkylthio, cyano, halo, C, -C ₄ alkyl or C _t -C ₄ haloalkyl of 1-3 halo radicals;

more preferably, each R ₃₀ may be independently

1) C 1 -C ₄ alkyl radical optionally substituted by 1-3 radicals of the groups (a) -NR ₃₁ R ₃₁ , (b) (C _t -C ₄ alkoxy) carbonyl or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1 -3 radicals, such as amino, alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C ₁ -C ₄ alkyl or trifluoromethyl; or (c) hydroxy, _C) -C ₄ alkoxy, C] _-C4 alkylthio, or phenyl-C ₁ -C ₄ alkoxy, phenyl-C ₁ -C ₄ -alkylthio, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of the radicals are amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₄ alkoxy, A C 1 -C ₄ alkylthio, cyano, halo, C 1 -C ₄ alkyl or C 1 -C ₄ haloalkyl group of 1-3 halo radicals;

(2) a C 1 -C ₄ haloalkyl group of 1-3 halo radicals; or (3) aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C] _-C4 alkylamino, di- (C, -C ₄ alkyl) amino, C _t -C ₅ alkanoylamino, (C, - C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C 1 -C ₄ alkyl or trifluoromethyl radicals;

more preferably, each R ₃₀ may be independently (1) a C 1 -C ₄ alkyl radical optionally substituted by 1-3 radicals of (a) amino, C 1 -C ₄ alkylamino, or di-C 3 -C, alkyl) amino, radicals; or (b) hydroxy, C 1 -C ₄ alkoxy, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino , C ^ -Cj alkanoylamino, (C] _-C4 alkoxy) carbonylamino, hydroxy, Cj-C ₄ alkoxy, C _t -C ₄ alkylthio, cyano, halo, C] _-C4 alkyl or trifluoromethyl radicals;

(2) a C 1 -C ₂ haloalkyl group of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 - C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C 1 -C ₄ alkyl or trifluoromethyl radicals;

more preferably, each R ₃₀ may be independently (1) C 1 -C ₄ alkyl radical optionally substituted by phenyl or heteroaryl radicals optionally substituted by 1-3 amino, di- (C 1 -C) radicals ₂ alkyl) amino, acetamido, hydroxy, C 1 -C ₂ alkoxy, halo, C ₃ -C ₄ alkyl or trifluoromethyl radicals;

(2) trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3-radicals of amino, di- (C 1 -C ₂ alkyl) amino, acetamido-, hydroxy, C 1 -C ₂ alkoxy, halo, C, -C ₄ alkyl or trifluoromethyl radicals;

more preferably, each R ₃₀ may be independently (1) C 1 -C ₄ alkyl radical optionally substituted by phenyl or heteroaryl radicals optionally substituted by 1-3 radicals such as amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;

(2) trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;

more preferably, each R ₃₀ may be independently (1) a C 1 -C ₄ alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1 -2 radicals of amino, dimethylamino, acetamido, hydroxy, halo , methoxy, methyl or trifluoromethyl radicals;

(2) trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;

each R ₂₉ may independently be a hydrogen radical or R ₃₀ ;

and most preferably R ₂₉ may be an aryl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals;

each R ₃₁ may be independently (1) hydrogen radicals;

(2) alkyl radicals optionally substituted by cycloalkyl, aryl, heterocyclyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonyl amino, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, hydroxy, alkyl or haloalkyl radicals; or (3) aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of the amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cycloalkyl, alkylthio, cycloalkyl;

preferably, each R ₃₁ can be independently (1) hydrogen radicals;

(2) a C 1 -C ₄ alkyl radical optionally substituted by a C ₃ -C ₈ cycloalkyl, aryl, heterocyclyl, or heteroaryl radical optionally substituted by 1-3 radicals of the amino, C 1 -C ₄ alkylamino, di- ( C ₁ -C ₄ alkyl) amino, C ₃ -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C (-C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C ₃ -C ₄ alkylthio, cyano , C 1 -C ₄ alkyl or C _t -C ₄ haloalkyl radicals of 1-3 halo radicals; or (3) arylene, heteroarylene, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino radicals di- (C, -C ₄ alkyl) amino, N-C .. alkanoyl ino, (C _{(-C 4} alkoxy) carbonylamino, Cj-C ₄ alkylsulfonylamino, hydroxy, C, _-C4 alkoxy, C, -C ₄ alkylthio, cyano, C] _-C4 alkyl or _(C4 haloalkyl from 1-3 haladicals;

more preferably, each R ₃₁ may be independently (1) hydrogen radicals;

(2) C 1 -C ₄ alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino groups, C ₃ -C ₄ alkylamino, flH- (C 1 -C ₄ alkyl) amino, C C ₁ -C ₅ alkanoylamino, (C ₁ -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, C 1 -C 4 alkyl or trifluoromethyl radicals;

more preferably each R ₃₁ may independently be hydrogen or C 1 -C ₄ alkyl radicals; and most preferably, each R ₃₁ can independently be a hydrogen, methyl or ethyl radical;

each R ₃₂ may be independently (1) hydrogen radicals;

(2) an alkyl radical optionally substituted by cycloalkyl, aryl, heterocyclyl, or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkyloxy, alkyloxy, alkyloxy, alkyloxy, alkoxy or a haloalkyl radical; or (3) aryl, heteroaryl, heterocyclyl, or cycloalkyl radical optionally substituted by 1-3 radicals such as amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, haloalkyl, or cycloalkyl;

preferably, each R ₃₂ can be independently (1) hydrogen radicals;

(2) C 1 -C ₄ alkyl radical optionally substituted by C ₃ -C ₈ cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 amino, C ₁ -C ₄ alkylamino, di- (C) radicals ₁ -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C ₁ -C alkoxy) carbonylamino, C ₁ -C ₄ alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, C 1 -C alkyl or C-C haloalkyl radicals of 1-3 halo radicals; or (3) aryl, heteroaryl, heterocyclyl or a C ₃ -C ₈ cycloalkyl radical optionally substituted by 1-3 radicals of amino, C 1 -C 6 alkylamino, di- (C 1 -C ₄ alkyl) amino, C-C alkanoylamino, ( C 1 -C 3 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, C 1 -C 6 alkyl or C 1 -C haloalkyl radicals of 1-3 halo radicals;

more preferably, each R ₃₂ may be independently (1) hydrogen radicals;

(2) C 1 -C 4 alkyl radical optionally substituted by one C 1 -C cycloalkyl, aryl, heterocyclyl, or heteroaryl radical optionally substituted by 1-3 amino, C 1 -C alkylamino, di- (C-C ₄ radical) alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, C 1 -C alkyl or C 1 -C haloalkyl radicals of 1-3 haloradicals; or (3) aryl, heteroaryl, heterocyclyl, or C 1 -C 10 cycloalkyl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 2 C 1 -C 6 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, C 1 -C 6 alkyl or C 1 -C haloalkyl radicals of 1-3 halo radicals;

more preferably, each R ₃₂ may independently be (1) hydrogen radicals;

(2) C-C alkyl radical optionally substituted by an phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, N-C alkylamino, di- _(C-C4 alkyl) amino, N-C alkanoylamino, (C 1 -C alkoxy) carbonylamino, hydroxy, C 1 -C alkoxy, C 1 -C 6 alkyl or trifluoromethyl radicals; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, hydroxy , C1-C6 alkoxy, C1-C6 alkyl or trifluoromethyl radicals;

more preferably, each R ₃₂ may be independently (1) hydrogen radicals;

(2) C 1 -C 6 alkyl radical or C 1 -C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical, optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals;

more preferably, each R ₃₂ can be independently (1) hydrogen or a C 1 -C 4 alkyl radical; or (2) phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; and in which formula each R ₃₃ may be independently (1) a hydrogen radical or (2) an alkyl radical optionally substituted by a heterocyclyl, arylene or heteroaryl radical, optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino , alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl;

preferably each R ₃₃ can be independently (1) a hydrogen radical; or (2) C 1 -C 4 alkyl radical optionally substituted by heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C, alkylthio, cyano, C ₍ -C ₄ alkyl or C ₁ -C ₄ haloalkyl radicals of Or more preferably, each R ₃₃ may be independently hydrogen or C 1 -C ₄ alkyl radical, and most preferably, each R ₃₃ may be independently hydrogen or methyl radical;

The following terms and conditions apply only to compounds of the invention and not to pharmaceutical compositions or methods of use that cover the full breadth of the compounds cited above (unless otherwise stated):

1. When R ¹ and R ¹² are the same and are a 5- or 6-atom ring having from 1 to 3 heteroatoms independently selected from N, S and O to which the ring is attached by fusion a benzene nucleus, R ¹¹ represents a phenyl- or a naphthyl radical optionally substituted by halo, C 1 -C 6 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 alkylthiol-, hydroxy, amino, C 1 -C 4 alkylamino or dialkylamino, or R ¹¹ represents a 5- or 6-atom ring having from 1-3 heteroatoms independently selected from N, S and O to which a benzene nucleus is attached and which ring is optionally substituted with C 1 -C 6 alkyl, then va R ² is other than OH or NH ₂ ;

2. When R ² is H, R ¹¹ is phenyl and R ¹² is phenyl or 4-pyridyl, then R ¹ is other than H, methyl or amino;

3. When R ² is H, R ¹¹ is 2-methylphenyl and R ¹² is 2-pyridyl, then R ¹ is other than n-propyl; and (4) When R ¹¹ and R ¹² each represent an optionally substituted phenyl radical, then R ¹ is different from the optionally substituted 2-pyridyl radical.

The compounds of this invention can generally have several asymmetric centers and are typically considered in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partial racemic mixtures, and individual enantiomers and diastereomers.

The compounds of interest include representatives with the following general

structural formula: r ₂ ^Ru > r k e R12 NR _x where R ² is H and R ¹¹ , R ¹² and R ¹ represent -

watts one of the combinations given in the table below:

R ¹¹ R12 R1 phenyl 4-Pyridyl 1-piperazinyl 4-fluorophenyl 4-Pyridyl 1-piperazinyl 3-fluorophenyl 4-Pyridyl 1-piperazinyl 2-fluorophenyl 4-Pyridyl 1-piperazinyl 4-chlorophenyl 4-Pyridyl 1-piperazinyl 3-chlorophenyl 4-Pyridyl 1-piperazinyl 2-chlorophenyl 4-Pyridyl 1-piperazinyl 4-tolyl 4-Pyridyl 1-piperazinyl 3-tolyl 4-Pyridyl 1-piperazinyl 2-tolyl 4-Pyridyl 1-piperazinyl 4-Trifluoromethylphenyl 4-Pyridyl 1-piperazinyl 3-Trifluoromethylphenyl 4-Pyridyl 1-piperazinyl 2,6-dichlorophenyl 4-Pyridyl 1-piperazinyl 2,6-dimethylphenyl 4-Pyridyl 1-piperazinyl 3,4-dichlorophenyl 4-Pyridyl 1-piperazinyl 3,4-dimethylphenyl 4-Pyridyl 1-piperazinyl 2,4-dichlorophenyl 4-Pyridyl 1-piperazinyl 2,4-dimethylphenyl 4-Pyridyl 1-piperazinyl phenyl 2-amino-4-pyridyl 1-piperazinyl 4-fluorophenyl 2-amino-4-pyridyl 1-piperazinyl 3-fluorophenyl 2-amino-4-pyridyl 1-piperazinyl 2-fluorophenyl 2-amino-4-pyridyl 1-piperazinyl 4-chlorophenyl 2-amino-4-pyridyl 1-piperazinyl 3-chlorophenyl 2-amino-4-pyridyl 1-piperazinyl 2-chlorophenyl 2-amino-4-pyridyl 1-piperazinyl 4-tolyl 2-amino-4-pyridyl 1-piperazinyl 3-tolyl 2-amino-4-pyridyl 1-piperazinyl 2-tolyl 2-amino-4-pyridyl 1-piperazinyl 4-Trifluoromethylphenyl 2-amino-4-pyridyl 1-piperazinyl 3-Trifluoromethylphenyl 2-amino-4-pyridyl 1-piperazinyl 2,6-dichlorophenyl 2-amino-4-pyridyl 1-piperazinyl 2,6-dimethylphenyl 2-amino-4-pyridyl 1-piperazinyl 3,4-dichlorophenyl 2-amino-4-pyridyl 1-piperazinyl 3,4-dimethylphenyl 2-amino-4-pyridyl 1-piperazinyl 2,4-dichlorophenyl 2-amino-4-pyridyl 1-piperazinyl 2,4-dimethylphenyl 2-amino-4-pyridyl 1-piperazinyl phenyl 2-acetamido-4-pyridyl 1-piperazinyl 4-fluorophenyl 2-acetamido-4-pyridyl 1-piperazinyl 3-phenylmethyl 2-acetamido-4-pyridyl 1-piperazinyl 2-phenylmethyl 2-acetamido-4-pyridyl 1-piperazinyl 4-chlorophenyl 2-acetamido-4-pyridyl 1-piperazinyl 3-chlorophenyl 2-acetamido-4-pyridyl 1-piperazinyl 2-chlorophenyl 2-acetamido-4-pyridyl 1-piperazinyl 4-tolyl 2-acetamido-4-pyridyl 1-piperazinyl 3-tolyl 2-acetamido-4-pyridyl 1-piperazinyl 2-tolyl 2-acetamido-4-pyridyl 1-piperazinyl 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 1-piperazinyl

3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 1-piperazinyl 2,6-dichlorophenyl 2-acetamido-4-pyridyl 1-piperazinyl 2,6-dimethylphenyl 2-acetamido-4-pyridyl 1-piperazinyl 3,4-dichlorophenyl 2-acetamido-4-pyridyl 1-piperazinyl ' 3,4-dimethylphenyl 2-acetamido-4-pyridyl 1-piperazinyl 2,4-dihydrophenyl 2-acetamido-4-pyridyl 1-piperazinyl 2,4-dimethylphenyl 2-acetamido-4-pyridyl 1-piperazinyl phenyl 2-amino-4-pyrimidinyl 1-piperazinyl 4-fluorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 3-fluorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 2-fluorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 4-chlorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 3-chlorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 2-chlorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 4-tolyl 2-amino-4-pyrimidinyl 1-piperazinyl 3-tolyl 2-amino-4-pyrimidinyl 1-piperazinyl 2-tolyl 2-amino-4-pyrimidinyl 1-piperazinyl 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 1-piperazinyl 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 1-piperazinyl 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 1-piperazinyl 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 1-piperazinyl 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 1-piperazinyl 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 1-piperazinyl phenyl 4-Pyridyl 2,6-dichlorobenzyl 4-fluorophenyl 4-Pyridyl 2,6-dichlorobenzyl 3-fluorophenyl 4-Pyridyl 2,6-dichlorobenzyl 2-fluorophenyl 4-Pyridyl 2,6-dichlorobenzyl 4-chlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 3-chlorophenyl 4-Pyridyl 2,6-dichlorobenzyl ' 2-chlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 4-tolyl 4-Pyridyl 2,6-dichlorobenzyl 3-tolyl 4-Pyridyl 2,6-dichlorobenzyl 2-tolyl 4-Pyridyl 2,6-dichlorobenzyl 4-Trifluoromethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 2,4-dimethylphenyl 4-Pyridyl 2,6-dichlorobenzyl phenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 4-fluorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3-fluorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2-fluorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 4-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl

3-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 4-tolyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3-tolyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2-tolyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 4-Trifluoromethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,4-dimethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl phenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 4-fluorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-fluorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2-fluorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 4-chlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-chlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2-chlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 4-tolyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-tolyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2-tolyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,4-dimethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl phenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-fluorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-fluorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2-fluorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-chlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-chlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2-chlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-tolyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-tolyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2-tolyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl

2,4-dimethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl phenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 4-fluorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 3-fluorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 2-fluorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 4-chlorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 3-chlorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 2-chlorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 4-tolyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 3-tolyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 2-tolyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 4-Trifluoromethylphenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 3-Trifluoromethylphenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 2,6-dichlorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 2,6-dimethylphenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 3,4-dichlorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 3,4-dimethylphenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 2,4-dichlorophenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 2,4-dimethylphenyl 4-Pyridyl 2- (2-chlorophenyl) ethylamino 4-fluorophenyl 4-Pyridyl 3- (3-fluorophenyl) propylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 3- (3-fluorophenyl) propylamino benzyl 4-Pyridyl 3-phenylpropylamino benzyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2-thienyl 4-Pyridyl 3-phenylpropylamino 2-thienyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino cyclohexyl 4-Pyridyl 3-phenylpropylamino cyclohexyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino tert-butyl 4-Pyridyl 3-phenylpropylamino tert-butyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 4-piperidinyl 3-phenylpropylamino 4-fluorophenyl 4-piperidinyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 4-pyranyl 3-phenylpropylamino 4-fluorophenyl 4-pyranyl 2- (4-fluorophenyl) ethylamino phenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-fluorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-fluorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 2-fluorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-chlorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-chlorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 2-chlorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-TOLYL 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-tolyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 2-tolyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-Trifluoromethylphenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino

2,6-dimethylphenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 3,4-dichlorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 3,4-dimethylphenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 2,4-dichlorophenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino 2,4-dimethylphenyl 2-amino-4-pyridyl 2- (2-chlorophenyl) ethylamino phenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-fluorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-fluorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 2-fluorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-chlorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-chlorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 2-chlorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-tolyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-tolyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 2-tolyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 3,4-dichlorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 3,4-dimethylphenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 2,4-dichlorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino 2,4-dimethylphenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl) ethylamino phenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 3-fluorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 2-fluorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 4-chlorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 3-chlorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 2-chlorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 4-tolyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 3-tolyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 2-tolyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl) ethylamino phenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2-fluorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-chlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-chlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2-chlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino

4-TOLYL 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-tolyl 4-Pyridyl 2- (4-Fluorophenyl) ethylamino 2-tolyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dichlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dichlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dichlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dimethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino phenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 4-fluorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 2-fluorophenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 4-chlorophenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 3-chlorophenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 2-chlorophenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 4-tolyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-tolyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-tolyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dichlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dichlorophenyl 2-amino-4-pyridyl 2- (4-Fluorophenyl) ethylamino 2,4-dimethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino phenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-fluorophenyl 2-acetamido-4-pyridyl 2- (4-Fluorophenyl) ethylamino 4-chlorophenyl 2-acetamido-4-pyridyl 2- (4-Fluorophenyl) ethylamino 3-chlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-chlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-tolyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-tolyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-tolyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 2- (4-Fluorophenyl) ethylamino 3,4-dichlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 2-acetamido-4-pyridyl 2- (4-Fluorophenyl) ethylamino 2,4-dichlorophenyl 2-acetamido-4-pyridyl 2- (4-Fluorophenyl) ethylamino 2,4-dimethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino phenyl 2-amino-4-pyrimidinyl 2- (4-Fluorophenyl) ethylamino

4-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 4-chlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-chlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2-chlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 4-tolyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-tolyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2-tolyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2,6-dihydrophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino phenyl 4-Pyridyl 3-phenylpropylamino 4-fluorophenyl 4-Pyridyl 3-phenylpropylamino 3-fluorophenyl 4-Pyridyl 3-phenylpropylamino 2-fluorophenyl 4-Pyridyl 3-phenylpropylamino 4-chlorophenyl 4-Pyridyl 3-phenylpropylamino 3-chlorophenyl 4-Pyridyl 3-phenylpropylamino 2-chlorophenyl 4-Pyridyl 3-phenylpropylamino 4-tolyl 4-Pyridyl 3-phenylpropylamino 3-tolyl 4-Pyridyl 3-phenylpropylamino 2-tolyl 4-Pyridyl 3-phenylpropylamino 4-Trifluoromethylphenyl 4-Pyridyl 3-phenylpropylamino 3-Trifluoromethylphenyl 4-Pyridyl 3-phenylpropylamino 2,6-dichloromethyl 4-Pyridyl 3-phenylpropylamino 2,6-dimethylphenyl 4-Pyridyl 3-phenylpropylamino 3,4-dichlorophenyl 4-Pyridyl 3-phenylpropylamino 3,4-dimethylphenyl 4-Pyridyl 3-phenylpropylamino 2,4-dichlorophenyl 4-Pyridyl 3-phenylpropylamino 2,4-dimethylphenyl 4-Pyridyl 3-phenylpropylamino phenyl 2-amino-4-pyridyl 3-phenylpropylamino 4-fluorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 3-fluorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 2-fluorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 4-chlorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 3-chlorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 2-chlorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 4-tolyl 2-amino-4-pyridyl 3-phenylpropylamino 3-tolyl 2-amino-4-pyridyl 3-phenylpropylamino 2-tolyl 2-amino-4-pyridyl 3-phenylpropylamino 4-Trifluoromethylphenyl 2-amino-4-pyridyl 3-phenylpropylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 3-phenylpropylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 3-phenylpropylamino

2,6-dimethylphenyl 2-amino-4-pyridyl 3-phenylpropylamino 3,4-dichlorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 3,4-dimethylphenyl 2-amino-4-pyridyl 3-phenylpropylamino 2,4-dichlorophenyl 2-amino-4-pyridyl 3-phenylpropylamino 2,4-dimethylphenyl 2-amino-4-pyridyl 3-phenylpropylamino phenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 4-fluorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 3-fluorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 2-fluorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 4-chlorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 3-chlorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 2-chlorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 4-tolyl 2-acetamido-4-pyridyl 3-phenylpropylamino 3-tolyl 2-acetamido-4-pyridyl 3-phenylpropylamino 2-tolyl 2-acetamido-4-pyridyl 3-phenylpropylamino 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 3,4-dichlorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 3,4-dimethylphenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 2,4-dichlorophenyl 2-acetamido-4-pyridyl 3-phenylpropylamino 2,4-dimethylphenyl 2-acetamido-4-pyridyl 3-phenylpropylamino phenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 3-fluorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 2-fluorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 4-chlorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 3-chlorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 2-chlorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 4-tolyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 3-tolyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 2-tolyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 4-Trifluoromethylphenyl. 2-amino-4-pyrimidinyl 3-phenylpropylamino 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 3-phenylpropylamino phenyl 4-Pyridyl 3-imidazolylpropylamino 4-fluorophenyl 4-Pyridyl 3-imidazolylpropylamino 3-fluorophenyl 4-Pyridyl 3-imidazolylpropylamino 2-fluorophenyl 4-Pyridyl 3-imidazolylpropylamino 4-chlorophenyl 4-Pyridyl 3-imidazolylpropylamino 3-chlorophenyl 4-Pyridyl 3-imidazolylpropylamino 2-chlorophenyl 4-Pyridyl 3-imidazolylpropylamino

4-tolyl 4-Pyridyl 3-imidazolylpropylamino 3-tolyl 4-Pyridyl 3-imidazolylpropylamino 2-tolyl 4-Pyridyl 3-imidazolylpropylamino 4-Trifluoromethylphenyl 4-Pyridyl 3-imidazolylpropylamino 3-Trifluoromethylphenyl 4-Pyridyl 3-imidazolylpropylamino 2,6-dichlorophenyl 4-Pyridyl 3-imidazolylpropylamino 2,6-dimethylphenyl 4-Pyridyl 3-imidazolylpropylamino 3,4-dichlorophenyl 4-Pyridyl 3-imidazolylpropylamino 3,4-dimethylphenyl 4-Pyridyl 3-imidazolylpropylamino 2,4-dichlorophenyl 4-Pyridyl 3-imidazolylpropylamino 2,4-dimethylphenyl 4-Pyridyl 3-imidazolylpropylamino phenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 4-fluorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 3-fluorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 2-fluorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 4-chlorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 3-chlorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 2-chlorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 4-tolyl 2-amino-4-pyridyl 3-imidazolylpropylamino 3-tolyl 2-amino-4-pyridyl 3-imidazolylpropylamino 2-tolyl 2-amino-4-pyridyl 3-imidazolylpropylamino 4-Trifluoromethylphenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 2,6-dimethylphenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 3,4-dichlorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 3,4-dimethylphenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 2,4-dichlorophenyl 2-amino-4-pyridyl 3-imidazolylpropylamino 2,4-dimethylphenyl 2-amino-4-pyridyl 3-imidazolylpropylamino phenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 4-fluorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 3-fluorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 2-fluorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropyl ino 4-chlorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 3-chlorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 2-chlorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 4-tolyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 3-tolyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 2-tolyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 3,4-dichlorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 3,4-dimethylphenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 2,4-d Ichlorophenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino 2,4-dimethylphenyl 2-acetamido-4-pyridyl 3-imidazolylpropylamino phenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino

4-fluorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 3-fluorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 2-fluorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 4-chlorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 3-chlorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 2-chlorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 4-tolyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 3-tolyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 2-tolyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 3-imidazolylpropylamino 4-fluorophenyl 4-Pyridyl 4-fluorobenzylamino 4-fluorophenyl 2-acetamido-4-pyridyl 4-fluorobenzylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 4-fluorobenzylamino 4-fluorophenyl 4-Pyridyl 2- (2-chlorophenyl-1-methyl) ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl 2- (2-chlorophenyl-1-methyl) ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl 2- (2-chlorophenyl-1-methyl) ethyl) amino 4-fluorophenyl 4-Pyridyl (3- (4-fluorophenyl) propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3- (4-fluorophenyl) propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3- (4-fluorophenyl) propyl) amino 4-fluorophenyl 4-Pyridyl (3- (4-fluorophenyl) -1-methylpropyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3- (4-fluorophenyl) -1-methylpropyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3- (4-fluorophenyl) -1-methylpropyl) amino 4-fluorophenyl 4-Pyridyl (1,1-dimethyl-3- (4fluorophenyl) propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (1,1-dimethyl-3- (4fluorophenyl) -propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (1,1-dimethyl-3- (4fluorophenyl) -propyl) amino 4-fluorophenyl 4-Pyridyl (3- (2-fluorophenyl) propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3- (2-fluorophenyl) propyl) amino

4-fluorophenyl 2-amino-4-pyrimidinyl (3- (2-fluorophenyl) propyl) amino 4-fluorophenyl 4-Pyridyl (3-methyl-3-phenylpropyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3-methyl-3-phenylpropyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3-methyl-3-phenylpropyl) amino 4-fluorophenyl 4-Pyridyl (2-methyl-3-phenylpropyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (2-methyl-3-phenylpropyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (2-methyl-3-phenylpropyl) amino 3-fluorophenyl 4-Pyridyl (C) -tetrahydroisoquinol-Zyl-methylenamino 2-fluorophenyl 2-amino-4-pyridyl (C) -C-benzylpiperazinyl 3-chlorophenyl 2-acetamido-4-pyridyl (C) -2-N-isopropylamino-3-phenylpropylamino 2-chlorophenyl 2-amino-4-pyrimidinyl (C) -2-1H-glycylamino-3-phenylpropylamino 4-tolyl 4-Pyridyl (C) -2-amino-3-phenylpropylamino 3-tolyl 2-amino-4-pyridyl (II) -2-amino-3-phenylpropylamino 2-tolyl 2-acetamido-4-pyridyl 3-amino-phenylpropylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl (C) -2-amino-3- (2-fluorophenyl) propylamino 3-Trifluoromethylphenyl 4-Pyridyl (s) -2-amino-3- (2-methyl phenyl) propylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 3-amino-3- (2-fluorophenyl) propylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 3-amino-3- (2-methylphenyl) propylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 2-amino-2-methyl-3-phenylpropylamino 3,4-dimethylphenyl 4-Pyridyl 3-yno-2-methyl-phenylpropylamino 3-fluorophenyl 2-amino-4-pyridyl (s) -2-aHHO-3phenylpropylamino 2-fluorophenyl 2-acetamido-4-pyridyl (C) -2-amino-3- (2-fluorophenyl) propylamino 3-chlorophenyl 2-amino-4-pyrimidinyl (C) -2-amino-3- (2-methylphenyl) propylamino 2-chlorophenyl 4-Pyridyl (C) -2-N-isopropylamino-3-phenylpropylamino 4-tolyl 2-amino-4-pyridyl (C) -2-N-glycylamino-3-phenylpropylamino

3-TOLYL 2-acetamido-4-pyridyl 2-amino-2-methyl-3-phenylpropylamino 2-tolyl 2-amino-4-pyrimidinyl (A) -2-amino-3-phenylpropylamino 4-Trifluoromethylphenyl 4-Pyridyl 3-amino-3-phenylpropylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 3-amino-3- (2fluorophenyl) propylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 3-amino-3- (2-methylphenyl) propylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 3-amino-2-methyl-phenylpropylamino 3,4-dichlorophenyl 4-Pyridyl (S) -tetrahydroisoquinol-3yl-methylenamino 3,4-dimethylphenyl 4-Pyridyl (C) -C-benzylpiperazinyl

where

R ² is -OH and R ¹¹ , R ¹² and R ¹ are one of the combinations given in the following table:

R ¹¹ R12 R ¹ phenyl 4-Pyridyl 4-pyridyl ' 4-fluorophenyl 4-Pyridyl 4-Pyridyl 3-fluorophenyl 4-Pyridyl 4-Pyridyl 2-fluorophenyl 4-Pyridyl 4-Pyridyl 4-chlorophenyl 4-Pyridyl 4-Pyridyl 3-chlorophenyl 4-Pyridyl 4-Pyridyl 2-chlorophenyl 4-Pyridyl 4-Pyridyl 4-tolyl 4-Pyridyl 4-Pyridyl 3-tolyl 4-Pyridyl 4-Pyridyl 2-tolyl 4-Pyridyl 4-Pyridyl 4-Trifluoromethylphenyl 4-Pyridyl 4-Pyridyl 3-Trifluoromethylphenyl 4-Pyridyl 4-Pyridyl 2,6-dichlorophenyl 4-Pyridyl 4-Pyridyl 2,6-dimethylphenyl 4-Pyridyl 4-Pyridyl 3,4-dichlorophenyl 4-Pyridyl 4-Pyridyl 3,4-dimethylphenyl 4-Pyridyl 4-Pyridyl 2,4-dichlorophenyl 4-Pyridyl 4-Pyridyl 2,4-dimethylphenyl 4-Pyridyl 4-Pyridyl phenyl 2-amino-4-pyridyl 4-Pyridyl 4-fluorophenyl 2-amino-4-pyridyl 4-Pyridyl 3-fluorophenyl 2-amino-4-pyridyl 4-Pyridyl 2-fluorophenyl 2-amino-4-pyridyl 4-Pyridyl 4-chlorophenyl 2-amino-4-pyridyl 4-Pyridyl 3-chlorophenyl 2-amino-4-pyridyl 4-Pyridyl 2-chlorophenyl 2-amino-4-pyridyl 4-Pyridyl 4-tolyl 2-amino-4-pyridyl 4-Pyridyl 3-tolyl 2-amino-4-pyridyl 4-Pyridyl 4-Trifluoromethylphenyl 2-amino-4-pyridyl 4-Pyridyl 3-Trifluoromethylphenyl 2-amino-4-pyridyl 4-Pyridyl 2,6-dichlorophenyl 2-amino-4-pyridyl 4-Pyridyl 2,6-dimethylphenyl 2-amino-4-pyridyl 4-Pyridyl 3,4-dichlorophenyl 2-amino-4-pyridyl 4-Pyridyl 3,4-dimethylphenyl 2-amino-4-pyridyl 4-Pyridyl 2,4-dichlorophenyl 2-amino-4-pyridyl 4-Pyridyl 2,4-dimethylphenyl 2-amino-4-pyridyl 4-Pyridyl phenyl 2-acetamido-4-pyridyl 4-Pyridyl 4-fluorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 3-fluorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 2-fluorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 4-chlorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 3-chlorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 2-chlorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 4-tolyl 2-acetamido-4-pyridyl 4-Pyridyl 3-tolyl 2-acetamido-4-pyridyl 4-Pyridyl 2-tolyl 2-acetamido-4-pyridyl 4-Pyridyl

4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 4-Pyridyl 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 4-Pyridyl 2,6-dichlorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 2,6-dimethylphenyl 2-acetamido-4-pyridyl 4-Pyridyl 3,4-dichlorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 3,4-dimethylphenyl 2-acetamido-4-pyridyl 4-Pyridyl 2,4-dichlorophenyl 2-acetamido-4-pyridyl 4-Pyridyl 2,4-dimethylphenyl 2-acetamido-4-pyridyl 4-Pyridyl phenyl 2-amino-4-pyrimidinyl 4-Pyridyl 4-fluorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 3-fluorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 2-fluorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 4-chlorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 3-chlorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 2-chlorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 4-tolyl 2-amino-4-pyrimidinyl 4-Pyridyl 3-tolyl 2-amino-4-pyrimidinyl 4-Pyridyl 2-tolyl 2-amino-4-pyrimidinyl 4-Pyridyl 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 4-Pyridyl 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 4-Pyridyl 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 4-Pyridyl 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 4-Pyridyl 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 4-Pyridyl 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 4-Pyridyl phenyl 4-Pyridyl 4-methyl sulfinylphenyl 4-fluorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 3-fluorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 2-fluorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 4-chlorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 3-chlorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 2-chlorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 4-tolyl 4-Pyridyl 4-methyl sulfinylphenyl 3-tolyl 4-Pyridyl 4-methyl sulfinylphenyl 2-tolyl 4-Pyridyl 4-methyl sulfinylphenyl 4-Trifluoromethylphenyl 4-Pyridyl 4-methyl sulfinylphenyl 3-Trifluoromethylphenyl 4-Pyridyl 4-methyl sulfinylphenyl 2,6-dichlorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 2,6-dimethylphenyl 4-Pyridyl 4-methyl sulfinylphenyl 3,4-dichlorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 3,4-dimethylphenyl 4-Pyridyl 4-methyl sulfinylphenyl 2,4-dichlorophenyl 4-Pyridyl 4-methyl sulfinylphenyl 2,4-dimethylphenyl 4-Pyridyl 4-methyl sulfinylphenyl phenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 4-fluorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 3-fluorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 2-fluorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl

4-chlorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 3-chlorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 2-chlorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 4-tolyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 3-tolide 2-amino-4-pyridyl 4-methyl sulfinylphenyl 2-tolyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 4-Trifluoromethylphenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 3-Trifluoromethylphenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 2,6-dichlorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 2,6-dimethylphenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 3,4-dichlorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 3,4-dimethylphenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 2,4-dichlorophenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl 2,4-dimethylphenyl 2-amino-4-pyridyl 4-methyl sulfinylphenyl phenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 4-fluorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 3-fluorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 2-fluorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 4-chlorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 3-chlorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 2-chlorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 4-tolyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 3-tolyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 2-tolyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 2,6-dichlorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 2,6-dimethylphenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 3,4-dichlorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 3,4-dimethylphenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 2,4-dichlorophenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl 2,4-dimethylphenyl 2-acetamido-4-pyridyl 4-methyl sulfinylphenyl phenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 4-fluorophenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 3-fluorophenyl 2-amino4-pyrimidinyl 4-methyl sulfinylphenyl 2-fluorophenyl 2-amino4-pyrimidinyl 4-methyl sulfinylphenyl 4-chlorophenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 3-chlorophenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 2-chlorophenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 4-tolyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 3-tolyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 2-tolyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl

2,4-dichlorophenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 4-methyl sulfinylphenyl phenyl 4-Pyridyl 2,6-dichlorobenzyl 4-fluorophenyl 4-Pyridyl 2,6-dichlorobenzyl 3-fluorophenyl 4-Pyridyl 2,6-dichlorobenzyl 2-fluorophenyl 4-Pyridyl 2,6-dichlorobenzyl 4-chlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 3-chlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 2-chlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 4-tolyl 4-Pyridyl 2,6-dichlorobenzyl 3-tolyl 4-Pyridyl 2,6-dichlorobenzyl 2-tolyl 4-Pyridyl 2,6-dichlorobenzyl 4-Trifluoromethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 4-Pyridyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 4-Pyridyl 2,6-dichlorobenzyl 2,4-dimethylphenyl 4-Pyridyl 2,6-dichlorobenzyl phenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 4-fluorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3-fluorophenyl 2-amino-4-pyridyl 1-piperazinyl 2-fluorophenyl 2-amino-4-pyridyl 1-piperazinyl 4-chlorophenyl 2-amino-4-pyridyl 1-piperazinyl 3-chlorophenyl 2-amino-4-pyridyl 1-piperazinyl 2-chlorophenyl 2-amino-4-pyridyl 1-piperazinyl 4-tolyl 2-amino-4-pyridyl 1-piperazinyl 3-tolyl 2-amino-4-pyridyl 1-piperazinyl 2-tolyl 2-amino-4-pyridyl 1-piperazinyl 4-Trifluoromethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl 2,4-dimethylphenyl 2-amino-4-pyridyl 2,6-dichlorobenzyl phenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 4-fluorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-fluorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2-fluorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 4-chlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-chlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2-chlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 4-tolyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-tolyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2-tolyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl

4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl 2,4-dimethylphenyl 2-acetamido-4-pyridyl 2,6-dichlorobenzyl phenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-fluorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-fluorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2-fluorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-chlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-chlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2-chlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-tolyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-tolyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2-tolyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 2,6-dichlorobenzyl phenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2-fluorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-chlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-chlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2-chlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-tolyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-tolyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2-tolyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dichlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dichlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dichlorophenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dimethylphenyl 4-Pyridyl 2- (4-fluorophenyl) ethylamino phenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-fluorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino

4-chlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-chlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-chlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-tolyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-tolyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-tolyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dichlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dichlorophenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dimethylphenyl 2-amino-4-pyridyl 2- (4-fluorophenyl) ethylamino phenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-fluorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-chlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-chlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-chlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-tolyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-tolyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2-tolyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dichlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dichlorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino 2,4-dimethylphenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) ethylamino phenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 4-chlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-chlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2-chlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 4-tolyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-tolyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2-tolyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino

2,4-dichlorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) ethylamino phenyl 4-Pyridyl 3-phenyl-propylamino 4-fluorophenyl 4-Pyridyl 3-phenyl-propylamino 3-fluorophenyl 4-Pyridyl 3-phenyl-propylamino 2-fluorophenyl 4-Pyridyl 3-phenyl-propylamino 4-chlorophenyl 4-Pyridyl 3-phenyl-propylamino 3-chlorophenyl 4-Pyridyl 3-phenyl-propylamino 2-chlorophenyl 4-Pyridyl 3-phenyl-propylamino 4-tolyl 4-Pyridyl 3-phenyl-propylamino 3-tolyl 4-Pyridyl 3-phenyl-propylamino 2-tolyl 4-Pyridyl 3-phenyl-propylamino 4-Trifluoromethylphenyl 4-Pyridyl 3-phenyl-propylamino 3-Trifluoromethylphenyl 4-Pyridyl 3-phenyl-propylamino 2,6-dichlorophenyl 4-Pyridyl 3-phenyl-propylamino 2,6-dimethylphenyl 4-Pyridyl 3-phenyl-propylamino 3,4-dichlorophenyl 4-Pyridyl 3-phenyl-propylamino 3,4-dimethylphenyl 4-Pyridyl 3-phenyl-propylamino 2,4-dichlorophenyl 4-Pyridyl 3-phenyl-propylamino 2,4-dimethylphenyl 4-Pyridyl 3-phenyl-propylamino phenyl 2-amino-4-pyridyl 3-phenyl-propylamino 4-fluorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 3-fluorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 2-fluorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 4-chlorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 3-chlorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 2-chlorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 4-tolyl 2-amino-4-pyridyl 3-phenyl-propylamino 3-tolyl 2-amino-4-pyridyl 3-phenyl-propylamino 2-tolyl 2-amino-4-pyridyl 3-phenyl-propylamino 4-Trifluoromethylphenyl 2-amino-4-pyridyl 3-phenyl-propylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 3-phenyl-propylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 2,6-dimethylphenyl 2-amino-4-pyridyl 3-phenyl-propylamino 3,4-dichlorophenyl 2-amino-4-pyridyl 3-phenyl-propylamino 3,4-dimethylphenyl 2-amino-4-pyridyl 3-phenyl-propylamino 2,4-dichlorophenyl 2-yno-4-pyridyl 3-phenyl-propylamino 2,4-dimethylphenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino phenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 4-fluorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 3-fluorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 2-fluorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 4-chlorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 3-chlorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 2-chlorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 4-tolyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 3-tolyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 2-tolyl 2-acetamido-4-pyridyl 3-phenyl-propylamino

4-Trifluoromethylphenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino ⁴ 3,4-dichlorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 3,4-dimethylphenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 2,4-dichlorophenyl 2-acetamido-4-pyridyl 3-phenyl-propylamino 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino phenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 3-fluorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 2-fluorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 4-chlorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 3-chlorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 2-chlorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 4-tolyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 3-tolyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 2-tolyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 2,6-dichlorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 2,4-dichlorophenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino 2,4-dimethylphenyl 2-amino-4-pyrimidinyl 3-phenyl-propylamino phenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 4-fluorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 3-fluorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 2-fluorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 4-chlorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 3-chlorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 2-chlorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 4-tolyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 3-tolyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 2-tolyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 4-Trifluoromethylphenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 3-Trifluoromethylphenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 2,6-dichlorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 2,6-dimethylphenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 3,4-dichlorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 3,4-dimethylphenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 2,4-dichlorophenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino 2,4-dimethylphenyl 4-Pyridyl (1-methyl-3-phenyl) propylamino phenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 4-fluorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 3-fluorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 2-fluorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino

4-chlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 3-chlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 2-chlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 4-tolyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 3-tolyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 2-tolyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 4-Trifluoromethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 2,6-dichlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 2,6-dimethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 3,4-dichlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 3,4-dimethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 2,4-dichlorophenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino 2,4-dimethylphenyl 2-amino-4-pyridyl (1-methyl-3-phenyl) propylamino phenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 4-fluorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 3-fluorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 2-fluorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 4-chlorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 3-chlorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 2-chlorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 4-tolyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 3-tolyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 2-tolyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 4-Trifluoromethylphenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 3-Trifluoromethylphenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 3,4-dichlorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 3,4-dimethylphenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 2,4-dichlorophenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino 2,4-dimethylphenyl 2-acetamido-4-pyridyl (1-methyl-3-phenyl) propylamino phenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 4-fluorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 3-fluorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 2-fluorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 4-chlorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 3-chlorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 2-chlorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 4-tolyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 3-tolyl 2-amino-4-pyrimidinyl · (1-methyl-3-phenyl) propylamino 2-tolyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 3-Trifluoromethylphenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 2,6-dichlorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 2,6-dimethylphenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 3,4-dimethylphenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino

2,4-dichlorophenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 2,4-dimethylphenyl 2-amino-4-pyrimidinyl (1-methyl-3-phenyl) propylamino 4-fluorophenyl 4-Pyridyl 4-fluorobenzylamino 4-fluorophenyl 2-acetamido-4-pyridyl 4-fluorobenzylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 4-fluorobenzylamino 4-fluorophenyl 4-Pyridinyl (2- (4-fluorophenyl) -1-methyl-ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (2- (4-fluorophenyl) -1-methyl-ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (2- (4-fluorophenyl) -1-methyl-ethyl) amino 4-fluorophenyl 4-Pyridyl (1,1-dimethyl-2- (4-fluorophenyl) ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (1,1-dimethyl-2- (4-fluorophenyl) ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (1,1-dimethyl-2- (4-fluorophenyl) ethyl) amino 4-fluorophenyl 4-Pyridyl 2- (4-fluorophenyl) -2-methyl-ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl 2- (4-fluorophenyl) -2-methyl-ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-fluorophenyl) -2-methyl-ethyl) amino 4-fluorophenyl 4-Pyridyl (2-methyl-2-phenylethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (2-methyl-2-phenylethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (2-methyl-2-phenylethyl) amino 4-fluorophenyl 4-Pyridyl methyl- (2-phenylethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl methyl- (2-phenylethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl methyl- (2-phenylethyl) amino 4-fluorophenyl 4-Pyridyl (2- (4-Trifluoromethyl-phenyl) ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (2- (4-Trifluoromethyl-phenyl) ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (2- (4-Trifluoromethyl-phenyl) ethyl) amino 4-fluorophenyl 4-Pyridyl 2- (4-Tolyl) ethylamino 4-fluorophenyl 2-acetamido-4-pyridyl 2- (4-Tolyl) ethylamino 4-fluorophenyl 2-amino-4-pyrimidinyl 2- (4-Tolyl) ethylamino 4-fluorophenyl 4-Pyridyl (2- (3-fluorophenyl) ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (2- (3-fluorophenyl) ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (2- (3-fluorophenyl) ethyl) amino 4-fluorophenyl 4-Pyridyl (2- (2-fluorophenyl) ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (2- (2-fluorophenyl) ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (2- (2-fluorophenyl) ethyl) amino 4-fluorophenyl 4-Pyridyl methyl- (2- (2-pyridyl) ethyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl methyl- (2- (2-pyridyl) ethyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl methyl- (2- (2-pyridyl) ethyl) amino 4-fluorophenyl 4-Pyridyl (1,1-dimethyl-3-phenyl-propyl) amino

4-fluorophenyl 2-acetamido-4-pyridyl (1,1-Dimethyl-3-phenyl-propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (1,1-Dimethyl-3-phenyl-propyl) amino 4-fluorophenyl 4-Pyridyl (3- (4-fluorophenyl) -propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3- (4-fluorophenyl) -propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3- (4-fluorophenyl) -propyl) amino 4-fluorophenyl 4-Pyridyl (3- (4-fluorophenyl) -1-methylpropyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3- (4-fluorophenyl) -1-methylpropyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3- (4-fluorophenyl) -1-methylpropyl) amino 4-fluorophenyl 4-Pyridyl (1,1-dimethyl-3- (4-fluoro-phenyl) propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (1,1-dimethyl-3- (4-fluoro-phenyl) propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (1,1-dimethyl-3- (4-fluoro-phenyl) propyl) amino 4-fluorophenyl 4-Pyridyl (3- (2-fluorophenyl) -propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3- (2-fluorophenyl) -propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3- (2-fluorophenyl) -propyl) amino 4-fluorophenyl 4-Pyridyl (3-methyl-3-phenyl-propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3-methyl-3-phenyl-propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3-methyl-3-phenyl-propyl) amino 4-fluorophenyl 4-Pyridyl (2-methyl-3-phenyl-propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (2-methyl-3-phenyl-propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (2-methyl-3-phenyl-propyl) amino 4-fluorophenyl 4-Pyridyl (3,3-dimethylbutyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3,3-dimethylbutyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3,3-dimethylbutyl) amino 4-fluorophenyl 4-Pyridyl isoamylamino 4-fluorophenyl 2-acetamido-4-pyridyl isoamylamino 4-fluorophenyl 2-amino-4-pyrimidinyl isoamylamino 4-fluorophenyl 4-Pyridyl amylamino 4-fluorophenyl 2-acetamido-4-pyridyl amylamino 4-fluorophenyl 2-amino-4-pyrimidinyl amylamino 4-fluorophenyl 4-Pyridyl (2,5-dimethyl) pentylamino 4-fluorophenyl 2-acetamido-4-pyridyl (2,5-dimethyl) pentylamino 4-fluorophenyl 2-amino-4-pyrimidinyl (2,5-dimethyl) pentylamino 4-fluorophenyl 4-Pyridyl piperazinyl 4-fluorophenyl 2-acetamido-4-pyridyl piperazinyl 4-fluorophenyl 2-amino-4-pyrimidinyl piperazinyl 4-fluorophenyl 4-Pyridyl (3- (3-fluorophenyl) -propyl) amino 4-fluorophenyl 2-acetamido-4-pyridyl (3- (3-fluorophenyl) -propyl) amino 4-fluorophenyl 2-amino-4-pyrimidinyl (3- (3-fluorophenyl) -propyl) amino benzyl 4-Pyridyl 3-phenylpropylamino benzyl 4-Pyridyl 2- (4-fluorophenyl) -ethylamino

2-thienyl 4-Pyridyl 3-phenylpropylamino 2-thienyl 4-Pyridyl 2- (4-fluorophenyl) -ethylamino cyclohexyl 4-Pyridyl 3-phenylpropylamino cyclohexyl 4-Pyridyl 2- (4-fluorophenyl) -ethylamino tert-butyl 4-Pyridyl 3-phenylpropylamino tert-butyl 4-Pyridyl 2- (4-fluorophenyl) -ethylamino 4-fluorophenyl 4-piperidinyl 3-phenylpropylamino 4-fluorophenyl 4-piperidinyl 2- (4-fluorophenyl) -ethylamino 4-fluorophenyl 4-pyranyl 3-phenylpropylamino 4-fluorophenyl 4-pyranyl 2- (4-fluorophenyl) -ethylamino phenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 4-fluorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 3-fluorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 2-fluorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 4-chlorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 3-chlorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 2-chlorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 4-tolyl 4-Pyridyl 3-phenyl-2-amino-propylamino 3-tolyl 4-Pyridyl 3-phenyl-2-amino-propylamino 2-tolyl 4-Pyridyl 3-phenyl-2-amino-propylamino 4-Trifluoromethylphenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 3-Trifluoromethylphenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 2,6-dichlorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 2,6-dimethylphenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 3,4-dimethylphenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 2,4-dichlorophenyl 4-Pyridyl 3-phenyl-2-amino-propylamino 2,4-dimethylphenylphenyl 4-Pyridyl 3-phenyl-2-amino-propylamino phenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 4-fluorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 3-fluorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 2-fluorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 4-chlorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 3-chlorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 2-chlorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 4-tolyl 4-Pyridyl 3-phenyl-3-amino-propylamino 3-tolyl 4-Pyridyl 3-phenyl-3-amino-propylamino 2-tolyl 4-Pyridyl 3-phenyl-3-amino-propylamino 4-Trifluoromethylphenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 3-Trifluoromethylphenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 2,6-dichlorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 2,6-dimethylphenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 3,4-dichlorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 3,4-dimethylphenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 2,4-dichlorophenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 2,4-dimethylphenyl 4-Pyridyl 3-phenyl-3-amino-propylamino 3-fluorophenyl 4-Pyridyl (c) -tetrahydroisoquinol-Zyl-methylenamino 2-fluorophenyl 2-amino-4-pyridyl (C) -C-benzylpiperazinyl

2-chlorophenyl 2-acetamido-4-pyridyl (e) -2-N-isopropylamino-3-phenylpropylamino 2-chlorophenyl 2-amino-4-pyrimidinyl (e) -2-1H-glycylamino-3-phenylpropylamino 4-tolyl 4-Pyridyl (c) -2-amino-3-phenylpropylamino 3-tolyl 2-amino-4-pyridyl (FO-2-amino-3-phenylpropylamino 2-tolyl 2-acetamido-4-pyridyl 3-amino-3-phenylpropylamino 4-Trifluoromethylphenyl 2-amino-4-pyrimidinyl (e) -2-amino-3- (2-fluorophenyl) propylamino 3-Trifluoromethylphenyl 4-Pyridyl (e) -2-amino-3- (2-methylphenyl) propylamino 2,6-dichlorophenyl 2-amino-4-pyridyl 3-amino-3- (2-fluorophenyl) propylamino 2,6-dimethylphenyl 2-acetamido-4-pyridyl 3-amino-3- (2-methylphenyl) propylamino 3,4-dichlorophenyl 2-amino-4-pyrimidinyl 2-amino-2-methyl-3-phenylpropylamino 3,4-dimethylphenyl 4-Pyridyl 2-amino-2-methyl-3-phenylpropylamino 3-fluorophenyl 2-amino-4-pyridyl (e) -2-amino-3-phenylpropylamino 2-fluorophenyl 2-acetamido-4-pyridyl (c) -2-amino-3- (2-fluoro phenyl) propylamino 3-chlorophenyl 2-amino-4-pyrimidinyl (C) -2-amino-3- (2-methylphenyl) propylamino 2-chlorophenyl 4-Pyridyl (C) -2-1M-isopropylamino-3-phenylpropylamino 4-TOLYL 2-amino-4-pyridyl (B) -2-N-glycylamino-3-phenylpropylamino 3-tolyl 2-acetamido-4-pyridyl 2-amino-2-methyl-3-phenylpropylamino 2-tolyl 2-amino-4-pyrimidinyl (R) -2-amino-3-phenylpropylamino 4-Trifluoromethylphenyl 4-Pyridyl 3-amino-3-phenyl-propylamino 3-Trifluoromethylphenyl 2-amino-4-pyridyl 3-amino-3- (2-fluoro-phenyl) propylamino 2,6-dichlorophenyl 2-acetamido-4-pyridyl 3-amino-3- (2-methylphenyl) propylamino 2,6-dimethylphenyl 2-amino-4-pyrimidyl 3-amino-2-methyl-3-phenylpropylamino 3,4-dichlorophenyl 4-Pyridyl (C) -tetrahydroisoquinol-3yl-methylenamino 3,4-dimethylphenyl 4-Pyridyl (C) -C-benzylpiperazinyl

Further preferred compounds are listed in the examples in the text.

As used throughout the text, the following concepts should be understood as follows:

"Alkyl", alone or in combination, means a straight- or branched-chain alkyl radical containing preferably 1-15 carbon atoms of greater preference 1-8 carbon atoms (Cj-Cg), even more preferred 1- 6 carbon atoms (C 1 -C ₆ ), and with increasing preference 1-4 carbon atoms (C 1 -C ₄ ), and even better with 1-3 carbon atoms (C 1 -CD and most) Preferred 1-2 carbon atoms (C 1 -C ₂ ) Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isoamyl, hex forces, octyl and the like.

"Hydroxyalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen radical is substituted by a hydroxyl radical, preferably 1-3 hydrogen radicals are substituted by hydroxyl radicals, more preferably 1-2 hydrogen radicals are substituted by hydroxyl radicals, and most preferably one hydrogen radical is substituted by one hydroxyl radical. Examples of such radicals are hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1,3-dihydroxy-butyl, 1,2,3,4,5,6- hexahydroxy-2-hexylradical and the like. similar.

"Alkenyl", alone or in combination, means a straight or branched chain hydrocarbon radical in which one or more double bonds are present, preferably 1-2 double bonds and more preferably one double bond, and preferably containing 2- 15 carbon atoms (C ₂ -C ₁₅ ), more preferably 2-8 carbon atoms (C ₂ -C ₈ ), even more preferably 2-6 carbon atoms (C ₂ -C ₆ ), and all again more preferably 2-4 carbon atoms (C ₂ -C ₄ ), and even more preferably 2-3 carbon atoms (C ₂ -C ₃ ). Examples of such alkenyl radicals are ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.

"Alkoxy" alone or in combination means a radical of the type "R-O-" wherein R is an alkyl radical as defined above and "O" represents an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, pbutoxy, isobutoxy, secondary butoxy, tertiary butoxy radicals and the like.

"Alkoxycarbonyl", alone or in combination, means a radical of the type "R-OC (O) -", where "R-O-" represents an alkoxy radical as defined above and "C (O)" is a carbonyl radical.

"Alkoxycarbonylamino", alone or in combination, means a radical of the type "RO-C (O) -NH", where "ROC (O) -" represents an alkoxycarbonyl radical, as defined above, in which the amino radical may be substituted by optionally with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl radicals and the like.

"Alkylthio", alone or in combination, means a radical of the type "R-S-" in which R represents an alkyl radical as defined above and S is a sulfur atom. Examples of such alkylthio radicals are methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, isobutylthio, secondary butylthio, tertiary butylthio and the like.

"Alsulfinyl" alone or in combination, means a radical of the type "R-S (O) -", where "R" represents an alkyl radical as defined above and "S (O)" represents a single monoxidized sulfur atom. Examples of such alkylsulfinyl radicals are methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl, secondary butylsulfinyl, tertiary-butylsulfinyl radicals.

"Alkylsulfonyl" alone or in combination, means a radical of the type "RS (O) ₂ -", where "R" represents an alkyl radical as defined above, and "S (O) ₂ " represents a double oxidized sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl, tertiary butylsulfonyl.

"Aryl", alone or in combination, means a phenyl or biphenyl radical which may be optionally benzo-fusene or heterocyclo-fusene and which is optionally substituted by one or more substituents selected from the radicals alkyl, alkoxy, halogen, hydroxy, Alkaline, Alkaline a alkylsulphinyl, alkylsulfonyl, oxo and the like radicals. Examples of aryl radicals are phenyl otolyl, 4-methoxyphenyl, 2- (tert-butoxy) phenyl, 3-methyl-4-methoxyphenyl, 2-C3 _3- phenyl, 2-fluorophenyl, 2-chlorophenyl, 3-nitrophenyl, 3 -aminophenyl, 3-acetamidophenyl, 2-amino-3- (aminomethyl) phenyl, 6-methyl-3-acetamidophenyl, 6-methyl-2-aminophenyl, 6-methyl-2,3-diaminophenyl, 2-amino-3- methylphenyl, 4,6-dimethyl-2aminophenyl, 4-hydroxyphenyl, 3-methyl-4hydroxyphenyl, 4- (2-methoxyphenyl) phenyl, 2amino-1-naphthyl, 2-naphthyl, 3-amino-2-naphthyl, 1methyl-3 -amino-2-naphthyl, 2,3-diamino-1-naphthyl, 4,8-dimethoxy-2-naphthyl, and the like.

"Aralkyl" and "arylalkyl", alone or in combination, mean one alkyl radical as defined above, in which at least one hydrogen atom, preferably 1-2, is substituted by an aryl radical as defined above, such as benzyl, 1-, 2-, phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 4-methoxyphenylmethyl and the like.

"Aralkoxy", alone or in combination, means an alkoxy radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyloxy-, 1 -, 2-phenylethoxy, dibenzylmethoxy-, hydroxyphenylmethoxy-, methylphenylmethoxy-, dichlorophenylmethoxy-, 4-methoxyphenylmethoxy-, and the like.

"Aralkoxycarbonyl", alone or in combination, means a radical of the type "R-OC (O) -", where "R-O-" represents an alkoxy radical as defined above, and -C (O) - is a carbonyl radical.

"Alkanoyl", alone or in combination, means a radical of the type "R-C (O) -", where "R" represents an alkyl radical as defined above and "-C- (O) -" represents a carbonyl radical. Examples include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methyl valeryl and the like.

"Alkanoylamino" alone or in combination, means a radical of the type "RC- (O) NH-" in which "RC (O) -" represents an alkanoyl radical, as defined above, in which the amino radical may optionally be substituted by groups such as alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like.

"Aminocarbonyl", alone or in combination, means an amino substituted carbonyl (carbamoyl) radical, wherein the amino radical may be optionally mono- or di-substituted with radicals such as alkylene, arylene, aralkylene, cycloalkylene, cycloalkylalkylalkanylcarbonyl, alkanocarbonyl similar ones.

"Aminosulfonyl", alone or in combination, means an amino substituted sulfonyl radical.

"Benzo", alone or in combination, means a bivalent radical C ₆ H ₄ = benzene derivative. "Benzo-fusional" forms a ring system in which benzene and cycloalkyl or aryl groups have two common carbon atoms, for example, tetrahydronaphthalene and the like.

"Bicyclen" is used to refer to both fusion ring systems such as naphthyl and beta-carbonyl and substituted ring systems such as biphenyl, phenylpyridyl and diphenylpiperazinyl.

"Cycloalkyl", alone or in combination, means saturated or partially saturated, preferably with one double bond, monocyclic, two-cyclic or tricyclic carbocyclic alkyl radical, preferably monocyclic, preferably containing 5-12 carbon atoms (C ₅ -C ₁₂ ), more preferably 5-10 carbon atoms ((C ₅ -C ₁₀ ), even more preferably 5-7 carbon atoms ((C ₅ -C ₇ ), which is optionally benzofuse or heterocyclofusion and which radical is optionally substituted as defined herein with respect to the definition of aryl such cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl, 2-indyl-indenyl, 2-indyl-indenyl,

"Heteroatoms" means nitrogen, oxygen and sulfur heteroatoms.

"Heterocyclofuzen" forms a ring system in which one heterocyclyl or heteroaryl group of 5-6 atoms and one cycloalkyl or aryl group have two common carbon atoms, for example, indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.

"Heterocyclyl" means a saturated or partially unsaturated, preferably one double bond, monocyclic or bicyclic, preferably a monocyclic, heterocyclic radical containing at least one, preferably up to 4, more preferably 1 to 3, even more preferably preferably 1-2 nitrogen, oxygen or sulfur atomic ring elements, preferably having 3-8 ring elements in each ring, more preferably 5-8 elements in the ring and even more preferably 5-6 elements in each ring. The term "heterocyclyl" is intended to include sulfonic and sulfoxide derivatives of sulfur ring atoms and N-oxides of tertiary nitrogen ring atoms as well as carbocyclic fusions, preferably 3-6 ring carbon atoms and more preferably 5-6 ring carbon atoms and benzofuse ring systems. The "heterocyclyl" radicals may be optionally substituted by at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2, carbon atoms of halogen, alkyl, alkoxy, hydroxy , oxo, aryl, aralk, heteroaryl, heteroaryl, alkyloalkyl, alkyloxycarbamide; , or aralkyl radicals. More preferably, the "heterocyclyl" group, alone or in combination, is a radical of a monocyclic or two-cyclic saturated heterocyclic ring system having 5-8 ring atoms, in which 1-3 atoms are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzofusion and optionally substituted by 1 -2 oxo or thioxodoricles. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, 4benzylpiperazin-1-yl, pyrimidinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl, and 2,3-sulfonhydroindine, sulfonylhydroxy, and sulfonidine, , 2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydro-1-oxoisoquinolinyl, 2,3-dihydrobenzofuryl, benzpyranyl, methylenedioxyphenyl, ethylenedioxyphenyl, and the like.

"Heteroaryl" means a monocyclic or bicyclic, preferably a monocyclic, aromatic heterocyclic radical having at least one, preferably 1 to 4, more preferably -1 to 3, even more preferably 1-2, nitrogen , oxygen or sulfur ring atoms, and preferably having 5-6 atoms in each ring, which may be optionally saturated carbocyclophuzene, preferably with 3-4 carbon atoms ((C ₃ -C ₄ ) forming 5-6- atomic rings and which may be optionally substituted as defined above in the description of aryl. Such heteroaryl groups may include imidazolyl, 1-benzyloxycarbonylimidazol-4yl, pyrrolyl, pyrazolyl, pyridyl, 3- (2methyl) pyridyl, 3- (4-trifluoromethyl) pyridyl, pyrimidinyl, 5- (4-trifluoromethyl). pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5,6,7,8tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, benzfuryl, benzimidazolyl.

"Heteroaralkyl" and "heteroarylalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2 atoms, is replaced by a heteroaryl radical as defined above, as 3 -furylpropyl, 2-pyrrolylpropyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl, and the like.

"Halogen" or "Halo", alone or in combination, means fluoro, chloro, bromo or iodo radicals. "Haloalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3 atoms, is replaced by a halogen radical "4 (3H) pyramidinone" (A) and " 4-hydroxy-pyrimidine ”(B) are the names of two tautomers of the same compound that can be used interchangeably. It is understood that the use of one of these two terms is understood to include the other.

About it

(Λ) ^<in>

"Pharmacologically acceptable salt" means salt prepared by conventional methods known to those skilled in the art. "Pharmacologically acceptable salt" includes the basic salts of organic and inorganic acids which include and are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methylphosphinic acid, ethanesulfinic acid, malic acid, acetic acid, oxalic acid , citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzene acid, phenylacetic acid, almond acid and the like.

When compounds of the invention have acidic functions such as the carbon group, then suitable pharmaceutically acceptable cationic pairs for the carbon group are known to those skilled in the art and include an alkali radical, an ammonium radical, quaternary ammonium cations, and the like. Other examples of "pharmacologically acceptable salts" see infra and Berge et al., J. Pharm. Sci. 66, 1 (1977).

"Cytokine" means a single protein that affects the functions of other cells, especially when it relates to the modulation of the interactions of cells of the immune system or cells involved in the inflammatory process.

Examples but not unique to cytokines are (IL1), preferably IL-1beta, (IL-6), (IL8), and TNF, preferably TNF-alpha (tumor necrosis factor-alpha).

"TNF, IL-1, IL-6, and / or IL-8 intermediate disease or disease state" means any disease state where TNF, IL-1, IL-6, and / or IL-8 participate or directly as TNF , IL-1, IL-6, and / or IL-8 alone or by TNF, IL-1, IL-6, and / or IL-8 inducing the release of other cytokines. For example, a disease condition in which IL-1 plays a major role, but in which the production or action of IL-1 results from TNF will be considered intermediate by TNF.

"Leaving group" generally refers to groups that are readily reduced by the following nucleophiles: amine, thiol or alcohol nucleophile.

Such leaving groups are well known in the art. Examples, but not unique to such leaving groups, are: N-hydroxyamide of succinic acid, N-hydroxybenzoltriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated where appropriate.

&Quot; Protective groups &quot; refers mainly to groups well known in the art that are used to protect certain reactive groups such as carboxyl, amino, hydroxy, mercapto and the like, from ongoing unwanted nucleophilic, electrophilic reactions, oxidation, reduction, and the like. Preferred protecting groups are indicated where appropriate.

Examples but not unique to amino protecting groups are aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples, but not unique to aralkyl, are benzyl, orthomethylbenzyl, trityl and benzhydryl, which may be substituted by halogen, alkyl, alkoxy, hydroxy, alkoxy, hydroxy, nitro, acylamino, acyl and the like, as well as salts such as phosphine and ammonium. Examples of aryl groups are phenyl, naphthyl, indanyl, anthracenyl, 9-phenylfluorenyl, phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl radicals, which preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl, methyl and the like. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, m-butoxycarbonyl, isobutoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, just as the primary amino group can be protected by both aralkyl and aralkyloxycarbonyl groups. Protective amino groups may form a heterocyclic ring with the nitrogen to which they are attached. For example, 1,2methylenebenzene, phthalimidyl, succinimidyl, maleimidyl, and the like such heterocyclic groups may further include joined aryl and cycloalkyl rings. In addition, the heterocyclic groups may be mono-, di- or tri-substituted such as nitrophthalimidyl. The amino groups can be protected against side effects such as oxidation by the formation of an additional salt of hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like. Most of the protecting amino groups are suitable for protecting carbonate, hydroxy and mercapto groups. For example, the aralkyl group. The alkyd groups are suitable for protecting hydroxy and mercapto groups such as tertbutyl.

Protective silyl groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethanyl and diphenylmethylsilyl. The silylation of the amino groups results in the formation of mono- and disilamine groups. Silylation of the amino alcohol compounds can lead to Ν, Ν, Ο-trisilyl derivatives. The removal of silyl function from silyl ethyl function is readily accomplished, for example, by metal hydroxide or by ammonium fluoride reagent, or as a separate reaction step or during reaction with an alcohol group. Suitable silylating reagents, for example, are trimethylsilyl chloride, tert-butyldimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride or their products in combination with imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known in the art. Methods for preparing these amine derivatives from the corresponding amino acids, amino acid amides or amino acid esters are well known to those skilled in the art of organic chemistry, including chemistry dealing with amino acids, esters of amino acids or amino alcohol chemistry.

The protecting groups are removed under conditions that do not affect the rest of the molecule. These methods are well known and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves the removal of a protecting group such as the removal of the benzyloxycarbonyl group by hydrogenolysis of palladium with carbon in a suitable solvent system such as alcohol, acetic acid and the like.

The butoxycarbonyl group may be removed using an organic or inorganic acid such as hydrogen chloride or trifluoroacetic acid in a suitable solvent system such as dioxane or metal chloride. The resulting aminosol can be easily neutralized to recover the free amine. The carboxide protecting group such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like can be removed by hydrolysis and hydrogenation well known to those skilled in the art.

-CR * R ^y -NR ^x R ^y

-NR-

-C (0) -C (NR) -S (0) ₂ -

Drugs of the compounds of this invention are also contemplated therein. A drug is an active or inactive compound that is chemically transformed by the physiological action of hydrolysis, metabolism, and other processes into a compound resulting from the invention following the prescription of the drug to the patient. Techniques associated with the preparation and use of drugs are well known to those skilled in the art. For a general discussion of drugs including esters, see Svenson and Tuneck's Papers on Drug Metabolism - 165/1988 / and Bungaard Design of prodrugs, Elsevier / 1985 /. Examples of masked carboxylate anions include a variety of esters such as alkyd (methyl, ethyl), cycloalkyl (cyclohexyl), aralkyl (benzyl, p-methoxybenzyl) and alkylcarbonyloxyalkyl (pivaloyloxymethyl).

The amines are masked as substituted derivatives of arylcarbonyloxymethyl which are cleaved by esterases in drug release and formaldehyde / Bungaard J. Med. Chem. 2503 (1989).

In addition, drugs containing an acidic NH group such as imidazole, imide, indole and the like are masked by N-acyloxymethyl groups (Bungaard Design of prodrugs, Elsevier (1985).

Hydroxy groups are masked as esters and ethers. EP 039, 051 (Sloan and Little, 4/11/81) deals with the preparation and use of Mannich-base hydroxamic acid drugs.

Compounds of the invention can be synthesized according to one or more of the following methods. It should be noted that only the basic procedures for the preparation of compounds of indeterminate stereochemistry are shown. However, such procedures are generally used for those compounds of a certain stereochemistry for which the stereochemistry of the group is / S / or ZR /. In addition, compounds with a single stereochemistry / e.g. R / are used to prepare compounds with opposite stereometry / e.g. S / using commonly known methods, such as inversion.

Pyramidine:

The basic method for preparing compounds of formula I involves the condensation of 1,3dicarbonyl, an intermediate IV with an N-C-N structure such as amidine V, guanidine VI or urea VII. (Scheme 1, for an overview of synthetic methods, see D. J. Brown, Heterocyclic Compounds: Pyramidines, Chapter 3, 1994, John Wiley & Sons).

Scheme 1

In addition, such as 1,3-dicarbonyl synthon, 6-dimethylamino-a, 6-unsaturated ketone IX can be reacted with amidine V or guanidine VI as described / G. B. Bennett et al., J. Med. Chem. 21, 623-628, 1978). These b-dimethylamino-a, b-non-Scheme 2 saturated ketones IX can be prepared by the amino formulation of an active metal ketone VIII with a Brederec reagent, namely bis / dimethylamino / methoxymethane / H. Bredereck et al., Chem. Ber. 101, 41-50 (1968); G. B. Bennett et al., J. Org. Chem. 43, 221-225 (1977).

Scheme 3

According to this approach, Scheme 3 illustrates the conversion of 2- (4-fluorophenyl) -1- (4-pyridyl) ethanone / VIII; Sheldrake, Synthetic communications 23, 1967 (1993) / in enamine IX. Intermediate IX can be condensed by a variety of amidines V and guanidines VI to give 2-substituted 5- (4-fluorophenyl) -4 (4-pyridyl) -pyrimidines I.

In addition, ketones VIII can be prepared (for example, according to Sheldrake, Synthetic communications 23 1967-1971 (1993)), using other heteroaryl carboxaldehydes as starting material, such as 2-methylpyridine-4-sarboxaldehyde, 2,6-dimethylpyridine- 4-carboxaldehyde / Mathes and Sauermilch, Chem. Ber. 88, 1276 - 1283 (1955) /, quinoline-4-carboxaldehyde, pyrimidine-4-carboxaldehyde,

6-methyl-pyrimidine-4-carboxaldehyde, 2-methylpyrimidine-4-carboxaldehyde, 2,6-dimethylpyrimidine-4-carboxaldehyde / Bredereck et al., Chem. Ber. 97, 3407-3417 (1964).

Furthermore, 2-nitropyridine-4-carboxaldehyde can be prepared from 2-nitro-4-methylpyridine / Stanonis, J. Org. Chem. 22, 475 (1957) / by methyl group oxidation / Venemalm et al. Tet. Lett. 34, 5495 - 5496 (1993).

Further conversion by ketone

VIII will yield the 12-nitro-4-pyridyl derivative (Scheme 4). The catalytic reduction of the nitro group in the amino group will give derivative I with R12 represented by the 2-amino-4-pyridyl group. Standard acetylation of the amino group yields the 2-acetamido-4-pyridyl derivative.

As shown in Scheme 5, reagent IX can be condensed with urea VII to give 2 (1H) -pyrimidinone derivative X. X is transformed into chloride XI by reaction of halogen reagents such as phosphorus oxychloride. Exposure to chloride XI by primary and secondary amines, thiolates or alcoholates results in the further preparation of pyrimidines I with R1 represented by the substituted N, S or O groups, 4θ as shown above.

Hydrazines can also be reacted with chloride IX to give 2-hydrazino substituted pyramidines I.

Figure 5

NH ₂

Figure 6

NH ₂

R ¹ = NH ₂

IR ¹ = NR ²² C (O) R ²¹

R ¹ = NR ²² SO ₂ R ² °

Palladium or nickel catalyzed pairs of chloride XI crossed with arylboronic acid or with aryl zinc halides give the compounds of formula I wherein R1 is aryl or heteroaryl.

Scheme 6 illustrates the reaction of intermediate IX with guanadine VI to give a 2-amino substituent 1.2-amino I is a useful intermediate for further acylation.

And for the sulfonation of the 2-amino group, for the preparation of acylamido and sulfonamido groups.

For the synthesis of 4-hydroxy-pyrimidine II, the approach shown in Scheme 7 can be followed (for an overview of the synthetic method see: D. J. Brown, Heterocyclic Compounds: Pyramidines, prop). This approach involves the cyclic reaction between ester XII of acrylic acid and amidine V, followed by oxidation of the resultant dihydropyrimidinone XIII to afford II.

Scheme 7

For the synthesis of 2-substituted-5/4-fluorophenyl) -6- (4-pyridyl-4-hydroxy-pyrimidine II (Scheme 8), the acrylic acid double-substituted ester XII can be obtained in a conventional manner by condensation of pyridine- 4-carboxaldehyde with 4-fluorophenylacetic acid followed by esterification. XII can react with a variety of amidines V at elevated temperature. Acetic acid / nitrite of soda is suitable as a dehydrogenating reagent for the conversion of XIII to II.

The following compounds of formula II, in which R12 is any other heteroaryl ring, can be prepared by a suitable choice of starting material. Such starting material includes, but is not limited to, 2-methylpyridine-4-carboxaldehyde, 2,6-dimethylpyridine-4-carboxaldehyde (Mathes and Sauermilch, Chem. Ber. 88, 1276 - 1283 (1955)), quinoline-4-carboxaldehyde, pyrimidine -4-carboxaldehyde, 6-methylpyrimidine-4-carboxaldehyde, 2-methylpyrimidine15 4-carboxaldehyde, 2,6-dimethylpyridine-4-carboxaldehyde (Bredereck et al., Chem. Ber. 97, 3407 3411 (1964)).

The use of 2-nitropyridine-4-carboxaldehyde will result in a derivative of Form20 mole II with R ¹² represented by the 2-nitro-4-pyridyl group. The catalytic reduction of the nitro group in the amino group will yield 2-amino-4-pyridyl derivative II. The approach shown in Scheme 8 is applicable to the use of 25 other acetic acid aryls leading to compounds of formula II with different aryl groups such as R ¹¹ .

Scheme 8

Another approach (Scheme 9) leading to 5,6-diaryl-4-hydroxy-pyrimidine involves the cyclization of 6-keto ester XIV with thiourea to give the XV niouracil derivative.

Reaction of XVI with primary and secondary 5 amines leads to 2-aminosubstituted 4-hydroxy-pyrimidine II.

Further, the derivative of 2-thioether II with R1 = SR21 can be obtained, for example, by alkylation of XV with alkyl halides. Treatment of XV or XVI with Nickel Wounds and a hydrogen molecule results in structure II, where R 1 is hydrogen.

Figure 9

h ₂ n

XIV

Although Scheme 9 illustrates a synthesis in which R12 is 4-pyridyl, this approach can be similarly applied to any other heteroaryl ring as defined by R12 through appropriate selection of starting material, such starting material being, but not only, ethyl 2-methyl isonicotinate (Efimovski and Rumf, Bull. Soc. Chim. FR. 648-649 (1954), methyl pyrimidine-4-carboxylate and methyl 2,6-dimethyl pyrimidine-4-carboxylate (Salaski et al., Heterocycles 13, 235 (1978). Also, methyl

2-Nitroisonicotinate (Stannonis, J. Org. Chem. 22,475 (1957)) can be reacted with an aryl acetic acid ester, followed by cyclization of the resultant β-ketoester with the thiurea shown in Figure 9, respectively.

Subsequent catalytic reduction of the nitro group in the amino group will yield 4-hydroxypyrimidine II, in which R ₁₂ is represented by the 2-amino-4-pyridyl group (Scheme 10).

Subsequently, methyl 2-acetamido-isonicotinate (Scheme 11) can be reacted according to Scheme 9 after appropriate protection of the nitrogen amide with the tert-butyldimethylsilyloxymethyl group (Benneche et al., Acta Chem. Scand. B 42 384-389 (1988)), c tert-butyldimethylsilyl group, benzyloxymethyl group, benzyl group 15 and others (PD

Scheme 11

Removal of the protecting group Pj of the resulting pyrimidine II with a suitable reagent (e.g. tetrabutylammonium fluoride in cases where P 1 is t-butyldimethylsilyloxymethyl) will give pyrimidine II with R ¹² represented by the 2-acetamido-4-pyridyl group. It is not necessary to note that ethyl p-fluorophenyl acetate can be substituted by any alkyl aryl acetate according to the procedure described in Scheme 9, thus yielding compounds of formula II with various R ¹¹ aryl substituents.

Further, in the process, the pyrimidine II compounds can be prepared by coupling suitable derivatives of XVIII (L is a leaving group such as a halogen radical and others, and P ₂ is a protecting group such as benzyl and the like) with a suitable aryl equivalent.

Such aryl and heteroaryl pairs are well known to those skilled in the art and include organic metal components for reaction with a reactive derivative, for example a halogen derivative, of the second compound in the presence of a catalyst. The organometallic species may be obtained either by pyrimidinone, in which case aryl components give the reactive halogen equivalent or the pyrimidinone may be in the form of a 5-halogen derivative for the reaction with a metallic organic aryl compound. Accordingly, the 5bromo and 5-iodo derivatives of XVIII (L = Br, I) can be treated with tin arylalkyl compounds such as trimethylstannylbenzene in an inert solution such as tetrahydrofuran in the presence of a palladium catalyst such as di (triphenylphosphine) palladium ( Ii) dichloride. (Peters et al., J. Heterocyclic Chem. 27, 2165-2173, (1990)).

Alternatively, the halogen derivative of XVIII may be converted to a trialkyltin derivative (L = Bu ₃ Sn) by reaction with, for example, tributylstannyl chloride, followed by lithiation with butyl lithium, and then may be reacted with acrylic

XVIII halide in the presence of a catalyst. (Sandosham and Undheim, Acta Chem. Scand. 43, 684-689 (1989). Both approaches can lead to pyramidins II in which R ¹¹ is represented by acrylic and heteroacrylic groups. 5

As described in the literature (Kabbe,

Lieb. Ann. Chem. 704, 144 (1967); DE 1271116

Scheme 12 (1968)) and shown in Scheme 12, 5-acryl-2,6-dipyridyl-4-hydroxy-pyramidine II can be prepared in one-step synthesis by reaction of cyanopyramidine with an acrylacetyl ester such as ethyl phenyl acetate in the presence of soda methylate .

In analogy to what was described (Kabbe, supra) and shown in Scheme 13,4-amino-5- (acryl) -2,6-dipyridyl-pyrimidines XIX were prepared in one Scheme 13 step synthesis by reaction between cyanopyramidine with acrylacetonitrile, such as 4-fluorophenylacetonitrile .

XIX

Modification of the fourth position (R ² of Formula I) of pyrimidine II is possible by conversion to chloro derivative XX by re-40 fraction with phosphorus oxychloride (Scheme 14) -4-alkoxy derivative can be obtained from chloro derivative XX by nucleophilic substitution with alkoxide. Alternatively, instead of the chloro group, other leaving groups such as tosylates, mesylates and the like can be used.

Also leaving groups may be replaced by amino, thiolates, alcoholates and other similar nucleophiles. For example, chloro derivative XX can be reduced by catalytic hydrogenation to give pyrimidine I, where R ² is H, or it can be reacted with alkyl or aryl boronic acid or alkyl or aryl zinc halide to produce pyrimidine I, where R ² is alkyl or aryl.

Figure 14

XXI R ² a OMe

IR ² = Η

In Scheme 15, the compounds of the present invention of formula XXXI can be readily obtained from the reaction of methylthio XXXI intermediate with the amine NHR ⁵ R ²¹ , for example by heating the mixture preferably at a temperature higher than 100 ° C or between 150 and

210 ° C. Alternatively, the compounds of formula XXX can be readily prepared by reaction of methylsulfonyl and intermediate XXXII with amine 15 NHR ⁵ R ² , for example by heating the mixture preferably at a temperature higher than 40 ° C or between 50-210 ° C. .

Scheme 15

XXXI

XXXII

The amines of formula NHR ⁵ R ² are commercially available or readily obtainable by those skilled in the art of starting materials, which may also be commercially available. For example, the amide, nitro and cyano groups may be reduced under reducing conditions, such as the reducing reagent lithium aluminum hydride and the like, to reduce the corresponding amine. The alkylation and acylation of amino groups are well known in the art. Chiral and achiral substituted amines may be derived from chiral amino acids and amino acid amides (e.g., alkyl, aryl, heteroaryl, 40 cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl, and other substituted glycines, beta-alanines, etc.) methods well known in the art as N. Brunner, R. Hankofer, U. Holsinger, V. Treyttinger and N. Shcoenen berger, 45 Eur. J. Med. Chem. 25, 35-44, 1990; M. Freiberger and R. B. Hasbroughck, J. Am. Chem. Soc. 82, 696-698, 1960; Domow and Faust Chem. Ber. 87, 984, 1954; M. Kojima and Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982; W. Wheeler and D. O '

Bannon, Journal of Labelled Compounds and Radiopharmaceuticals XXXI, 306, 1992; and S. Davies, N. Garrido, O. Ichihara and I. Walters, J. Chem. Soc., Chem. Commun. 1153, 1993.

The following examples are for illustration and are not intended, nor should they be construed so as not to limit the disclosure in any way. Those skilled in the art will appreciate that the modifications and variations of the substances set forth above can be made without disturbing the spirit and integrity of the discovery.

Examples of carrying out the invention

Example 1.

Basic procedure for the preparation of two-component 5- (4-fluorophenyl) -4- (4-pyridyl) pyrimidines

a. 3- (dimethylamino) -2- (4-fluorophenyl) 1- (4-pyridyl) -3 propen-1-one:

(According to Bennet et al., J. Org. Chem. 43, 221 (1977)).

A mixture of 2- (4-fluorophenyl) -1- (4pyridinyl) ethanone (300 mg, 1.39 mmol) and bis (dimethylamino) methoxymethane (300 ml, 1.95 mmol) was heated to 110 ° C for 1.5 h in the presence of argon. The mixture was evaporated and the yellow crystallized substance was dried in an oil vacuum pump before being used in the next reaction. MS (m / z): 270.8 (M + H) ⁺ ;

C ₁₆ H _{] 5} FN ₂ O 270.3 is recommended. 1 H-NMR (CDCl ₃ ): d 8.57, 7.25 (2m, each 2H, pyridine),

7.36 (s, 1H, CH =), 7.13, 6.99 (2H, each 2H, PhF), 3.00 (bs, 6H, 2CH ₃ )

b. Basic procedure:

(According to Bennet et al., J. Med. Chem. 21, 623 (1978)).

A solution of 3- (dimethylamino) -2- (4fluorophenyl) -1- (4-pyridinyl) -3-propen-1-one (1.39 mmol) in pure ethanol (9 ml) was transferred to a solution of Rl-C (ΝΗ ) ΝΗ2 (1.67 mmol) in ethanol (2 ml) obtained from soda (1.67 mmol) and amidine or guanidine hydrochloride (1.67 mmol). At reflux for 1.5 to 24 hours, the solution was evaporated and the resulting substance was applied directly to a colloidal silica (1-5% methanol / dichloromethane) distillation column or placed in dichloromethane, followed by washing with water, drying organic compound and evaporation before column chromatography.

The following pyrimidines were prepared by these basic procedures by reactions of 3 (dimethylamino) -2- (4-fluorophenyl) -1- (4-pyridinyl) -3-propen-1 with the amidines:

-1. 5- (4-fluorophenyl) -2-methyl-4 (pyridyl) -pyrimidine: MS (m / z): 266.0 (M + H) ⁺ ; C ₁₆ H ₁₂ FN ₃ recommended265.3. Ή-NMR (CDCl ₃ ): d 8.70, (d, 1H, H-6, pyrimidine), 8.59, 7.32 (2m, each 2H, pyridine), 7.20-7.00 (m, 4H, PhF), 2.88 ™ (s , 3H, CH 2).

R, = CH ₃ 1 -2.5- (4-fluorophenyl) -2-isopropyl-4- (4-pyridyl) -pyrimidine: MS (m / z): 294.4 ( M + H) ^+; C ₁₈ H ₁₆ FN ₃ Recommended 293.4. 1 H-NMR (CDCl ₃ ): d 8.73, (s, 1H, H-6, pyrimidine), 8.60, 7.35 (2m, each 2H, pyridine), 7.20-7.04 (m, 4H, PhF), 3.37 (m, 1H, CH (CH ₃ ) ₂ ), 1.50, 1.47 (2S, each 3H, 2CH ₃ ).

R ₁ = (CH ₃ ) ₂ CH 1 -3,2-tert-butyl-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 307.8 (M + H) ⁺ ; C ₁₉ H ₁₈ FN ₃ Recommended 307.4. 1 H-NMR (CDCl ₃ ): d 8.72, (s, 1H, H-6, pyrimidine), 8.59, 7.38 (2m, each 2H, pyridine), 7.21-7.06 (m, 4H, PhF), 1.52, (s , 9H, CHCl ₃ ).

R] = (CH ₃ ) ₃ C

1-4. 2- (1-Chloro-2-methoxyethyl) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z):

344.2 (M + H) ⁺ ; C ₁₈ H ₁₅ C1FN ₃ Recommended 343.8. Ή-NMR (CDCl ₃ ): d 8.81, (s, 1H, H-6, pyrimidine), 8.61, 7.35 (2m, each 2H, pyridine), 7.227.08 (m, 4H, PhF), 5.29, (dd , 1H, CHCl 1), 4.31,

4.04 (2dd, each 1H, CH ₂ O), 3.47 (s, 3H, CH ₃ O).

R, = CH ₃ OCH ₂ CH (C1) 1 -5. 2- (cyclopropyl) -5- (4-fluorophenyl) 4- (4-pyridyl) -pyrimidine: MS (m / z): 292.0 (M + H) ⁺ ; C ₁₈ H ₁₄ FN ₃ Recommended 291.3. Ή-NMR (CDCl ₃ ): d 8.60, (s, 1H, H-6, pyrimidine), 8.57, 7.32 (2d, each 2H, pyridine), 7.16-7.00 (m, 4H, PhF), 2.32, (m , 1H, -CH-), 1.2, 1.1 (2m, each 2H, 2 CH,).

^R = = 1-6.2- (adamant-1-yl-) -5- (4-fluorophenyl) 4- (4-pyridyl) -pyrimidine: MS (m / z): 386.0 (M + H) ⁺ ; C ₂₅ H ₂₄ FN ₃ 385.5 recommended. Ή-NMR (CDCl ₃ ): d 8.76, (s, 1H, H-6, pyrimidine), 8.61, 7.51 (2m, each 2H, pyridine), 7.22-7.08 (m, 4H, PhF), ~ 1.9-1.5 , (broad, 15H, CH ₂ , CH).

-7. 2-Benzyl-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 342.2 (M + H) ⁺ ; C ₂₂ H ₁₆ FN ₃ Recommended 341.4. Ή-NMR (CDCl ₃ ): d 8.71, (s, 1H, H-6, pyrimidine), 8.60, 7.48 (2m, each 2H, pyridine), 7.42-7.04 (m, 9H, PhF, Ph), 4.42 ( s, 2H, CH ₂ , Ph).

^R,. -1 -8. 2- (2,6-dichlorobenzyl) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 410.2 (M) ⁺ ; C ₂₂ H ₁₄ C1 ₂ FN ₃ 410.3 recommended. Ή-NMR (CDCl ₃ ): d 8.68, (s, 1H, H-6, pyrimidine), 8.57, (d, 2H, pyridinyl), 7.44-7.03 (m, 9H, pyridyl, PhF, PhCl ₂ ), 4.93 (s, 2H, CH ₂ ).

Cl

-9. 5- (4-fluorophenyl) -2-phenoxymethyl-4 (4-pyridyl) -pyrimidine: MS (m / z): 358.2 (M + H) ⁺ ; C ₂₂ H ₁₆ FN ₃ O 357.4 recommended. Ή NMR (CDCl ₃ ): d 8.83, (s, 1H, H-6, pyrimidine), 8.60, (m, 2H, pyril), 7.36-6.98 (m, 11H, pyridinyl PhF, Ph), 5.43 (s, 2H, CH ₂ ).

^E · 1-10.5- (4-fluorophenyl) -2-phenylthiomethyl 4- (4-pyridinyl) -pyrimidine: MS (m / z): 374.2 (M + H) ⁺ ; C ₂₂ H ₁₆ FN ₃ S 373.5 recommended. NMR (CDCl ₃ ): d 8.72, (s, 1H, H-6, pyrimidine), 8.56, 7.49 (2m, each 2H, pyridinyl), 7.32-7.02 (m, 9H, PhF, Pr), 4.50 (s, 2H, CH ₂ ).

^E -Cr ^

1-11. 5- (4-fluorophenyl) 2-phenyl-4- (4-pyridyl) -pyrimidine: MS (m / z): 328.2 (M + H) ⁺ ; C ₂₁ H ₁₄ FN ₃ Recommended 327.4. Ή-NMR (CDCl ₃ ): d 8.85, (s, 1H, H-6, pyrimidine), 8.63, 7.4 (2m, each 2H, pyridinyl), 8.56, 7.6-7.5, 7.25-7.05 (m, 9H, PhF , Ph).

^R > =

1-12. 5- (4-fluorophenyl) -2- (4-hydroxyphenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z):

344.2 (M + H) ^&lt; ^{+ &gt};; C ₂₁ H _{] 4} FN ₃ O recommended 343.4. Ή-NMR (DMSO-d ₆ ): d 10.2, (bs, 1H, OH) 8.90, (s, 1H, H-6, pyrimidine, pyrimidine), 8.60, 7.42 (2m, each 2H), 8.35, 7.40- 6.92 (m, 8H, PhF, PhOH).

^R - «oXT

-13. 5- (4-fluorophenyl) -2- (4-aminophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 343.2 (M + H) ⁺ ; C ₂₁ H _1S FN ₄ Recommended 342.4. Ή-NMR (CDCl ₃ ): d 8.75, (s, 1H, H-6, pyrimidine), 8.60, 7.41 (2m, each 2H, pyridinyl), 8.40, 7.22-6.79 (m, 8H, PhF, Ph), 4.00 (bs, 2H, NH ₂ ).

^R1 =

1-14. 5- (4-fluorophenyl) -2- (3-pyridyl) 4- (4-pyridyl) -pyrimidine: MS (m / z): 329.0 (M + H) ⁺ ; C ₂₀ H ₁₃ FN ₄ Recommended 328.4. 1 H-NMR (CDCl ₃ ): d 9.80, (bs, H-2, 3-pyridinyl), 8.90, (s, 1H, H-6, pyrimidine), 8.84, 8.80 (2m, each 1H, 3-pyridinyl) 8.66, 7.45 (2m, each 2H, 4pyridinyl), 7.50 (m, 1H, 3-pyridinyl), 7.28-7.10 (m, 4H, PhF).

1-15.5- (4-fluorophenyl) -2- (2-pyridyl) -4 (4-pyridyl) -pyrimidine: MS (m / z): 329.0 (M + H) ⁺ ; C ₂₀ H _{] 3} FN ₄ recommended 328.4. 1 H-NMR (CDCl ₃ ): d 9.01, (s, 1H, H-6, pyrimidine), 8.92, 8.66, 7.94, 7.48 (4m, each 1H, 2-pyridinyl), 8.66,7.47 (2m, each 2H, 4-pyridinyl), 7.26, 7.14 (2m, each 2H, PhF).

1-16.5- (4-fluorophenyl) -2- (2-pyrazinyl) 4- (4-pyridyl) -pyrimidine: MS (m / z): 330.2 (M + H) ⁺ ; C ₁₉ H ₁₂ FN ₅ Recommended 329.3. 1 H-NMR (CDCl ₃ ): 9.84, (m, 1H, H-3, pyrazinyl), 9.01, (s, 1H, H-6, pyrimidine), 8.84, 8.76 (2m, each 1H, H-5, H -6, pyrazinyl), 8.65, 7.44 (2m, each 2H, pyridinyl), 7.26, 7.13 (2m, each 2H, PhF).

^R 1 = Ο

1-17. 5- (4-fluorophenyl) -2- (2-methylthiazol-4-yl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 349.0 (M + H) ⁺ ; C ₁₉ H ₁₃ FN ₄ S Recommended 384.4. Ή-NMR (CDCl ₃ ): d 8.90, (s, 1H, H-6, pyrimidine), 8.63, 7.42 (2m, each 2H, pyridyl), 8.32 (s, 1H, H-5, Thiazole), 7.22. 7.10 (2m, each 2H, PhF), 2.88 (s, 3H, CH ₃ ).

-18. 5- (4-fluorophenyl) -4- (4-pyridyl) -2 (2-thienyl) -pyrimidine: MS (m / z): 334.2 (M + H) ⁺ ; C ₁₉ H _l2 FN ₃ S recommended 333.4. Ή-NMR (CDCl ₃ ): d 8.74, (s, 1H, H-6, pyrimidine), 8.63, 7.41 (2m, each 2H, pyridyl), 8.13, 7.55 (2m, each 1H, thiophenyl), 7.20 (m , 3H, PhF, thiophenyl),

7.10 (m, 2H, PhF).

The pyrimidines listed below have been prepared according to the basic procedures in which we react with 3- (dimethylamines) -2- (4fluorophenyl) -1- (4-pyridinyl) -3-propen-1-one with guanadines:

1-19. 2-amino-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 267.0 (M + H) ⁺ ; C ₁₅ H _h FN ₄ 266.3 recommended. Ή-NMR (DMSO-d ₆ ): d 8.54, 7.26 (2m, each 2H, pyridinyl), 8.35 (s, 1H, H-6, pyrimidine), 7.227.12 (m, 4H, PhF), 6.97 (s , 2H, NH ₂ ).

Rj = NH ₂ 1-20.2-ethylamino-5- (4-fluorophenyl) -4 (4-pyridyl) -pyrimidine: MS (m / z): 295.0 (M + H) ⁺ ; C ₁₇ H ₁₅ FN ₄ recommended294.3. 1 H-NMR (CDCl ₃ ): d 8.56, 7.32 (m, each 2H, pyridinyl),

8.36 (s, 1H, H-6, pyrimidine), 7.12-6.99 (m, 4H, PhF), 5.33 (insoluble, 1H, NH), 3.58 (m, 2H, CH ₂ ), 1.32 (1, 3H, CH ₃ ).

R, = CH ₃ CH ₂ -NH 1-21.5- (4-fluorophenyl) -4- (4-pyridyl) 2- (2-sulfoethylamino) -pyrimidine: MS (m / z):

375.2 (M + H) ^&lt; ^{+ &gt};; C ₁₇ H _{] 5} FN ₄ O ₃ S is recommended

374.4. Ή-NMR (DMSO-d ₆ ): d 8.51,7.25 (2d, each 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.32 (t, 1H, NH), 7.2-7.1 (m , 4H, PhF), 3.62 (q, 2H, CH ₂ N), 2.72 (t, 2H, CH ₂ ).

Rj = HO ₃ S-CH ₂ -NH1-22. 2- (2-diethylaminoethylamino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 365.8 (M + H) ⁺ ; C ₂₁ H ₂₄ FN ₅ recommended

365.5. Ή-NMR (CDCl ₃ ): d 8.55, 7.28 (2m, each 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.08-7.01 (2m, each 2H, PhF), 5.98 (bs. 1H, NH), 3.60 (q, 2H, CH ₂ N), 2.76 (t, 2H, CH ₂ ), 2.65 (q, 4H, 2CH ₂ CH ₃ ), 1.08 (t, 6H, 2CH ₃ ).

Rj = (CH ₃ CH ₃ ) ₂ nch ₂ ch ₂ nh1 −23. (4-fluorophenyl) -4- (4-pyridyl) -2 (thioureid) -pyrimidine: MS (m / z): 326.2 (M + H) ⁺ ; C ₁₆ H ₁₂ FN ₅ S Recommended 325.4. 1 H-NMR (DMSO-d 6: d 10.84, 10.11, 9.20 (3s, each 1H,

NH, 5H), 8.75 (s, 1H, H-6, pyrimidine), 8.59,7.32 (2m, each 2H, pyridinyl), 7.28, 7.21 (2m, each 2H, Ph) F.

with ^R l =

H

-24. 2- (2,6-dichlorophenylamine) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 410.8 (M) ⁺ ; C ₂₁ H _{] 3} C1 ₂ FN ₄ recommended

411.3. Ή-NMR (CDCl ₃ ): d 8.54, 7.30 (2m, each 2H, pyridinyl), 8.45 (s, 1H, H-6, pyrimidine), 7.45 (d, 2H, PhCl ₂ ), 7.21, (t, 1H , PhCl ₂ ), 7.12.7.04

1-25. 2- (2,6-dimethylphenylamino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 371.0 (M + H) ⁺ ; C ₂₃ H _{] 9} FN ₄ recommended

370.4. Ή-NMR (CDCl ₃ ): d 8.56, 7.32 (2d, each 2H, pyridinyl), 8.40 (s, 1H, H-6, pyrimidine), 7.20 (s, 3H, PhCl ₂ ), 7.11, 7.04 (2m, each 2H, PhF), 6.66 (s, 1H, NH), 2.20 (s, 6H, 2CH ₃ ).

-26. 5- (4-fluorophenyl) -4- (4-pyridyl) pyrimidine: MS (m / z): 373.0 (M + H) ⁺ ; C ₂₂ H ₁₇ FN ₄ O recommended 372.4. Ή-NMR (CDCl ₃ ): d 8.62, 7.40 (2m, each 2H, pyridinyl), 8.60 (m, 1H, PhOMe), 8.52 (s, 1H, H-6, pyrimidine), 7.99 (c, 1H, NH ), 7.18-6.94 (m, 7H, PhF, PhOMe), 3.96 (s, 3H, CH ₃ O).

-27. 5- (4-fluorophenyl) -2- (4-fluorophenylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 361.0 (M + H) ⁺ ; C ₂₁ H _{] 4} F ₂ N ₄ ce recommends 360.4.

Ή-NMR (CDCl ₃ ): d 8.58, 7.32 (m, 2H, pyridinyl), 8.46 (s, 1H, H-6, pyrimidine), 7.62 (m, 2H, PhF), 7.24 (bs, 1H, NH) , 7.13-7.00 (m, 6H, PhF).

-28.2- (4-ethylphenylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z):

371.2 (M + H) ^&lt; ^{+ &gt};; C ₂₃ H ₁₉ FN ₄ Recommended 370.4. Ή-NMR (CDCl ₃ ): d 8.61, 7.41 (2m, each 2H, pyridinyl), 8.49 (s, 1H, H-6, pyrimidine), 7.60, 7.23 (2d, each 2H, PhETh), ~ 7.28 (NH ), 7.13, 7.06 (2m, each 2H, PhF), 2.67 (q, 2H, CH ₂ ), 1.27 (t, 3H, CH 2).

-29. 5- (4-fluorophenyl) -4- (4-pyridyl) -2 (3-trifluoromethylphenylamino) -pyrimidine: M5 (m / z): 411.0 (M + H) ⁺ ; C ₂₂ H ₁₄ F ₄ N ₄ recommended

410.4. Ή-NMR (CDCl3): d 8.60, 7.35 (2m, each 2H, pyridinyl), 8.52 (s, 1H, H-6, pyrimidine), 8.23, 7.73, 7.46 (s, dd, t, each 1H, PhCF ₃ ), 7.44 (s, 1H, NH), 7.31 (dd, 1H, PhCF ₃ ), 7.13, 7.05 (2m, each 2H, PhF).

I CF ₃

1-30. 2- (benzylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 357.0 (M + H) ⁺ ; C ^H ^FNN, 356.0 is recommended. Ή-NMR (CDCl3): d 8.55,7.28 (2m, each 2H, pyridinyl),

8.36 (s, 1H, H-6, pyrimidine), 7.44-4.28 (m, 5H, Ph), 7.09, 7.02 (2m, each 2H, PhF), 5.71 (t, 1H, NH), 4.75 (d, 1H , CH ₂ ).

1-31.5- (4-fluorophenyl) -2- (2-phenylethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 371.0 (M + H) ⁺ ; C ₂₃ H ₁₉ FN ₄ ce recommends 370.4. 1 H NMR (CDCl ₃ ): d 8.56 (m, 2H, pyridinyl), 8.35 (s, 1H, H-6, pyrimidine), 7.38-7.22 (m, 7H, Ph, pyridinyl), 7.08,7.02 (2m, each 2H , PhF), 5.32 (t, 1H, NH), 3.80 (q, 2H, CH ₂ N), 2.92 (t, 2H, CH ₂ ).

1-35. 5- (4-fluorophenyl) -4- (4-pyridyl) 2- (3,5-bis (trifluoromethyl) benzenesulfamyl) pyrimidine: MS (m / z): 542.8 (M + H) ⁺ ; C ₂₃ H ₁₃ F ₇ N ₄ O ₂ S 542.4 recommended. Ή-NMR (DMSO-d ₆ ): d 8.63 (s, 1H, N-6, pyrimidine), 8.56 (m, 2H, pyridinyl), 8.49, 8.43 (2s, 2H, 1H, Ph (CF ₃ ) ₂ ) 7.26-7.15 (m, 6H, PhF, pyridinyl).

H

1-32.5- (4-fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine: MS (m / z): 321.2 (M + H) ⁺ ; C ₁₉ H _{] 7} FN ₄ Recommended 320.4. Ή-NMR (CDCl ₃ ): d 8.54, 7.32 (2d, each 2H, pyridinyl), 8.37 (s, 1H, H-6, pyrimidine), 7.06, 7.00 (2m, each 2H, PhF), 3.68, 2.05 ( 2m, each 4H, 4CH ₂ ).

^R '= Q · 1-33.5- (4-fluorophenyl) -2-morpholino-4 (4 pyridyl) -pyrimidine: MS (m / z): 337.2 (M + H) ⁺ ; C _{] 9} H ₁₇ FN ₄ O recommended 336.4. Ή-NMR (CDCl ₃ ): d 8.56,7.31 (2m, each 2H, pyridinyl), 8.40 (s, 1H, H-6, pyrimidine), 7.10,7.03 (2m, each 2H, PhF), 3.94, 3.83 ( 2m, each 4H, 4CH ₂ ).

(/ n—

R _{1 =} ^λ

1-34. 2- (3,5-dimethylpyrazyl) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 346.0 (M + H) ⁺ ; C ₂₀ H ₁₁ FN ₅ recommended 345.4. Ή-NMR (CDCl ₃ ): d 8.80 (2s, 1H, H-6, pyrimidine), 8.60, 7.35 (2m, each 2H, pyridinyl), 7.18, 7.08 (2m, each 2H, PhF), 6.08 (s. 1H, pyrazyl), 2.70, 2.30 (2s, each 3H, 2CH ₃ ).

1-36. 2- (4-aminobenzenesulfamyl) -5- (4fluorophenyl) -4- (4 pyridyl) -pyrimidine: MS (m / z): 421.8 (M + H) ⁺ ; C ₂₁ H ₁₆ FN ₅ O ₂ recommended

421.5. Ή-NMR (DMSO-d ₆ ): d 8.58 (s, 1H, H-6, pyrimidine), 8.575 (m, 2H, pyridinyl), 7.64, 6.56 (2d, each 2H, PhNH ₂ ), 7.28-7.15 ( m, 6H, PhF, pyridinyl), 5.99 (s, 2H, NH ₂ ).

1-37. 2- (2-dimethylaminoethylthio) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine was prepared according to basic procedures by reaction of 3- (dimethylamino) -2- (4-fluorophenyl) -

1- (4-Pyridinyl) -3-propen-1-one with S- (2-dimethylaminoethyl) isothiourea. MS (m / z):

355.2 (M + H) ⁺ ; C ₁₉ H ₁₉ FN ₄ S 354.5 recommended. 1 H-NMR (CDCl ₃ ): d 8.59, 7.32 (2m, each 2H, pyridinyl), 8.58 (s, 1H, H-6, pyrimidine), 7.16, 7.08 (2m, each 2H, PhF), 3.40, 2.76 ( 2m, each 2H, 2CH ₂ ), 2.37 (s, 6H, 2CH ₃ ).

R ₃ = (CH ₃ ) ₂ NCH ₂ CH ₂ S Example 2.

Basic Procedures for Obtaining

2- N substituted 2-amino-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidines

a. 5- (4-fluorophenyl) -4- (4-pyridyl) -2 (1H) -pyrimidinone:

Urea (0.67 g, 11.15 mmol) was added to ethanol stirred 0.62 N ethyl acetate (15 ml). Ethanol solution (60 ml) of 3- (dimethylamino) -2- (4-fluorophenyl) -1- (4pyridinyl) -3-propen-1-one (9.29 mmol) was added and the mixture was refluxed overnight. . The mixture was evaporated, followed by column chromatography (5% methanol / dichloromethane to 100% methanol). Crystals (probably urea) 20 were formed as a result of treatment of the resulting dichloromethane / methanol product, which were filtered. The filtrate was evaporated and the residue was chromatographed again with silica (chloroform / methanol / water = 70: 20: 1) to afford the title compound as a yellowish foam.

MS (m / z): 286.2 (M + H) ⁺ ; C ₁₅ H ₁₀ FN ₃ O recommended 267.3. 1 H-NMR (DMSO-d ₆ ): d 8.55, 7.24 (2m, each 2H, pyridinyl), 8.22 (bs, 1H, H-6, pyrimidine), 7.20-7.10 (m, 4H, PhF).

b. 2-chloro-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine:

A mixture of 5- (4-fluorophenyl) -4- (4-pyridyl) 2- (1H) -pyrimidinone (2.41 mmol) and phosphorus oxychloride (3 ml) was heated for 45 min. It was then evaporated to dryness in a water bath at> 50 ° C. The flask was cooled in an ice bath and ice water was added. If the pH was still acidic, then the mixture was neutralized with 5% aqueous ammonium hydroxide solution. The substance was recovered with dichloromethane, followed by washing the organic solution with aqueous sodium chloride, subjected to drying and evaporation to recover the title compound as a yellowish foam, which was used without further purification.

MS (m / z): 286.1 (M + H) ⁺ ; C ₁₅ H ₁₉ CIFN ₃ Recommended 285.7. 1 H-NMR (CDCl ₃ ): d 8.68 (s, 1H, H-6, pyrimidine), 8.62, 7.42 (2m, each 2H, pyridinyl), 7.23-7.10 (m, 4H, PhF).

Another way is: 2-chloro-5- (3-methylphenyl) 4- (4-pyridyl) -pyrimidine MS (m / z): 282 (M + H) ⁺ ; C15H] 2CIFN3 281.7) and 2-chloro-4 (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine MS recommended (m / z): 336.0 (M) ⁺ ; C16H ₉ C1F ₃ N ₃ recommended 335.7) were synthesized by the same reaction sequence, but starting from 2- (3-methylphenyl) -1- (4-pyridinyl) ethanone (prepared according to: I. Lantos et al., J. Organ Chem. 53, 4223-4227, 1988) and 1- (4-pyridinyl) -2- (3-trifluoromethylphenyl) ethanone (prepared according to R. W. Sheldrake, Synth. Commun. 23 (24), 1967-1971 , 1993); and WO 1997/012876). Also thionyl chloride / N, N-dimethylformamide (excess of / 3 eq., Reflux) can be used in place of phosphorus oxychloride.

C. Basic procedure:

Typically, a mixture of 2-chloro-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine (50-120 mg, 0.18-0.42 mmol) and the amine, HNR ⁵ R ²¹ , (0.5-5.5 mmol) ) was heated to 50-100 ° C for 5-60 min (thin layer for chromatographic analysis) the mixture was applied directly to a silica gel column which was extracted with dichloromethane-methanol or dichloromethane / methanol / conc. ammonium hydroxide.

An alternative procedure that uses ethanol as the solvent was used in the cases described in Examples 2-6, 2-11, 2-12, 2-20 and 2-26. 20

The following pyrimidines were prepared according to this procedure using the corresponding amine and substituted 2-chloropyrimidine:

2-1. 2- (2-aminoethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: 25 MS (m / z): 310.2 (M + H) ⁺ ; C ₁₇ H ₁₆ FN ₅ - HC1 309.4 + 36.5 recommended. 1 H-NMR (CD ₃ OD): d 8.84, 8.10 (2m, each 2H, pyridinyl), 8.58 (s, 1H, H6, pyrimidine), 7.28, 7.15 (2m, each 2H, PhF), 3.83 (t, 2H , CH ₂ ), 3.27 (t, 2H, CH ₂ ). ³⁰

R ₃ = NH ₂ CH ₂ CH ₂ NH 2-2. 2- (3-Aminopropylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 324.0 (M + H) ⁺ ; C ₁₈ H ₁₈ FN ₅ - HCl 35 recommended 323.4 + 36.5. Ή-NMR (CD ₃ OD): d 8.85, 8.10 (m, 2H, pyridinyl), 8.54 (s, 1H, H-6, pyrimidine), 7.24,7.14 (2m, each 2H, PhF), 3.84, 3.68 ( 2t, each 2H, 2CH ₂ N), 2.18 (m, 2H, CH ₂ ).

R ^ NI ^ C ^ C ^ C ^ NH- ⁴⁰

2-3.2- (4-aminobutylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 338.0 (M + H) ⁺ ; C ₁₉ H ₂₀ FN ₅ - HCl recommended 337.4 + 36.5. Ή-NMR (CD ₃ OD): d 8.80, 45 8.05 (2m, each 2H, pyridinyl), 8.50 (s, 1H, H6, pyrimidine), 7.25, 7.14 (2m, each 2H, PhF), 3.58 (bt. 2H, CH,), 3.02 (bt, 1H, CH _2), 1.80 (m, 4H, 2CH,).

R, = ΝΗ, ΟΗ ^ Η, ΝΗ ^ ΝΗ2-4.2- (2-dimethylaminoethylamino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 338.2 (M + H) ⁺ ; C _{] 9} H ₂₀ FN ₅ recommended

337.4. 1 H-NMR (CDCl ₃ ): d 8.57, 7.30 (2m, each 2H, pyridinyl), 8.37 (s, 1H, H-6, pyrimidine), 7.10, 7.03 (2m, each 2H, PhF), 6.00 (t, 1H, NH), 3.66 (q, 2H, CH,), 2.71 (t, 2H, CH,), 2.41 (s, 6H, 2CH _3).

^ = (CH ₃ ) ₂ CCl ₂ CH ^ H2-5. 5- (4-fluorophenyl) -2- (2-phenylaminoethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 386 (M + H) ⁺ ; C ₂₃ H, ₀ FN ₅ recommended

385.5. Ή-NMR (CDCl ₃ ): d 8.57, 7.28 (2m, 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.18 (t, 2H, Ph), 7.08, 7.02 (2m, each 2H , PhF), 6.73 (t, 1H, Ph), 6.64 (d, 2H, Ph), 5.62 (bt, 1H, NH), 3.80 (q, 2H, CH,), 3.47 (t, 2H, CH,) .

2-6. 5- (4-Fluorophenyl) -2- (2- (4-fluorophenylamino) ethylamino) -4- (4-pyridyl) -pyrimidine: A solution of 2-chloro-5- (4-fluorophenyl) -4 (4-pyridyl) ) -pyrimidine (103 mg, 0.36 mmol) and No. (4-fluorophenyl) ethylenediamine (1 ml) in ethanol (1 ml) were heated to reflux for 3 h. Evaporation was followed by column chromatography (3% methanol / dichloromethane) to give the bulk of the substance yellowish and solid. MS (m / z): 404.2 (M + H) ⁺ ; C ₂₃ H _{] 9} F ₂ N ₅ 403.4 recommended. 1 H-NMR (CDCl ₃ ): d 8.60, 7.31 (2m, each 2H, pyridinyl), 8.40 (s, 1H, H6, pyrimidine), 7.11-7.02 (2m, each 2H, PhF), 6.90, 6.60 (t, dd, each 2H, PhF), 5.62 (t, 1H, NH), 3.82 (q, 2H, CH ₂ ), 3.44 (t, 2H, CH,).

449.3. Ή-NMR (CDCl ₃ ): d 8.58, 7.47 (m, 2H, pyridinyl), 8.37 (s, 1H, H-6, pyrimidine), 7.29, 7.17 (2d, each 2H, PhCl), 7.10, 7.02 (2d , each 2H, PhF), 5.34 (t, 1H, NH), 3.80 (q, 2H, CH ₂ N), 2.97 (t, 2H, CH ₂ ).

2-7. 5- (4-fluorophenyl) -2- (4-methylbenzylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z):

371.2 (M + H) ⁺ ; C ₂₃ H ₁₉ FN ₄ ce recommends 370.4. 1 H NMR (CDCl ₃ ): d 8.55, 7.34 (2m, each 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.307.18 (2d, each 2H, PhMe), 7.08, 7.02 (2m. each 2H, PhF), 5.69 (bs, 1H, NH), 4.69 (d, 2H, CH ₂ ),

2.36 (s, 3H, CH ₃ ).

2-8. 5- (4- (fluorophenyl) -2- (2- (4-fluorophenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 389.2 (M + H) ⁺ ; C ₂₃ H ₁ F ₂ N ₄ 388.4 is recommended. Ή-NMR (CDCl ₃ ): d 8.57 (m, 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.327.20,7.12-6.98 (2m , 10H, 2PhF, pyridinyl), 5.37 (br, 1H, NH), 3.79 (q, 2H, CH ₂ N), 2.97 (t, 2H, CH ₂ ).

2-9. 2- (2- (4-chlorophenyl) -ethylamino) -5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: M8 (m / z): 405.0 (M + H) ⁺ ; C ₂₃ H ₁₈ C1FN ₄ recommended

404.9. Ή-NMR (CDCl ₃ ): d 8.56 (bs, 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.29 (m, d, 4H, pyridyl, PhCl), 7.20 (d, 2H. PhCl), 7.08, 7.02 (2m, each 2H, PhF), 5.35 (t, 1H, NH), 3.78 (q, CH ₂ N), 2.96 (t, 2H, CH ₂ ).

2-10. 2- (2- (4-bromophenyl) -ethylamino) -5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: M8 (m / z): 449.0 (M) ⁺ ; C ₂₃ H ₁₈ BrFN ₄ recommended

2-11. 5- (4-Fluorophenyl) -2- (2- (4-hydroxyphenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: Mixture of 2-chloro-5- (4-fluorophenyl) -4- (4-pyridyl) ) -pyrimidine (63 mg, 0.21 mmol), tyramine hydrochloride (186 mg, 1.01 mmol) and sodium bicarbonate (90 mg, 1.07 mmol) in aqueous ethanol (1 ml) were heated to reflux for 1 h. Evaporation of the solution was followed by column chromatography (5% methanol / dichloromethane) to give the bulk of the substance yellowish and solid. MS (m / z):

387.2 (M + H) ⁺ ; C ₂₃ H _{] 9} FN ₄ O 386.4 recommended. Ή NMR (DMSO-d ₆ ): d 9.12 (bs, 1H, OH), 8.54, 7.26 (2m, each 2H, pyridinyl), 8.38 (s, 1H, H6, pyrimidine), 7.52 (t, 1H, NH) , 7.20-7.10 (m, 4H, PhF), 7.05, 6.69 (2d, each 2H, PhOH), 3.52 (q, 2H, CH ₂ N), 2.78 (t, 2H, CH ₂ ).

2-12.2- (2- (4-aminophenyl) -ethylamino) -5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: The solution of 2-chloro-5- (4-fluorophenyl) -4- ( 4-Pyridyl) -pyrimidine (71 mg, 0.25 mmol) and 2- (4-aminophenyl) ethylamine (0.05 ml, 3.80 mmol) in ethanol (1.5 ml) were heated to reflux for 20 min. Evaporation of the solution was followed by silica gel column chromatography (2% methanol / dichloromethane) to give the bulk of the substance as a yellow syrup. MS (m / z): 386.4 (M + H) ⁺ ; C ₂₃ H ₂₀ FN ₅ 385.5 recommended. 1 H-NMR (CDCl ₃ ): d 8.56, 7.32 (2m, each 2H, pyridinyl), 8.35 (s, 1H, H-6, pyrimidine), 7.126.99 (m, 6H, PhF, PhNH ₂ ), 6.68 (d, 2H, PhNH ₂ ),

5.37 (t, 1H, NH) 3.75 (q, 2H, CH ₂ N), 2.88 (t, 2H, CH 2).

2-13. 5- (4-fluorophenyl) -2- (2- (2-fluorophenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 389.2 (M + H) ⁺ ; C ₂₃ H _lg F ₂ N ₄ 388.4 is recommended. Ή-NMR (CDCl ₃ ): d 8.57 (m, 2H, pyridinyl), 8.35 (s, 1H, H-6, pyrimidine), 7.34-7.20, 7.14-7.00 (2m, 10H, 2 PhF, pyridinyl), 5.42 (bt, 1H, NH), 3.82 (q, 2H, CH ₂ N), 3.05 (t, 2H, CH ₂ ).

2-14. 2- (2- (2-chlorophenyl) -ethylamino) -5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 405.0 (M + H) ⁺ ; C ₂₃ H ₁₈ C1FN ₄ recommended

404.9. Ή-NMR (CDCl ₃ ): d 8.57 (m, 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.40-7.00 (m, 10H, PhF, PHC1 ₂ , pyridinyl), 5.44 (bt , 1H, NH), 3.84 (q, 2H, CH ₂ N), 3.15 (t, 2H, CH ₂ ).

2-15.5- (4-fluorophenyl) -2- (2- (2-methoxyphenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 401.2 (M + H) ⁺ ; C ₂₄ H _2] FN ₄ O 400.5 recommended. Ή-NMR (CDCl ₃ ): d 8.56, 7.30 (2m, each 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.24, 7.08, 7.02, 6.92 (4m, each 2H, PhF, PhOMe ), 5.50 (bt, 1H, NH), 3.87 (s, 3H, CH ₃ ), 3.78 (q, 2H, CH ₂ N), 3.02 (t, 2H, CH ₂ ).

2-16. 2- (2- (2,4-dichlorophenyl) -ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 439.0 (M) ⁺ ; C ₂₃ H ₁₇ C1 ₂ FN ₄ Re-order 439.3. Ή-NMR (CDCl ₃ ): d 8.56 (bs, 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.37 (s, 1H, PhCl), 7.30 (bd, 2H, pyridinyl), 7.227 .15 (m, 2H, PhCl), 7.08, 7.05 (2m, each 2H, PhF), 5.40 (1, 1H, NH), 3.80 (q, 2H, CH ₂ N), 3.10 (t, 2H. CH ₂ ).

2-17. 2- (2- (2,6-dichlorophenyl) -ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 439.0 (M) ⁺ ; C ₂₃ H ₁₇ C1 ₂ FN ₄ 439.3 recommended. Ή-NMR (CDCl ₃ ): d 8.57 (m, 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.35 (d, 2H, PhCl), 7.11 (m, 3H, PhF, PhCl) , 7.03 (m, 2H, PhF), 5.45 (t, 1H, NH), 3.86 (q, 2H, CH ₂ N),

3.38 (t, 2H, CH ₂ ).

2-18. 5- (4-fluorophenyl) -2- (2- (3-methoxyphenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 401.2 (M + H) ⁺ ; C ₂₄ H ₂₁ FN ₄ O 400.5 recommended. Ή-NMR (CDCl ₃ ): d 8.56 (m, 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.327.22,7.11-6.98,6.89-6.77 (3m, 10H, PhF, PhOMe , pyridinyl), 5.38 (t, 1H, NH), 3.82 (m, 5H, CH ₂ N, CH ₃ ), 2.96 (t, 2H, CH 3).

2-19.2- (2- (3-chlorophenyl) -ethylamino) -5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 405.4 (M + H) ⁺ ; C ₂₃ H _1g ClFN ₄ is recommended

404.9. Ή-NMR (CDCl ₃ ): d 8.60 (d, 2H, pyridinyl), 8.38 (s, 1H, H-6, pyrimidine), 7.32-7.24 (m, 5H, pyridinyl, PhCl), 7.18 (m, 1H. NH), 3.83 (q, 2H, CH ₂ N), 3.00 (t, 2H, CH 2).

5.38 (t, 1H, NH), 3.58 (q, 2H, CH ₂ N), 2.78 (t, 2H, CH ₂ ), 2.03 (m, 2H, CH ₂ ).

Cl

2-20. 5- (4-fluorophenyl) -2- (2- (2-hydroxy-2-phenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: Mixture of 2-chloro-5- (4-fluorophenyl) 4 - (4-pyridyl) -pyrimidine (87 mg, 0.31 mmol) and

2-Amino-1-phenylethanol (300 mg, 2.19 mmol) in ethanol (2 ml) was heated to reflux for 2 h. Evaporation of the solution was followed by silica gel column chromatography (4% methanol / dichloromethane) to give the substance as a yellowish foam. MS (m / z): 387.0 (M + H) ⁺ ; C ₂₃ H ₁₉ FN ₄ recommended

386.4. 1 H-NMR (CDCl ₃ ): d 8.58 (d, 2H, pyridinyl), 8.38 (s, 1H, H-6, pyrimidine), 7.47 (d, 2H, Ph), 7.41 (t, 2H, Ph), 7.34 (t, 1H, Ph), 7.28 (d, 2H, pyridinyl), 7.10, 7.02 (2m, 2H, PhF), 5.72 (t, 1H, NH), 5.06 (m, CHOH), 4.02-3.92 (m. 2H, OH, 1CH ₂ ), 3.72 (ddd, 1H, 1CH ₂ ).

2-21.5- (4-fluorophenyl) -2- (methyl- (2-phenylethyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 385.0 (M + H) ⁺ ; C ₂₄ H ₂₁ FN ₄ recommended

384.5. Ή-NMR (CDCl ₃ ): d 8.57, 7.35 (2m, each 2H, pyridinyl), 8.40 (s, 1H, H-6, pyrimidine), 7.34-7.21 (m, 5H, Ph), 7.10, 7.03 (2m , each 2H, PhF), 3.96 (t, 2H, CH ₂ N), 3.23 (s, 3H, CH ₃ ), 3.00 (t, 2H, CH ₂ ).

CH ₃ ^r '- O'

2-22. 5- (4-Fluorophenyl) -2 - ((3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 385.2 (M + H) ⁺ ; C ₂₄ H ₂₁ FN ₄ 384.5 recommended. Ή-NMR (CDCl ₃ ): d 8.56 (2m, 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.34-7.20 (m, 7H, Ph, pyridinyl), 7.08, 7.01 (2m, each 2H, PhF),

2-23. 5- (4-fluorophenyl) -2 - ((1-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 399.0 (M + H) ⁺ ; C ₂₅ H ₂₃ FN ₄ 398.5 recommended. Ή-NMR (CDCl ₃ ): d 8.56 (m, 2H, pyridinyl), 8.32 (s, 1H, H-6, pyrimidine), 7.32-7.17 (m, 7H, pyridinyl, Ph), 7.09-7.02 (2m, each 2H, PhF), 5.16 (d, 1H, NH) 4.28 (m, 1H, CH), 2.77 (m, 2H, CH ₂ ), 1.94 (m, 2H, CH ₂ ), 1.34 (d, 3H, CH) ₃ ).

2-24. 5- (4-fluorophenyl) -2 - ((3-imidazolylpropyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 375.0 (M + H) ⁺ ; C _2] H ₁₉ FN ₆ 374.4 recommended. Ή-NMR (CDCl ₃ ): d 8.57,7.26 (2m, each 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine),

7.56 (s, 1H, Imid.), 7.16-6.96 (m, 6H, PhF, Imid.), 5.38 (br, 1H, NH), 4.12 (t, 2H, CH ₂ N).

3.56 (q, 2H, CH ₂ NH), 2.20 (m, 2H, CH ₂ ).

2-25. 5- (4-fluorophenyl) -2 - ((4-phenyl-butyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 399.0 (M + H) ⁺ ; C ₂₅ H ₂₃ FN ₄ 398.5 recommended. Ή-NMR (CDCl ₃ ): d 8.56 (m, 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.33-7.17 (m, 7H, Ph, pyridinyl), 7.08,7.02 (2m, each 2H, PhF), 5.33 (bt, 1H, NH), 3.56 (q, 2H, CH ₂ N), 2.71 (s, 2H, CH ₂ ), 1.76 (m, 4H, 2CH ₂ ).

H

2-26. 5- (4-fluorophenyl) -2- (1-piperazinyl) -4- (4-pyridyl) -pyrimidine: Mixture of 2-chloro-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine ( 71 mg, 0.25 mmol) and piperazine (214 mg, 2.48 mmol) in ethanol (1 ml) was heated to reflux for 5 min. Evaporation of the solution was followed by silica gel column chromatography (5% methanol / dichloromethane) to give the substance as a yellowish solid. MS (m / z): 336.2 (M + H) ⁺ ; C _{] 9} H ₁₈ FN ₅ Recommended 335.4. 1 H-NMR (CDCl ₃ ): d 8.54,7.29 (2m, each 2H, pyridinyl), 8.37 (s, 1H, H-6, pyrimidine), 7.08-7.00 (2m, each 2H, PhF), 3.95 (t, 4H, 2CH,), 3.01 (t, 4H, 2CH,).

2-30. 5- (4-fluorophenyl) -2- (2-morpholinoethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 380.4 (M + H) ⁺ ; C ₂₁ H ₂₂ FN ₅ O recommended

379.4. Ή-NMR (CDCl ₃ ): d 8.58, 7.30 (2m, 2H, pyridinyl), 8.38 (s, 1H, H-6, pyrimidine), 7.107.03 (2m, each 2H, PhF), 5.91 (ps, 1H , NH), 3.79 (bs, 4H, 2CH ₂ ), 3.66 (bs, 2H, CH,), 2.71 (bs, 2H, CH,), 2.59 (bs, 4H, 2CH ₂ ).

H

2-27. 5- (4-fluorophenyl) -2- (1-piperidinyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 335.2 (M + H) ⁺ ; C ₂₀ H ₁₉ FN ₄ Recommended 334.4. 1 H-NMR (CDCl ₃ ): d 8.55,7.30 (2m, each 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.08,7.01 (2m, 2H, PhF), 3.91 (t, 4H , 2CH, N) 1.74, 1.68 (2t, 6H, CHF ₂ ).

^{R1 =} θ-

2-28. 5- (4-fluorophenyl) -2- (4-methyl-1-piperazinyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 350.0 (M + H) ⁺ ; C ₂₀ H ₂₀ FN ₅ Recommended 349.4. 1 H-NMR (CDCl ₃ ): d 8.58, 7.32 (2m, each 2H, pyridinyl), 8.40 (s, 1H, H-6, pyrimidine), 7.10, 7.04 (2m, each 2H, PhF), 4.00 (t, 4H, 2CH ₂ ), 2.57 (t, 4H, 2CH ₂ ), 2.42 (s, 3H, CH 2).

R _{1 =}

2-29. 5- (4-Fluorophenyl) -2- (4-phenyl-1 piperazinyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 412.2 (M + H) ⁺ ; C ₂₅ H ₂₂ FN ₅ 411.5 recommended. 1 H-NMR (CDCl 3): d 8.58 (bd, 2H, pyridinyl), 8.42 (s, 1H, H-6, pyrimidine), 7.38-7.30 (m, 4H, pyridinyl, Ph), 7.15-7.00 (m, 6H , PhF, Ph), 6.94 (t, 1H, Ph), 4.13 (t, 4H, 2CH,), 3.33 (t, 4H, 2CH ₂ ).

2-31. 5- (4-fluorophenyl) -2- (2-piperidinoethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 378.2 (M + H) ⁺ ; C ₂₂ H ₂₄ FN ₅ recommended

377.5. Ή-NMR (CDCl ₃ ): d 8.54, 7.27 (2d, each 2H, pyridinyl), 8.34 (s, 1H, H-6, pyrimidine), 7.06, 7.000 (2m, each 2H, PhF), 6.04 (bt. 1H, NH), 3.66 (q, 2H, CH ₂ NH), 2.74 (t, 2H, CH ₂ ), 2.61 (bs, 4H, 2CH,), 1.68 (m, 4H, 2CH ₂ ), 1.50 (m. 2H, CH2).

2-32.5- (4- (fluorophenyl) -4- (4-pyridyl) 2- (2-pirolidinoetilamino) -pyrimidine: MS (m / z): 364.0 (M + H) +; C 2I H ₂₂ FN ₅ recommend 363.4. Ή-NMR (CDCl ₃ ): d 8.55, 7.28 (2m, 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.08, 7.02 (2m, each 2H, PhF), 6.28 ( t, 1H, NH), 3.86 (q, 2H, CH ₂ NH), 3.18 (t, 2H, CH, N), 3.10 (bs, 4H, 2CH, N), 2.02 (bs, 4H, 2CH ₂ ).

R ,.

2-3 3. 5- (4- (Fluorophenyl) -2- (3-morpholinopropylamino) -4- (4-pyridyl) -pyrimidine: M8 (m / z): 394.2 (M + H) ⁺ ; C ₂₂ H ₂₄ FN ₅ O is recommended

393.5. 1 H-NMR (CDCl ₃ ): d 8.54, 7.27 (2m, each

2H, pyridinyl), 8.33 (s, 1H, H-6, pyrimidine), 7.06, 7.00 (2m, each 2H, PhF), 6.00 (t, 1H, ΝΗ), 3.76 (t, 4Η, 2CH ₂ O), 3.60 (q, 2H, CH ₂ NH), 2.52 (t, 2H, CH ₂ N), 2.50 (m, 4H, CH ₂ N), 1.86 (m, 2H, CH ₂ ).

2-34. 5- (4-fluorophenyl) -2- (3- (2-pyrrolidinon-1-yl) -propylamino) -4- (4-pyridyl) pyrimidine: MS (m / z): 392.2 (M + H) ⁺ ; C ₂₂ H ₂₂ FN ₅ O 391.5 recommended. Ή-NMR (CDCl ₃ ): d 8.58, 7.30 (m, 2H, pyridinyl), 8.36 (s, 1H, H-6, pyrimidine), 7.10,7.04 (m, 2H, PhF), 5.88 (t, 1H. NH), 3.56 (q, 2H, CH ₂ NH), 3.48, 3.45 (2t, each 2H, 2CH ₂ ), 2.46 (t, 2H, CH ₂ ), 2.08 (m, 2H, CH ₂ ), 1.90 (m , 2H, CH ₂ ).

2-35. 2 - (((S) -2-amino-3-phenylpropyl) amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 400.1 (M + H) ⁺ ; C ₂₄ H ₂₂ FN ₅ 399.5 recommended. (free hydroxide).

2-36. 2 - (((S) -2-amino-3-phenylpropyl) amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2-chloro-4- (4-pyridyl) -5 - (3-Trifluoromethylphenyl) -pyrimidine and (S) -1,2-benzylethylenediamine were reacted according to the basic procedure, step C (70 ° C for 75 min) to give the title compound: MS (m / z): 450.4 ( M + H) ⁺ ; C ₂₅ H ₂₂ F ₃ N ₅ Recommended

4449.5. (free hydroxide).

2-37. 2 - (((S) -2-amino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyridine hydrochloride: 2-chloro-5- (3-methyl phenyl) 4- (4-Pyridyl) -pyrimidine and (S) -1,2-benzylethylenediamine were reacted according to the basic procedure, step C (100 ° C for 20 min) to give the title compound: MS (m / z): 396.2 (M + H) ⁺ ; C ₂₅ H ₂₅ N ₅ 395.5 recommended. (free hydroxide).

2-38. 2 - (((S) -2-N, N-dimethylamino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: 2-chloro-5- (4-fluorophenyl) - 4- (4-Pyridyl) -pyrimidine and (S) -2-N, N-dimethylamino-3-phenylpropylamine were reacted according to the basic procedure, step C (100 ° C for 45 min) to give the title compound: MS (m / m z): 427.8 (M + H) ⁺ ; C ₂₆ H ₂₆ FN ₅ 427.5 recommended.

2-39. 2 - ((((S) -2-N, N-trifluoromethyl-3H-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine: 2-chloro-5- (3-methylphenyl) - 4- (4-Pyridyl) -pyrimidine and (S) -2-N, N-dimethylamino-3-phenylpropylamine were reacted according to the basic procedure, step C (100 ° C for 30 min) to give the title compound: MS (m / m z): 424.2 (M + H) ⁺ ; C _2? H ₂₉ FN ₅ 423.6 recommended.

“SOS ⁸ ”

2-40. 2 - ((3-amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: 2-chloro-5- (4-fluorophenyl) -4- ( 4-Pyridyl) -pyrimidine and 1-phenyl-1,3-propanediamine were reacted according to the basic procedure, step C (100 ° C for 30 min) to give the title compound: MS (m / z): 4001. (M + H) ) ⁺ ; C ₂₄ H ₂₂ FN ₅ 399.5 recommended.

ΝΗο

2-41.2 - ((3-amino-3-phenylpropyl) -amino) 4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2-chloro-4- (4-pyridyl) -5 ( 3-Trifluoromethylphenyl) -pyrimidine and 1-phenyl 1,3-propanediamine were reacted according to the basic procedure, step C (100 ° C for 1 h) to give the title compound: MS (m / z): 409.5 (M + H) ⁺ ; C ₂₅ H ₂₂ F ₃ N ₅ 449.5 recommended. (free hydroxide).

ΝΗο

2-42.2 - ((3-amino-3- (2-fluorophenyl) propyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2-chloro-4- (4-pyridyl) ) -5- (3-Trifluoromethylphenyl) -pyrimidine and 1- (2-fluorophenyl) phylen-1,3-propanediamine were reacted according to the basic procedure, step C (100 ° C for 30 min) to give the title compound: MS (m / z): 468.4 (M + H) ⁺ ; C ₂₅ H ₂₁ F ₄ N ₅ 467.5 recommended. (free hydroxide).

2-43. 2 - ((3-amino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: 2-chloro-5- (3-methylphenyl) -4- ( 4-Pyridyl) -pyrimidine and 1-phenyl-1,3-propanediamine were reacted according to the basic procedure, step C (100 ° C for 30 min) to give the title compound: MS (m / z): 396.1 (M + H) +; C ₂₅ H ₂₅ N ₅ 395.5 recommended. (free hydroxide).

2-44. 2 - ((2-amino-2-methyl-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine hydrochloride: 2-chloro-5- (3-methylphenyl) - 4- (4-Pyridyl) -pyrimidine and 2-amino-2methyl-3-phenylpropylamine were reacted according to the basic procedure, step C (100 ° C for 30 min) to give the title compound: MS (m / z): 410.2 (M + H) ⁺ ; C ₂₆ H ₂₇ N ₅ 409.5 recommended. (free hydroxide).

2-45. 2 - ((3-hydroxy-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine: 2-chloro-5- (3-methylphenyl) -4- (4- pyridyl) -pyrimidine and 3-hydroxy-3-phenylpropylamine were reacted according to the basic procedure, step C (100 ° C for 30 min) to give the title compound: MS (m / z): 397.2 (M + H) ⁺ ; C ₂₅ H ₂₄ N ₄ O 396.5 recommended.

2-46. 2 - ((((2R, 3R) -3-amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2-chloro-4- (4-Pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine and (1 R, 2R) -2-Meran-1-phenyl-1,3-propanediamine were reacted according to the basic procedure, step C (50 ° C for 1 h), to give the title compound: MS (m / z): 464.4 (M + H) ⁺ ; C ₂₆ H ₂₄ F ₃ N ₅ Recommended 463.5 (free hydroxide).

2-47. 2 - ((((28,38) -3-amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2 chloro-4- ( 4-Pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine and (18,28) -2-methyl-1-phenyl-1,3-propanediamine were reacted according to the basic procedure, step C (90 ° C for 45 min) to gave the title compound: MS (m / z):

464.1 (M + H) ⁺ ; C ₂₆ H ₂₄ F ₃ N ₅ Recommended 463.5 (free hydroxide).

2-48. 2 - ((S) -3-Benzylpiperazinyl) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2-chloro-4- (4-pyridyl) -5- (3-trifluoromethylphenyl) - pyrimidine and (S) -2-6eHzylpiperazine were reacted according to the basic procedure, step C (70 ° C for 30 min) to give the title compound: MS (m / z): 475.5 (M + H) ⁺ ; C ₂₇ H ₂₄ F ₃ N ₅ 476.1 (free hydroxide) recommended.

2-49.4- (4-Pyridyl) -2 - (((8-tetrahydroisoquinol-3-ylmethylene) amino) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: 2-chloro-25 4- (4-pyridyl) - 5- (3-Trifluoromethylphenyl) -pyrimidine and (S) -tetrahydroisoquinol-3-ylmethylene min were reacted according to the basic procedure, step C (50 ° C for 1.5 h) to give the title compound: MS (m / z): 462.4 (M + H) ⁺ ; C ₂₆ H ₂₂ F ₃ N _s 461.5 (free hydroxide) recommended.

2-50. 5- (3-methylphenyl) -4- (4-pyridyl) -2 ((((8-tetrahydroisoquinol-3-ylmethylene) amino) pyrimidine hydrochloride: 2-chloro-5- (3-methylphenyl) -4- (4- pyridyl) -pyrimidine and (S) -tetrahydroisoquinol-3-ylmethyleneamine were reacted according to the basic procedure, step C (100 ° C for 45 min) to give the title compound: MS (m / z): 408.2 (M + H) ⁺ ; C ₂₆ H ₂₅ N ₅ 407.5 (free hydroxide) recommended.

Example 3.

Basic procedure for the preparation of 2-acylamino-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

Chlorocarbonyl RC (O) C1 (0.57 mmol) was added dropwise to a solution of 2-amino-5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine (0.38 mmol) in pyridine (3 ml) in an ice bath. . It was then stirred for 3 h at room temperature, filtered through a thin chromatographic layer, poured into ice water, extracted with dichloromethane, subjected to drying and evaporation. The crude product can be purified by chromatography on silica gel (hexane-acetone) and recrystallized from a suitable solution such as ethyl acetate.

The following compounds were obtained using appropriate hydrochloric acid according to the following procedures:

3-1.2-acetamido-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine:

MS (m / z): 309.0 (M + H) ⁺ ; C ₁₇ H ₁₃ FN ₄ O recommended 308.3. 1 H-NMR (CDCl ₃ ): d 8.63 (s, 1H, H-6, pyrimidine), 8.60, 7.29 (2m, each 2H, pyridinyl), 8.26 (bs, 1H, NH), 7.14, 7.08 (2m, each 2H, PhF), 2.58 (s, 3H, CH ₃ CO).

R = CH ₃ -

3-2. 2-Butyramido-5- (4-fluorophenyl) -4 (4-pyridyl) -pyrimidine:

MS (m / z): 337.2 (M + H) ^&lt; ^{+ &gt};; C ₁₉ H _{] 7} FN ₄ O ce recommends 336.4. 1 H-NMR (CDCl ₃ ): d 8.64 (s, 1H, H-6, pyrimidine), 8.60, 7.31 (2m, each 2H, pyridinyl), 8.17 (bs, 1H, NH), 7.14, 7.08 (2m, each 2H, PhF), 2.80 (t, 2H, CH ₂ CO), 1.82 (m, 5 2H, CH ₂ ), 1.62 (t, 3H, CH ₃ N).

R = CH ₃ CH ₂ CH ₂ 3 -3.5- (4-fluorophenyl) -2-pivalamide 0-4- (4-pyridyl) -pyrimidine: IC

MS (m / z): 351.0 (M + H) ^&lt; ^{+ &gt};; C ₂₀ H ₁₉ FN ₄ O ce recommends 350.4. Ή-NMR (CDCl ₃ ): d 8.69 (s, 1H, H-6, pyrimidine), 8.60, 7.35 (2m, each 2H, pyridinyl), 8.25 (bs, 1H, NH), 7.15, 7.08 (2m, each 2H, PhF), 1.4 (s , 9H, 3CH _{3). 15}

R = (CH ₃ ) ₃ C ₃ -4. 2-Benzamido-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 371.0 (M + H) ⁺ ;

3-5. 5- (4-fluorophenyl) -2-phenylacetamido-4- (4-pyridyl) -pyrimidine: MS (m / z): 385.0 (M + H) ⁺ ; C ₂₃ H ₁₇ FN ₄ O Recommended 384.4. Ή NMR (CDCl ₃ ): d 8.66 (s, 1H, H-6, pyrimidine), 8.59, 7.28 (2m, each 2H, pyridinyl), 8.21 (bs, 1H, NH), 7.43-7.30 (m, 5H, Ph ), 7.14, 7.08 (2m, each 2H, PhF), 4.13 (s, 2H, CH ₂ ).

3-6.5- (4-fluorophenyl) -2-hydrocinnamamido-4- (4-pyridyl) -pyrimidine: MS (m / z): 399.2 (M + H) ⁺ ; C ₂₄ H ₁₉ FN ₄ O Recommended 398.4. NMR (CDCl ₃ ): d 8.60 (s, 1H, H-6, pyrimidine), 8.54 (m, 2H, pyridinyl), 8.20 (bs, 1H, NH), 7,317.16 (m, 7H, Ph, pyridinyl) , 7.11.7.05 (2m, each 2H, PhF), 3.20, 3.09 (2t, each 2H, 2CH ₂ ).

C ₂₂ H ₁₅ FN ₄ O Recommended 370.4. Ή-NMR (CDCl ₃ ): d 8.75 (s, 2H, NH, H-6, pyrimidine), 8.61, 7.36 (2m, each 2H, pyridinyl), 8.00, 7.63, 7.55 (d, t, t, 2H. 1H, 2H, Ph), 7.18, 7.10 (2m, each 2H, PhF).

Example 4.

the preparation of 2L) -6- (4-pyridyl) 70

a. 2- (4-fluorophenyl) -3- (4-pyridyl) -acrylic acid: Mixture of 4-fluorophenylacetic acid (9 g, 58.4 mmol), 4-pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine (6 ml) and acetic anhydride (6 ml) was heated to 150 ° C for 1 h, followed by evaporation and codification with water. The resultant product crystallizes upon the addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to give the title compound.

MS (m / z): 244.0 (M + H) ⁺ ; C, ₄ H ₁₀ FNO ₂ recommended 243.2. 1 H-NMR (DMSO-d 6): d 8.43, 6.98 (2d, each 2H, pyridinyl), 7.73 (s, 1H, CH =), 7.21 (d, 4H, PhF).

b. Ethyl 2- (4-fluorophenyl) -3- (4-pyridyl) acrylate:

Concentrated sulfuric acid (2.2 ml) was carefully added to a suspension of 2- (4-fluorophenyl) -3- (4-pyridyl) -acrylic acid (6.7 g, 27.5 mmol) in ethanol (120 ml) and the mixture heated to reflux for 24 hours. h. The solution was evaporated, the residue was reacted with dichloromethane and the organic solution was reacted with aqueous sodium hydrogen carbonate and water, followed by drying and evaporation. Column chromatography on silica gel (hexanacetone 2: 1) gave the title compound pure.

MS (m / z): 271.8 (M + H) ⁺ ; C ₁₆ H ₁₄ FNO ₂ Recommended 271.3. 1 H-NMR (CDCl ₃ ): 8.44, 6.88 (2m, each 2H, pyridinyl), 7.72 (s, 1H, CH =), 7.16,7.06 (2h, each 2H, PhF), 4.28 (q, 2H, CH ₂ ), 1.28 (t, 3H, CH ₃ ).

c. General procedure: A stirred mixture of ethyl 2- (4-fluorophenyl) -3- (4-pyridyl) -acrylate (357 mg, 1.38 mmol), amidine hydrochloride (2.61 mmol) and sodium methoxide (250 mg, 4.62 mmol) in ethanol (5 ml) was heated in a sealed chamber at 120 ° C for 3 h. Before evaporation, it was neutralized with 2N hydrochloric acid.

The precipitate was reacted with acetic acid (25 ml) and treated with sodium nitrite (670 mg, 9.71 mmol) at 44 ° C for 20 min. After evaporation, the resultant product was reacted with dichloromethane and the solution was washed with aqueous sodium bicarbonate and water before drying and evaporation. The product was purified by recrystallization from methanol. If the crude product of nitrate oxidation was soluble in water, as it turned out to be 5- (4-fluorophenyl) -2-methyl-6 (4-pyridyl) -4 (3H) -pyrimidine, then aqueous procedures were not required, and the resulting evaporation material was added to column silica gel (5% methanol / dichloromethane) before recrystallization.

The following compounds were obtained using the appropriate amidine hydrochloride:

4-1. 5- (4-Fluorophenyl) -2-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 282.2 (M + H) ⁺ ; C ₁₆ H _{] 2} FN ₃ O 281.3 is recommended. 1 H NMR (DMSO-d ₆ ): d 8.46 (m, 2H, pyridinyl), 7.27.03 (m, 6H, PhF, pyridinyl), 2.38 (s, 3H, CH ₃ ).

R ^ CH ₃

4-2. 5- (4-fluorophenyl) -2-isopropyl-6 (4-pyridyl) -4- (3H) -pyrimidinone: MS (m / z): 310.0 (M + H) ⁺ ; C ₁₈ H ₁₆ FN ₃ O Recommended 309.4. NMR (DMSO-d ₆ ), 8.45 (m, 2H, pyridinyl), 7.21-7.03 (m, 6H, PhF, pyridinyl), 2.90 (m, 1H, CH (CH ₃ ) ₂ ), 1.26, 1.24 (2s , each 3H, 2 CH ₃ ).

R, = (CH ₃ ) ₂ CH-

4-3. 2- (2,6-dichlorobenzyl) -5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone: M8 (m / z): 426.0 (M + H) ⁺ ; C ₂₂ H _{] 4} C1 ₂₂ FN ₃ O 426.3 is recommended. NMR (DMSO-dg), 8.37 (m, 2H, pyridinyl), 7.50 (d, 2H, PhCl ₂ ), 7.35 (t, 1H, PhCl ₂ ), 7.18-7.08 (m, 4H, PhF), 6.96 ( m, 2H, pyridinyl), 4.36 (s, 2H, CH ₂ ).

4-4. 5- (4-fluorophenyl) -2-phenyl-6- (4-pyridyl) -4- (3H) -pyrimidinone: MS (m / z): 344.2 (M + H) ⁺ ; C ₂₁ H ₁₄ FN ₃ O Recommended 343.4. NMR (DMSO-dg), 8.49 (d, 2H, pyridinyl), 8.20 (d, 2H, Ph), 7.66-7.50 (m, 3H, pyridinyl, Ph), 7.32-7.11 (m, 6H, PhF, Ph ).

4-5. 5- (4-fluorophenyl) -2- (4-phenylbutyl) -6- (4-pyridyl) -4- (3H) -pyrimidinone: Ethyl 2 (4-fluorophenyl) -3-oxo-3- (4-pyridyl) ) -propionate (293 md, 1.02 mmol), 4-phenylbutanecarboxamidine (315 mg, 1.79 mmol) and the toluenesulfonic acid pyridinium ester (10 mg) were suspended in p-xylene (10 ml). By stirring effectively, the mixture was heated to reflux using a Dean-Stark apparatus to continuously remove water. After 16 h, the solvent was evaporated and the resulting product was purified by column chromatography on silica gel (3% methanol / dichloromethane) followed by recrystallization of acetone. MS (m / z): 400.3 (M + H) ⁺ ; C ₂₅ H ₂₂ FN ₃ O Recommended 399.5.

R ₁ = Ph (CH ₂ ) ₄ Example 5.

General procedure for the preparation of 5 (4-fluorophenyl) -6- (4-pyridyl) -2-thioalkyl-4 (3H) -pyrimidinones

Step A. Ethyl 2- (4-fluorophenyl) -3-oxo-3- (4-pyridyl) -propionate:

(According to Legrand and Lozac 'H, Bull. Soc. 20 Chim. Fr., 79-81 (1955)).

A mixture of ethyl 4-fluorophenyl acetate (13 g, 71.35 mmol), ethyl isonicotinate (10.7 ml, 71.4 mmol) and sodium beads (1.64 g, 71.34 mmol) was heated to 90-95 ° C in the presence of argon. 25 The mixture began to reflux and gradually became a solid. After 2.5 h, the mixture was neutralized with diluted acetic acid with cooling followed by extraction with dichloromethane. The organic solution was washed with water, dried and evaporated. Instant silica gel column chromatography (hexane-acetone = 4: 1, 3: 1, 2: 1) provides the bulk of the substance in the form of an oil. MS (m / z): 287.8 (M + H) ⁺ ; C ₁₆ H ₁₄ FNO ₃ Recommended 287.3. NMR (CDC1 ₃ ), (ketone: enol = 1: 0.33): d 13.50 (s, 0.3 H, OH - E), 8.81 (m, 2H, pyridinyl-K), 7.38 (m, 2H, PhF-K) , 7.14-7.04 (m, 2H, PhF-K; ~ 0.65H, pyridinyl-E; -0.65 h, PhF-E), 6.96 (t, 0.64 Η, PhF-E), 5.51 (s, 1Η, CH- K), 4.23-4.2 (m, CH ₂ - K, E), 1.26 (t, CH ₃ - K, E).

Step B: 5- (4-Fluorophenyl) -6 O (4-pyridyl) -2-thiouracil:

A stirred mixture of ethyl 2- (4-fluorophenyl) -3-oxo-3- (4-pyridyl) -propionate (22.3 ml, 77.6 mmol) and thiourea (5.9 g, 77.6 mmol) was reacted at 190 ° C in the presence of argon in 40 45 min. The reaction mixture was allowed to reach room temperature, dissolved in acetone, and the precipitate was filtered to give the bulk of the substance. MS (m / z): 300.2 (M + H) ⁺ ; C _i5 H ₁₀ FN ₃ OS 299.3 recommended. Ή NMR 59 (DMSO-dg): d 12.74,12.65 (2s, 2H, pyridinyl), 7.26 (m, 2H, pyridinyl), 7.09 and 7.03 (2m, each 2H, PhF).

In another embodiment, ethyl 2- (4-fluorophenyl) -

3-Oxo- (4-pyridyl) -propionate (2.87 g, 10 mmol) and thiourea (2.28 g, 30 mmol) were suspended in anhydrous p-xylene (50 ml) with very effective stirring. Toluenesulfonic acid p-ester (100 mg) was added and refluxed for 12-16 h using a DeanStark apparatus with continuous removal of water (0.2 ml). The reaction mixture was cooled and the dark brown solid was filtered using a Bucher funnel. The resulting solid was suspended in acetone (25 ml) and filtered. The acetone washed product contained a negligible amount of thiourea, which was removed with hot water (20-30 ml). The product was filtered and dried.

Step C. Basic procedure:

Arylalkyl bromide (0.36 mmol) was added dropwise to a stirred mixture of 5- (4-fluorophenyl) -6- (4-pyridyl) -2-thiourasyl (100 mg, 0.33 mmol) and potassium carbonate (46 mg, 0.33 mmol) in Ν , N-dimethylformamide (4.6 ml). After 3 h of stirring, evaporation began. Flash column chromatography on silica gel (hexanacetone = 3: 1, 2: 1, 1: 1) and recrystallization from hot methanol provide the desired substance.

The following substances were obtained using the appropriate arylalkyl bromide according to the following procedure:

5-1.5- (4-fluorophenyl) -2- (2-phenylethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 404.2 (M + H) ⁺ ; C ₂₃ H ₁₈ FN ₃ OS 403.4 recommended. 1 H-NMR (DNSO-d ₆ ): d 13.08 (bs, 0.7H), 8.49 (m, 2H, Pyridinyl), 7.30-7.06 (m, 11H, Pyridinyl, Ph, PhF), 3.41 (dd, 2H, 2H) , CH ₂ S), 3.00 (t, 2H, CH ₂ ).

^ri - C ''

5-2. 5- (4-fluorophenyl) -2- (3-phenylpropyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 418.0 (M + H) ⁺ ; C ₂₄ H ₂₀ FN ₃ OS recommended417.5. Ή-NMR (DMSO-dgkd 13.10 (bs, 0.7H), 8.47 (m, 2H, Pyridinyl), 7.29-7.06 (m, 11H, Pyridinyl, Ph, PhF), 3.18 (t, 2H, CH ₂ S), 2.71 (t, 2H, CH ₂ Ph), 2.03 (m, 2H, CH ₂ ).

5-3. 5- (4-fluorophenyl) -2- (2-phenoxyethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 420.0 (M + H) ⁺ ; C ₂₃ H _lg FN ₃ O ₂ S 419.5 recommended. 1 H-NMR (DMSO-d 6): d 13.20 (bs, 0.7H),

8.46 (m, 2H, Pyridinyl), 7.24-7.07 (m, 8H, Pyridinyl, PhF, Ph), 6.95 (d, 2H, Ph), 6.92 (t, overlaid, 1H, Ph), 4.30 (t, 2H, CH ₂ O), 3.58 (t, 2H, CH ₂ S).

5-4.5- (4-fluorophenyl) -2- (2-phenylaminoethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 419.0 (M + H) ⁺ ; C ₂₃ H _{] 9} FN ₄ OS 418.5 recommended. Ή-NMR (DMSO-d ₆ ): d 13.20 (bs, 0.8H), 8.48,7.22 (2m, each 2H, Pyridinyl), 7.16-7.10 (2m, each 2H, PhF), 6.89 (t, 2H, Ph ), 6.54 (d, 2H, Ph), 6.48 (t, 1H, Ph), 5.90 (bs, 0.6H, NH), 3.43-3.25 (m, 2CH ₂ ).

Example 6

General procedure for the preparation of 2N substituted 2 amino-5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) pyrimidinones:

Step A. 5- (4-Fluorophenyl) -2-methylthio-

6- (4-pyridyl) -4 (3H) -pyrimidinone:

Methyl iodide (90 ml, 1.44 mmol) was added dropwise to a stirred mixture of 5- (4-fluorophenyl) -6- (4-pyridyl) -2-thiouracil (430 mg, 1.44 mmol) potassium carbonate (198 mg, 1.43 mmol) in N, N-dimethylformamide (13 ml) at ice bath temperature. After 40 min it was evaporated and the crude product was purified by flash chromatography on a silica gel column (hexane-acetone = 2 1, 1: 1, 1: 2) to give the title compound as a solid. MS (m / z): 314.2 (M + H) ⁺ ; C ₁₆ H ₁₂ FN ₃ OS recommended 313.3. 1 H NMR (DMSO-d ₆ ): d 13.10 (bs), 8.47, 7.22 (2m, each 2H, Pyridinyl), 7.16,7.10 (2m, each 2H, PhF), 2.56 (s, 3H, CH,).

Step C. Basic procedure:

F ·

F

A mixture of 5- (4-fluorophenyl) -2-methylthio-6 (4-pyridyl) -4 (3H) -pyrimidinone (100 mg, 0.32 mmol) and amine HMR ⁵ R ²¹ (1 mmol) was heated at 180 ° C for 2 h. The resultant product was purified by flash chromatography on a silica gel column (hexane-acetone or ethanone-dichloromethane or dichloromethane-methanone-concentrate of ammonium hydroxide) to give the desired compound. The following substances were obtained using the basic procedure above and the appropriate amine:

6-1.2- (2- (2-chlorophenyl) ethylamino) -5- (4fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 421.2 (M + H) ) ⁺ ; C ₂₃ H ₁₈ C1FN ₄ O recommended 420.9. Ή-NMR (DMSO-d ₆ ): d 11.24 (bs), 8.44,7.16 (2m, each 2H, Pyridinyl), 7.43, 7.38 (2dd, each 1H, PhCl), 7.30, 7.26 (2dt, each 1H, PhCl ), 7.10-7.00 (m, 2H, PhF), 6.74 (bs, 1H, NH), 3.60 (q, 2H, CH ₂ N), 3.03 (t, 2H, CH ₂ ).

H

6.94 (m, 2H, PhF), 5.67 (bs, 1H, NH), 4.08 (m, 1H, CHCH ₃ ), 2.61 (t, 2H, CH ₂ Ph), 1.67 (m, 2H, CH,), 1.08 (d, 3H, CH ₃ ).

6-4. 5- (4- (fluorophenyl) -2 - ((3-imidazolylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 391.0 (M + H) ⁺ ; C ₂₎ H ₁₉ FN ₆ O 390.4 is recommended. 1 H-NMR (DMSO-d ₆ ): d 11.24 (bs) 8.42,7.12 (2m, each 2H, Pyridinyl), 7.62, 7.18 (2s, each 1H, Imid.), 7.06-6.99 (m, 4H, PhF) , 6.88 (s, 1H, Imid.), 4.02 (t, 2H, CH, N), 3.28 (water-covered, CH ₂ NH), 2.00 (m, 2H, CH,).

6-5. 2 - (((S) -2-amino-3-phenylpropyl) amino) -5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) pyrimidinone hydrochloride: The reaction was carried out at 170 ° C. in 7 h. MS (m / z): 416.1 (M + H) ⁺ ; C ₂₂ H ₂₂ FN ₅ O 415.5 recommended.

6-2. 5- (4- (fluorophenyl) -2 - ((3-phenylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 401.2 (M + H) ⁺ C ₂₄ H ₂₁ FN ₄ O 400.55. NMR (DMSO-d ₆ ) recommended: d 11.16 (bs), 8.44, 7.14 (2m, each 2H, Pyridinyl), 7.32-7.01 (m, 9H, Ph. PhF), 6.78 (bs, NH), 3.36 (q, 2H, CH ₂ N), 2.67 (t, 2H, CH ₂ Ph), 1.89 (m, 2H, CH,).

6-3.5 - (4-fluorophenyl) -2 - ((1-methyl-3-phenylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone: The reaction time required is 15 h at 180 ° C. MS (m / z): 415.0 (M + H) ⁺ ; C ₂₅ H ₂₃ FN ₄ O 414.5 recommended. Ή-CDCl 3: d 8.48 (m, 2H, Pyridinyl), 7.28-7.08 (m, 9H, Pyridinyl, Ph, PhF),

Example 7.

5- (4-fluorophenyl) -2-hydrazino-6- (4-pyridyl) -4 (3H) -pyrimidinone:

A mixture of 5- (4-fluorophenyl) -6- (4-pyridyl) -2-thiouracil (500 mg, 1.66 mmol) and hydrazine hydrate (800 ml, ~ 14 mmol) was heated at 120 ° C for 40 min. It was evaporated and the reaction product was recrystallized from warm methanol to give the title compound. MS (m / z): 298.0 (M + H) ⁺ ; C ₁₅ H ₁₂ FN ₅ O Recommended 297.3. 1 H-NMR (DMSO-d ₆ ): d 8.41, 7.12 (2m, each 2H, Pyridinyl), 7.05, 7.00 (2m, each 2H, PhF).

Rl = NH-NH ₂

Example 8.

General procedure for the preparation of 5aryl-2,6 dipyridyl- (3H) -pyrimidinones:

These compounds were prepared according to the literature (Kabbe, supra; German Patent 1271116 (1968)) as follows:

A stirred mixture of ethyl phenyl acetate (3.13 mmol), cyano pyridine (6.24 mmol) and sodium methoxide (3.5 mmol) in n-butanol (1.2 ml) was heated at 110 ° C for 2 h. The reaction mixture was concentrated and dissolved in water (4 ml), followed by the addition of aqueous saturated ammonium chloride (2 ml). The precipitate was filtered and recrystallized from warm methanol.

The compounds below were prepared according to this procedure using the appropriate starting materials:

8-1.5-phenyl-2,6-bis- (4-pyridyl) -4- (3H) - 45 pyrimidinone: MS (m / z): 327.2 (M + H) ⁺ ; C ₂₀ H ₁₄ N ₄ O 326.4 recommended. 1 H-NMR (DMSO-d ₆ ): d 8.78, 8.47, 8.13 (3m, each 2H, Pyridinyl), 7.40-7.14 (m, 7H, Ph, Pyridinyl).

8-2. 5- (4-fluorophenyl) -2,6-bis- (4-pyridyl) -4- (3H) pyrimidinone: MS (m / z): 345.2 (M + H) ⁺ ; C ₂₀ H _{] 4} N ₄ O recommended 344.4. 1 H-NMR (DMSO-d ₆ ): d 8.80, 8.49, 8.13 (3m, each 2H, Pyridinyl), 7.40-7.08 (m, 6H, PhF, Pyridinyl).

8-3,2,5,6-Tris- (4-pyridyl) -4- (3 H) -pyrimidinone: It was prepared according to the basic procedure for the reaction of ethyl 4-pyridyl acetate and

4-cyanopyridine in the presence of sodium methoxide. MS (m / z): 328.2 (M + H) ⁺ ; C ₁₉ H ₁₃ N ₅ O recommended 327.4. 1 H-NMR (DMSO-d ₆ ): d 8.65, 8.45, 8.35, 8.18, 7.25, 7.13 (6m, each 2H, pyridinyl).

8-4. 5- (4-fluorophenyl) -2,6-bis- (3-pyridyl) -4- (3H) -pyrimidinone: MS (m / z): 345.2 (M + H) ⁺ ; C ₂₀ H _{] 3} N ₄ O recommended 344.4. 1 H-NMR (DMSO-d ₆ ): d 9.34, 8.77, 8.54, 8.48, 7.78, 7.60, 7.34 (7m, 3x 1 Η, 2H, 3x 1X, Pyridinyl), 7.26,7.15 (2m, each 2H, PhF) .

Example 9.

4-amino-5- (4-fluorophenyl) -2,6-bis- (4-pyridyl) -pyrimidine.

4-amino-5- (4-fluorophenyl) -2,6-bis- (4-pyridyl) -pyrimidine was prepared according to the literature of 15 (Kabbe, supra):

Sodium methoxide (180 mg, 3.33 mmol) was added to a stirred solution of 4-cyanopyridine (650 mg, 6.24 mmol) and 4-fluorophenylacetonitrile (375 ml, 3.12 mmol) in n-butanol (1.5 20 ml). The mixture was stirred for 20 min at room temperature before being heated to 110 ° C for 1 h and 30 min. After the mixture was returned to room temperature, ethanol was added thereto. The precipitate was filtered off and recrystallized from acetic acid / water (3.5 / 10 ml) to give the title compound. MS (m / z): 344.2 (M + H) ⁺ ; C ₂₀ H _{] 4} FN ₅ recommended 343.4. Ή-NMR (DMSO-d ₆ ): 8.76, 8.47, 8.22 (3m, each 2H, Pyridinyl), 7.4,7.16 (m, 6H, PhF, Pyridinyl).

Example 10.

4-methoxy-5-phenyl-2,6-bis- (4-pyridyl) pyrimidine

A mixture of 5-phenyl-2,6-bis- (4-pyridyl) -44 (3H) -pyrimidinone (360 mg, 1.10 mmol) and phosphorus oxychloride (2 ml) were heated to reflux for 1 h and 30 min. Mixing was performed as described to give 2-chloro-5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine. To a solution of crude 4-chloro-5-phenyl-2,6-bis- (4-pyridyl) -pyrimidine (250 mg, 0.73 mmol) in methanol methanol 0.5 N sodium methoxide (1.45 ml, 0.73 mmol) was added and refluxed for 1 h. After evaporation the resultant material was partitioned between ethyl acetate and water. The organic solution was washed with water, dried and evaporated. The title compound was obtained by chromatography on the crude product of a column of silica gel (ethyl acetate). MS (m / z): 340.4 (M + H) ⁺ ; C ₂₁ H ₁₆ N ₅ O Recommended 340.4. 1 H-NMR (CDCl ₃ ): 8.82, 8.54, 8.40 (3m, each 2H, Pyridinyl), 7.40-7.18 (m, 7H, Ph, Pyridinyl), 4.15 (s, 3H, CH ₃ O).

Example 11. Procedure for Obtaining

5- (4-fluorophenyl) -2,4-bis- (4-pyridyl) pyrimidine.

Step A. 4-Chloro-5- (4-fluorophenyl) 2,6-bis- (4-pyridyl) -pyrimidine:

A mixture of 5- (4-fluorophenyl) -2,6-bis- (4-pyridyl) -4- (3H) -pyrimidinone (760 mg, 2.21 mmol) in phosphorus oxychloride (3 ml) was heated to reflux for 1 h.

Mixing was performed as described to give 2-chloro-5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine. Part (290 mg) of the resultant product (495 mg) was purified by flash chromatography (ethyl acetate, a small portion of triethyl amine) on silica gel. MS (m / z): 363.2 (M + H) ⁺ ; C _{2 O} H ₁₂ C1FN ₄ 362.8 is recommended. Ή-NMR (CDCl ₃ ): d 8.84,8.60,8.38, 7.30 (4m, each 2H, Pyridinyl), 7.22,7.13 (2m each 2H, PhF).

Step B. 5- (4-Fluorophenyl) -2,4-bis- (4-pyridyl) -pyrimidine:

A stirred mixture of 4-chloro-5- (4fluorophenyl) -2,6-bis- (4-pyridyl) -pyrimidine (99 mg, 0.27 mmol) and 10% palladium on carbon (70 mg) in ethanol (10 ml ) was hydrogenated under a hydrogen atmosphere for 28 h. The filtration and evaporation of the solvent was followed by flash chromatography (ethyl acetate) on a silica gel column to give the title compound. MS (m / z): 329.2 (M + H) ⁺ ; C ₂₀ H ₁₃ FN ₃ Recommended 328.8. Ή-HMR (CDCl ₃ ): d 8.91 (s, 1H, H-6, Pyrimidine), 8.83,8.65,8.40,7.45 (4m, each 2H, Pyridinyl), 7.30-7.06 (m, each 2H, PhF).

Example 12.

Preparation procedure for Ha (((S) -2-N-phenylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethyl-phenyl) -pyrimidine hydrochloride

12-1. 2 - (((S) -2-N-glycylamino-3-phenyl propyl) amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride:

Ethyl chloroformate (86 microl, 0.901 mmol) was added at ice bath temperature to a stirred mixture of N- (tert-butoxy carbonyl) glycine (160 mg, 0.911 mmol) and 4-methylmorpholine (110 microl, 1.00 mmol) in tetrahydrofuran (10 ml). After 40 min, a solution of (((S) -2-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine (409 mg, 0.911 mmol) in tetrahydrofuran was added at ice bath. Within 1 hour the medicine reached room temperature. It was diluted with dichloromethane, washed with aqueous sodium bicarbonate, then dried over organic solution and evaporated. The resultant material was purified on a silica gel column and (5% methanol / dichloromethane) then dissolved in methanol (2 ml) and 4N hydrogen chloride / dioxane (2 ml) was added. After 1 h at room temperature, it was evaporated and the precipitate was reacted with dichromethane, then washed with aqueous sodium bicarbonate, followed by drying of the organic solution and evaporation. Column chromatography on silica gel (dichloromethane-methanol-concentrate of ammonium hydroxide = 95: 5: 0; 90: 10: 0.6) gave the title compound as the basic hydroxide, which was converted to hydrochloride by the addition of 4N hydrogen chloride / dioxane ( 85 microl) to methanol solution (3 ml) followed by evaporation. MS (m / z): 329.2 (M + H) ⁺ ; C ₂₇ H ₂₅ F ₃ N ₆ O 506. 5 (free hydroxide) recommended.

The compound below was prepared using the above procedure and appropriate starting materials:

12-2 2 - (((S) -2-L1-glycylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) - (4-pyridyl) pyrimidine hydrochloride:

MS (m / z): 453.2 (M + H) ⁺ ; C ₂₇ H ₂₈ N ₆ O 452.6 (free hydroxide) recommended.

Example 13.

Procedure for the Preparation of (S) -l, 2-6eHylethylenediamine

(S) -1,2-benzylethyleneamine:

Diamine is obtained according to the literature (N. Brunner, R. Hankofer, U. Holzunger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem., 35-44, (1990)) by reduction of L-phenylalanine amide with lithium aluminum hydride. The reantiomer was prepared in the same way from Dphenylalanine amide.

Example 14 Procedure for Preparation of 2 (((S) -2-N-acetamide-3-phenylpropyl) amino) -5 (4-fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone

2 - (((S) -2-acetamido-3-phenylpropyl) amino) -5- (4-fluorophenyl) -3-methyl-6- (4-pyridyl) 4 (3H) -pyrimidinone:

Solution of 2 - ((((3) -2-amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -3-methyl-6- (4- 30 pyridyl) -4 (3H) -pyrimidinone ( 25 mg, 0.058 mmol) and acetic anhydride (200 ml) in ethanol (2 ml) was maintained at room temperature for 1 h. Evaporation followed by silica gel column chromatography (10% methanol / dichloromethane) resulted in 35 to give the title compound. MS (m / z): 472.3 (M + H) ⁺ ; C ₂₇ H ₂₆ FN ₅ O 471.5 recommended.

Example 15.

Procedure for the Preparation of 2 - (((S) -2-Nisopropylamino-3-phenylpropyl) amino) -4- (4- 40 pyridyl) -5- (3-trifluoromethyl phenyl) -pyrimidine hydrochloride

15-1. 2 - (((S) -2-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride:

Sodium triacetoxyborohydride (184 mg, 0.868 mmol) was added to the stirred mixture of 2 - (((S) -2-amino-3-phenylpropyl) amino) -4 (4-pyridyl) -5- (3-trifluoromethylphenyl) - pyrimidine (300 mg, 0.668 mmol) and acetone (50 microl, 0.675 mmol) in 1,2-dichloroethane (4ml). After 16 h, the reaction was quenched by the addition of saturated sodium bicarbonate solution. followed by extraction with dichloromethane, drying of the organic solution and evaporation.

Chromatography on a silica gel column (5% methanol / chloroform) provided the isolation of the title compound as a free base which was converted to monohydrochloride by adding 6N hydrochloric acid (73 microl) to its methanol solution (3 ml) and subsequent evaporation. MS (m / z): 491.7 (M) ⁺ ; C ₂₈ H ₂₈ F ₂ N ₅ Requirement 491,6 (free base).

The above procedure and the use of suitable starting materials gave the following compounds:

15-2. 2 - (((S) -2-1M-cyclohexylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: MS (m / z): 532.0 (M + H) ⁺ ; C ₃₁ H ₃₂ F ₃ N ₅ Requirement 531.6 (free base).

478.3 (M + H) ⁺ ; C ₃₁ H ₃₅ N ₅ requirement 477.7 (free base).

R1

15-3. 2 - (((S) -2-] N-isopropylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 439.1 (M + H) ⁺ ; C ₂₈ H _3] N ₅ requirement 437.6 (free base).

15-6. 5- (4-fluorophenyl) -2 - (((S) -2-misopropylamino-3-phenyl-propyl) -amino) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 442.1 (M + H) ⁺ ; C ₂₇ H ₂₈ FN ₅ requirement 441.6 (free base).

15-4. 2 - (((S) -2-N-Butylamino-3-phenylpropyl) amino) -5- (3-methyl-phenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 452.1 (M + H) ⁺ ; C ₂₉ H ₃₃ N ₅ requirement 451.6 (free base).

15-7. 5- (4-fluorophenyl) -2 - ((3-L4-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 422.2 (M + H) ⁺ ; C ₂₇ H ₂₈ FN ₅ requirement 441.6 (free base).

R1

15-5. 2 - (((S) -2-N-cyclohexylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z):

Example 16.

Method for Preparation of 2 - (((S) -2-Amino-3-phenylpropyl) -amino) -5- (3-chloro-4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride

Step A: 4- (4-Pyridyl) -2 (1H) -pyrimidinone: A mixture of 4-acetylpyridine (25 ml, 26.0 mmol) and bis (dimethylamino) methoxymethane (44 ml, 293.8 mmol) was heated at 85 ° C in for 30 min, followed by evaporation to dryness to recover crystalline 3- (dimethylamino) -1- (4-pyridyl) -3-propen-1-one. Its ethanol solution (200 ml) was converted into ethanol 1.13 N sodium ethoxide (200 ml) containing urea (16.3 g, 271 mmol). The mixture was refluxed overnight and then cooled in an ice bath. The precipitate was filtered off, dissolved in a minimum amount of water and the aqueous solution was washed with dichloromethane. The title compound was precipitated from the aqueous solution by neutralization with 6N hydrochloric acid and filtered. An additional amount was obtained from the filtrate obtained from the basic reaction, which was concentrated, diluted with a minimum amount of water and washed with dichloromethane. The aqueous solution was neutralized with 6N hydrochloric acid and the precipitate was filtered off. MS (m / z): 174.1 (M + H) ⁺ ; C ₉ H ₇ N ₃ O - Requirement 173.2.

Step B: 2-Chloro-4- (4-pyridyl) -pyrimidine: By cooling to zero in argon, 4- (4-pyridyl) -2 (H) -pyrimidinone (13.45 g, 77.7 mmol) was coupled to (92 ml) thionyl chloride. N, N-dimethylformamide (13.2 ml, 170.5 mmol) was added slowly and the mixture was refluxed for 1 h, evaporated and distilled simultaneously with toluene. At 0 ° C, water was added to the residue, followed by 10% ammonium hydroxide until neutral, followed by extraction with dichloromethane. Drying of the organic solution was followed by evaporation and the resulting solid was recrystallized from acetone. MS (m / z): 192.1,194.0 (M + H) ⁺ ; C ₉ H ₆ C1N ₃ - Requirement 191.6.

Step C: 2 - (((S) -2-Amino-3-phenylpropyl) amino) -4- (4-pyridyl) -pyrimidine: Mixture of 2-chloro-4- (4-pyridyl) -pyrimidine (4.5 g , 23.7 mmol) and (S) -1,2-benzylethylenediamine (8.0 g, 53.3 mmol) was heated at 100 ° C for 25 min. Silica gel column chromatography (dichloromethane-methanol-concentrated ammonium hydroxide = 95: 5: 0.4) provides isolation of the title compound. MS (m / z): 306.5 (M + H) ⁺ ; C ₁₈ H ₁₉ N ₅ Requirement 305.4.

Step D: 2 - (((S) -2-Amino-3-phenylpropyl) amino) -5-bromo-4- (4-pyridyl) -pyrimidine: With stirring to a solution of 2 - (((8) -2 -amino-

3-Phenylpropyl-amino) -4- (4-pyridyl) -pyrimidine (2.33 g, 7.64 mmol) 6 chloroform (25 ml) was added bromine (787 microl, 15.28 mmol). Stirring continued for two days. The mixture was partitioned between dichloromethane and aqueous sodium bicarbonate. The organic solution was washed with brine, dried and evaporated. The resulting product was purified on a silica gel column chromatography column (dichloromethane-methanol-conc. Ammonium hydrochloride = 92: 8: 0.6). MS (m / z): 384.0, 386.0 (M + H) ⁺ ; C ₁₈ H _{] 8} Brl ₅ - Requirement 384.3.

Step E: 2 - (((S) -2-Amino-3-phenylpropyl) amino) -5- (3-chloro-4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: Mixture of 2 ((8) -amino-3-phenylpropyl) -amino) -5-bromo-4 (4-pyridyl) pyrimidine (204 mg, 0.53 mmol), liquid 2M sodium carbonate (1.6 ml, 3.32 mmol) and 3-chloro-4-fluorobenzene boron acid (103 mg, 0.637 mmol) in toluene (5 ml) was stirred under argon. The mixture was completely degassed (10 times) before the addition of tetrax (triphenylphosphine) palladium (0) (18 mg, 0.016 mmol). After refluxing for 16 h, the reaction mixture was diluted with toluene and washed with brine. The organic solution was dried and evaporated. Subsequent silica gel column chromatography (dichloromethane-methanol-concentrated ammonium hydrochloride = 95: 5: 0.4) afforded the title compound, which was converted to the hydrochloride by adding 6M hydrochloric acid (64 microl) to its methanol solution (2 ml) ), followed by evaporation. MS (m / z): 434.1 (M) ⁺ ; C ₂₄ H ₂₁ ClEM ₅ - requirement 384.3.

The following compounds were obtained by the step E of this procedure using the appropriate boronic acid and 5-bromopyridine:

16-2. 2 - (((S) -2-amino-3-phenylpropyl) amino) -5- (3-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 400.1 (M + H) ) ⁺ ; requirement 399.5 (free base).

16-3. 2 - (((S) -2-amino-3-phenylpropyl) amino) -5- (3-isopropylphenyl) -4- (4-pyridyl) pyrimidine hydrochloride: MS (m / z): 424.2 (M + H) ⁺ ; C ₂₇ H ₂₉ N ₅ - Requirement 423.6 (free base).

16-4. 5- (3-acetamidophenyl) -2 - (((S) -2 amino-3-phenylpropyl) amino) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 439.1 (M + H) ⁺ ; C ₂₆ H ₂₆ K ₆ O-requirement 423.6 (free base).

16-5. 2 - (((S) -2-amino-3-phenyldropyl) amino) -5- (4-chlorophenyl) -4- (4-pyridyl) -pyridine-5-midine hydrochloride: MS (m / z): 416.3 ( M + H) ⁺ ; C ₂₄ H _{22 US 5 -} Requirement 415.9 (free base).

16-6. 2 - (((S) -2-amino-3-phenylpropyl) amino) -5- (benzothienyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 438.3 (M + H) ⁺ ; 10 C ₂₆ H ₂₃ N ₅ S - requirement 437.6 (free base).

16-7. 2 - (((S) -2-amino-3-phenylpropyl) amino) -5- (2-naphthyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 432.5 (M + H) ) ⁺ ; C ₂₈ H ₂₅ N ₅ requirement 431.5 (free base). 15

Example 17.

Method for the preparation of (S) -2-benzylpiperazine

(S) -2-Benzylpiperazine: In an ice bath, lithium aluminum hydride (1.6 g, 42.16 mmol) was added portionwise to a mixture of (S) -2-benzylpiperazine-3,6-dione (3.0 g, 14.70 mmol) and tetrahydrofuran (80 ml), subjected to continuous stirring. After 30 min in an ice bath, the mixture was refluxed with stirring for 4 h. The reaction was quenched by adding sufficient sodium sulfate decahydrate and methanol until hydrogen evolution ceased. Filter and wash the solid residue with dichloromethane. The combined filtrates were evaporated to give white crystals. MS (m / z): 177.1 (M + H) ⁺ ; C _n H _I6 N ₂ - requirement 176.3.

Example 18

Method for Preparation of (S) -2-N, N-Phenylmethylamino-3-phenylpropylamine

(S) -2-N, N-dimethylamino-3-phenylpropylamine: To a mixture of phenylalaninamide (3.6 g, 21.9 mmol) and 37% formaldehyde solution (4.4 ml, 58.7 mmol) in 1,2-dichloroethane (77 ml) sodium triacetohydride (13.0 g, 61.3 mmol) was added with stirring. Stirring was continued for 2 h after which time the mixture was quenched by the addition of saturated aqueous sodium bicarbonate. Potassium hydroxide granules are added, followed by extraction with dichloromethane, drying the organic extract and evaporation. The obtained (S) -2-L1, N-dimethylamino-3-phenylpropylamide was reduced with lithium aluminum hydride according to literature data (N. Brunner, R. Hankofer, U. Holzinger, V. Treittinger & N. Schoenenberger, Eur, J. Med. Chem. 25, 35-44 (1990)) to obtain the desired compound.

Example 19.

Method for Preparation of 2 - (((S) -2-N, N-Dimethylamino-3-phenylpropyl) -amino) -5- (4fluorophenyl-3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride

Step A. 5- (4-Fluorophenyl) -3-methyl-2-methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone: Mixture of 5- (4-fluorophenyl) -2-methylthio-6- (4-pyridyl) ) -4 (3H) -pyrimidinone (400 mg, 1.22 mmol), Oxone ^R (sodium peroxymonosulfate, 2.3 g, 3.74 mmol) in methanol (100 ml) and boiling water (45 ml) was stirred for 13 h. The solvent was concentrated about 50 ml volume, followed by extraction with dichloromethane, drying the organic extract and evaporation. The resulting white solid was used without further purification in the next step.

Step B. 2 - (((S) -2-N, N-dimethylamino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) - Pyrimidinone hydrochloride: A mixture of untreated 5- (4-fluorophenyl) -3methyl-2-methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (430 mg g 1.19 mmol) and (S) -2-N. N-dimethylamino-3-phenylpropyl) -amine (600 ml, ~ 3.4 mmol) was stirred at room temperature for 1 h and then rapidly heated to 50 ° C. Silica gel column chromatography (3-5% methanol / chloroform) provided the isolation of the desired compound as a free base which was converted to monohydrochloride by the addition of 4N hydrochloric acid / dioxane (160 ml, 0.64 mmol) to its methanol solution (4 ml) and subsequent evaporation. MS (m / z): 458.0 (M + H) ⁺ ; C ₂₇ H _2g FN ₅ O requirement 457.5 (free base).

Example 20.

4- (4-fluorophenyl) -6- (4- (2-acetamido) pyridyl) -2-thioalkyl-4 (3H) -pyrimidinones

Step A. Ethyl 2- (4-fluorophenyl) -3-oxo 3- (4- (2-acetamido) -pyridyl)) -propionate:

A mixture of 2-chloroisonicotinic acid (2.0 g, 0.16 mol) in 65 ml of concentrated ammonium hydroxide was heated at 205 ° C in a steel bottle for 72 h. After cooling to 23 ° C, the solution was acidified to pH 1 using 6N hydrochloric acid and then filtered to remove the unreacted feedstock. The solution was concentrated to one quarter of the original volume (approx. 200 ml) in vacuo and carefully basified to pH 6 using 1H NaOH. After the solution was stirred at 0 ° C for 20 h, the desired 2-aminoisonicotinic acid was filtered off. To a suspension of 2-aminoisonicotinic acid in ethanol (600 ml) was added 47.1 ml of 4N anhydrous hydrochloric acid in dioxane. After refluxing for 20 h, an additional amount of 47.1 ml of 4N anhydrous hydrochloric acid in dioxane was added. The reaction was continued under reflux for a further 20 h. Concentration in a stream of nitrogen into the jacket was followed by Concentration in vacuo, dilution of the solid with saturated bicarbonate (200 ml), extraction with ethyl acetate (2x200 ml), drying (sodium sulfate). Concentration in vacuo gave the desired ethyl-2-aminoisonicotinate. To a solution of ethyl 2-aminoisonicotinic acid in pyridine (45 ml) at 0 ° C in argon atmosphere, a sufficient amount of acetyl chloride was carefully added dropwise over at least 5 minutes. After 2 h at 0 ° C, the reaction mixture was poured onto 300 g of ice, extracted with ethyl acetate (2x300 ml), washed with water (2x100 ml), then brine (2x100 ml) and dried (sodium sulfate). ). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate-hexane 1: 4, then ethyl acetate-hexane 1: 1) to give ethyl-2-acetamidoisonicotinate.

To a solution of diisopropylamine (14.15 ml, 101 mmol) and THF (40 ml) at -78 ° C was added pbutyl lithium (38.1 ml, 95 mmol) dropwise for at least 5 min. After 10 minutes, ethyl was added

4-fluorophenyl acetate (17.3 g, 95 mmol) in 40 ml dry THF. After 10 minutes, ethyl-2-acetamidoisonicotinate (6.0 g, 29 mmol) in 20 ml of dry THF was added. The reaction mixture was heated to 23 ° C overnight, then the entire amount of acetic acid (95 mmol) was added at once. The reaction mixture was concentrated in vacuo, then fractionated repeatedly between saturated bicarbonate (200 ml) and ether (300 ml), neutralizing the combined carbonate layers with 10% citric acid and extracting with ethyl acetate (2x300 ml). The organic layers were dried (sodium sulfate) and concentrated in vacuo to give ethyl-2 (4-fluorophenyl) -3-oxo-3- (4- (2-acetamido) pyridyl) -propionate.

Step B. 5- (4-Fluorophenyl-6- (4- (2-acetamido) pyridyl)) -2-thiouracil:

Ethyl-2- (4-fluorophenyl) -3-oxo-3- (4- (2-acetamido) pyridyl) propionate (1.3 g, 3.78 mmol) and thiourea (863 g, 11.3 mmol) were suspended in anhydrous p-xylene (15 ml) with vigorous stirring. Pyridine p-toluenesulfonate (38 mg) was added to the mixture and concentrated for 12-16 h using a Dean-Stark apparatus with continuous withdrawal of water (0.1 ml). The reaction mixture was cooled and the dark brown solid was filtered off using a Buchner funnel. The resulting filtrate was suspended in acetone (25 ml) and filtered again. The product, washed with acetone, contains traces of thiourea, which are removed by washing with hot water (20-30 ml). The product is filtered and air-dried, followed by the formation of an azeotropic mixture with toluene.

Example 21.

Method for Preparation of (S) -2-N-Ethylamino-3-phenylpropylamine

(S) -2-N-ethylamino-3-phenylpropylamine: To a solution of L-phenylalanine amide (1.0 g, 6.1 mmol) in methanol (25 ml) was added with acetic anhydride (1.2 ml, 12.7 mmol) with stirring. After 1.5 h at room temperature, evaporation is carried out, followed by drying with the aid of an oil vacuum pump. The resulting LN-ethylphenylalanine amide (6.1 mmol) was reduced with lithium aluminum hydride (570 mg, 15.0 mmol) in tetrahydrofuran (65 ml) at 55 ° C for 4 h. The reaction mixture was poured into saturated aqueous sodium bicarbonate, followed by extraction with dichloromethane, drying and evaporation. Silica gel column chromatography (chloroform: methanol: triethylamine = 90: 7: 3) provides isolation of the amine as an oily yellowish liquid. MS (m / z): 179.1 (M + H) ⁺ ; C _n H _lg N ₂ requirement 178.3.

Example 22

Method for Preparation of 2-Amino-2-methyl-3-phenyl propylamine

OH."·

2-Amino-2-methyl-3-phenylpropylamine: A solution of commercially available DjL-6-methylphenylalanine methyl ester (5.0 g, 25.7 mmol) in aqueous 28% ammonium hydroxide (50 ml) was stored at room temperature for 45 h. three days. The resulting white precipitate of D, L6-methylphenylalanine amide was filtered and dried (2.5 g). The product (2.0 g, 11.22 mmol) was reduced with lithium aluminum hydride (1.3 g, 34.26 5θ mmol) in boiling tetrahydrofuran for 24 h. The reaction was terminated by the addition of sodium sulfate decahydrate in an ice bath. The salts were filtered off, followed by evaporation to give the title compound as an oily liquid. MS 5 (m / z): 165.1 (M + H) ⁺ ; C ₁₀ H ₁₆ N ₂ required. 164.2. An alternative method of preparation is reported by M. Freiberger & R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698 (1960).

Example 23. 10

Method for Preparation of 2-Methyl-3-phenylpropylamine

2-Methyl-3-phenylpropylamine: A mixture of commercially available 2-methyl-3-phenylpropylamide (4.32 g, 26.5 mmol) and lithium aluminum hydride (1.3 g, 34.3 mmol) in THF (184 ml) was stirred at room temperature. 5 h. It was poured into aqueous saturated sodium sulfate and extracted with dichloromethane, followed by drying of the organic solution and evaporation to give the amine as an oily liquid. Other synthesis methods have been reported, e.g. Domow and Fust, Chem. Ber. 87, 984 (1954).

Example 24

Method for Preparation of 5- (4fluorophenyl) -3-methyl-2 - ((2-methyl-3-phenylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride

5- (4-fluorophenyl) -3-methyl-2 - ((2-methyl-3-phenylpropyl) amino-6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride:

A mixture of crude 5- (4-fluorophenyl) 3-methyl-2-methylsulfonyl-6- (4-pyridyl) -4 (3H) pyrimidinone (520 mg, 1.45 mmol) and 2-methyl-3-35 phenylpropylamine (1.5 g , 10.1 mmol) was heated to 50 ° C for 30 min. Silica gel carrier chromatography (2-5% methanol / dichloromethane; hexane-acetone = 2: 1) provided isolation of the title compound. MS 40 (m / z): 429.4 (M + H) ⁺ ; C ₂₆ H ₂₅ FN ₄ O requirement 428.5 (free base).

Example 25

Method for the preparation of 1-phenyl-1,3-propanediamine 45

-phenyl-1,3-propandiamine: 3-phenyl-Zaminopropionic acid (SGCohen and SY Weinstein, J. Am. Chem. Soc. 86, 7255-728, 1964) is converted to 1-phenyl-1,3-propandiamine on literature (M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459 (1982)).

Similarly. 1- (2-fluorophenyl) -1,3-propanediamine. 1 (Methylphenyl) -1,3-propandiamine and 1- (2-chlorophenyl) -1,3-propandiamine were prepared by the procedure described using appropriate starting materials.

Example 26.

Method for Preparation of 3-Ethyl-5- (4fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) pyrimidinone

3-ethyl-5- (4-fluorophenyl) -2-methylthio-6 (4-pyridyl) -4 (3H) pyrimidinone: Ethyl bromide (600 ml, 8.03 mmol) was added at room temperature to a mixture of 5- (4 -fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone (1.8 5 g, 5.97 mmol) and sodium hydride (60% fat suspension, 320 mg, 8 mmol) in Ν, Ν- dimethylformamide (60 ml), previously stirred. After 2 and 3.5 h, additional amounts of ethyl bromide (2x600 ml, 10 2x8.03 mmol) were added. After 8 h, the reaction mixture was neutralized with acetic acid and evaporated. The residue was extracted with dichloromethane, the organic solution was washed with water, dried and evaporated, flash chromatography on a silica gel column (hexane-acetone = 3: 1.2: 1) provided the title compound as a solid in the second main fraction.

Sample 27.

Method of Preparation of 3-Ethyl-5- (4fluorophenyl) -2-ethylsulfonyl - (- 6- (4-pyridyl) 4 (3H) -pyrimidinone

3-ethyl-5- (4-fluorophenyl) -2-methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone: Mixture of 3-ethyl-5- (4-fluorophenyl) -2-methylthio-6 - (4pyridyl) -4 (3H) -pyrimidinone (300 mg, 0.88 mmol) and Oxone ^R (sodium peroxymonosulfate, 2.54 g, 4.14 mmol) in methanol (71 ml) and water (33 ml) was stirred for 14 h . The solvent was concentrated to about 35 ml followed by extraction with dichloromethane, drying and evaporation. The resulting white solid was used without the need for purification in the next step.

Example 28.

Method for Preparation of 2 - (((S) -2-amino-3-phenyl propyl) amino) -3-ethyl-5- (4fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride at 190 ° C for 4.5 h. Column chromatography performed on Iatrobeats ^R (chloroform-methanol: triethylamine = 90: 7: 3) provided isolation of the title compound as a free base which was converted to crystallization monohydrochloride by the addition of 2N hydrochloric acid (165 ml, 0.33 mmol) and methanol (1.5 ml). Filtration afforded the title compound. MS (m / z): 444.0 (M + H) ⁺ ; C ₂₆ H _2? FN ₅ O required. 443.5 (free base).

Example 29.

Method for Preparation of 3-Ethyl-5- (4fluorophenyl) -2 - ((2-methyl-3-phenylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride

2 - ((((S) -2-amino-3-phenylpropyl) -amino) 3-ethyl-5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) pyrimidinone hydrochloride: Mixture of 3- ethyl-5- (4fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) pyrimidinone (150 mg, 0.44 mmol) and (S) -1, 2-6 eHzilylethylenediamine (200 ml, ~ 1.3 mmol) is heated

3-ethyl-5- (4-fluorophenyl) -2 - ((2-methyl-3-phenylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: A mixture of crude 3-ethyl-5- (4 -fluorophenyl) -2-methylsulfonyl-6- (4pyridyl) -4 (3H) -pyrimidinone (320 mg, 0.89 mmol) and 2-methyl-3-phenylpropylamine (600 ml, 4 mmol) was heated at 60 ° C for 2 h. . Silica gel column chromatography (hexane-acetone = 2: 1; 2-5% methanol / dichloromethane) column chromatography provides isolation of the title compound. MS (m / z): 443.2 (M + H) ⁺ ; C ₂₇ H ₂₇ FN ₄ O required. 442.5.

Sample 30.

Method for the preparation of 3- (2-methylphenyl) propylamine

3- (2-methylphenyl) propylamine: Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added with stirring to a suspension of sodium hydride (60% fat suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml) under argon. After 30 min, 2-methylbenzaldehyde (3.6 ml, 31.1 mmol) was added and stirring was continued for one hour. The reaction was quenched by the addition of water and extraction with dichloromethane, followed by drying and evaporation of the organic solvent. Column chromatography (hexane; hexane: ethyl acetate = 3: 1) provides isolation of 2- (2-methylphenyl) acrylinitrile as an oily liquid. The resulting product (3.8 g), cat. 10% palladium / carbon (3.8 g) and 12N hydrochloric acid (11.8 ml, 142 mmol) in methanol (125 ml) were hydrogenated with hydrogen at a pressure of one atmosphere for two days. The catalyst was removed by filtration and the solvent was evaporated. The resulting material was fractionated between dichloromethane and water. The aqueous layer was brought to basic pH with 10N sodium hydroxide and extracted with dichloromethane, followed by drying and evaporation. The resulting product was purified by a silica gel column (chloroform: methanol: triethylamine = 85: 10: 5) to isolate the title compound as an oily liquid.

Example 31

Method for Preparation of 2-Amino-3- (2fluorophenyl) -propylamine

Step A: Methyl 2-amino-3- (2-fluorophenyl) -propionate: 5 g (27.3 mmol) (DL) - (2fluorophenyl) alanine were suspended in 50 ml of methanolic hydrochloric acid and stirred for three days at room temperature. The reaction mixture was concentrated in vacuo and dried to give a yellow oily liquid. MS (m / z): 198 (M + H) ⁺ ; C ₁₀ H ₁₂ FNO _{2 -} Requirement 197.2.

Step B: 2-amino-3- (2-fluorophenyl) protunamide: methyl 2 amino-3- (2-fluorophenyl) propionate was suspended in 50 ml of 30% ammonium hydroxide with continuous stirring for 18 h at room temperature. The mixture was filtered, washed with cold water, and the 2-amino-3- (2-fluorophenyl) -protunamide was obtained as a white solid. MS (m / z): 183.1 (M + H) ⁺ ; C ₉ H _n FN ₂ O - requirement 182.2.

Step C: 2-amino-3- (2-fluorophenyl) propylamine: 2-amino-3- (2-fluorophenyl) -propionamide was carefully added to a cooled (5 ° C) mixture of LAH (1.0 g, 26.3 mmol) and 20 ml THF in argon atmosphere. The reaction mixture was refluxed for 10 h, then cooled to 5 ° C and carefully treated with Na ₂ SO ₄ .10 H ₂ O. The resulting mixture was stirred for 18 h, then filtered to remove the solid residue, the filtrate was concentrated in vacuo to give an amber-colored oily liquid. MS (m / z): 169 (M + H) ⁺ ; C ₉ H ₍₃ FN ₂ - requirement 168.19.

Example 32

Method of Preparation of (1R, 2R) -2-Methyl-1-phenyl-1,3-propanediamine

Step A: methyl (2S, 3R ^ 4SaS) -3- (N-6eH3iVi-alfamethylbenzylamino) -2-methyl-3-phenylpropionate was prepared according to the literature analogous to the 2R, 3S, 6 R-enantiomer (S). G. Davies and I. A. S. Walters, J. Chem. Soc. Perkin Trans. I, 1129-1139 (1994).

Step B: methyl (2S, 3R) -3-amino-2-methyl-3-phenylpropionate: Mixture of methyl (2S, 3R, 6S) -3 (N-benzyl-N-6-ethylbenzylamino) -2-methyl-3- phenylpropionate (13 g, 33.55 mmol) and a catalyst of 10% palladium / carbon (13.0 g) in glacial acetic acid (260 ml) were hydrogenated in hydrogen medium in a steel bottle for 24 h. The catalyst was removed by filtration followed by evaporation and codestillation with toluene to give the title compound as a white solid. MS (m / z): 194.2 (M + H) ⁺ ; C _and H _{] 5} TY ₂ - requirement 193.3.

Step C: methyl (28, 3R) -3-amino-2-methyl3-phenylpropionamide: Solution of methyl (2S, 3R) 3-amino-2-methyl-3-phenylpropionate (6.3 g, 33 mmol) in 2N methanol solution of ammonia (20 ml) and ammonium hydroxide (28-30%, 40 ml) was stirred at room temperature. After four days, it was subjected to evaporation and silica gel column chromatography (dichloromethane-methanol-conc. Ammonium hydroxide = 93: 7: 0.7; 90: 10: 0.8) to isolate the amide as a white solid. MS (m / z): 179.2 (M + H) ⁺ ; C _{] 0} H _{] 4} N ₂ O - requirement 178.2

Step D: (1R, 2R) -2-Methyl-1-phenyl-1,3-propanediamine: Lithium aluminum hydride (2.3 g, 60.60 mmol) was added portionwise to a stirred solution of (2S, 3R) -3-aHH -2-methyl-3-phenylpropionamide (2.6 g, 14.59 mmol) in tetrahydrofuran (54 ml) in an ice bath.

After 45 min, the mixture was refluxed for 16 h. Upon cooling the ice bath, the reaction is terminated by the addition of sufficient amount of sodium decahydrate and methanol until hydrogen evolution ceases. The solid residue was filtered off and washed with dichloromethane. The combined filtrate was evaporated to give the title compound. MS (m / z): 165.2 (M + H) ⁺ ; C ₁₀ H _{] 6} N ₂ requirement 164.3.

Similarly, the enantiomer of (2S, 2S) -2-Methyl-1-phenyl-1,3-propanediamine is obtained from methyl (2R, 3S, 6R) -3- (N-benzyl-14-6-methylbenzylamino) -2- methyl-3-phenylproteinate. MS (m / z): 165.3 (M + H) ⁺ ; C ₁₀ H ₁₆ b [ _2- Requirement 164.3.

Similarly, the enantiomers of (1S, 2R) -2-Methyl-1-phenyl-1,3-propanediamine and (1R, 2S) -2-Methyl-1-phenyl-1,3-propane-diamine can be obtained quaternary butyl (2S, 3S, 6R) -h- (2R, 3R, alpha) -3- (N-benzyl-N-alpha-methylbenzylamino) -2-methyl-3 phenylpropionate. (Davies et al., J. Chem. Soc. Chem. Commun. 1153-1155, 1993).

Example 33.

Method for Preparation of 5- (4-Fluorophenyl) -2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H) pyrimidinone

5- (4-Fluorophenyl) -2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone:

Ethyl-2- (4-fluorophenyl) -3-oxo-3- (4-pyridyl) -propionate (293 mg, 1.02 mmol) and 4-phenylbutanecarboxamidine (315 mg, 1.79 mmol) and pyridine p-toluenesulfonate (10 mg) were suspended in p-xylene (10 ml). With vigorous stirring, 5 the mixture was refluxed using a Dean-Stark apparatus with continuous withdrawal of water. After 16 h, the solvent was evaporated and the product was purified on a silica gel column chromatography (3% methanol / 10 dichloromethane), followed by recrystallization from acetone. MS (m / z): 400.3 (M + H) ⁺ ; C ₂₅ H, ₂ FN ₃ O required. 399.5.

Example 34

Method for Preparation of 5- (4-Fluoro-15-phenyl) -2- (1-methyl-N- (2-phenylethyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-Fluorophenyl) -2- (X-methyl-X- (2-phenylethyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone was prepared by the methods described above. MS (m / z): 401.2 (M + H) ⁺ ; C ₂₄ H ₂₁ FN ₄ O required. 400.5.

Example 35

The compounds listed in Table. Ι-II can be obtained using the procedures of samples 1-33

Table 1.

Table 2.

Example 36

Biological research

The following samples were used to characterize the ability of the compounds of the invention to inhibit the production of tumor necrosis factor THF-alpha and IL-1-beta. The second sample measures the inhibition of THF-alpha and / or IL-1-beta in mice after oral administration of the test compounds. The third sample, the glucagon binding agent in vitro, can be used to characterize the ability of the compounds of the invention to inhibit glucagon. The inhibitory capacity of the fourth in vitro sample, the cyclooxygenase enzyme (COX-1 and COX2), can be used to characterize the ability of the compounds of the invention to inhibit COX-1 and / or COX-2.

Biological sample of TNF derived from lipopolysaccharide-activated monocytes

Monocyte isolation

Test compounds were evaluated in vitro for their ability to inhibit the resulting THF by activated bacterial lipopolysaccharide (LPS) monocytes. Fresh residual leukocyte culture obtained from local blood bank and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient separation by centrifugation in Ficol-Paque Plus (Pharmacia). PBMCs were suspended in 2 x 10 ⁶ / ml DMEM supplemented with 2% FCS, 10 mM, 0.3 mg / ml glutamate, 100 U / ml penicillin G and 100 mg / ml streptomycin sulfate (complete medium). The cells were introduced into flat-bottomed Falcon bottles, 96 units (200 microl / vessel) and cultured overnight at

37 ° C and 6% CO ₂ . Non-adhesive cells were removed by washing with 200 µl of fresh medium in one petri dish. The vessels containing adhesive cells (~ 70% monocytes) were refilled with 100 µl of fresh medium.

Preparation of stock solutions of test compounds

Test compounds were dissolved in DMZ. Reference solutions were prepared at a starting concentration of 10-50 microM, and then diluted to 20-200 microM in complete media. Nine double batch solutions of each test compound are then prepared in complete medium.

Treat cells with test compounds and activate TNF production by lipopolysaccharide

One hundred microliters of each diluted test compound was added to microtiter tubes containing adhesive monocytes and 100 μl of complete medium. Monocytes were cultured with test compounds for 60 min, during which time 25 µl of complete medium containing 30 ng / ml lipopolysaccharide from E. coli K532 was added to each vessel. The cells were cultured for a further 4 h. The supernatant was removed and the presence of TNF in the supernatant was quantified by ELISA.

Tumor necrosis factor ELISA

Using a Falcon flat-bottomed vessel, 150 µl / vessel of 3 µg / ml murine anti-human THF-alpha Mab (R&D Systems # MAB210) was applied and maintained overnight on 96 well CHB ELISA plates. The dishes were then left for 1 h at room temperature with 200 µl / vessel of CaCl _2- free ELISA buffer to which 20 mg / ml BSA was added (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mM CaCl ₂ , 0.15 tM thimerosal, pH 7.4). The plates were washed and re-embedded with 100 microl test supernatants (1: 3 dilution) or standard solution. The standard solutions consist of eleven 1.5-fold serial dilutions of a 1 ng / ml recombinant human THF reference solution (R&D Systems). The plates were incubated at room temperature for an hour of orbital vibrator (300 rpm), washed and plated with 100 µm / vessel of 0.5 mirog / ml goat anti-human THF-alpha (R&D Systems # AB-210-Α) with a concentration of 4: 1. The plates were incubated for 40 min, washed and plated with 100 microl / vessel alkaline phosphatase-bound streptavidin (Jackson Immuno Research # 016-050-084) at a concentration of 0.02 microg / ml. The plates were incubated for 30 min, washed and refilled with 200 [mu] l / vessel of 1 mg / ml p-nitrophenyl phosphate. After 30 min, the plates were read at 405 nm with V reading ^g max max device.

Data analysis

The standard data curve corresponds to a second-order polynomial, and the required THFalpha values are determined by the measured extinction when resolved relative to the concentration. THF concentrations are derived as a function of the concentrations of test compounds using the second-order equation, which calculates the concentration of test compounds causing a 50% decrease in THF obtained.

It can also be shown that the compounds of the present invention inhibit the LPS-induced secretion of IL-1beta, IL-6 and / or IL-8 from monocytes by measuring the concentrations of IL-16eTa, IL-6 and / or IL-8 by methods well known in the art. Thus, the compounds of the invention may reduce elevated levels of THF-alpha, IL1, IL-6 and IL-8. Reducing the elevated levels of these inflammatory cytokines to baseline levels or lower levels is beneficial in controlling, slowing the progression and alleviating multiple disease states. All of the compounds discussed are applicable 6 methods of treating disease states in which THF-alpha, IL-1beta, IL-6 and IL-8 play a role in the full meaning of the definition of THF-alpha intermediate diseases described herein.

Inhibition of LPS induced TNF-alpha in mice

Male DBA / 1LACJ mice were injected with solvent or test compound (solvent consisted of 0.5% tragacanth in 0.03 N hydrochloric acid) 30 min before injection of lipopolysaccharide (2 mg / kg I.V.). Blood samples were collected 90 min after lipopolysaccharide injection and THF serum levels were analyzed by ELISA.

The following compounds show activity in the monocyte sample (LPS induced THF release) with an IC ₅₀ value of less than or equal to 20 microM:

5- (4-fluorophenyl) -2- (4-pyridyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-methylthiazol-4yl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -4- (4-pyridyl) -2- (2-thienyl) -pyrimidine

2- (2-diethylaminoethylamino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2-aminoethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (3-aminopropylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (4-aminobutylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2,6-dichlorobenzyl) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2,6-dichlorophenylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2,6-dimethylphenylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-methoxyphenylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (4-fluorophenylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2-phenylthiomethyl-4 (4-pyridyl) -pyrimidine

2- (benzylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-phenylethylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (methyl- (2-phenylethyl) -amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2 - ((2-hydroxy-2-phenylethyl) amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2- (4-hydroxyphenyl) ethylamino) -4- (4-pyridyl) -pyrimidine

2- (2- (4-aminophenyl) ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2- (4-fluorophenyl) ethylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2- (2-fluorophenyl) ethylamino) -4- (4-pyridyl) -pyrimidine

2- (2- (2-chlorophenyl) ethylamino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2- (4-chlorophenyl) ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2- (3-chlorophenyl) ethylamino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2- (2,4-dichlorophenyl) ethyl-amino) -5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2- (4-bromophenyl) ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2- (2-methoxyphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2- (3-methoxyphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2 - ((3-phenylpropyl) amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2 - ((1-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) amino) -

5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-phenylaminoethylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2 - ((3-imidazolylpropyl) -amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2 - ((4-phenylbutyl) amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine

5- (4-fluorophenyl) -2-morpholino-4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (1-piperazinyl) -4 (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -4- (4-pyridyl) -2- (2-pyrrolidinoethylamino) -pyrimidine

5- (4-fluorophenyl) -2- (2-morpholinoethylamino) -4- (4-pyridyl) pyrimidine

5- (4-fluorophenyl) -2- (2-piperidinoethylamino) -4- (4-pyridyl) pyrimidine

5- (4-fluorophenyl) -2- (3- (2-pyrrolidinol-1-yl) propyl-amino-4- (4-pyridyl) -pyrimidine

2- (2,6-dichlorobenzyl) -5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2- (2-phenylethyl) thio-

6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2- (3-phenylethyl) thio-6 (4-pyridyl) -4 (3H) -pyrimidinone

- (4-fluorophenyl) -2- (2-pheno 1 ^l diethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2- (2-phenylaminoethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone

2- (2- (2-chlorophenyl) ethylamino) -5- (4fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2 - ((3-phenylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2 - ((1-methyl-3-phenylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2 - ((3-imidazolylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone

2 - (((S) -2-amino-3-phenylpropyl) amino) -

4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) amino) -

5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-L (, N-dimethylamino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) pyrimidine

2 - (((S) -2-N, N-dimethylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine

2 - ((3-amino-3-phenylpropyl) -amino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine

2 - ((3-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((3-amino-3- (2-fluorophenyl) propyl) amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((3-amino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - ((2-amino-2-methyl-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - ((3-hydroxy-3-phenylpropyl) -amino) -5 (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - ((((2R, 3R) -3-amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((((28,38) -3-amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((S) -3-benzylpiperazinyl) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

4- (4-pyridyl) -2 - (((S) -tetrahydroisoquinol-3-ylmethylene) amino-5- (3-trifluoromethylphenyl) -pyrimidine

5- (3-methylphenyl) -4- (4-pyridyl) -2 - ((((8) tetrahydroisoquinol-3-ylmethyl) amino) -pyrimidine

2 - (((S) -2-L4-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-] N -cyclohexylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-14-isopropylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-N-Butylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-L1-cyclohexylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2 - (((S) -2-N-isopropylamino-3-phenylpropyl) amino) -4- (4-pyridyl) pyrimidine

5- (4-fluorophenyl) -2 - ((3-b [-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-L [-glycylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-N-glycylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) -amino) 5- (3-chloro-4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) -amino) 5- (3-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2 - ((((S) -2-amino-3-phenylpropyl) -amino) 5- (3-isopropylphenyl) -4- (4-pyridyl) -pyrimidine

5- (3-acetamidophenyl) -2 - (((S) -2-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine

2 - ((((S) -2-amino-3-phenylpropyl) -amino) 5- (4-chlorophenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) -amino) 5- (benzothienyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (2-naphthyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone

The following compounds demonstrate activity in monocyte assay (LPS induced TNF release) with IC ₅₀ values less than or equal to 5 µM.

2- (2-aminoethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (3-aminopropylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2-benzylamino) -5- (4-fluorophenyl) -4 (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-phenylethylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (L [-methyl-N- (2-phenylethyl) amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-hydroxy-2-phenyl-ethyl) amino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2- (4-hydroxyphenyl) ethylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2- (2-fluorophenyl) ethylamino) -4- (4-pyridyl) -pyrimidine

2- (2- (2-chlorophenyl) ethylamino)) - 5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2- (4-chlorophenyl) ethylamino)) - 5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine

2- (2- (2,4-dichlorophenyl) ethylamino)) - 5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (3-phenylpropyl) amino-4- (4-pyridyl) -pyrimidine

2 - ((S) -2-amino-3-phenylpropyl) amino-5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-phenylaminoethylamino) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (3-imidazolylpropyl) amino-4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine

5- (4-fluorophenyl) -2- (1-piperazinyl) -4 (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2- (2-phenylethyl) thio-6 (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2- (3-phenylpropyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone

2- (2- (2-chlorophenyl) ethylamino)) - 5- (4fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2- (3-phenylpropyl) amino-6- (4-pyridyl) -4 (3H) -pyrimidinone

5- (4-fluorophenyl) -2- (1-methyl-3-phenylpropyl) amino-6- (4-pyridyl) -4 (3H) -pyrimidinone

2 - (((S) -2-amino-3-phenylpropyl) amino) -

4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) amino) -

5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-NK-dimethylamino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) pyrimidine

2 - (((S) -2-N, N-dimethylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine

2 - ((3-amino-3-phenylpropyl) -amino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine

2 - ((3-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((3-amino-3- (2-fluorophenyl) propyl) amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((3-amino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - ((3-amino-2-methyl-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - ((3-hydroxy-3-phenylpropyl) -amino) 5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - ((((28,38) -3-amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((((2R, 3R) -3-amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - ((S) -3-benzylpiperazinyl) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

4- (4-pyridyl) -2 - (((S) -tetrahydroisoquinol-3-ylmethyl) amino-5- (3-trifluoromethylphenyl) -pyrimidine

5- (3-methylphenyl) -4- (4-pyridyl) -2 - (((8) tetrahydroisoquinol-3-ylmethyl) amino-pyrimidine

2 - (((S) -2-1 \ [- isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-1 \ [- cyclohexylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-N-isopropylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine

2 - (((S) -2-N-Butylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-14-cyclohexylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

5- (4-fluorophenyl) -2 - (((S) -2-N-isopropylamino-3-phenylpropyl) amino) -4- (4-pyridyl) pyrimidine

5- (4-fluorophenyl) -2 - ((3-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-N-glycylamino-3-phenylpropyl) amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine

2 - (((S) -2-N-glycylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) -amino) 5- (3-chloro-4-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) -amino) 5- (3-fluorophenyl) -4- (4-pyridyl) -pyrimidine

2 - ((((S) -2-amino-3-phenylpropyl) -amino) 5- (3-isopropylphenyl) -4- (4-pyridyl) -pyrimidine

5- (3-acetamidophenyl) -2 - (((S) -2-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine

2 - ((((S) -2-amino-3-phenylpropyl) -amino) 5- (4-chlorophenyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) -amino) 5- (benzothienyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (2-naphthyl) -4- (4-pyridyl) -pyrimidine

2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (4-fluorophenyl) -6- (4-pyridyl) -4- (3H) pyrimidinone.

It can be shown that the compounds of the present invention have anti-inflammatory properties in animal models of inflammation, incl. paw carrageenan edema, collagen-induced arthritis and accessory arthritis, similar to the model of carrageenan edema. (C. A. Winter et al. Proc. Soc. Exp. Biol. Med. (1962) vol. 111, p 544; K. F. Swingle, in R. A. Scherrer and M. W. Whitehouse, Eds., Anti-inflammatory Agents, Chemistry and Pharmacology, Vol. 13-11, Academic, New York, 1974, p.33) and collagen-induced arthritis (D. E. Trentham et al. J. Exp. Med. (1977) vol. 146, p 857; JS Countenay, Nature (new Biol.) (1980), Vol 283, p 666)

Screening for ¹²⁵ 1-glucagon binding to CHO / hGLUR cells. The assay is described in WO 1997/016442, which is incorporated herein by reference in its entirety.

Reagents

The reagents can be prepared as follows:

(a) preparation of fresh 1M o-phenanthroline (Aldrich) (198.2 mg / ml ethanol);

(b) preparation of fresh 0.5 M DTT (Sigma);

(c) preparation of protease inhibitory mixture (1000X): 5 mg leupeptin, 10 mg benzamidine, 40 mg bacitracin and 5 mg soybean trypsin inhibitor per ml DMSO and storage of aliquots at -20 ° C;

(d) 250 microM human glucagon (Peninsula): solubilization of 0.5 mg vial in 575 microl 0.1 N acetic acid (1 microl gives microM final concentration in nonspecific binding assay) and storage of aliquots at -20 ° C;

(e) Sample buffer: 20 mM Tris (pH 7.8), 1 mM DTT and 3 mM o-phenanthroline;

(f) 0.1% BSA sample buffer (proforma dilution; 0.01% final analysis percentage); 10 microl 10% BSA (heat activated) and 990 microl sample buffer;

(g) ¹²⁵ 1-glucagon (NEN, receptor class, 2200 Ci / mmol): dilution to 50,000 cpm / 25 ml in BSA assay buffer (about 50 pM final concentration in assay).

Reading the results of CHO / hGLUR cells for analysis

1. The medium is removed from the refluxing flask, after which each is washed once with PBS (Ca containing no Mg) and enzyme free dissociating fluid (Specialty Media, Inc.).

2. Add 10 ml of enzyme-free dissociating fluid followed by a 4 min stay at 37 ° C.

3. The cells were carefully removed, triturated, an aliquot removed for counting, and the residue centrifuged for 5 min at 1000 rpm.

4. The granules are resuspended in a buffer sample: 75,000 cells per 100 microl.

Instead of whole CHO / hGLUR cells, a membrane preparation may be used while maintaining the same sample volume. The final protein concentration in the membrane preparation is determined in batch

Sample

Determination of glucagon binder inhibition can be accomplished by measuring the reduction of ¹²⁵ 1-glucagon binder in the presence of compounds of general formula 1. The reagents are combined as follows:

Substance / carrier 250 μΜ glucagon ~ I35j2 ----------- glucagon CHO / h GLUR cells Total connection - / 5 μΐ 25 μΐ 100 μΐ + 5µ1 / ~ 25 μΐ 100 μΐ Non-specific binding - / 5 μΐ 125 μΐ 25 μΐ 100 μΐ

The mixture was incubated for 60 min at 22 ° C in a mixer at 275 rpm. The mixture was filtered through a pre-wet (0.5% polyethyleneimine (PEI)) GF / C filter using an Innotech Harvester or Totec Harvester with 4 washes with ice-cold 20 mM Tris buffer (pH 7.8). The radioactivity of the filters is determined by a gamma-scintillation counter.

Thus, it can also be shown that the compounds of the invention can inhibit glucagon binding to glucagon receptors.

Cyclooxygenase enzyme activity assay

Human monocyte leukemia cell line, THP-1, differentiated by phorbol esters, expresses COX1 only; human osteosarcoma cell line 143B, predominantly expressing COX-2. THP-1 cells were routinely cultured in RPMI complete medium enriched with 10% FBS and human osteosarcoma cell line (HOSC), cultured in a minimal amount of medium enriched with 10% fetal calf serum (MEM-10% FBS); Cell incubation was performed at 37 ° C in a humidified medium containing 5% CO ₂ .

Analysis of COX-1

In the preparation for COX-1 analysis, THP-1 cells were grown to confluence, divided 1: 3 into RPMI containing 2% FBS and 10 mM phorbol 12 myristate 13-acetate (TPA) and incubated for 48 h in a vibrator prevent adhesion. The cells were granulated and resuspended in Hank salt buffer (HBS) to a concentration of 2.5 x 10 ⁶ cells / ml and plated in 96-well plates at a density of 5 x 10 ⁵ cells / ml. The test compounds were diluted in HBS and added to the desired final concentration and the cells incubated for an additional 4 h. Arachidonic acid was added to the final dilution at a concentration of 30 mM, the cells were incubated for 20 min at 37 ° C and the enzyme activity was determined as described below.

Analysis of COX-2

For the purposes of COX-2, subconfluent HOSCs were trypsinized and resuspended at a concentration of 3 x 10 ⁶ cells / ml in MEM-FBS containing 1 ng human IL-1b / ml, embedded in 96 tissue culture wells with a density of 3 x 10 ⁴ cells / well, incubated on a vibrator for 1 h to distribute the cells evenly, followed by an additional two-hour static incubation to ensure fusion. The medium was then replaced with a MEM containing 2% FBS (MEM-2% FBS); and 1 ng of human IL-1b / ml and the cells were incubated for 1822 h. Subsequent replacement of the medium with 190 ml MEM, 10 ml of the test compound diluted in HBS was added to achieve the desired concentration and the cells were incubated for 4 h. The supernatants were removed and replaced with MEM containing 30 mM arachidonic acid, the cells were incubated for 20 min at 37 ° C, and the enzyme activity was determined as described below.

Determination of cyclooxygenase activity

After incubation with arachidonob acid, the reactions were terminated by the addition of 1N hydrochloric acid, followed by neutralization with 1 N sodium hydroxide and centrifugation to a granulated cellular residue. Cyclooxygenase enzyme activity in HOSC and ΤΉΡ-1 cell supernatants was determined by measuring the concentration of PGE ₂ (prostaglandin E ₂ ) using an commercially available ELISA (Neogen # 404110). The standard PGE curve is used for calibration, with commercially available COX-1 and COX-2 inhibitors included as standard controls.

Therefore, the compounds of the present invention or a pharmaceutical combination thereof may find use in the preparation of a medicament for the prevention and treatment of rheumatoid arthritis; Paget's disease; osteoporosis; multiple myeloma; uveitis; acute and chronic myelogenous leukemia; destruction of β cells of the paresis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; intestinal inflammation; adult respiratory failure syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption; transplant rejection response; ischemia in transfusion; atherosclerosis; brain injury; Alzheimer's disease; blow; myocardial infarction; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever and muscle pain in infections. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses (incl. HSV-1, HSV-2) and herpes zoster, all of which are sensitive to THF-6 and / or IL-1 inhibition or glucagon antagonism may also be positively affected by the compounds of the present invention.

The compounds could also have analgesic properties and find use in the preparation of a medicament for the treatment of pain, for example in hyperalgesia due to an increase in IL-1. These compounds could also prevent the production of prostaglandins by inhibiting enzymes from the prostaglandin pathway following the synthesis of arachidonic acid in man, including cyclooxygenase (WO 1996/003387 enclosed herein with detailed guidance).

Because of their ability to decrease the concentrations of THF-alpha and IL-1 or to inhibit glucagon binding to receptors, the compounds of the present invention may find application as research models to study the physiology of blocking these effects.

Methods include determining the effective dosage regimen of the compounds in question and the pharmaceutically acceptable salts thereof, or a pharmaceutical combination thereof, of an administered subject (e.g., an animal, preferably a mammal and especially a human) with a need to reduce levels of THF-alpha, IL-

1, IL-6 and / or IL-8 and / or a decrease in plasma glucose levels, and / or which subject may be suffering from rheumatoid arthritis; Paget's disease; osteoporosis; multiple myeloma, uveitis; acute and chronic myelogenous leukemia; destruction of β cells of the paresis; osteoarthritis; rheumatoid spondylitis; gouty arthritis; renal inflammation; adult respiratory failure syndrome (ARDS); psoriasis; Crohn's disease; allergic rhinitis; ulcerative colitis; anaphylaxis; contact dermatitis; asthma; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption; transplant rejection response; ischemia in transfusion; atherosclerosis; brain injury; Alzheimer's disease; blow; myocardial infarction; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever and muscle pain in infections; or which entity could be the carrier of HIV-1, HIV-

2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses (incl. HSV-1, HSV2), shingles.

In another aspect, the present invention includes the use of the corresponding compounds and their pharmaceutically acceptable salts in the manufacture of a medicament for the treatment of acute or chronic THF-alpha, IL-1beta, IL6 and / or IL-8 intermediate conditions, including those described above. Also, said compounds may be useful in the manufacture of an analgesic drug and a medicament for the treatment of painful diseases such as hyperalgesia. The compounds of the present invention may find application in the manufacture of a medicament preventing the production of prostaglandins by inhibiting enzymes of the prostaglandin pathway in the synthesis of arachidonic acid in man.

In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound lowering the levels of THF-alpha, 1Ibeta, IL-6 and / or IL-8 and an effective amount of reducing the plasma glucose levels of a compound with a pharmaceutically acceptable carrier or a diluent and, if necessary, other active ingredients. The compounds of the present invention are administered by all appropriate routes, preferably in the form of a pharmaceutical composition adapted to the respective route and at a dose effective for the purposes of treatment. The therapeutically effective doses of the present compounds requiring the cessation of progression or prevention of the underlying disorders associated with the disease can be readily determined by one skilled in the art by standard methods. For the treatment of THFalpha, IL-1beta, IL-6 and / or IL-8 intermediate diseases and / or hyperglycaemia, the compounds of the present invention may be administered orally, parenterally, by inhalation spray, rectally or topically in dosage forms dosage forms containing conventional pharmaceutically acceptable carriers and excipients. The term parenteral includes subcutaneous, intravenous, intramuscular, intrasternal or intraperitoneal infusion techniques. The dosage regimen for the treatment of THP ^7- alpha, 1b-1beta, IL-6 and / or IL-8 intermediate diseases and / or hyperglycemia of the compounds of the present invention and / or a combination thereof is based on a variety of factors, including the type of disease, age, weight, sex and health status of the patient, the severity of the disease, the route of administration and the particular compound. Therefore, the dosage regimen may vary widely but could be routinely determined by standard methods. Dose levels in the range of 0.01 mg to 30 mg per kilogram body weight per day, preferably from 0.1 mg to 10 mg / kg, and even more than 0.25 mg to 1 mg / kg, are applicable to all methods described in this material.

The pharmaceutically active compounds of the present invention can be treated in accordance with conventional pharmaceutical methods for the manufacture of medicines for human and veterinary use.

The pharmaceutical compositions for oral administration may be formulated as capsules, tablets, suspensions or liquid dosage forms, the pharmaceutical composition generally being prepared in the form of a dosage form containing a given amount of active ingredient. For example, the dosage form may contain an active substance of from 1 to 2000 mg, preferably from 1 to 500 mg, especially from 5 to 150 mg. The appropriate daily dosage for a human or other mammal may vary widely depending on the patient's condition and other factors, but, once again, could be determined using routine methods.

The active ingredient can be injected in the form of a composition with suitable carriers including salts, dextrose or water. The daily parenteral dosage regimen may be from 0.1 to 30 mg / kg body weight, preferably from 0.1 to 10 mg per kilogram, and in particular from 0.25 to 1 mg / kg.

Injectable dosage forms, such as sterile injectable aqueous or oily suspensions, can be formulated using suitable dispersion or wetting agents. Sterile injectable dosage forms may also be sterile injectable solutions or suspensions in non-toxic, parenterally acceptable diluents or solvents, for example in the form of a solution in 1,3-butanediol. Suitable carriers and solvents include: water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils have traditionally been used as solvents or suspending agents. For this purpose, any non-drying oil, including synthetic mono- or diglycerides, may be used.

Fatty acids, such as oleic acid, are also used in the preparation of injectable dosage forms. Suppositories for rectal administration may

100 are prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols, which are solid at room temperature but liquefy at rectal temperature and therefore melt in the rectum, releasing the drug.

For topical administration, the appropriate dose of active ingredient is from 0.1 to 150 mg, once to four times, preferably once or twice daily. The active substance may comprise from 0.001 to 10% by weight of the dosage form, e.g. from 1 to 2% but may reach up to 10% mg / mg, preferably not more than 5% mg / mg and especially from 0.1 to 1% of the dosage form.

Dosage forms suitable for topical administration include liquid or semi-liquid preparations which penetrate well through the skin (eg liniments, lotions, ointments, creams, or pastes) and eye, nose, or nose applications.

For purposes of administration, the compounds of the present invention are typically combined with one or more excipients according to the route of administration. The compounds can be mixed with lactose, sucrose, starch, cellulose esters or alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acid, arabic gum, gelatin, polyvinyl alginate and / or polybinyl alcohol, tableted or insulated for conventional use.

In addition, the compounds of the present invention can be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, cottonseed oil, sesame oil, tragacanth, peanut oil, corn oil and / or various buffers. Other excipients and routes of administration are well known in the pharmaceutical art. Carriers or diluting auxiliaries may include prolonged ingredients such as glyceryl monostearate or glyceryl distearate alone or in combination with wax or other materials known in the art.

The pharmaceutical compositions may be formulated as a solid dosage form (including powders, granules or suppositories) or a liquid dosage form (eg solutions, suspensions, emulsions). They may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional excipients, e.g. preservatives, stabilizers, wetting agents, emulsifiers, buffers and more.

Solid dosage forms for oral administration may include capsules, tablets, dragees, powders and granules. In these, the active ingredients may be mixed with at least one inert diluent such as sucrose, lactose or starch. Solid dosage forms may contain, in practice, other excipients other than the diluents, e.g. gliding and lubricating like magnesium stearate. Capsules, tablets and dragees may also contain buffering agents. The tablets and dragees can be made with a gastric resistant coating.

Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing commonly used inert diluents, e.g. water. They may also contain other excipients, e.g. moisturizing, sweetening, flavoring and other corrigents.

The compounds of the present invention may have one or more asymmetric carbon atoms and may therefore exist in the form of optical isomers and racemic or non-racemic mixtures. Optical isomers can be isolated by degradation of the racemic mixture by conventional processes, e.g. formation of diastereomeric salts, treatment with optically active acids or bases. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluyltartaric and camphorsulfonic, whereby the separation of the diastereomeric mixture by crystallization followed by the release of optically active isomers is based on their salts. Another process of separating optically active isomers involves the use of an optimally selected chiral chromatography column in order to maximize the separation of the enantiomers. Another available method involves the synthesis of covalent diastereomeric molecules of the compounds of the present invention with optically pure acids in active form or optically pure isocyanate. The synthesized diastereomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation and then hydrolyzed to give an enantiometrically pure compound. The optically active compounds can also be prepared using active starting materials. These isomers can be in the form of free acid, free base or salt.

The compounds of the present invention can be used in the form of salts of inorganic and organic acids. Salts include, without being exhausted, the following examples: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentane propionate, dodecyl sulfate, ethane sulfate, ethane sulfate hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmate, pectinate, persulfate, 2-persulfate, 2-sulfate , Thiocyanate, tosylate, mesylate, and undecanoate. In addition, the basic nitrogen-containing groups can be quaternized using low molecular weight alkyl halides such as methyl, ethyl, propyl and butyl chloride, bromide and iodide; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfate, long chain halides such as decyl, lauryl, myristyl and stearyl chloride, bromide and iodide, arylalkyl halides such as benzyl and phenethyl bromide, and others. In this way, water-or fat-soluble or dispersible products are obtained.

Examples of acids that can be used to prepare pharmaceutically acceptable salts include inorganic acids such as hydrochloric, sulfuric and phosphoric acids and organic acids such as oxalic, maleic, succinic and citric. Other examples include alkali or alkaline earth metal salts such as sodium, potassium, calcium, magnesium or other organic bases.

The compounds of the invention may be used as stand-alone pharmacological agents, in combination with one or more of the present substances, or in combination with other pharmacological agents. When administered as a combination, the drugs may be formulated as separate compositions to be taken at different or the same time, or may be formulated into a single composition.

The foregoing examples are an illustration of the invention and are not intended to be limiting to the foregoing compounds. Variations and changes that are apparent to the person skilled in the art are intended to fit the scope and nature of the invention as defined in the appended claims.

From the foregoing description, one skilled in the art can readily understand the main features of the present invention and without departing from the spirit and purpose of the foregoing, make numerous changes and modifications to adapt it to a variety of applications and conditions.

Claims (30)

Claims (1) C, -C ₆ alkyl radicals optionally substituted by 1-3 radicals of amino, methylamino, dimethylamino, hydroxyl radicals, or phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio , halogen, methyl or trifluoromethyl radicals; (1) -C (O) -R ₂₀ radical; (1) C 1 -C ₄ alkyl radicals optionally substituted at 1-3 position by amine, methylamine, dimethylamine, I-butoxycarbonylamine, N ((1-butoxy) carbonyl) -14- (methyl) amine, aminocarbonylamine, hydroxyl, butoxyl, methoxy, butylthiol, methylthiol, methylsulfinyl, methylsulfonyl, halogen or C ₅ -C ₆ cycloalkyl, heterocyclyl, phenyl radicals or heteroaryl radicals optionally substituted at 1-2 sites by amines, dimethylamine, acetylmethoxy, methyloxy, methyloxy , methyl or trifluoromethyl radicals; (1) a hydrogen radical; (1) connection; or (2) a C 1 -C ₄ alkyl radical optionally for 111 substituted at 1-2 with amine, t-butoxycarbonylamines, dimethylamines, hydroxyl, methoxy, methylthiol or halogen radicals; Ye: (1) connection; or (2) a C 1 -C ₄ alkyl radical optionally substituted on 1-2 sites by an amine, di- (C 1 -C ₄ alkyl) amine, (C ₃ -C ₄ alkoxy) carbonylamine, hydroxyl, C ₁ -C ₂ alkoxy, C] -C ₂ alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 hydroxyl, Cj-C, alkoksilovov, C _t -C ₂ alkylthio, halo, C, -C ₄ alkyl or trifluoromethyl radicals ; each R _s is independently a hydrogen or C 1 -C ₄ alkyl radical; each R ₁₀ independently represents (1) C 1 -C 8 alkyl radicals optionally substituted at the 1-3 position with amine, C 1 -C ₄ alkylamines, di- (C 1 -C ₄ alkyl) amines, C ₃ -C ₅ alkanoylamines , carbonylamines, N- (C 1 -C ₄ alkoxy) carbonyl) N - di- (C ₁ -C ₄ alkyl) amines, aminocarbonylamines, hydroxyl, C 1 -C ₄ alkoxyl, C 1 -C ₄ alkylthiols, C ₁ -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halogen or C ₃ -C ₆ cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted at 1-2 positions by amine, di- (C ₃ -C ₄ alkyl) amines, C 1 -C ₅ alkanoylamines, (C 1 -C ₄ alkoxy) carbonylamines, C 1 -C ₄ alkylsulf onylamines, hydroxyls, C 1 -C ₄ alkoxyls, C ₃ -C ₄ alkylthiols, halogen, C 1 -C ₄ alkyl or trifluoromethyl radicals; (1) a hydrogen or C 1 -C ₄ alkyl radical; or (2) a phenyl or heteroaryl radical optionally substituted in 1-2 positions by amine, dimethylamine, acetamide, hydroxyl, methoxy, methyl or trifluoromethyl radicals. (1) a C ₍ -C ₄ alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted on 1-2 sites by amine, dimethylamine, acetamide, hydroxyl, halogen, methoxy, methyl or trifluoromethyl radicals; each R, ₉ is independently a hydrogen radical or R ₃₀ and R ₃₂ independently means: (1) hydrogen radicals; (1) R ₃₀ radicals; (1) Cj-C ₈ alkyl or C _{(-C 5} alkenyl radicals optionally substituted by 1-3 radicals of amino, Cj-C ₄ alkylamino, di- (C ₁ -C ₄ alkyl) amino, Cj-C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamines, N- (C ₁ -C ₄ alkoxy) carbonyl) N-1 H-C ₁ -C ₄ alkyl) amines, aminocarbonylamines, hydroxyl, C ₃ -C ₄ alkoxyls, C 1 -C ₄ alkylthiols , C ₁ -C ₄ alkylsulfinyl, C ₁ -C ₄ alkylsulfonyl, halogen or aryl-C ₁ -C ₄ alkylsulfonyl, C ₃ -C ₆ cycloalkyl, heterocyclic, aryl radicals or heteroaryl radicals optionally substituted at 1-3 site by amine substituents, 1-3 site C 1 -C ₄ alkylamines, di- (C 1 -C ₄ alkyl) amines, C C 1 -C ₆ alkanoylamines, (C 1 -C ₄ alkoxy) carbonylamines, C 1 -C ₄ alkylsulfonyl, C ₃ -C ₅ alkanoyl, hydroxyl, C 1 -C ₄ alkoxyl, C 1 -C ₄ alkylthiols, halogen, C, - C ₄ alkyl radicals or C ₁ -C ₂ haloalkyl radicals in 1-3 position with halogen radicals; (1) a hydrogen radical; (1) a hydrogen radical; (1) connection; (1) a hydrogen radical; (1) C 1 -C ₄ alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted at 1-3 position by amine, di- (C 1 -C ₂ alkyl) amine, acetamide, hydroxyl, C 1 -C ₂ alkoxyl, halogen, C 1 -C ₄ alkyl or trifluoromethyl radicals; (1) a hydrogen radical; (1) connection; (1) hydrogen radicals; (1) a C 1 -C ₄ alkyl radical optionally substituted by (a) amino, C 1 -C 4 alkylamino or di- (C 1 -C ₄ alkyl) amino radicals; or (b) hydroxy, C1-C6 alkoxy, heterocyclic, phenyl or heteroaryl radical optionally substituted by 1-3 amino, C1-C6 alkylamino, di- (C1-C6 alkyl) amino, C1-C6 alkanoylamino, (C1- C 1-4 alkoxycarbonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, C 1 -C alkyl or trifluoromethyl radicals; (1) a hydrogen radical; (1) C 1 -C ₈ alkyl or C ₂ -C ₈ alkenyl radical optionally substituted by 1-3 amino, C ₁ -C ₄ alkylamino, di- (C ₁ -C ₄ alkyl) amino, C ₍ -C ₅ alkanoylamino) , (C 1 -C ₄ alkoxy) carbonylamino, N ((C 1 -C ₄ alkoxy) carbonyl) -N - ((C 1 -C ₄ alkyl) amino, aminocarbonylamino, hydroxy, C 1 -C ₄ alkoxy, C] - C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halo or aryl-C 1 -C ₄ alkoxy, aryl-C 1 -C ₄ -alkylthio, aryl-C 1 -C ₄ alkylsulfonyl, C ₃ -C ₆ cycloalkyl, heterocyclic, aryl or heteroaryl radicals possibly including 1-3 amino N-C alkylamino, di- _{(C] -C4} alkyl) amino, N-C alkanoilami O (C ₁ -C ₄ alkoxy) carbonylamino, C] -C ₄ Akil-sulfonylamino, C-C alkanoyl, hydroxy, C-C alkoxy, C-C alkylthio, halo, C-C alkyl or C-C ₂ haloalkyl from 1-3 halo-rows; (1) hydrogen radicals; (1) a hydrogen radical; (1) bond (2) C 1 -C 6 alkyl or C 1 -C alkenyl radical optionally substituted by: (a) 1-3 amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio or halogen radicals and (b) 1-2 heterocyclic, aryl or heteroaryl 106 radicals optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C ₁ -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C 6 alkylthio, halogen, C 1 -C ₄ alkyl or C 1 -C ₄ alkyl halide of 1-3 halo radicals; (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclic radicals in each R 1 is from 0 to 3; Ze: (1) hydrogen radicals; (1) hydrogen radicals; or (2) a C 1 -C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical, in turn substituted by 1-3 amino, C 1 -C 6 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 2 -C 1 alkoxycarbonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, C 1 -C alkyl or trifluoromethyl radicals, and where each R ₃₂ independently represents: (1) C1-C alkyl radical optionally substituted by 1-3 radicals of the type: (a) -NR _3] R ₃₁ . (b) W-W alkoxycarbonyl or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1-3 radicals of amino, alkylamino, di- (CS ₄ alkyl) amino, N-C alkanoylamino, (C W alkoxycarbonylamino, CS ₄ alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, halo, C 1 -C 6 alkyl or trifluoromethyl, or (c) hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, or phenyl-C 1 -C alkoxy, phenyl-C-Calkylthio, heterocyclic, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 6 alkylamino, di- (C 1 -C 6 alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, hydroxy, C-C alkoxy, C-C alkylthio, cyano, halo, C-C alkyl or C-C haloalkyl of 1-3 halo radicals; (1) C 1 -C ₈ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl radical optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino , C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, N - ((C 1 -C ₄ alkoxy) carbonyl) N - ((C 1 -C ₄ alkyl) amino, aminocarbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, halo or aryl-C 1 -C ₄ alkoxy, aryl-C 1 -C ₄ -alkylthio, aryl-C] -C ₄ alkylsulfonyl, C ₃ -C ₈ cycloalkyl, heterocyclic, aryl or heteroaryl radicals optionally substituted by 1-3 amino C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) a mino, C 1 -C ₅ alkanoylamino, (C 1 -C 4 alkoxy ^ arbonylamino, C 1 -C ₄ alkylsulfonylamino, C 1 -C ₅ alkanoyl, hydroxy, 105 C _{[-C 4} alkoxy, C, -C ₄ alkylthio, C, -C ₄ alkylsulfinyl, C _t -C ₄ alkylsulfonyl, halo, C-C alkyl or C] _-C4 haloalkyl of 1-3 halo radicals; (1) a hydrogen atom; (1) bond (2) C 1 -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl radical optionally substituted by M (a) 1-3 amino, C-C ₄ alkylamino, di- ( C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio or halogen radicals and ( b) 1 -2 heterocyclic, aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (Cj-C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, halogen, C-C. alkyl or C-C. alkyl halides of 1-3 halogen radicals and; (1) when R ₃ and R ₁₂ are the same and represent a 5- or 6-membered ring containing 13 heteroatoms selected independently from N, S or O, to which the ring is optionally attached to a benzene nucleus, R _n is phenyl or naphthyl optionally substituted by halo, C 1 -C ₆ alkyl, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthiol, hydroxy, amino, C ₃ -C ₄ alkylamino, or dialkylamino; (1) a hydrogen atom; or (2) a C 1 -C ₄ alkyl radical optionally substituted by heterocyclic, aryl or heteroaryl 104 hunting radical, in turn substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C ₍ -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, C 1 -C ₄ alkyl or C 1 -C ₄ alkyl halides of 1-3 halogen radicals, and wherein the heterocyclic radical is monocyclic or bicyclic saturated a heterocyclic system consisting of 5 to 8 ring members, of which 1 to 3 are heteroatoms of oxygen, sulfur or N, which may be partially unsaturated or attached to a benzene nucleus and substituted and optionally with 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is a monocyclic or bicyclic aromatic 5-6 membered hetero-ring system involving 1-3 heteroatoms (O, S or N ) and which may be optionally attached with benzene or a saturated C ₃ -C ₄ carbocyclic attached radical, provided that: (1) a hydrogen atom; (1) C 1 -C ₄ alkyl, C ₂ -C ₄ alkenyl or C ₂ -C ₄ alkynyl radical optionally substituted by 1-3 radicals of the type -NR ₃₁ R ₃₁ , hydroxy, C ₁ -C ₄ alkoxy, C ] -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C _t -C ₄ alkylsulfonyl, cyano, halo or arilCj-C ^ alkoxy, aryl-C ^ C-alkylthio, aryl-C Tsalkilsulfonil, heterocyclic, aryl or heteroaryl with the possibility of inclusion of 1-3 radicals of amino, C ₍ -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C ₁ -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C ₁ -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, cyano, halo, C 1 -C ₄ alkyl or C 1 -C ₄ alkyl halides of 1-3 halogen radicals; (1) R ₃ o (2) halo and cyano radicals (3) -C (O) -R ₃₀ , -C (O) -OR ₂₉ , -C (O) -NR ₃ R ₃₂ or -C (NR ₃₁ ) -NR ₃₁ R ₃₂ radicals; (1) a hydrogen atom; (1) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl radical optionally substituted by 1-3 amino, C ₁ -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, N - ((C 1 -C ₄ alkoxy) carbonyl) -N - ((C 1 -C ₄ alkyl) amino, aminocarbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C-C alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfinyl, C 1 -C 6 alkylsulfonyl, halo or aryl C 1 -C 6 alkoxy, aryl-C 1 -alkylthio, aryl-C 1 -alkylsulfonyl, C-C cycloalkyl, heterocyclic, heterocyclic, radicals optionally substituted by 1-3 radicals of amino N-C alkylamino, di- _(C-C4 alkyl) amino, C-C and canoylamino, (C1-C4 alkoxy) carbonylamino, C1-C6 alkylsulfonylamino, C1-C6 alkanoyl, hydroxy, C1-C6 alkoxy, C1-C6 alkylthio, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, halo, C1-C6 alkyl or C1-C6 alkyl or -C1 alkyl halide of 1-3 halogen-containing substituents; (1) a hydrogen atom; (1) a hydrogen atom; (1) bond (2) a C 1 -C ₈ alkyl, C ₁ -C alkenyl or C ₂ -C _g alkynyl radical substituted by: (a) 1-3 amino, N-C alkylamino, di- _(C-C4 alkyl) amino, Cj-C ₅ alkanoylamino, (C-C alkoxy), C-C ₄ alkylsulfonylamino, hydroxy, C] -L alkoxy, C ₍ -C ₄ alkylthio or halogen radicals; and (b) 1-2 heterocyclic, aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C ₁ -C ₄ alkyl) ) amino, C 1 -C ₅ alkanoylamino, (C ₁ -C ₄ alkoxy) carbonylamino, C ₁ -C ₄ alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C ₍ -C ₄ alkylthio, halogen, C 1 -C alkyl or C 1 -C ₄ alkyl halides of 1-3 halogen radicals; 1-3 heteroatoms independently selected from N, S or O, to which ring is connected optionally a benzene nucleus, R _n is phenyl or naphthyl optionally substituted with halo, C _t -C ₆ alkyl, Cj-C alkoxy, C C ₁ -C ₄ alkylthiol, hydroxy, amino, C 1 -C 4 alkylamino, or dialkylamino; (1) when R, and R ₁₂ are the same and represent a 5- or 6-membered ring containing 102 (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclic radicals in each -Y-Y is from 0 to 3; and (2) the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclic radicals in R 1 and R ₂ is from 0 to 4; in case that: 1. Substituted pyrimidine Compounds with general formula * 2 ^R ll \ Ιί ^ Ν s' La * 12 NR _x or a pharmaceutically acceptable salt thereof, wherein R 1 and R ₂ are independently denoted by -Ζ-Y, provided that: 2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3 H) pyrimidinone or a pharmaceutically acceptable salt thereof. 2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (2-naphthyl) -4- (4-pyridyl) -pyrimidine, or 2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (benzothienyl) -4- (4-pyridyl) -pyrimidine, 2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (4-chlorophenyl) -4- (4-pyridyl) -pyrimidine, 2 - ((((S) -2-amino-3-phenylpropyl) -amino) 5- (3-isopropylphenyl) -4- (4-pyridyl) -pyrimidine, 2 - (((S) -2-amino-3-phenylpropyl) -amino) 5- (3-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2 - (((S) -2-amino-3-phenylpropyl) amino) 5- (3-chloro-4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2 - (((S) -2-N-glycylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine, 2 - (((S) -2-L1-glycylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2 - (((S) -2-1 \ [- butylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine, 2 - (((S) -2-N-isopropylamino-3-phenylpropyl) amino) -5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine, 2 - (((S) -2-] 4-cyclohexylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2 - (((S) -2-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2 - ((S) -3-benzylpiperazinyl) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2 - ((((28,28) -3-amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2 - ((3-hydroxy-3-phenylpropyl) -amino) -5 (3-methylphenyl) -4- (4-pyridyl) -pyrimidine, 2 - ((2-amino-2-methyl-3-phenylpropyl) amino) -5. (3-methylphenyl) -4- (4-pyridyl) -pyrimidine, 2 - ((3-amino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine, 2 - ((3-amino-3- (2-fluorophenyl) propyl (-amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2 - ((3-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2 - ((3-amino-3-phenylpropyl) -amino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2 - ((S) -2-B1,1,1-1-dimethylamino-3-phenylpropyl) -amino-5- (3-methylphenyl) -4- (4-pyridyl) pyrimidine, 2 - ((S) -2-amino-3-phenylpropyl) amino) -5 (3-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2 - ((S) -2-amino-3-phenylpropyl) amino) -4 (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine, 2- (2- (2-chlorophenyl) ethylamino) -5- (4 113 fluorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 2- (2- (2-chlorophenyl) ethyl-amino) -5- (4fluorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 2- (2,6-dichlorobenzyl) -5- (4-fluorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 2 - ((2 (S) -amino-3-phenylpropyl) -amino-5 (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (benzylamino) -5- (4-fluorophenyl) -4 (4-pyridyl) -pyrimidine, 2- (3-aminopropylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2-aminoethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2- (2,4-dichlorophenyl) ethyl-amino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2- (3-chlorophenyl) ethyl-amino) -5- (4fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2- (4-aminophenyl) ethyl-amino) -5- (4fluorophenyl-4- (4-pyridyl) -pyrimidine, 2- (2,6-dimethylphenylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2,6-dichlorobenzyl) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (4-aminobutylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2-diethylaminoethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, (2) a heterocyclyl radical; or (3) aryl or heteroaryl radicals optionally substituted 1-2 sites by amine, dimethylamines, hydroxyl, methoxy, methylthiol, halogen, methyl or trifluoromethyl radicals; R ₂₁ is an unsubstituted phenyl radical or a phenyl radical optionally substituted in 1-2 position by amine, dimethylamine, acetamide, hydroxyl 112 powerful, halogen, cyan, methoxy, methylthiol, methylsulfonyl, methyl or trifluoromethyl radicals; and R ₁₂ is a 4-pyridyl radical optionally substituted by amine, dimethylamine, acetamide, hydroxyl, halogen, cyan, methoxy, methyl or trifluoromethyl radicals; (2) a heterocyclyl radical; or (3) aryl or heteroaryl radicals optionally substituted in 1-2 positions by amine, dimethylamine, hydroxyl, methoxy, methylthiol, halogen, methyl or trifluoromethyl radicals; and in turn each R ₂₁ is a hydrogen radical or R ₁₀ . (2) -OR ,,, -SR ,,, -S (O) -R, _O , -S (O), - R, _O or -S (O) ₂ -NR ₅ R ₂₁ radical; or (3 ) -NR ₅ R ', -NR ₂₂ -C (O) -R' or -NR ₂₂ S (O), - R ₁₀ radical; each of R ₂₀ is (1) C 1 -C ₆ alkyl radicals optionally substituted at the 1-3 position with amine, methylamine, dimethylamine, t-butoxycarbonylamine, N ((t-butoxy) carbonyl) -L- (methyl ) amine, aminokarbonilaminov, hydroxy, butoxy, methoxy, butiltiolov, methylthio, methylsulfinyl, methylsulfonyl, halo or C ₅ -C ₆ cycloalkyl, heterocyclyl, phenyl radical or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy , methoxy, methylthiol, halogen, methyl or trifluoromethyl in radicals; (2) heterocyclyl radical optionally substituted by 1-2 hydroxyl or C, -C ₄ alkyl radicals; or (3) aryl or heteroaryl radicals optionally substituted at 1-2 by amine, dimethylamine, hydroxyl, methoxy, methylthiol, halogen, methyl or trifluoromethyl radicals; each R ₂₁ is independently a hydrogen radical or R ₂₀ ; each R ₂₂ is independently a hydrogen or methyl radical; R1 is an unsubstituted phenyl or naphthyl radical or phenyl radical optionally substituted on the 1-2 site by amine, dimethylamine, acetamide, hydroxyl, halogen, cyan, methoxy, methylthiol, methyl or trifluoromethyl radicals; and R, ₂ is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-pyrimidinyl radical optionally substituted on the 1-2 site by amine, dimethylamine, acetamide, hydroxyl, halogen, cyan, methoxy, methyl or trifluoromethyl radicals. (2) -C (O) -R ₂₀ radical; (2) heterocyclic radical optionally substituted at 1-2 sites by hydroxyl, C 1 -C ₄ alkoxyl, C 1 -C alkylthiol or C 1 -C ₄ alkyl radicals; or (3) aryl or heteroaryl radicals optionally substituted on 1-2 sites by (C 1 -C ₄ alkoxy) carbonyl, amine, C 1 -C ₄ alkylamines, di- (C 1 -C ₄ alkyl) amine, hydroxyl, C 1 -C ₄ alkoxyl, C 1 -C ₄ alkylthiols, cyan, halogen, azide, C 1 -C ₄ alkyl or trifluoromethyl radicals; each R ₂₁ is independently a hydrogen radical or R ₂₀ ; R ₂ is hydrogen, methyl, ethyl, fluoro, chloro, hydroxyl, methoxy, trifluoromethoxyl, amine, methylamine, dimethylamine, acetylamine or trifluoromethyl radical; R _n is an aryl radical optionally substituted at 1-2 position by amine, dimethylamine, acetamide, hydroxyl, halogen, cyan, methoxy, methylthiol, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and R ₁₂ is a heteroaryl radical optionally substituted at 1-2 position by amine, dimethylamine, acetamide, hydroxyl, halogen, cyan, methoxy, methyl or trifluoromethyl radicals; (2) halogen or cyan radicals; or (3) -C (O) -NR _3] R ₃₂ , -or ₂₉ , -SR 1, -NR 4, or -NR ₃₃ -C (O) -R ₂₉ radicals; provided that the total number of aryl, heteroaryl, cycloaryl and heterocyclyl radicals substituted at each R _u and R ₁₂ is 0-1; R ₃₀ independently means: (2) halogen or cyan radicals; or (3) -C (O) - ^ D ₂ , -OR 3, -SR ₂₉ , -SiOl-R 2, -S (O) ₂ -R ₃₀ , -SCO 4 -NRjjRj, -NRjjRj, or -NR ₃₃ C (O) -R, ₉ radicals; and R ₁₂ is a heteroaryl radical optionally substituted at 1-2 sites by the radicals of: (!) R ₃₀ ; (2) a C 1 -C ₄ alkyl radical or a C 1 -C ₂ alkyl radical substituted with a phenyl or heteroaryl radical optionally substituted at 1-3 position by amine, dimethylamine, acetamide, hydroxyl, methoxy, methyl or trifluoromethyl radicals; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 site with amine, dimethylamines, acetamides, hydroxyl, methoxy, methyl or trifluoromethyl radicals. (2) trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted at 1-3 position by amine, dimethylamine, acetamide, hydroxyl, halogen, methoxy, methyl or trifluoromethyl radicals; each R ₂₉ is independently a hydrogen radical or R ₃₀ ; each R ₃₁ is independently hydrogen, methyl or ethyl radicals; and each R ₃₂ independently means: (2) halogen or cyan radicals; or (3) -C (O) -CK ₃ D ₂ , -OR ₂₉ , -SR ₂₉ , -S (O) -R ₃₀ , -S (O) ₂ -R ₃₀ , -S (O) ₂ -R ₃₀ , -S (O) ₂ , -NR ₃₁ R ₃₂ or -NR ₂₂ C (O) -R ₂₉ radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocycloalkyl radicals substituted at each R _n and R ₁₂ is 0-1; each R ₃₀ is independently (1) a C 1 -C ₄ alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted at 1-3 position by amine, dimethylamine, acetoamide, hydroxylene, halogen, methoxy or trifluoromethyl radicals; (2) heterocyclyl radical optionally substituted by 1-2 radicals of amino, flH- (C _t -C ₄ alkyl) amino, (C] _-C4 alkoxy) carbonylamino, hydroxy, Cj-C ₄ alkoksilovov, W-C ^ alkylthio , C 1 -C ₄ alkyl; or (3) aryl or heteroaryl radicals optionally substituted 1-2 sites with amine, C 1 -C ₄ alkylamines, C 1 -C ₄ alkylamines, acetamides, (C ₃ -C ₄ alkoxy) carbonylamines, C ₁ -C ₄ alkylsulfonylamines, acetamides, (C ₃ -C ₄ alkoxy) carbonyl, hydroxyl, C 1 -C ₄ alkoxyl, C 1 -C ₄ alkylthiols, cyano, halogen, azide, C ₃ -C ₄ alkyl or trifluoromethyl radicals; each R ₂₁ is independently a hydrogen radical or R ₂₀ ; R ₂₁ is hydrogen, C 1 -C ₄ alkyl, halogen, hydroxyl, C 1 -C ₄ alkoxyl, trifluoromethyl, thiol, C 1 -C ₄ alkylthiol, amine, C 1 -C ₄ alkylamine, di- (C] -C ₄ alkyl) amines, C 1 -C ₅ alkanoylamines, (C 1 -C ₄ alkoxy) carbonylamines, C 1 -C ₄ alkylsulfonylamines or trifluoromethyl radicals; R _H is an aryl radical and R _{1 2} is a heteroaryl radical in which the aryl and heteroaryl radicals are optionally substituted at 1-2 with: (2) a C ₁ -C ₄ alkyl radical optionally substituted at 1-3 position by halogen radicals; or (3) _phenyl-C) -C ₂ alkyl or heteroarylC -C ₂ -alkyl radicals optionally substituted by 1-3, dimethylamine, hydroxyl, methoxy, methylthio, methyl or trifluoromethyl radicals; each R ₂₀ independently means: (2) -C (O) -R ₂₀ , radical; (2) C 1 -C ₄ alkyl or C ₂ -C ₅ alkenyl radicals optionally substituted (a) at 1-3 position by amine, di- (C 1 -C ₂ alkyl) amines, C 1 -C 8 alkanoyl amines, ( C 1 -C ₄ alkoxy) carbonylamine, hydroxyl, C 1 -C ₂ alkoxyl, C 1 -C ₂ alkylthiol or halogen radicals, and (c) at the 1-2 position with aryl or heteroaryl radicals optionally substituted at the 1-2 position by amine, di- (C 1 -C ₂ alkyl) amine, acetamide, (C 1 -C ₄ alkoxy) carbonylamine, hydroxyl, C 1 -C ₂ alkylthiol, halogen, C 1 -C ₄ alkyl or trifluoromethyl radicals; or (3) aryl or heteroaryl radicals optionally substituted at 1-3 position with amine, di- (C 1 -C ₂ alkyl) amine, acetamide, alkoxyl, acetamide, (C 1 -C ₄ alkoxy) carbonylamine, hydroxyl, C, - C ₂ alkoxyl, C 1, C ₂ alkylthiol, cyan, halogen, C 1 -C ₄ alkyl or trifluoromethyl radicals; Ye: (2) a C 1 -C ₄ alkyl radical or a C 1 -C ₂ alkyl radical substituted with a phenyl or heteroaryl radical optionally substituted at the 1-3 position with amine, di- (C 1 -C ₂ alkyl) amines, acetamides, hydroxyl, C 1 -C ₂ alkoxyl, C 1 -C ₄ alkyl or trifluoromethyl radicals; or (3) a phenyl or heteroaryl radical optionally substituted in 1-3 position by amine, di (C 1 -C ₂ alkyl) amine, acetamides, hydroxyl, C 1 -C ₂ alkyl, C 1 -C ₄ alkyl or trifluoromethyl radicals ; and wherein the heterocyclic radical is a monocyclic saturated heterocyclic ring system having 5-6 ring elements in which the 12 ring elements are oxygen, sulfur or nitrogen heteroatoms which is optionally benzene fused and optionally substituted at the 12th position by oxo- or thiooxadicals; the aryl radical is phenyl or naphthyl; and heteroaryl radical is a monocyclic aromatic heterocyclic ring system having 5-6 ring elements in which 1-2 ring elements are oxygen, sulfur or nitrogen heteroatoms which is optionally benzene fused. (2) trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted at the 1-3 position by amine, di- (C 1 -C ₂ alkyl) amine, acetamide, hydroxyl, C 1 -C ₂ alkoxy, halogen radicals, C 1 -C ₄ alkyl or trifluoromethyl radicals; each R ₂₉ is an independent hydrogen radical or R ₃₀ ; and each R ₃₂ independently means: (2) halogen or cyan radicals; (2) a C 1 -C 6 alkyl radical optionally substituted at 1-3 position by an amine, di- (C 1 -C 6 alkyl) amine, hydroxyl, C 1 -C alkosyl, C 1 -C alkylthiol or halogen radical; 108 or (3) phenyl-C 1 -C 4 alkyl, heteroaryl-C 1 -C ₂ alkyl, heterocyclyl-C 1 -C ₂ -alkyl, or C ₃ -C ₆ cycloalkyl-C 1 -C ₂ -alkyl radicals optionally substituted in 1-3 position with amine, di-C 1 -C 6 alkyl) amine, hydroxyl, C 1 -C ₂ alkoxyl, C 1 -C ₂ alkylthiol, methoxy, methylthiol, C 1 -C ₄ alkyl or trifluoromethyl radicals; each R ₂₂ is a hydrogen or C 1 -C ₄ alkyl radical; R 1 is an aryl radical and R _{1 2} is a heteroaryl radical, where the aryl and heteroaryl radicals are optionally substituted at 1-2 by the radicals of: (1Hz ₀ ; (2) C 1 -C 6 alkyl or C 1 -C alkenyl radicals optionally substituted (a) at 1-3 position with amine, di- (C 1 -C ₂ alkyl) amine, C 1 -Calkanoylamine, (C 1 -C alkoxy) carbonylamines, hydroxyl, C1-C6 alkoxyl, C1-C6 alkylthiol or halogen radicals, and (c) 1-2 sites with heterocyclyl, aryl or heteroaryl radicals optionally substituted with 1-3 amine, C1-C6 alkylamine, di- (C1- C ₂ alkyl) amino, N-C alkanailaminovi, W-W alkoxyl, C-C alkylthio, halogen, _C} -C ₂ alkyl or trifluoromethyl radicals; (2) C 1 -C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical, in turn substituted by 1-3 amino, C 1 -C alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C -C 3 alkoxycarbonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkyl or trifluoromethyl radicals, or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 amino, C 1 -C alkylamino, di- (C 1 -C ₄ alkyl) ) amino, C 1 -C alkanoylamino, (C 1 -C alkoxycarbonylamino, hydroxy, C 1 -C alkoxy or trifluoromethyl radicals; and each R ₃₃ is independently a hydrogen or methyl radical; and wherein the heterocyclic a radical is a monocyclic saturated heterocyclic system consisting of 5-6 ring members, of which 1-3 are heteroatoms (O, S or N), which is optionally attached to benzene and optionally substituted by 1-2 oxo- or thioxo-radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is a monocyclic or bicyclic aromatic 5-6 membered hetero ring system involving 1-3 heteroatoms (O, S or N) and which is optionally attached with benzene or saturated A C-C carbocyclic radical. (2) C1-C6 alkyl halides of 1-3 halogen-containing radicals; 2 radicals of the type: (PCO (2) halo and cyano radicals (3) -C (O) -C ₀ , -C (O) -OR ₂₉ , -C (O) -NR ₃₁ R ₃₂ or -C (NR ₃₁ ) -NR _{3 |} R ₃₂ paflHKanH; or (4) -OR _29, -SR _29, -S (O) -R _30, -S (O) ₂ -R _30, -S (O) ₂ -NR ₃₁ R _32, or - NR ₃₃ -C (O) -R ₂₉ radicals; in case of: the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of R,] and R _j2 is 0-1; each R ₃₀ independently means: (2) C 1 -C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 amino, di (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, halo, C 1 -C ₄ alkyl or C 1 -C haloalkyl of 1-3 halo radicals; wherein R ₂ is a hydrogen radical, C 1 -C ₄ alkyl, halo, hydroxy, C 1 -C alkoxy, C 1 -C haloalkoxy of 1-3 halo radicals, thiol, C 1 -C alkylthio, aminosulfonyl, C 1 -C aminosulfonyl, di- (C 1 -C ₄ alkyl) aminosulfonyl, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino (C 1 -C ₄ alkoxy) carbonyl amino, C 1 -C 4 alkylsulfonylamino or C 1 -C 4 alkyl halides of 1-3 halo radicals; wherein R 1 is an aryl radical and R ₁₂ is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1107 (2) heterocyclic radical optionally substituted by 1-2 amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -Calkoxy) carbonylamino, hydroxy, C 1 -C alkoxy , C1-C6 alkylthio or C1-C6 alkyl radicals; or (3) an aryl or heteroaryl radical optionally substituted by 1-Zamino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -Calkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino , (C 1 -C ₄ alkoxy) carbonyl, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or C 1 -C ₂ haloalkyl of 1-3 halo radicals; each R ₂₁ is independently a hydrogen radical or R ₂₀ ^ each R ₂₂ independently means: (2) C 1 -C ₄ alkyl, C ₂ -C ₅ alkenyl radical optionally substituted by 1-3 amino, di- (C 1 -C ₄ alkyl) amino, hydroxy, C 1 -C ₄ alkoxy, C- C1-6 alkylthio, -S (O) ₃ H or halogen radicals; or (3) _phenyl-C) -C ₂ -alkyl, heteroaryl-C-C ₂ alkyl, hetero-cyclic-C] -C ₄ -alkyl or C ₃ -C ₆ cycloalkyl-C-C ₄ -alkyl radicals, substituted optionally with 1-3 amino, di- (C 1 -C ₄ alkyl) amino, hydroxy, C 1 -C ₄ alkoxy, C ₍ -C ₄ alkylthio, C 1 -C ₄ alkyl or C 1 -C ₂ alkyl halogenidone 1- 3 halo radicals; where each R ₂₀ independently means: (2) a halogen radical; (2) a C 1 -C 8 alkyl radical optionally substituted by a C 1 -C cycloalkyl, aryl, heterocyclic or heteroaryl radical, in turn substituted by 1-3 amino, C 1 -C alkylamino, di- (C 1 -C 6 alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxycarbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, C 1 -C alkyl or C 1 -C alkyl halides of 1-3 halo radicals; or (3 ) A C 1 -C 10 cycloalkyl, aryl, heterocyclic or heteroaryl radical capable of including 1-3 amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxycarbonylamino, C 2 -C1 alkyl sulfonylamino, hydroxy, C-C alkoxy, C-C alkylthio, cyano, C-C alkyl or C-C haloalkyl of 1-3 halo radicals; and each Rj ₃ is independently hydrogen or C-C alkyl radical. (2) C1-C6 alkyl halides of 1-3 halogen radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxycarbonylamino, C 1 -C alkoxy, C1-C6 alkylthio, cyano, halo, C1-C6 alkyl or trifluoromethyl radicals; each R ₂₉ is independently a hydrogen atom or! where each R ₃₁ independently means: (2) heterocyclic radical optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C 4 alkoxycarbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy , C 1 -C 6 alkoxy, C 1 -C alkylthio, C 1 -C 4 alkyl or C 1 -C haloalkyl of 1-3 halo radicals, or (3) aryl or heteroaryl radical optionally substituted with 1-3 amino C- C 1-6 alkylamino, di- (C 1 -C 6 alkyl) amino, C 1 -C alkanoylamino, (C 1 -C) carbonylamino, C 1 -C 4 alkylsulfonylamino, (C 1 -C alkoxy) carbonyl, hydroxy, C 1 -C alkoxy, C 1 -C alkylthio, cyano, halo , azido, C 1 -C ₄ alkyl or C 1 -C ₄ hal ogenoal kil s of 1-3 halo radicals; wherein each R ₂₁ is independently a hydrogen atom or R ₂₀ : where each R ₃₀ independently means: (2) C 1 -C ₄ alkyl, C ₂ -C ₅ alkenyl or C ₂ -C ₅ alkynyl radical optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino , hydroxy, C ₃ -C ₄ alkoxy, C 1 -C ₄ alkylthio, -S (O) ₃ H or halogen radicals; or (3) aryl, heteroaryl, aryl-C 1 -C ₆ alkyl, heteroaryl-C ₁ -C ₄ -alkyl, heterocyclic, heterocyclic-C 1 -C ₄ -alkyl, C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ -cycloalkyl-C 1 -C ₄ alkyl radicals capable of including 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, hydroxy, C 1 -C ₄ alkoxy, C ₃ -C ₄ alkylthio, C 1 -C ₄ alkyllyl C 1 -C ₄ alkyl halide of 1-3 halo radicals; where each R ₂₀ independently means: A compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein: where each Z independently means: (2) when, R ₂ is H, R _n is phenyl and R ₁₂ is 4-pyridyl, R ₂ is other than -H, methyl or amino and (3) when R ₂ is H, R ₂ is 2-methylphenyl and R ¹² is 4-pyridyl, then Rj is different from n-propyl. (2) a C 1 -C ₄ alkyl radical optionally substituted by a C ₃ -C ₈ cycloalkyl, aryl, heterocyclic or heteroaryl radical, which in turn is substituted by 1-3 amino, C ₂ -C ₄ alkylamino, di- ( C ₁ -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, C _3- C ₄ alkyl or C 1 -C ₄ alkyl halides of 1-3 halogen radicals; or (3) C ₃ -C ₈ cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C _t -C ₄ alkylamino, di-C] _-C4 alkyl) amino, C ₃ -C ₅ alkanoyl amino, (C] _-C4 alkoxy) carbonylamino, C _t -C ₄ alkylsulfonylamino, hydroxy, Cj-C ₄ alkoxy, C ₁ -C ₄ alkylthio, cyano, Cj-C ₄ alkyl or C, -C ₄ haloalkyl of 1-3 halo radicals; and where each R ₃₃ independently means: (2) heterocyclic radical optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di-C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, C 1 -C 6 alkyl or C 1 -C 4 alkyl halides of 1-3 halo radicals; or (3) aryl or heteroaryl radicals substituted with 1-3 amino, C 1 -C ₅ , alkylamino, di (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C , -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C 1 -C ₄ alkyl or C 1 -C ₄ alkyl halides of 1-3 halo radicals; wherein each R ₂₉ independently represents a hydrogen radical or R ₃₀ each R ₃₁ and R ₃₂ independently mean: (2) C 1 -C ₄ alkyl radical optionally substituted by heterocyclic, aryl heteroaryl radical optionally substituted by 1-3 amino, C ₁ -C ₄ alkylamino, di-C 1 -C 4 alkyl) amino, C 1 -C ₅ alkanoylamino, (C ₂ -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkylsulfinyl, C 1 -C ₄ alkylsulfonyl, cyano , halo, C _t -C ₄ alkyl or Cj-C ^ haloalkyl of 1-3 halo-radicals; (2) heterocyclic radical optionally substituted by 1-3 amino, C 1 -C 4 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, C 1 -C alkylsulfonylamino, hydroxy , C-C alkoxy, C-C alkylthio, C-C alkyl or _C-C4 haloalkyl of 1-3 halogenosadarzhashti radicals; or (3) an aryl or heteroaryl radical, for 103 optionally substituted with 1-3 amino C 1 -C ₄ alkylamino, 1 H- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, (C ₁ -C ₄ alkoxy) carbonyl, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, azido, C 1 -C ₄ alkyl or C ₍ -C ₄ haloalkyl of 1-3 halogen-containing radicals; wherein each R ₂₁ independently represents a hydrogen radical or R ₂₀ : where each R ₂₂ independently means: (2) Cj-C _g alkyl, C ₂ -C ₈ alkenyl or C ₂ -C ₈ alkynyl radical optionally substituted by 1-3 radicals of amino, Cj-C ₄ alkylamino, di- (C Tsalkil) amino, hydroxy, C1-C6 alkoxy, C1-C4 alkylthio, -S (O) ₃ H or halogenated; or (3) aryl, heteroaryl, aryl-C 1 -C ₄ alkyl, heteroaryl-C 1 -C 6 alkyl, heterocyclyl-C 1 -C ₆ alkyl, C ₃ -C ₈ cycloalkyl or C ₃ -C ₈ cycloalkyl-C 1 -C ^ alkyl radicals possible for eligibility of 1-3 amino, C ^ C alkylamino, di- (C ₁ -C ₄ alkyl) amino, hydroxy, C-C alkoxy, C-C alkylthio, C-C alkyl or C-C haloalkyl of 1-3 halogen-containing substituents; where each R 2 independently represents: (2) a halogen or nitro radical; (2) when, R 1 is H, R _n is phenyl and R ₁₂ is 4-pyridyl, R ₂ is other than -H, methyl or amino and (3) when R ₂ is H, R _n is 2-methylphenyl and R _{] 2} is 4-pyridyl, then R1 is different from n-propyl each Z independently means: (3) -OR 3, -SR 1, -S (O) -R, _O , -S (O), - R ₂₀ or -S (O) ₂ -NR ₅ R ₂ , radicals; or (4) NR ₅ R _2] , -NR 4 -CCOFR 3, -NR ₂₂ -S (O) ₂ -R ₂₀ radical; R ₅ is a hydrogen radical; each R, _o independently means: (3) -OR ,,, -SR ,,, -S (O) -R, _O , -S (O) ₂ -R ₂₀ , or 109 -S (O) ₂ -NR ₅ R ₂₁ radicals; or (4) NR ₅ R ₂₁ , -NR ₂₂ -C (O) -R ₂₁ , -NR ₂₂ -C (O) r ₂₀ , -NR ₂₂ -C (O) -NR ₅ R ₂₁ , -nr ₂₂ - s (O) ₂ -r ₂₀ , -nr ₂₂ S (O) ₂ -NR ₅ R ₂₁ radical; each R ₅ independently means: (3) -C (O) -R ₃₀ , -C (O) -OR ₂₉ , -C (O) NR ₃₁ R ₃₂ , or -C (NR ₃₁ ) -NR _{3 [} R ₃₂ radicals; or (4) -OR ₂₉ , -SR ₂₉ , -S (O) -R ₃₀ , -S (O) ₂ -R ₃₀ , -S (O) ₂ -NR ₃₁ R ₃₂ , -NR ₃₁ R _32, or - NR ₃₃ -C (O) -R ₂₉ radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclic radicals substituted at each R 1 and R ₁₂ is 0-1; each R ₃₀ independently means: (3) heterocyclyl radical optionally substituted (c) in 1-2 position with amine, di- (C 1 -C ₂ alkyl) amine, (C 1 -C alkoxy) carbonylamines, hydroxylene, C 1 -C alkoxyl, C 1 -C 6 alkylthiol or C- C1-4 alkyl radicals; or (4) an aryl or heteroaryl radical optionally substituted in 1-3 position by amine, di- (C 1 -C ₂ alkyl) amine, C 1 -C alkanoylamines, (C 1 -C alkoxy) carbonylamines, hydroxyl, C 1 -C alkoxyl, C1-C6 alkylthiol, cyanogen halogen C1-C4 alkylthiol or trifluoromethyl radicals; each R ₅ independently means: (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, C 1 -C 6 alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C 3 alkoxycarbonylamino, hydroxy, C 1 -C alkoxy C1-C6 alkylthio, cyano, halo, C1-C6 alkyl or trifluoromethyl radicals; wherein each R ₂₉ is independently a hydrogen radical or R ₃₀ ; wherein R1 is independently a hydrogen or C1-C6 alkyl radical; and where R ₃₂ independently means: (3) -C (O) R ₂₀ hhh -CCNRjj-NRjRj] radical; (3) heterocyclic radical optionally substituted by 1-2 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, (C 1 -C ₄ alkoxy) carbonylamino, hydroxy, C] -C ₄ alkoxy, C1-C4 alkylthio or C1-C6 alkyl substituents; or (4) aryl or heteroaryl radicals optionally substituted is 1-3 amino, C ₁ -C ₄ alkylamino, di- (C ₁ -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halogeno, C 1 -C ₄ alkyl or C 1 -C ₄ alkyl halides of 1-3 halogen radicals; Ye: The compound of claim 2 or the pharmaceutically acceptable salt thereof, wherein R ₁ is denoted by -Ζ-Y, provided that: (3) heterocyclic radical optionally substituted by 1-2 amino, C 1 -C ₄ alkylamino, di-C 1 -C 4 alkyl) amino, C 1 -C ₅ alkanoylamino, (C ₃ -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, C 1 -C ₄ alkyl or C 1 -C ₄ alkyl halide of 1-3 halogen radicals; or (4) aryl or heteroaryl radicals optionally substituted by 1-3 amino, C ₃ -C ₄ alkylamino, flH- (C 1 -C ₄ anKHn) aMHHO, C ₃ -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halogen, C 1 -C ₄ alkyl or C 1 -C ₄ alkyl halides of 1-3 halogen radicals; where each R ₅ independently means: (3) heterocyclic, aryl or heteroaryl radical optionally substituted by 1-3 amino, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C ₃ -C ₄ alkoxy) carbonylamino, C (-C ₄ alkylsulfonylamino, hydroxy, C _t -C ₄ alkoxy, C, -C ₄ alkylthio, C, -C ₄ alkylsulfinyl, C] _-C4 alkylsulfonyl, cyano, halo, C, -C alkyl or C1-C6 alkyl halides of 1-3 halogen radicals; in the case where Z is a bond and Y is -NR ₂₂ -C (O) -NR ₂ R ₂₂ is other than a substituted aryl radical; each R _u is an aryl radical and R ₁₂ is a heteroaryl radical, where the aryl and heteroaryl radicals are substituted by 1-2 radicals: (3) -C (O) R ₂₀ hhh -C (NR _s ) -NR ₅ R ₂₁ radical; (3) heterocyclic radical optionally substituted by 1-3 amino radicals, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C alkanoylamino, (C 1 -C alkoxy) carbonylamino, C -C 1-4 alkylsulfonylamino, hydroxy, C 1 -C 6 alkoxy, C 1 -C 6 alkylthio, halogen, C ₁ -C ₄ alkyl or C ₁ -C ₄ alkyl halide of 1-3 halogen radicals; or (4) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, C 1 -C ₄ alkylamino, di- (C 1 -C ₄ alkyl) amino, C 1 -C ₅ alkanoylamino, (C 1 -C ₄ alkoxy) carbonylamino, C 1 -C ₄ alkylsulfonylamino, hydroxy, C 1 -C ₄ alkoxy, C 1 -C ₄ alkylthio, cyano, halo, C 1 -C 4 alkyl or C 1 -C ₄ alkyl halides of 1-3 halogen radicals; where each Y is independently: 4- (4-pyridyl) -2-2 (((S) -tetrahydroisoquinol-3-ylmethylene) amino) -5- (3-trifluoromethylphenyl) -pyrimidine, The compound of claim 3 or the pharmaceutically acceptable salt thereof, wherein: Ze: (4) -OR _2] , -OC (O) R ₂₁ , -OC (O) -NR ₅ R ₂₁ radical; (4) -OR ₂₉ , -SR ₂₉ , -S (O) -R ₃₀ , -S (O) ₂ -R ₃₀ , S (O) ₂ -NR ₃₁ R ₃₂ , -NR ₃₁ R ₃₂ , or -NR ₃₃ -C (O) -R ₂₉ radicals; if the total number of aryl, heteroaryl, cycloalkyl and heterocyclic radicals at each of R _H and R ₁₂ is 0-1; where each R ₃₀ independently means: (4) -OR ₂₁ -OC (O) R ₂₁ , -OC (O) -NR ₅ R _{21 or} O-C (O) -NR ₂₂ -S (O) ₂ -R ₂₀ radical; 5- (3-acetamidophenyl) -2 - (((S) -2-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2 - ((3-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) pyrimidine, 5- (4-fluorophenyl) -2 - (((S) -2-T4-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine, 5- (3-methylphenyl) -4- (4-pyridyl) -2 - ((((3) tetrahydroisoquinol-3-ylmethylene) amino) -pyrimidine, 5- (4-fluorophenyl) -2 - ((1-methyl-3-phenylpropyl) -amino) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-fluorophenyl) -2 - ((3-phenylpropyl) amino) -6- (4-pyridyl) -4-hydroxyl-pyrimidine, 5- (4-fluorophenyl) -2- (3-phenylethyl) thio6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-fluorophenyl) -2- (2-phenylethyl) thio6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-fluorophenyl) -2- (1-piperazinyl) -4 (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine, 5- (4-fluorophenyl) -2 - ((3-imidazolylpropyl) -amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2-phenylaminoethylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2 - ((3-phenylpropyl) amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2- (4-hydroxylphenyl) ethylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2- (2- (2- (4-hydroxyphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2-2 (2-hydroxy-2-phenyl-ethyl) amino-4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (N-methyl-L- (2-phenylethyl) -amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2-phenylethylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2-phenylaminoethyl) thio-6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-fluorophenyl) -2- (2-phenoxyethyl) thio-6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-fluorophenyl) -2- (3- (2-pyrrolidin-1-yl) propyl-amine) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2-piperidinoethylamino) -4 - (- pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2-morpholinoethylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -4- (4-pyridyl) -2- (2-pyrrolidinoethylamino) -pyrimidine, 5- (4-fluorophenyl) -2-morpholino-4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2 - ((4-phenyl-butyl) amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2 - ((1-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2- (3-methoxyphenyl) ethyl-amino) -4- (4-pyridine) -pyrimidine, 5- (4-fluorophenyl) -2- (2- (2-methoxyphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2-phenylthiomethyl-4- (4-pyridinyl) -pyrimidine, 5- (4-fluorophenyl) -2- (4fluorophenylamino) -4- (4pyridyl) -pyridine 5- (4-fluorophenyl) -2- (2-methoxyphenylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -4- (4-pyridyl) -2- (2-thienyl) -pyrimidine, 5- (4-fluorophenyl) -2- (2-methylthiazol-4yl) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (4-pyridyl) -4- (4-pyridyl) -pyrimidine, The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein R _t is -ZY, provided that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R is 0-2; Ze: (5) -SR ₂₁ , -S (O) -R ₂₀ , -S (O) ₂ -NR ₂₀ or -S (O) ₂ -NR ₅ R ₂₁ ; or (6) NR ₅ R ₂₁ , -NR 4 -CCCO-R 1, -NR ₂₂ -C (O) -R ₂₀ , -NR ₂₂ -C (O) -NR _with R ₂₁ , -NR ₂₂ -C (NR ₅ ) -NR ₅ R _2I , -nr ₂₂ S (O) ₂ -R ₂₀ hhh -NR ₂₂ -S (O) ₂ NR ₅ R ₂₁ radical; where each R ₅ independently means: (5) -SR ₂₁ , -S (O) -R ₂₀ , -S (O) ₂ -NR ₂₀ , -S (O) ₂ NR _with R ₂₁ , -SCO ^ -NR ^ -CCCO-R ^, - S (O) ₂ -NR ₂₂ -C (O) - R ₂₀ hhh S (O) ₂ -NR ₂₂ -C (O) -NR ₅ R ₂₁ radical; or (6) NR ₅ R ₂₁ , -NR ₂₂ -C (O) -R ₂₁ , -NR ₂₂ -C (O) r ₂₀ , -NR ₂₂ -C (O) -NR ₅ R _2i , -NR ₂₂ - C (NR ₅ ) -NR ₅ R _2] , NR ₂₂ -S (O) ₂ -R ₂₀ or -NR ₂₂ -S (O) ₂ NR _{with a} R ₂₁ radical; where each R ₅ independently means: The compound of claim 5, or a pharmaceutically acceptable salt thereof, wherein 110 R _n is an aryl radical optionally substituted at 1-2 positions by (1) R ₃₀ radicals; A compound according to claim 6, or a pharmaceutically acceptable salt thereof, wherein R 1 is -Ζ-Y, provided that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R is 0-1; Ze: The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein Ze: A compound according to claim 8, or a pharmaceutically acceptable salt thereof, wherein Ye: A compound according to claim 9, or a pharmaceutically acceptable salt thereof, wherein Y is -OR ₂₁ , -SR ₂₁ or -NR ₅ R ₂₁ radical; each R ₂₀ independently means: The compound of claim 1, which is: A pharmaceutical composition comprising a compound of any one of claims 1 to 11 and a pharmaceutically acceptable carrier. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for the prevention or treatment of inflammation. 14. Use of effective amount 114 of the pharmaceutical composition of claim 12 for the preparation of a medicament for the prevention or treatment of inflammation. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for the prevention or treatment of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis (inflammation of the iris pigmentation layer), acute or chronic myelogenous leukemia, pancreatic beta-cell destruction, osteoarthritis, rheumatoid spondylitis, gouty arthritis, bowel inflammation, adult respiratory failure syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, purulent colitis ilexia, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, diabetes mellitus, diabetes mellitus, bone resorptive diseases, graft response, Alzheimer's disease, stroke, myocardial infarction, ischemic reperfusion, ischemic reperfusion, brain injury, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgia due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, viral herpes or herpes zoster, infection in a mammal. Use of an effective amount of the pharmaceutical composition of claim 12 for the preparation of a medicament for the prevention or treatment of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis (inflammation of the pigment layer of the iris), acute or chronic myelogenous, pancreatic beta cells, osteoarthritis, rheumatoid spondylitis, grafting reaction, gouty arthritis, bowel inflammation, adult respiratory failure syndrome (ARDS), psoriasis, Crohn's disease, allergic p nits, purulent colitis, anaphylaxis, contact dermatitis, asthma, muscular degeneration, cachexia, Reiter's syndrome, diabetes mellitus, diabetes mellitus, bone resorption, bone grafting, Alzheimer's disease, stroke, myocardial infarction ischemic reperfusion injury, atherosclerosis, brain injury, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgia due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), cytomegalovirus (CMV) adenovirus, viral herpes or shingles, infection in a mammal. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for reducing plasma concentrations of each or both of THF-alpha and IL-1. Use of an effective amount of the pharmaceutical composition of claim 12 for the preparation of a medicament for reducing plasma concentrations of each or both of THF-alpha and IL-1. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for lowering the plasma concentrations of each or both of IL-6 and IL-8. The use of an effective amount of the pharmaceutical composition of claim 12 for the preparation of a medicament for lowering the plasma concentrations of each or both of IL6 and IL-8. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for producing a glucagon antagonist effect in the prophylaxis or treatment of a mammalian diabetes mellitus. Use of an effective amount of the pharmaceutical composition of claim 12 for the preparation of a medicament for producing a glucagon antagonist effect in the prevention or treatment of a mammalian diabetes mellitus. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for the prevention or treatment of a disease disorder in a mammal. 24. Use of effective amount 115 of the pharmaceutical composition of claim 12 for the preparation of a medicament for the prophylaxis or treatment of a disease disorder in a mammal. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for reducing the secretion of prostaglandins in a mammal. The use of an effective amount of the pharmaceutical composition of claim 12 for the preparation of a medicament for reducing the secretion of prostaglandins in a mammal. Use of an effective amount of the compound of any one of claims 1 to 11 for the preparation of a medicament for reducing cyclosignase enzyme activity in a mammal. The use according to claim 27, wherein the cyclosignase enzyme is COX-2. The use of an effective amount of the pharmaceutical composition of claim 12 for the preparation of a medicament for reducing the cyclosignase enzyme activity in a mammal. The use according to claim 29, wherein the cyclosignase enzyme is COX-2.