MXPA99005168A - Substituted pyrimidine compounds and their use - Google Patents

Abstract

Selected novel substituted pyrimidine compounds are effective for prophylaxis and treatment of diseases, such as TNF-&agr;, IL-1&bgr;, IL-6 and/or IL-8 mediated diseases, and other maladies, such as pain and diabetes. The invention encompasses novel compounds, analogs, prodrugs and pharmaceutically acceptable salts thereof, pharmaceutical compositions and methods for prophylaxis and treatment of diseases and other maladies or conditions involving inflammation, pain, diabetes and the like. The subject invention also relates to processes for making such compounds as well as to intermediates useful in such processes.

Description

SUBSTITUTE PIRIMIDINE COMPOUNDS AND THEIR USE BACKGROUND OF THE INVENTION This is a non-provisional application, derived from US Provisional Application Serial No. 60 / 032,128 filed December 5, 1996, US Provisional Application Serial No. 60 / 050,950 filed June 13, 1997. and the non-provisional, North American patent application, serial number not yet assigned, filed on November 21, 1997, each of which is incorporated herein. or reference in its entirety. The present invention comprises a new class of compounds useful in the treatment of diseases, such as diseases mediated by TNF-α, IL-1β, IL-6 and / or IL-8 and other diseases, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions that involve inflammation. This invention also relates to intermediates and methods useful in the preparation of such compounds. Interleukin-1 (IL-1) and Tumor Necrosis Factor a (TNF-a) are pro-inflammatory cytokines, secreted by a variety of cells, REF: 03042.4 including monocytes and macrophages, in response to many inflammatory stimuli ( for example, lipopolysaccharide-LPS) or external cellular tension (for example, osmotic shock and peroxide). Elevated levels of TNF-a and / or IL-1 over basic levels have been implicated in the mediation or exacerbation of a number of disease states including rheumatoid arthritis; Paget's disease; osteoporosis; multiple myeloma; uveitis; acute and chronic myelogenous leukemia; destruction of pancreatic ß cells; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress 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 diseases; graft versus host reaction; reperfusion injury of ischemia; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes virus (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-a. It has been reported that TNF-a plays a role in head trauma, stroke and ischemia. For example, in models of trauma animals in the head (rat), TNF-a levels increased in the bruised hemisphere (Shoha i et al, J. Cereb. Bl ood Fl ow Me tab., 14, 615 (1994)) . In a rat model of ischemia in which the middle cerebral artery was occluded, TNF-a mRNA levels of TNF-α increased (Feurstein et al., Neurosci, Le t 164, 125 (1993)). The administration of TNF-a in rat cortex has been reported to result in significant accumulation of neutrophils in capillaries and adherence in small blood vessels. TNF-a promotes the infiltration of other cytokines (IL-lß, IL-6) and also chemokines, which promote the infiltration of neutrophils in the infarct area (Feurstein, Stroke 25, 1481 (1994)). TNF-α has also been implicated as playing a role in type II diabetes (Endocrinol 130, 43-52, 1994 and Endocrinol 136, 1474-1481, 1995). TNF-a seems to play a role in promoting certain viral life cycles and disease states associated with them. For example, TNF-α secreted by monocytes induced high levels of HIV expression in a chronically infected T cell clone (Clouse et al, J. Immunol., 142, 431 (1989)). Lahdevirta et al., (Am. J. Med. 85, 289 (1988)) discussed the role of TNF-a in the HIV-associated conditions of cachexia and muscle degradation. TNF-a is upstream in the inflammation cytokine cascade. As a result, elevated levels of TNF-α can lead to elevated levels of other inflammatory and proinflammatory cytokines, such as IL-1, IL-6, and IL-8. Elevated levels of IL-1 over basic levels have been implicated in the mediation or exacerbation of a number of disease states including rheumatoid arthritis; Osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress syndrome (ARDS); psoriasis; Crohn's disease; Ulcerative colitis; anaphylaxis; muscle degeneration; cachexia; Reiter's syndrome; type I and type II diabetes; bone resorption diseases; reperfusion injury of ischemia; atherosclerosis; trauma in the brain; Multiple sclerosis: sepsis; septic shock; toxic shock syndrome. Viruses sensitive to TNF-α inhibition, eg, HIV-1, HIV-2, HIV-3, are also affected by IL-1. TNF-a and IL-1 appear to play a role in the destruction of pancreatic β cells and diabetes. Pancreatic β cells produce insulin which helps mediate the homeostasis of blood glucose. Deterioration of pancreatic β cells frequently accompanies type I diabetes. Functional abnormalities of pancreatic β cells may occur in patients with type II diabetes. Type II diabetes is characterized by functional resistance to insulin. In addition, type II diabetes is also frequently accompanied by elevated levels of glucagon in the plasma and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates the inhibition of gluconeogenesis in the liver by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue. In this manner, glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated herein by reference in its entirety). By antagonizing glucagon receptors, it is believed that insulin sensitivity in the liver will improve, thereby decreasing gluconeogenesis and decreasing the rate of hepatic glucose production. In rheumatoid arthritis models in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Cli ni cal Immunol Immunopa th 55, 382 (1990)). In studies using synovial, rheumatoid, cultured cells, IL-1 is a more potent inducer of stromelysin than THF-a (Firestein, Am. J. Pa th ol., 140, 1309 (1992)). At sites of local injection, the migration of neutrophils, lymphocytes and monocytes has been observed. Emigration is attributed to the induction of chemokines (for example, IL-8), and the up-regulation of adhesion molecules (Dinarello, Eur. Cyt oki ne Ne t w, 5, 517-531 (1994)). It also seems that IL-1 plays a role in the promotion of certain viral life cycles. For example, the cytokine-induced increase of HIV expression in a line of chronically infected macrophages has been associated with a concomitant and selective increase in the production of IL-1 (Folks et al., J. Im unol. 40 (1986)). Beutler et al. (J. Immunol., 135, 3969 (1985)) discussed the role of IL-1 in cachexia. Baracos et al. (New Eng. J. Med. 308 553 (1983)) discussed the role of IL-1 in muscle degeneration. In rheumatoid arthritis, both IL-1 and TNF-a induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic junctions. In an arthritis model (collagen-induced arthritis (CIA) in rats and mice), intra-articular administration of TNF-a either before or after the induction of CIA led to the accelerated onset of arthritis and one more course of the disease (Brahn et al., Lymph oci ne Cyt oci ne Res. 11, 253 (1992) and Cooper, Cl in. Exp. Immunol., 898, 244 (1992)). IL-8 has been implicated in the exacerbation and / or the cause of many disease states in which massive infiltration of neutrophils at sites of inflammation or injury (eg, ischemia) is mediated by the chemotactic nature of the IL- 8, which includes, but is not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal reperfusion injury, thrombosis and glomerulonephritis. In addition to the chemotaxis effect in neutrophils, IL-8 also has the ability to activate neutrophils. In this way, the reduction in the levels of IL-8 can lead to decreased infiltration of neutrophils. Various approaches have been taken to block the effect of TNF-a. One approach involves using soluble receptors for TNF-α (for example TNFR-55 or TNFR-75), which have demonstrated efficiency in animal models of disease states mediated by TNF-α. A second approach to neutralize TNF-a using a monoclonal antibody specific for TNF-α, cA2, has shown an improvement in a swollen junction count in a Phase II human trial of rheumatoid arthritis (Feldmann et al., Immunol ogi cal Revi ews, pp. 195-223 (1995)). These approaches block the effects of TNF-a and IL-1 through either protein removal or receptor antagonism. Bennett et al (J. Med. Ch., 21, 623 (1978)) synthesized a number of pyrimidines of the form: where, Inter to the a, Ra: is 2-, 3- or 4-pyridyl, Rx is H, methyl or phenyl, and Ra3 is H, amino. They reported that none of these compounds tested against rat adjuvant-induced edema exhibited a sufficient level of activity to ensure further investigation and that additional testing confirmed that the compounds accounted for a series of false positives in the carrageenan-induced edema model. Ife et al. (Bioorg, Med. Chem. Lett. , 543 (1995)) reported that another pyrimidine (Rax = 2-methylphenyl, Ra2 = 2-pyridyl and Ra3 = n-propyl, where Ra1, Ra2 and Ra3 are as in structure i, supra) had inhibitory activity of H + / K + -ATPase several times lower than the related 4- (2-pyridyl) -5-phenylthiazole compounds. WO 97/33883 discloses substituted pyrimidine compounds useful in the treatment of cytokine mediated diseases.

BRIEF DESCRIPTION OF THE INVENTION The present invention comprises a new class of compounds useful in the prophylaxis and treatment of diseases, such as diseases mediated by TNF-a, IL-lß, IL-6 and / or IL-8 and other ills , such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions that involve inflammation. Accordingly, the invention also comprises pharmaceutical compositions comprising the compounds, methods for the prophylaxis and treatment of diseases mediated by TNF-α, IL-1β, IL-6 and / or IL-8, such as inflammatory diseases, pain and diabetes, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention. The compounds of the invention are represented by the following general structure: wherein R1, R2, R11 and R are as defined below. The foregoing only summarizes certain aspects of the invention and is not proposed, nor should be constructed, as limiting the invention in any way. All patents and other publications cited herein by this act are incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, compounds of the formula: R2 are provided RIJ RI (I) or a pharmaceutically acceptable salt thereof, wherein R: and R2 are each independently -Z-Y, with the proviso that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of -Z-Y is 0-3; preferably 0-2; more preferably 0-1; and (2) the total, combined number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 and R2 is 0-4; preferably 0-3; more preferably 0-2; much more preferably 0-1; Preferably, R 2 is a radical of hydrogen, alkyl of 1 to 4 carbon atoms, halo, hydroxy, alkoxy of 1 to 4 carbon atoms, haloalkoxy of 1 to 2 carbon atoms of 1-3 halo radicals, thiol , alkylthio of 1 to 4 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 carbon atoms) aminosulfonyl, amino, alkylamino of 1 to 4 carbon atoms, di- ( alkyl of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; more preferably R2 is a radical of hydrogen, alkyl of 1 to 4 carbon atoms, halo, hydroxy, alkoxy of 1 to 4 carbon atoms, trifluoromethoxy, thiol, alkylthio of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 carbon atoms), di- (alkyl of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms carbon or trifluoromethyl; more preferably, R 2 is a radical of hydrogen, methyl, ethyl, fluoro, chloro, hydroxy, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, acetylamino or trifluoromethyl; and more preferably, R2 is a hydrogen or hydroxy radical; wherein each Z is independently (1) a bond (2) an alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio radicals or halo, and (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl radicals; (3) a heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl radicals; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl radicals; preferably, each Z is independently (1) a bond; (2) an alkyl radical of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms , di- (C 1 -C 4 alkyl) amino, C 1-5 alkoxylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halo and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkoxylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (3) a heterocyclyl radical optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1-4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 4 carbon atoms of 1 to 3 halo radicals; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms of carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each Z is independently (1) a link; (2) an alkyl radical of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms , di- (C 1 -C 4 alkyl) amino, C 1-5 alkoxylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halo and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkoxylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (3) a heterocyclyl radical optionally substituted by 1-2 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1-4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 4 carbon atoms of 1-3 halo radicals; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms of carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each Z is independently (1) a bond; (2) an alkyl radical of 1 to 8 carbon atoms or alkenyl of 2 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halo and (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 2 carbon atoms of 1-3 halo radicals; (3) a heteroaryl radical optionally substituted by 1-2 amino radicals, di (alkyl-1 to 4 carbon atoms) amino, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; more preferably, each Z is independently (1) a link; (2) an alkyl radical of 1 to 4 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino, alkanoylamino 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or halo and (b) 1-2 radicals of heterocyclyl , aryl or heteroaryl optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 2 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (3) a heterocyclyl radical optionally substituted by 1-2 amino, di (alkyl-1 to 2 carbon atoms) amino, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy radicals from 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or alkyl radicals of 1 to 4 carbon atoms; or (4) aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, di- (alkyl- of 1 to 2 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 atoms) carbon) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each Z is independently (1) a link; (2) an alkyl radical of 1 to 4 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino, (alkoxy) from 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or halo and (b) 1-2 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, di- (alkyl-1 to 4 carbon atoms) amino, acetamido, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms carbon, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; or (3) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino, acetamido, (1-alkoxy) 4 carbon atoms) carbonylamino, hydroxy, alkoxy 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each Z is independently (1) a link; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-2 amino radicals, di (alkyl-1 to 2 carbon atoms) amino, (C 1 -C 4 alkoxy) carbonylamino , hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, halo or aryl or heteroaryl optionally substituted by 1-2 hydroxy radicals, alkoxy of 1 to 2 carbon atoms, alkylthio having 1 to 2 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; Y much more preferably, each Z is independently (1) a bond; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-2 amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio radicals or halo radicals; each Y is independently (1) a hydrogen radical; (2) a halo or nitro radical; (3) a radical of -C (O) -R20 or -C (NR5) -NR5R2?; (4) radical -OR2 ?, -0-C (0) -R21, -O-C (O) -NR5R2? or -0-C (0) -NR22-S (0) 2-R20; (5) a radical of -SR2 ?, -S (O) -R20, -S (O) 2 -R20, -S (0) 2 -NR5R2 ?, -S (0) 2 -NR22-C (0) -R21, -S (O) 2-NR22-C (O) -OR20 or -S (0) 2-NR22-C (0) -NR5R21; or (6) a radical of -NR5R2 ?, -NR22-C (0) -R2 ?, -NR22-C (0) -OR20, -NR22-C (0) -NR5R21, -NR22-C (NR5) - NR5R2? -NR22-S (O) 2-R20 or -NR22-S (0) 2-NR5R2 ?; preferably, each Y is independently (1) a hydrogen radical; (2) a halo radical; (3) a radical of -C (O) -R20 or -C (NR5) -NR5R21; (4) a radical of -0R2i, -0-C (0) -R2 ?, or -O-C (0) -NR5R2?; (5) a radical of -SR2 ?, -S (0) -R20, -S (O) 2 -R20, or (6) a radical of -NR5R21, -NR22-C (0) -R2 ?, -NR22 -C (0) -OR20, -NR22-C (0) -NR5R2 ?, -NR22-C (NR5) -NR5R21, -NR22-S (0) 2 -R20 or -NR22-S (0) 2-NR5R21; in more preferred form, each Y is independently (1) a hydrogen radical; (2) a radical of -C (0) -R20; (3) a radical of -0R21, -SR2 ?, -S (0) -R20, -S (O) 2 -R20 or -S (0) 2 -NR5R2 ?; or (4) a radical of -NR5R21, -NR22-C (0) -R21, -NR22-C (0) -OR20, -NR22-C (0) -NR5R21, -NR22-S (0) 2-R20 , or -NR22-S (0) 2-NR5R21; more preferably, each Y is independently (1) a hydrogen radical; (2) a radical of -C (0) -R20; (3) a radical -0R2 ?, -SR21, -S (0) -R20, -S (0) 2-R2o or (4) a radical of -NR5R2 ?, -NR22-C (0) -R2 ?, or -NR22-S (O) 2-OR20; more preferably, each Y is independently (1) a radical of -C (O) -R20; (2) a radical of -OR2 ?, -SR2 ?, -S (O) -R20, -S (O) 2 -R20 or -S (0) 2-NR5R21; or (3) a radical of -NR5R2 ?, -NR22-C (0) -R2? , or -NR22-C (0) 2-OR20. much more preferably, each Y is independently a radical of -0R2 ?, -SR2? or -NR5R21; wherein each R5 is independently (1) hydrogen radicals; (2) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, -S03H or halo radicals; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl radicals; preferably, each R5 is independently (1) hydrogen radicals; (2) alkyl radicals of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, -S03H or halo; or (3) aryl, heteroaryl, aryl-alkyl radicals of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, heterocyclyl, heterocyclyl-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl-3C-8C-alkyl of 1 to 4 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R5 is independently (1) hydrogen radicals; (2) alkyl radicals of 1 to 4 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkynyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, -S03H or halo; or (3) aryl, heteroaryl, aryl-alkyl radicals of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, heterocyclyl, heterocyclyl-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl-3C-8C-alkyl of 1 to 4 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1 to 3 halo radicals; more preferably, each R5 is independently (1) hydrogen radicals; (2) alkyl radicals of 1 to 4 carbon atoms, alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 4 carbon atoms) amino, hydroxy, alkoxy from 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, -S03H or halo; or (3) phenyl-alkyl radicals of 1 to 2 carbon atoms, heteroaryl-alkyl of 1 to 2 carbon atoms, heterocyclyl-alkyl of 1 to 2 carbon atoms or cycloalkyl-3C-6C-alkyl of 1 to 2 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl- of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; preferentially, each R5 is independently (1) a hydrogen radical; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or halo; or (3) phenyl-alkyl radicals of 1 to 2 carbon atoms, heteroaryl-alkyl of 1 to 2 carbon atoms, heterocyclyl-alkyl of 1 to 2 carbon atoms or cycloalkyl-3C-6C-alkyl of 1 to 2 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl- of 1 to 2 carbon atoms) amino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, methoxy, methylthio, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R5 is independently (1) a hydrogen radical; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-3 halo radicals; or (3) phenyl-alkyl radicals of 1 to 2 carbon atoms or heteroaryl-alkyl of 1 to 2 carbon atoms optionally substituted by 1-3 amino, dimethylamino, hydroxy, methoxy, methylthio, methyl radicals or trifluoromethyl radicals; more preferably, each R5 is independently a hydrogen or alkyl radical of 1 to 4 carbon atoms; and much more preferably each R5 is a hydrogen radical; wherein each R2o is independently (1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl) -N- (alkyl) amino, aminocarbonylamino, alkylsulfonylamino radicals , hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl radicals, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, alkyl or haloalkyl; (2) a heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl radicals; preferably, each R2o is independently (1) alkyl radicals of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by 1-3 amino, alkylamino radicals from 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, N- ((alkoxy of 1 to 4 carbon atoms) carbonyl) -N- (alkyl-1 to 4 carbon atoms) amino, aminocarbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocyclyl, aryl or heteroaryl radicals or optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 atoms) carbon) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl of 1 to 5 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms carbon, alkylsulfonyl of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1-4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) mino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (C 1 -C 4 alkoxy) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkynyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, N- ((alkoxy) from 1 to 4 carbon atoms) carbonyl) -N- (alkyl of 1 to 4 carbon atoms) amino, aminocarbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 atoms of carbon, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, aryl-alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4) carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl of 1 to 5 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 atoms of carbon, alkylsulfonyl of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1-4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (C 1 -C 4 alkoxy) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, 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 1-4 -alkyl) amino, aminocarbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo, aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, aryl-alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms carbon, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl of 1 to 5 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 radicals of halo; (2) a heterocyclyl radical optionally substituted by 1-2 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (C 1 -C 4 alkoxy) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; more preferably, each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, 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- (alkyl of 1 to 4 carbon atoms) amino, aminocarbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, aryl-alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms , heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 atom carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl from 1 to 5 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1 3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-2 amino radicals, di (C 1 -C 4) alkyl amino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, acetamido, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4) carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, N- ((alkoxy of 1 to 4 carbon atoms) carbonyl) -N- (alkyl-de 1) to 4 carbon atoms) amino, aminocarbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or cycloalkyl radicals of 3 to 6 carbon atoms, heterocyclyl, aryl or heteroaryl optionally substituted by 1-2 amino radicals, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (2) a heterocyclyl radical optionally substituted by 1-2 hydroxy radicals, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (C 1 -C 4 alkoxy) carbonyl, amino, alkylamino of 1 to 4 carbon atoms, di (alkyl) of 1 to 4 carbon atoms carbon) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R20 is independently (1) alkyl radicals of 1 to 6 carbon atoms optionally substituted by 1-3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N- ((t-butoxy) carbonyl radicals) -N- (methyl) amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or cycloalkyl of 5 to 6 carbon atoms, heterocyclyl phenyl or heteroaryl radicals optionally substituted by 1-2 amino radicals , dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; (2) a heterocyclyl radical optionally substituted by 1-2 hydroxy or alkyl radicals of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl radicals or trifluoromethyl radicals; more preferably, each R2o is independently (1) alkyl radicals of 1 to 6 carbon atoms optionally substituted by 1-3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N- ((t-butoxy) carbonyl) -N- (methyl) amino, aminocarbonylamino radicals , hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulphinyl, methylsulfonyl, halo or cycloalkyl of 5 to 6 carbon atoms, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, acetamino, hydroxy, methoxy radicals , methylthio, halo, methyl or trifluoromethyl radicals; (2) a heterocyclyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl radicals or trifluoromethyl radicals; much more preferably, each R20 is independently (1) alkyl radicals of 1 to 6 carbon atoms optionally substituted by 1-3 amino, methylamino, dimethylamino, hydroxy or phenyl radicals or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; (2) a heterocyclyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl radicals or trifluoromethyl radicals; every R2? is independently a hydrogen radical or R20; each R22 is independently (1) a hydrogen radical; (2) an alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl radicals; with the proviso that when Z is a bond and Y is NR22-C (0) -NH2, then R22 is different from an optionally substituted aryl radical; preferably, each R2 is independently (1) a hydrogen radical; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1) to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio from 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1 3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; with the condition when Z is a bond and Y is NR22-C (O) -NH2, then R22 is different from an optionally substituted aryl radical; more preferably, each R22 is independently (1) a hydrogen radical; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino, di (alkyl-1 to 2 carbon atoms) amino, alkanoylamino radicals of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms carbon or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; more preferably, each R22 is independently a hydrogen or alkyl radical of 1 to 4 carbon atoms; and much more preferably, each R22 is independently a hydrogen or methyl radical; R n and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of (1) R 30; (2) halo or cyano radicals; (3) radicals of -C (O) -R30 / -C (0) -OR29, -C (O) -NR31R32 or -C (NR31) -NR3? R32; (4) radicals of -OR29, -0-C (0) -R29, -O-C (O) -NR3? R32 or -0-C (0) -NR33-S (0) 2-R30; (5) -SR29 radicals, -S (O) -R30, -S (O) 2 -R30, -S (0) 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) -NR3? R32; or (6) radicals of -NR3? R32, -NR33-C (O) -R29, -NR33-C (O) -OR30, -NR33-C (0) -NR3? R32, -NR33-C (NR3i) -NR31R32, -NR33-S (O) 2-R30 or -NR33-S (0) 2-NR5R32; provided that (1) Ru is different from a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of substituted aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of Rp and Ri2 is 0-1; preferentially, Rn and Ri2 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; (3) radicals of -C (0) -R30, -C (0) -OR29, -C (O) -NR3? R32 or -C (NR3?) -NR3? R32; (4) radicals of -OR29, -0-C (0) -R29, -O-C (O) -NR31R32 or -0-C (0) -NR33-S (0) 2-R30; (5) -SR29 radicals, -S (0) -R30, -S (O) 2 -R30, -S (0) 2 -NR31R32, -S (O) 2 -NR33-C (O) -R30, -S (O) 2-NR33-C (O) -OR30 or -S (O) 2-NR33-C (O) -NR3? R32; or (6) radicals of -NR3? R32, -NR33-C (O) -R29, -NR33-C (O) -OR30, -NR33-C (0) -NR31R32, -NR33-C (NR3a) -NR3 R32, -NR33-S (O) 2-R30 or -NR33-S (O) 2-NR3? R32; with the proviso that (1) Rn is different from a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of substituted aryl, hateroaryl, cycloalkyl and heterocyclyl radicals in each of Rn and Ri2 is 0-1; more preferably, Rn and Ri2 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; (3) radicals of -C (O) -R30, -C (0) -OR29, -C (O) -NR31R32 or -C (NR3?) -NR31R32; or (4) radicals of -OR29, -SR29, -S- (0) -R30, -S (O) 2 -R30 -S (0) 2-NR31R32, -NR3? R32, -NR33-C (O) -R29 or NR33 ~ C (0) -OR30; more preferably, Rp is an aryl radical and R12 is a heteroaryl radical, wherein the aryl or heteroaryl radicals are optionally substituted by 1-2 radicals of (2) halo or cyano radicals; (3) radicals of -C (O) -R30, -C (0) -OR29, -C (0) -NR3? R32 or -C (NR31) -NR3? R32; or (4) radicals of -OR29, -SR29, -S (O) -R30 -S (O) 2 -R30, -S (O) 2 -NR3? R32, NR3 R32 or NR33-C (O) -OR29; more preferably, Rp is an aryl radical and R12 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of (1) R3o; (2) halo or cyano radicals; or (3) radicals of -C (O) -NR3? R32 -OR29, -SR29, -S (O) -R30, -S (O) 2 -R30, -S (0) 2 -NR31R32, -NR31R32 or NR33-C (O) -OR29; more preferably, Rp is an aryl radical optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; or (3) radicals of -C (O) -NR31R32"OR29, -SR29, -S (O) -R30 -S (O) 2 -R30, -S (O) 2-NR31R32, -NR31R32 or NR33-C (O) -OR29; more preferably, Rp is an aryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or radical radicals of trifluoromethyl, more preferably Rn is unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl radicals , methyl or trifluoromethyl radicals, and much more preferably, Rn is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio radicals, methylsulfonyl, methyl or trifluoromethyl radicals; more preferably, R 2 is a heteroaryl radical optionally substituted by 1-2 radicals of (1) R 30; (2) halo or cyano radicals; or (3) radicals of -C (0) -NR3? R32 -OR29, -SR29, -NR3? R32 or NR33-C (0) -OR29; more preferably, Ri2 is a heteroaryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl radicals, or trifluoromethyl radicals; more preferably, R12 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-pyrimidinyl radical optionally substituted by an amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl radical or trifluoromethyl radicals; and much more preferably, Ri2 is a 4-pyridyl radical optionally substituted by an amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl radical or trifluoromethyl radicals; wherein each R30 is independently (1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of -NR31R3 ?, -C02R23, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl , heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl radicals; preferably, each R30 is independently (1) alkyl radicals of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms optionally substituted by 1-3 radicals of -NR3? R3 ?, -C02R23, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo or arylalkoxy of 1 to 4 carbon atoms, arylalkylthio of 1 to 4 carbon atoms, arylalkylsulfonyl of 1 to 4 carbon atoms, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 carbon atoms) carbon) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms carbon or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R30 is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-3 radicals of (b) alkoxy of 1 to 4 carbon atoms-carbonyl or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1-3 amino, alkylamino, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl; or (c) hydroxy radicals, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, or phenyl-alkoxy of 1 to 4 carbon atoms, phenyl-alkylthio of 1 to 4 carbon atoms, heterocyclyl, phenyl or heteroaryl optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino , alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R3o is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted (a) amino, alkylamino radicals of 1 to 4 carbon atoms or di- (alkyl-1 to 4 carbon atoms) amino; or (b) hydroxy, alkoxy of 1 to 4 carbon atoms, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4) carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo , alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (2) haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R3o is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino, acetamido, hydroxy, alkoxy of 1 to 2 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (2) a trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, di (alkyl-1 to 2 carbon atoms) amino, acetamido, hydroxy, alkoxy of 1 to 2 carbon atoms, halo, alkyl 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R30 is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, halo radicals, methoxy, methyl or trifluoromethyl radicals; (2) a trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or trifluoromethyl radicals; much more preferably, each R3o is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo radicals , methoxy, methyl or trifluoromethyl radicals; (2) a trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or trifluoromethyl radicals; each R29 is independently a hydrogen radical or R30; and much more preferably, R29 is an aryl or heteroaryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or trifluoromethyl radicals; every R3? is independently (1) hydrogen radicals; (2) an alkyl radical optionally substituted by a cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; preferably, each R3? it is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a cycloalkyl radical of 3 to 8 carbon atoms, aryl, heterocyclyl or heteroaryl optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 atoms carbon, 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 1-4 -alkyl or haloalkyl with 1 to 4 C atoms of 1-3 halo radicals; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical of 3 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 atoms) carbon) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R3i is independently (1) hydrogen radicals; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1) to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano , alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R3? is independently hydrogen or alkyl radicals of 1 to 4 carbon atoms; and much more preferably, each R3i is independently hydrogen, methyl or ethyl radicals; each R32 is independently (1) hydrogen radicals; (2) an alkyl radical optionally substituted by a cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; preferentially, each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a cycloalkyl radical of 3 to 8 carbon atoms, aryl, heterocyclyl or heteroaryl optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 atoms carbon, 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 4 -alkyl or haloalkyl of 1 to 4 C atoms of 1-3 halo radicals; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical of 3 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 atoms) carbon) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a cycloalkyl radical of 3 to 6 carbon atoms, aryl, heterocyclyl or heteroaryl optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 atoms carbon, 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 1-4 -alkyl or haloalkyl with 1 to 4 C atoms of 1-3 halo radicals; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical of 3 to 6 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl) of 1 to 4 atoms carbon) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or radicals of trifluoromethyl; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms carbon, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; more preferably, each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms or an alkyl radical of 1 to 2 carbon atoms substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy radicals, methoxy, methyl or trifluoromethyl radicals; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, methoxy, methyl radicals or trifluoromethyl radicals; much more preferably, each R32 is independently (1) a hydrogen or alkyl radical of 1 to 4 carbon atoms; or (2) a phenyl or heteroaryl radical optionally substituted by a 1-2 amino, dimethylamino, acetamido, hydroxy, methoxy, methyl radicals or trifluoromethyl radicals; Y wherein each R33 is independently (1) a hydrogen radical; or (2) an alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; preferably, each R33 is independently (1) a hydrogen radical; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-) from 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms , alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; more preferably, each R33 is independently a hydrogen or alkyl radical of 1 to 4 carbon atoms; and much more preferably, each R33 is independently a hydrogen or methyl radical.

The following conditions refer to compounds of this invention, only, and not to pharmaceutical compositions or methods of use, which encompass the full extent of the compounds recited above (unless otherwise expressly stated): 1. When R1 and R12 are the same and are a 5 or 6 membered ring having 1-3 heteroatoms, independently selected from N, S and 0, ring to which a benzene ring is optionally fused, R11 is phenyl or optionally substituted naphthyl with halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, hydroxy, amino, alkylamino of 1 to 4 carbon atoms or dialkylamino, or R11 is a ring of 5 or 6 members having from 1-3 heteroatoms independently selected from N, S, and 0, ring to which is optionally fused a benzene ring and optionally substituted with alkyl of 1 to 6 carbon atoms and R2 is different from OH or NH2; when R is H, R is phenyl, 12 is phenyl or 4-pyridyl, then R 1 is different from H, methyl or amino; 3. when R2 is H, R11 is 2-methylphenyl and R12 is 2-pyridyl, then R1 is different from n-propyl; and 4. when R11 and R12 are each an optionally substituted phenyl radical, then R1 is different from an optionally substituted 2-pyridyl radical. The compounds of this invention can generally have several asymmetric centers and are typically represented in the form of racemic mixtures. This invention is proposed to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diastereomers. The compounds of interest include the following: R2 Ru? where R2 is H and R11, R12 and R1 are one of the combinations given in the following table: wherein R2 is -OH and R11, R12 and R1 are one of the combinations given in the following table: Additional, preferred compounds are listed in the Examples, infra.

As used herein, the following terms will have the following meanings: "Alkyl", alone or in combination, means a straight chain or branched chain alkyl radical preferably containing 1-15 carbon atoms (1C-15C) ), most preferably 1-8 carbon atoms dC-BC), even more preferably 1-6 carbon atoms dC-6C), even more preferably 1-4 carbon atoms dC-C), still more preferably 1-3 carbon atoms dC-3C), and much more preferably 1-2 carbon atoms dC-2C). Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like. "Hydroxyalkyl", alone or in combination, means an alkyl radical as defined above wherein at least one hydrogen radical is replaced with a hydroxyl radical, preferably 1-3 hydrogen radicals are replaced by hydroxy radicals, more preferably 1-2 hydrogen radicals are replaced by hydroxyl radicals, and much more preferably a hydrogen radical is replaced by a hydroxyl radical. Examples of such radicals include hydroxymethyl, 1-, 2-hydroxyethyl, 1-, 2-, 3-hydroxypropyl, 1,3-dihydroxy-2-propyl, 1/3-dihydroxybutyl, 1, 2, 3, 4, 5, 6-hexahydroxy-2-hexyl and the like. "Alkenyl", alone or in combination / means a straight chain or branched chain hydrocarbon radical having one or more double bonds, preferably 1-2 double bonds and most preferably a double bond, and containing 2-15 carbon atoms (2C ~? 5C), more preferably 2-8 carbon atoms (2C-8C), even more preferably 2-6 carbon atoms (2C-6C), even more preferably 2-4 carbon atoms (2C-4C), and still more preferably 2-3 carbon atoms (2C- 3C). Examples of such alkenyl radicals include 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 "0" is an oxygen atom. Examples of such alkoxy radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.

"Alkoxycarbonyl", alone or in combination, means a radical of the type "R-O-C (O) -" wherein "R-0" is an alkoxy radical as defined above and "C (0)" is a carbonyl radical. "Alkoxycarbonylamino", alone or in combination, means a radical of the type "ROC (0) -NH-" wherein "ROC (O)" is an alkoxycarbonyl radical as defined above, wherein the amino radical may be substituted optionally, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, and the like. "Alkylthio", alone or in combination, means a radical of the type "R-S-" wherein "R" is an alkyl radical as defined above and "S" is a sulfur atom. Examples of such alkylthio radicals include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio and the like. "Alkylsulfinyl", alone or in combination, means a radical of the type "RS (O) -" wherein "R" is an alkyl radical as defined above and "S (0)" is a mono-oxygenated sulfur atom . Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfinyl, isopropylsulfinyl, n-butylsulfinyl, iso-butylsulfinyl, sec-butylsulfinyl, tert-butylsulfinyl, and the like. "Alkylsulfonyl", alone or in combination, means a radical of the type "RS (0) 2-" where "R" is an alkyl radical as defined above and "S (0) 2" is a sulfur atom di -oxigenado. Examples of such alkylsulfonyl radicals include methanesulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfonyl, n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl, and the like. "Aryl", alone or in combination, means a phenyl or biphenyl radical, which is optionally benzo-fused or heterocycle-fused and which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino , azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, amidino, alkoxycarbonylamino, N-alkylamidoino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, N-alkylamido, N, N-dialkylamido, aralkoxycarbonylamino, alkyl, alkylsulfinyl, alkylsulfonyl, oxo and the like. Examples of aryl radicals are phenyl, o-tolyl, 4-methoxyphenyl, 2- (tert-butoxy) phenyl, 3-methyl-4-methoxyphenyl, 2-CF 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-2-aminophenyl, 4-hydroxyphenyl, 3-methyl-4-hydroxyphenyl, 4- (2-methoxyphenyl) phenyl, 2-amino-1-naphthyl, 2-naphthyl, 3-amino -2-naphthyl, l-methyl-3-amino-2-naphthyl, 2,3-diamino-l-naphthyl, 4,8-dimethoxy-2-naphthyl and the like. "Aralkyl" and "arylalkyl", alone or in combination, mean an alkyl 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 benzyl, 1-, 2-phenylethyl, dibenzylmethyl, hydroxyphenylmethoxy, 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 "ROC (O) -" wherein "R-0-" is an aralkoxy radical as defined above and "-C (O) -" is a radical of carbonyl. "Alkanoyl", alone or in combination, means a radical of the type "R-C (O)" wherein "R" is an alkyl radical as defined above and "-C (O) -" is a carbonyl radical. Examples of such alkanoyl radicals include acetyl, trifluoroacetyl, hydroxyacetyl, propionyl, butyryl, valeryl, 4-methylvaleryl and the like. "Alkanoylamino", alone or in combination, means a radical of the type "RC (0) -NH-" wherein "RC (O) -" is an alkanoyl radical as defined above, wherein the amino radical may be optionally substituted, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl and the like. "Aminocarbonyl", alone or in combination, means a carbonyl radical (carbamoyl) substituted with amino, wherein the amino radical may be mono- or di-substituted optionally, such as with alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, alkanoyl, alkoxycarbonyl, aralkoxycarbonyl and the like. "Aminosulfonyl", alone or in combination, means a sulphonyl radical substituted with amino. "Benzo", alone or in combination, means a divalent radical C6H4 = benzene derivative. "Benzofused" forms a ring system in which benzene and a cycloalkyl or aryl group have two carbons in common, for example tetrahydronaphthylene and the like. "Bicyclic" as used herein is proposed to include both fused ring systems, such as naphthyl and β-carbolinyl and substituted ring systems, such as biphenyl, phenylpyridyl and diphenylpiperazinyl. "Cycloalkyl", alone or in combination, means a carbocyclic, monocyclic, bicyclic or tricyclic alkyl radical, preferably a double bond, saturated or partially saturated, preferably monocyclic, preferably containing 5-12 carbon atoms (5C) -? 2C), more preferably 5-10 carbon atoms (5C-10C), even more preferably 5-7 carbon atoms (5C-7C), which is optionally benzo-fused or heterocycle-fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-1H-indenyl, azabicyclo [3.2.1] octyl and the like. "Heteroatoms" means heteroatoms of nitrogen, oxygen and sulfur. "Heterocycle-fused" forms a ring system in which a heterocyclyl or heteroaryl group of 5-6 ring members and a dichloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like. "Heterocyclyl" means a monocyclic or bicyclic heterocycle radical, preferably monocyclic, preferably a double, saturated or partially unsaturated bond, containing at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, ring members of nitrogen, oxygen or sulfur atoms and preferably having 3-8 ring members in each ring, most preferably 5-8 ring members in each ring and even more preferably 5-6 ring members in each ring. "Heterocyclyl" is intended to include sulfone and sulfoxide derivatives of sulfur ring members and N-oxides of tertiary nitrogen ring members, and carbocyclic-fused ring systems, preferably 3-6 carbon atoms in the ring and more preferably 5-6 carbon atoms in the ring, and benzo fused. The "heterocyclyl" radicals may be optionally substituted in at least one, preferably 1-4, more preferably 1-3, even more preferably 1-2 carbon atoms by halogen, alkyl, alkoxy radicals, hydroxy, oxo, thioxo, aryl, aralkyl, heteroaryl, heteroaralkyl, amidino, N-alkylamidoino, alkoxycarbonylamino, alkylsulfonylamino and the like, and / or at a secondary nitrogen atom by hydroxy, alkyl, aralkoxycarbonyl, alkanoyl, alkoxycarbonyl, heteroarylalkyl radicals, aryl or aralkyl. More preferably, "heterocyclyl", alone or in combination, is a radical of a heterocyclic, monocyclic or saturated bicyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or hydrogen heteroatoms. nitrogen, which is optionally unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals. Examples of such heterocyclyl radicals include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiamorpholinyl, 4-benzo-piperazin-1-yl, pyrimidinyl, tetrahydrofuryl, pyrazolidinyl, pyrazolinyl, pyridazinonyl, pyrrolidonyl, tetrahydrothienyl and their sulfoxide and sulfone derivatives, 2, 3-dihydroindolyl, tetrahydroquinolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl, 1, 2, 3, 4-tetrahydro-1-oxo-isoquinolinyl, 2,3-dihydrobenzofuryl, benzopyranyl, methylenedioxyphenyl, ethylenedioxyphenyl and the like. "Heteroaryl" means an aromatic, monocyclic or bicyclic heterocycle radical, preferably monocyclic, having at least one, preferably 1 to 4, more preferably 1 to 3, even more preferably 1-2, members of the ring of nitrogen, oxygen or sulfur atoms and having preferably 5-6 ring members in each ring, which is optionally saturated, carbocyclic-fused, preferably 3-4 carbon atoms (3C-4C) , to form rings of 5-6 ring members and which is optionally substituted as defined above with respect to the definitions of aryl. Examples of such heteroaryl groups include imidazolyl, 1-benzyloxycarbonylimidazol-4-yl, pyrrolyl, pyrazolyl, pyridyl, 3- (2-methyl) pyridyl, 3- (4-trifluoromethyl) iridyl, pyrimidinyl, 5- (4-trifluoromethyl) pyrimidinyl. , pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5, 6, 7, 8-tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like. "Heteroaralkyl" and "heteroarylalkyl", alone or in combination, mean an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above , such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like. "Halogen" and "halo", alone or in combination, mean 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, is replaced by a halogen radical, more preferably fluoro radicals or chlorine. Examples of such haloalkyl radicals include 1,1,1-trifluoroethyl, chloromethyl, 1-bromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, bis (trifluoromethyl) methyl and the like. "4 (3H) -pyrimidinone" (A) and "4-hydroxy-pyrimidine" (B) are names of two tautomers of the same compound that can be used interchangeably. It is proposed that the use of one of those terms inherently includes the other.

"Pharmacologically acceptable salt" means at least one salt prepared by conventional means, and are well known to those skilled in the art. "Pharmacologically acceptable salts" include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, acid tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When the compounds of the invention include an acidic function such as a carboxy group, then pharmaceutically acceptable cation pairs suitable for the carboxy group are well known to those skilled in the art and include alkali metal, alkaline earth, quaternary ammonium cations and similar. For additional examples of "pharmacologically acceptable salts", see i nfra and Berge et al., J. Ph arm. Sci. 66, 1 (1977). "Cytokine" means a secreted protein that affects the functions of other cells, particularly as it relates to the modulation of interactions between cells of the immune system or cells involved in the inflammatory response. Examples of cytokines include, but are not limited to, interleukin 1 (IL-1), preferably IL-1β, interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-a (tumor necrosis factor a). "Disease or disease state mediated by TNF, IL-1, IL-6 and / or IL-8" means all disease states where TNF, IL-1, IL-6 and / or IL-8 play a role, either directly as TNF, IL-1, IL-6 and / or IL-8 themselves, or by TNF, IL-1, IL-6 and / or IL-8 including another cytokine to be released. For example, a disease state in which IL-1 plays a major role, but in which the production of or action of IL-1 is a result of TNF, would be considered mediated by TNF. "Leaving group" in general refers to groups easily displaceable by a nucleophile, such as an amine, a thiol or a nucleophile of alcohol. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, and the like. Preferred leaving groups are indicated herein where appropriate. "Protective group" generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from being subjected to undesired reactions, such as nucleophilic, electrophilic , oxidation, reduction and the like. Preferred protective groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl, alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as salts of phosphonium and ammonium. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-phenylfluorenyl), phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals, 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, t-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, such that a primary amino group can thus be protected by an aralkyl group and an aralkoxycarbonyl group. Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1/2-bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups can additionally include aryl rings and adjacent cycloalkyl. In addition, the heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl. Amino groups can also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluene sulfonic acid, trifluoroacetic acid and the like. Many of the amino protecting groups are also suitable to protect the carboxy, hydroxy and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups to protect the hydroxy and mercapto groups, such as tert-butyl.

The silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and diphenylmethylsilyl . Silylation of amino groups provides mono- or di-silylamino groups. The silylation of aminoalcohol compounds can lead to a N, N, 0-tris-silyl derivative. Removal of the silyl function of a silyl ether function is easily accomplished by treatment with, for example, a metal hydroxide reagent or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride or their combination products with imidazole or DMF. Methods for the silylation of amines and the removal of silyl protecting groups are well known to those skilled in the art. Methods for the preparation of these amine derivatives of corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry which includes the amino acid / amino acid ester or aminoalcohol chemistry. The protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves the removal of a protecting group, such as the removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed using an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride. The resulting amino salt can be easily neutralized to produce the free amine. The carboxy protecting group, such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art. The symbols used previously have the following meanings: Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is chemically modified through a physiological action in vivo, such as hydrolysis, metabolism and the like, in a compound of this invention after administration of the prodrug to a patient. The appropriateness and techniques involved in the preparation and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (e.g., methyl, ethyl), cycloalkyl (e.g., cyclohexyl), aralkyl (e.g., benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (e.g. example, pivaloyloxymethyl). The amines have been masked as derivatives substituted by arylcarbonyloxymethyl which are divided by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). The hydroxy groups have been masked as esters and ethers. European patent No. 039, 051 (Sloan and Little, 11/4/81) describes prodrugs of Mannich-based hydroxamic acid, their preparation and use. The compounds according to the invention can be synthesized according to one or more of the following methods. It should be noted that the general procedures are shown as referring to the preparation of compounds having non-specific stereochemistry. However, such procedures are generally applicable to those compounds of a specific stereochemistry, for example, where the stereochemistry on a group is (S) or (R). In addition, compounds having a stereochemistry (for example (R)) can frequently be used to produce those that have opposite stereochemistry (ie (S)) using well-known methods, for example, by inversion.

Pyrimidines: A general method for the preparation of compounds of formula I involves the condensation of an IV dicarbonyl intermediate with an NCV containing a structure such as an amidine V, a gunidin VI or urea VII (Scheme 1) for a review of synthetic methods see DJ Brown, Het erocycl ic Compounds: th e Pyrimi di nes, Chapter 3, 1994, John Wiley &Sons).

Scheme 1 IV V, VI, VII Additionally, as a 1,3-dicarbonyl syntone, a b-dimethylamino-a, b-unsaturated ketone IX can be reacted with amidines V or guanidines VI as described (GB Bennett et al., J. Med. Chem. 21, 623-628, 1978). (Scheme 2). Such b-dimethylamino-a, b-unsaturated IX ketones can be prepared by the aminoformylation of an active methylene ketone VIII with Bredereck's reagent, specifically bis (dimethylamino) methoxymethane (H. Bredereck et al., Chem. Ber. 101, 41 -50 (1968), GB Bennett et al, J. Org. Chem. 43, 221-225 (1977)).

Scheme 2 I In accordance with this approach, Scheme 3 illustrates the conversion of 2- (4-fluorophenyl) -1- (4-pyridyl) ethanone (VIII; Sheldrake, Synth e ti c Communi ca ti ons 23, 1967 (1993)) in enamine IX. Intermediate IX can be condensed with a variety of amidines V and guanidines VI to provide the 5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidines 2-substituted I. Additional ketones VIII can be prepared (e.g., according to Sheldrake, Synthetic Communications 23, 1967-1971 (1993)), by using other heteroaryl carboxaldehydes as the starting material, such as 2-methylpyridin-4- carboxaldehyde, 2,6-dimethylpyridine-4-carboxaldehyde (Mathes and Sauermilch, Ch., Ber. 88, 1276-1283 (1995)), quinoline-4-carboxaldehyde, pyrimidine-4-carboxaldehyde, 6-methylpyridine-4-carboxaldehyde , 2-methylpyrimidine-4-carboxaldehyde, 2,6-dimethylpyrimidine-4-carboxaldehyde (Bredereck et al., Ch em. Ber. 97, 3407-3417 (1964)). In addition, 2-nitropyridine-4-carboxaldehyde can be prepared from 2-nitro-4-methylpyridine (Stanonis, J. Org. Ch., 22, 475 (1957)) by oxidation of the methyl group (Venemalm et al., Tet. Lett 34, 5495-5496 (1993)). Its further conversion by means of a ketone VIII will lead it to a derivative of 2-nitro-4-pyridyl I (Scheme 4). The catalytic reduction of the nitro group to an amino group will provide a derivative of I with R12 represented by a 2-amino-4-pyridyl group. Conventional acetylation of the amino group then leads to the 2-acetamido-4-pyridyl derivative.

Scheme 4 As shown in Scheme 5, intermediate IX can also be condensed with urea VII to give the derivative of 2 (1 H) -pyrimidinone X. X is transformed into chloride XI by reaction with a halogenating agent such as phosphorus oxychloride. The treatment of the XI chloride with primary and secondary amines, thiolates or alcoholates allows the preparation of additional pyrimidines I with R1 represented by the substituted N, S or O groups, as mentioned above. Similarly, the hydrazines can be reacted with the chloride XI to provide the pyrimidines I substituted with 2-hydrazino.

Scheme 6 R = NH2 R * = NR22C (0) R21 R1 = NR22S02R ° Palladium or nickel-catalyzed cross couplings of the XI chloride with arylboronic acids or arylzinc halides provide the compounds of the formula I wherein R1 is aryl or heteroaryl.

Scheme 6 illustrates the reaction of intermediate IX with guanidine VI to give the I substituted with 2-amino. The I substituted with 2-amino is a useful intermediate for the acylations and the additional sulfonilations of the 2-amino group to give the acylamido and sulfonamido derivatives. For the synthesis of the 4-hydroxy-pyrimidines II, the approach shown in Scheme 7 can be followed (for a review of the synthetic methods see: D.J. Brown, Heterocyclic Compounds: the Pyrimidines, s upra). This approach involves the cyclization reaction between an ester of acrylic acid XII and an amidine V followed by the oxidation of the resulting dihydropyrimidinone XIII to give II.

Scheme 7 For the synthesis of 5- (4-fluorophenyl) -6-! 4-pyridyl) -4-hydroxy-pyrimidines 2-substituted II Scheme 8), the ester of disubstituted acrylic acid XII can be conveniently prepared by the condensation of pyridine-4-carboxaldehyde with 4-fluorophenylacetic acid followed by esterification. The XII can be reacted with a variety of amidines V at elevated temperature. As a dehydrogenation agent for the conversion of XIII to II, sodium nitrite / acetic acid is suitable. Accordingly, additional compounds of the formula II can be obtained in which R12 is any other heteroaryl ring within the definition of R12 by appropriate selection of the starting material. Such starting materials include, but are not limited to 2-methylpyridine-4-carboxaldehyde, 2,6-dimethylpyridine-4-carboxaldehyde (Mathes and Sauermilch, Chem. Ber. 88, 1276-1283 (1995)), quinoline-4-carboxaldehyde, pyrimidine-4-carboxaldehyde, 6-methylpyrimidine-4-carboxaldehyde, 2-methylpyrimidine-4-carboxaldehyde, 2,6-dimethylpyrimidine-4-carboxaldehyde (Bredereck et al., Ch em. Ber. 97, 3407-3417 1964)). The use of 2-nitropyridine-4-carboxaldehyde will lead it to a derivative of formula II with R12 represented by a 2-nitro-4-pyridyl group. The catalytic reduction of the nitro group to an amino will be provided by the 2-amino-4-pyridyl derivative of II. The approach taught in Scheme 8 is applicable to the use of other acetic acid aryl which leads to the compounds of formula II with different aryl groups such as R 11.

Scheme 8 XSXX II Another approach (Scheme 9) leading to the 5,6-diaryl-4-hydroxy-pyrimidines involves the cyclization of the b-keto ester XIV with thiourea to give the thiouracil derivative XV. The XV can be S-monominated to XVI. The reaction of XVI with primary and secondary amines leads to the 4-hydroxy-pyrimidines substituted with 2-amino II. Additional 2-thioether derivatives of II with R1 = SR21 can be obtained, for example by alkylating the XV with alkyl halides. The treatment of XV or XVI with Raney nickel and H2 provides the compounds of structure II wherein R1 is H.

Scheme 9 Although Scheme 9 illustrates the synthesis in which R12 is 4-pyridyl, this approach can equally be applied to any other heteroaryl ring within the definition of R12 by appropriate selection of the starting material. Such starting materials include but are not limited to ethyl 2-methyl isonicotinate (Efimovsky and Rumpf, Bul 1. Soc. Chim. FR 648-649), methyl pyrimidine-4-carboxylate, 2-methylpyrimidin-4-. methyl carboxylate, methyl 6-methylpyrimidine-4-carboxylate and methyl 2,6-dimethylpyrimidine-4-carboxylate (Sakasi et al., He t erocycl is 13, 235 (1978)). Likewise, the methyl 2-nitroisonicotinate (Stanonis, J. Org. Ch., 22, 475 (1957)) can be reacted with an aryl acetic acid ester followed by cyclization of the resulting b-keto ester with thiourea. in a manner analogous to Scheme 9. The subsequent catalytic reduction of the nitro group to an amino group will give it a 4-hydroxy-pyrimidine II in which R12 is represented by a 2-amino-4-pyridyl group (Scheme 10).

Scheme 10 In addition, the methyl 2-acetamido isonicotinate (Scheme 11) can be reacted analogously to Scheme 9 after appropriate protection of the amide nitrogen with for example a tert-butyldimethylsilyloxymethyl group (Benneche et al., Ac ta Ch em. Scand. B 42 384-389 (1988)), a tert-butyldimethylsilyl group, a benzyloxymethyl group, a benzyl group or the like (Pi).

Scheme 11 Removal of the Px protective group from pyrimidine II with a suitable reagent (eg, tetrabutylammonium fluoride in the case where Pi is t-butyldimethylsilyloxymethyl) then lead to a pyrimidine II with R12 represented by a 2-acetamido group -4-pyridyl. Needless to say, the p-fluorophenyl ethyl acetate can be substituted by any alkyl arylacetate in the process illustrated in Scheme 9 thereby providing the compounds of the formula II with different aryl substituents R11.

In a further process, the compounds of the pyrimidines II can be prepared by coupling a suitable derivative of XVIII (L is a leaving group, such as a halogen radical and the like, and P2 is a protecting group, such as benzyl and similar) with an appropriate aryl equivalent.

V II Such aryl / heteroaryl couplings are well known to those skilled in the art and involve an organic-metal component for the reaction with a reactive derivative, eg, a halogen derivative, of the second compound in the presence of a catalyst. The etalo-organic species can be provided either by the pyrimidinone case in which the aryl component provides the reactive halogen equivalent or the pyrimidinone can be in the form of a reactive 5-halogen derivative for reaction with a compound of metallo-organic aryl. Accordingly, the derivatives of 5-bromo and 5-iodo of XVIII (L = Br, I) can be treated with arylalkyl tin compounds, for example, trimethylstanyl benzene, in an inert solvent such as tetrahydrofuran in the presence of a palladium catalyst, such as di (triphenylphosphine) palladium (II) dichloride. (Peters et al, J. He t erocycl ic Ch em.27, 2165-2173, (1990) Alternatively, the halogen derivative of XVIII can be converted to a trialkyltin derivative (L = Bu3Sn) by the reaction with for example tributylstannyl chloride following lithiation with butyllithium and then reacted with an aryl halide in the presence of a catalyst (Sandosham and Undheim, Acta Ch., Scand., 43, 684-689 (1898). approaches would lead to pyrimidines II in which R11 is represented by the aryl or heteroaryl groups, as reported in the literature (Kabbe, Li eb, Ann, Ch., 704, 144 (1967), German patent 1271116 (1968)) and is shown in Scheme 12, the 5-aryl-2,6-dipyridyl-4-hydroxy-pyrimidines II can be prepared in a one-step synthesis by reacting the cyanopyridine with an arylacetyl ester, such as ethyl phenylacetate in the presence of sodium methoxide.

Scheme 12 Analogously, as reported (Kabbe, upra) and exhibited in Scheme 13, the 4-amino-5- (aryl) -2,6-dipyridyl-pyrimidines XIX are obtained in a one-step synthesis by reaction of cyanopyridine with arylacetonitrile, such as 4-fluorophenylacetonitrile.

Scheme 13 XIX The modification at position 4 (R2 of formula I) of pyrimidine II is possible by conversion to chlorine derivative XX by reaction with phosphorus oxychloride (Scheme 4). A 4-alkoxy XXI derivative can be prepared from chlorine derivative XX by nucleophilic substitution with alkoxide. Alternatively, other leaving groups, such as tosylates, mesylates, and the like may be used in place of the chloro group. Also, such leaving groups can be displaced by amino, thiolates, alcoholates, and similar nucleophiles. For example, the chloro derivative XX can be reduced by catalytic hydrogenation to give a pyrimidine I where R2 is H, or it can be reacted with an alkyl or aryl boronic acid or an alkyl or aryl zinc halide to provide a pyrimidine I wherein R2 is alkyl or aryl.

In Scheme 15, the compounds of the present invention of the formula XXX can be easily prepared by reacting the methylthio intermediate XXXI with the amine NHR5R21, for example by heating the mixture preferably at a temperature greater than 100 ° C, more preferably 150-210 ° C. Alternatively, compounds of formula XXX can be easily prepared by reacting the methylsulfonyl intermediate XXXII with the amine NHR5R21, for example, by heating the mixture preferably at a temperature greater than 40 ° C, more preferably 50- 210 ° C.

Scheme 15 XXXI XXXII Amines of the formula NHR5R21 are commercially available or can be easily prepared by those skilled in the art from commercially available starting materials. For example, a group of amide, nitro or cyano can be reduced under reducing conditions, such as in the presence of a reducing agent similar to lithium aluminum hydride and the like, to form the corresponding amine. Alkylation and acylation of amino groups are well known in the art. The substituted, chiral and achiral amines can be prepared from chiral amino acids and amino acid amides (eg, glycine, β-alanine and the like substituted with alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and the like) using well known methods in the art, such as H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, 1990; M. Freiberger and R. B. Hasbrouck, J. Am. Chem. Soc. 82, 696-698, 1960; Dornow and Fust, Chem. Ber. 87, 984, 1954; M. Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459, 1982; W. Wheeler and D. O'Bannon, Journal of Labeled 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 presented for purposes of illustration only and are not intended, nor should be constructed, as limiting the invention in any way. Those skilled in the art will appreciate that modifications and variations of the compounds described herein can be made without departing from the spirit or scope of the present invention.

EXAMPLES Example 1 General procedure for the preparation of 5 - (4-f l uorofenyl) -4- (4-pyridyl) -pyrimidines 2-their thi utes a. 3- (Dimethylamino) -2- (4-fluorophenyl) -1- (4-pyridyl) -3-propane-1-one: (According to Bennett et al., J. Org. Chem, 43, 221 (1977) ).

A mixture of 2- (4-fluorophenyl) -1- (4-pyridinyl) ethanone (300 mg, 1.39 mmol) and bis (dimethylamino) methoxymethane (300 mmol, 1.95 mmol) was heated at 110 ° C for 1.5 hours under argon. . It was evaporated and the yellow crystallization residue was dried in an oil pump vacuum before being used in the subsequent reaction. MS (m / z): 270.8 (M + H) +; C? 6H? 5FN20 required. 270.3. NMR-: H (CDC13): d 8.57, 7.25 (2m, every 2H, Pirid.), 7.36 (s, 1H, CH =), 7.13, 6.99 (2m, every 2H, PF), 3.00 (s broad, 6H , 2CH3). b. General procedure: (According to Bennett et al., J. Med. Chem. 21, 623 (1978)).

A solution of 3- (dimethylamino) -2- (4-fluorophenyl) -l- (4-pyridinyl) -3-propen-1-one (1.39 mmol) in pure ethanol (9 ml) was transferred into a solution of R ^ CfNHJ Hz (1.67 mmoles) in ethanol (2 ml) prepared from sodium (1.67 mmoles) and amidine or guanidine hydrochloride (1.67 mmoles). After heating under reflux for 1.5 to 24 hours, it was evaporated and the resulting material was applied either directly to a column of silica gel (1-5% methanol / dichloromethane) or was taken in dichloromethane followed by washing with water , drying the organic solution and evaporation before column chromatography. The following pyrimidines were prepared according to this general procedure by reacting 3- (dimethylamino) -2- (4-fluorophenyl) -1- (4-pyridinyl) -3-propen-l-one with amidines: 1-1 5- (4-Fluorophenyl) -2-methyl-4- (4-pyridyl) -pyrimidine: MS (m / z): 266.0 (M + H) +; C16H? 2FN3 required 265. 3. NMR ^ H (CDC13): d 8.70 (d, 1H, H-6, Pirim.), 8.59, 7.32 (2m, every 2H, Pirid.), 7.20-7.00 (m, 4H, PhF), 2.88 ( s, 3H, CH 3). 1-2 5- (4-F1-uorophenyl) -2-isopropyl-4- (4-pyridyl) -pyrimidine: MS (m / z): 294.4 (M + H) +; C? 8H? 6F 3 required. 293. 4. NMR-XH (CDC13): d 8.73 (s, 1H, H-6, Pirim.), 8.60, 7.35 (2m, every 2H, pyrid.), 7.20-7.04 (m, 4H, PhF), 3.37 (m, 1H, CH (CH3) 2), 1.50, 1.47 (2s, every 3H, 2CH3). R1 = (CH3) 2CH-1-3 2-tert-Butyl-5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 307.8 (M + H) +; C19H? 8FN3 required 307.4. NMR-XH (CDC13): d 8.72 (s, 1H, H-6, Pirim.), 8.59, 7.38 (2m, each 2H, Pirid.), 7.21-7.06 (m, 4H, PhF), 1.52 (s, 9H, 3CH3) Rl = (CH3) 3C- 1-4 2- (1-Chloro-2-methoxyethyl) -5- (-f luorofenyl) -4- (4-pridyl) -pyrimidine: MS (m / z): 344.2 (M + H) +; C? 8H? 5ClFN30 required. 343.8. NMR ^ H (CDC13): d 8.81 (s, 1H, H-6, Pirim.), 8.61, 7.35 (2m, every 2H, Pirid.), 7.22-7.08 (m, 4H, PhF), 5.29 (dd, 1H, CHC1), 4.31, 4.04 (2dd, each 1H, CH20), 3.47 (s, 3H, CH30). Rl = CH30CH2CH (C1) - 1-5 2- (Cyclopropyl) -5- (4-fluorophenyl) -4- (4-pyridyl) -Pyrimidine: MS (m / z): 292.0 (M + H) +; C? 8H? 4FN3 required. 291.3. NMR ^ H (CDC13): d 8.60 (s, 1H, H-6, Pirim.), 8.57, 7.32 (2d, every 2H, Pirid.), 7.16-7.00 (m, 4H, PhF), 2.32 (, 1H , -CH-), 1.2, 1.1 (2m, every 2H, 2CH2).

Rl = • > - 1-6 2- (Adamant-1-yl) -5- (-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 386.0 (M + H) +; C25H24FN3 required 385.5. NMR-aH (CDC13): d 8.76 (s, 1H, H-6, Pirim.), 8.61, 7.51 (2m, every 2H, Pirid.), 7.22-7.08 (m, 4H, PhF), -1.9-1.5 (broad, 15H, CH2, CH).

Rl 1-7-2-Bacillil- 5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 342.2 (M + H) +; C22H? 6FN3 required 341. 4. RMN ^ H (CDC13): d 8.71 (s, 1H, H-6, Pirim.), 8.60, 7.48 (2m, each 2H, Pirid.), 7.42-7.04 (m, 9H, PhF, Ph), 4.42 (s, 2H, CH2Ph). 1-8 2- (2,6-Dichlorobenzyl) -5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 410.2 (M) +; C22H? 4Cl2FN3 required. 410.3. NMR-aH (CDC13): d 8.68 (s, 1H, H-6, Pirim.), 8.57 (d, 2H, pyrid.), 7.44-7.03 (m, 9H, pyrid., PhF, PhCl2), 4.93 ( s, 2H, CH2). to 1 -- . 1 -9 5- < (4-Fluorophenyl) -2-phenoxymethyl-4- (4-pyridyl) -pyrimidine: MS (m / z): 358.2 (M + H) +; C22H16FN30 required 357.4. H-NMR (CDC13): d 8.83 (s, 1H, H-6, Pirim.), 8.60 (m, 2H, Pirid.), 7.36-6.98 (m, 11H, Pirid., PhF, Ph), 5.43 ( s, 2H, CH2). < ^ - Rl -s 1-105- (4-Fluorophenyl) -2-phenylthi ornethi 1-4- (4-pyridinyl) -pyrimidine: MS (m / z): 374.2 (M + H) +; C22H16FN3S required 373.5. NMR-aH (CDC13): d 8.72 (s, 1H, H-6, Pirim.), 8.56, 7.49 (2m every 2H, Pirid.), 7.32- 7.02 (m, 9H, PhF, Ph), 4.50 (s) , 2H, CH2). 1-11 5- (4-Fluorophenyl) -2-phenyl- - (4-pyridyl) -pyrimidine: MS (m / z): 328.2 (M + H) +; C2? H14FN3 required 327.4. NMR-2H (CDC13): d 8.85 (s, 1H, H-6, Pirim.), 8.63, 7.4 (2m, every 2H, Pirid.), 8.56, 7.6-7.5, 7.25- 7.05 (m, 9H, PhF , Ph). 1-125- (Fluorophenyl) -2- (4-hydroxyphenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 344.2 (M + H) +; C2? H?, FN30 required. 343.4. NMR-aH (DMSO-d6): d 10.2 (broad s, 1H, OH), 8.90 (s, 1H, H-6, Pirim., Pirim.), 8.60, 7.42 (2m, every 2H, Pirid.), 8.35, 7.40-6.92 (m, 8H, PhF, PhOH). 1-135- (4-Fluorophenyl) -2- (4-aminophenyl) -4- (4-pyridyl) pyrimidine: MS fm / z); 343.2 (M + H) +; C2? H? 5FN4 required. 342.4. NMR-aH (CDC13): d 8.75 (s, 1H, H-6, Pirim.), 8.60, 7.41 (2m, every 2H, Pirid.), 8.40, 7.22-6.79 (m, 8H, PhF, Ph ), 4.00 (broad s, 2H, NH2). 1-145- (4-Fluoro-phenyl) -2- (3-pyridyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 329.0 (M + H) +; C20H13FN4 required 328.4. NMR ^ H (CDC13): d 9.80 (broad s, H-2, 3-pyrid.), 8.90 (s, 1H, H-6, pyrim.), 8.84, 8.80 (2m, each 1H, 3-pyrid. ), 8.66, 7.45 (2m, each 2H, 4-Pirid.), 7.50 (m, 1H, 3-Pirid.), 7.28-7.10 (m, 4H, PhF) Rl -x 1-155- (4-Fluoro-phenyl) -2- (2-pyridyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 329.0 (M + H) +; C2oH? 3FN4 required. 328.4. NMR-XH (CDC13): d 9.01 (s, 1H, H-6, Pirim.), 8.92, 8.66, 7.94, 7.48 (4m, each 1H, 2-Pirid.), 8.66, 7.47 (2m, each 2H, 4-Pirid.), 7.26, 7.14 (2m, every 2H, PhF) 1-165- (4-Fluorophenyl) -2- (2-pyrazinyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 330.2 (M + H) +; C? 9H? 2FN5 required. 329. 3. NMR-aH (CDC13): 9.84 (, 1H, H-3, Piraz.), 9.01 (s, 1H, H-6, Pirim.), 8.84, 8.76 (2m, each 1H, H-5, H-6 Piraz.), 8.65, 7.44 (2m, each 2H, Pirid.), 7.26, 7.13 ( 2m, every 2H, PhF). 1-17 5- (4-Fluorophenyl) -2- (2-methylthiazol-4-yl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 349.0 (M + H) +; C19H? 3FN4S required 348.4. NMR-: H. (CDC13): d 8.90 (s, 1H, H-6, Pirim.), 8.63, 7.42 (2m, every 2H, Pirid.), 8.32 (s, 1H, H-5, Tiaz.), 7.22, 7.10 ( 2m, every 2H, PhF), 2.88 (s, 3H, CH3). 1-185- (4-Fluorophenyl) -4- (4-pyridyl) -2- (2-thienyl) -pyrimidine: MS (m / z): 334.2 (M + H) +; C? 9H? 2FN3S required. 333.4. NMR-aH (CDC13): d 8.74 (s, 1H, H-6, Pirim.), 8.63, 7.41 (2m, each 2H, Pirid.), 8.13, 7.55 (2m, each 1H, Tiof.), 7.20 ( m, 3H, PhF, Tiof.). 7.10 (m, 2H, PhF).

The following pyrimidines were prepared according to the general procedure by reacting 3- (dimethylamino) -2- (4-fluorophenyl) -1- (4-pyridinyl) -3-propen-1-one with guanidines: 1-192-Amino-5- (4-fluorophenyl) -4- (4-pyridyl-pyrimidine: MS (m / z): 267.0 (M + H) +; C? 5HnFN4 required 266.3 .XMR-NMR (DMSO -d6): d 8.54, 7.26 (2m, every 2H, Pirid.), 8.35 (s, 1H, H-6, Pirim.), 7.22-7.12 (m, 4H, PhF), 6.97 (s, 2H, NH2 Rl = NH2- 1-202-Ethylamino-5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 295.0 (M + H); C 7H? 5FN4 Required 294.3 NMR-aH (CDC13): d 8.56, 7.32 (m, every 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 7.12-6.99 (m, 4H, PhF), 5.33 (t without resolv., 1H, NH), 3.58 (m, 2H, CH2), 1.32 (t, 3H, CH3) Rl = CH3CH2-NH- 1-215- (4-Fluorophenyl) -4- (4- pyridyl) -2- (2-sulfethylethyl) -pyrimidine: MS (m / z): 375.2 (M + H) +; C17H15FN403S required 374.4 NMR-aH (DMSO-d6): d 8.51, 7.25 (2d , each 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 7.32 (t, 1H, NH), 7.2-7.1 (m, 4H, PhF), 3.62 (q, 2H, CH2N) 2.72 (t, 2H, CH2). Rl = H03S-CH2-CH2-NH- 1-222- (2-Diethylaminoethylamino) -5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 365.8 (M + H) +; C2? H24FN5 required. 365.5. NMR-aH (CDC13): d 8.55, 7.28 (2m, every 2H, Pirid.), 8.34 (s, 1H, H-6, Pirim.), 7. 08, 7.01 (2m, every 2H, PhF), 5.95 (broad s, 1H, NH), 3.60 (q, 2H, CH2N), 2.76 (t, 2H, CH2), 2.65 (q, 4H, 2CH2CH3), 1.08 (t, 6H, 2CH3). R1 = (CH3CH2) 2NCH2CH2NH-1-23 (4-Fluoro-phenyl) -4- (4-pyridyl) -2- (thioureido) -pyrimidine: MS (m / z): 326.2 (M + H) +; C16H12FN5S required 325.4. NMR-XH (DMSO-d6): d 10.84, 10.11, 9.20 (3s, each 1H, NH, SH), 8.75 (s, 1H, H-6, Pirim.), 8.59, 7.32 (2m, each 2H, Pirid .), 7.28, 7.21 (2m, every 2H, Ph) F. 1-24 2- (2,6-Di chloro phenyl amino) -5- (-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 410.8 (M) +; C2? H? 3 Cl2FN4 required. 411.3. NMR-aH (CDC13): d 8.54, 7.30 (2m, every 2H, Pirid.), 8.45 (s, 1H, H-6, Pirim.), 7.45 (d, 2H, PhCl2). 7.21 (t, 1H, PhCl2), 7.12, 7.04 (2m, every 2H, PhF). 1-25 2- (2,6-Dimethyl phenylamino) -5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 371.0 (M + H) +; C23H19FN4 required 370.4. NMR-XH (CDC13): d 8.56, 7.32 (2d, each 2H, Pirid.) / 8.40 (s, 1H, H-6, Pirim.), 7.20 (s, 3H, PhCl2), 7.11, 7.04 (2m, every 2H, PhF), 6.66 (s, 1H, NH), 2.20 (s, 6H, 2CH3). 1-26 5- (4- Fluoro-phenyl) -4- (4-pyrid-di-1) -pyrimidine: MS (m / z): 373.0 (M + H) +; C22H17FN40 required 372.4. RN ^ H (CDC13): d 8.62, 7.40 (2m, every 2H, Pirid.), 8.60 (m, 1H, PhOMe), 8.52 (s, 1H, H-6, Pirim.), 7.99 (s, 1H, NH) 7.18-6.94 (m, 7H, PhF, PhOMe), 3.96 (s, 3H, CH30). 1-27 5- (4-Fluorophenyl) -2- (4-f luorofenylamino) -4- (4-pyridyl) -pyrimidine: MS fm / z): 361.0 (M + H) +; C2? H? 4F2N4 required. 360.4. X-NMR (CDC13): d 8.58, 7.32 (m, 2H, pyrid.), 8.46 (s, 1H, H-6, pyrim.), 7.62 (m, 2H, PhF), 7.24 (broad s, 1H, NH), 7.13-7.00 (m, 6H, PhF).

H N, Rl-O 1-28 2- (4-Ethyl phenylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 371.2 (M + H) +; C23H? 9FN4 required 370.4. RMN-1 !! (CDC13): d 8.61, 7.41 (2m, every 2H, Pirid.), 8.49 (s, 1H, H-6, Pirim.), 7.60, 7.23 (2d, every 2H, PhEth), -7.28 (NH), 7.13, 7.06 (2m, every 2H, PhF), 2.67 (q, 2H, CH2), 1.27 (t, 3H, CH3). 1-295- (4- Fluoro-phenyl) -4- (4-pyridyl) -2- (3-trifluoromethyl-phenylamino) -pyrimidine: MS (m / z): 411.0 (M + H) +; C22H14F4N4 required 410.4. NMR ^ H (CDC13): d 8.60, 7.35 (2m, every 2H, Pirid.), 8.52 (s, 1H, H-6, Pirim.), 8.23, 7.73, 7.46 (s, dd, t, each 1H, PhCF3), 7.44 (s, 1H, NH), 7.31 (dd, 1H, PhCF3), 7.13, 7.05 (2m, every 2H, PhF). 1-30 2- (Benzylamino) -5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 357.0 (M + H) +; C22HnFN4 required 356.4. NMR-aH (CDC13): d 8.55, 7.28 (2m, every 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 7.44-7.28 (m, 5H, Ph), 7.09, 7.02 ( 2m, every 2H, PhF), 5.71 (t, 1H, NH), 4.75 (d, 1H, CH2). 1-31 5- (4-Fluorophenyl) -2- (2-phenylethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 371.0 (M + H) +; C23H19FN4 required 370.4. NMR-XH (CDC13): d 8.56 (m, 2H, pyrid.) 8.35 (s, 1H, H-6, pyrim.), 7.38-7.22 (m, 7H, Ph, pyrid.), 7.08, 7.02 (2m , each 2H, PhF), 5.32 (t, 1H, NH), 3.80 (q, 2H, CH2N), 2.92 (t, 2H, CH2). 1-32 5- (4- Fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine: MS (m / z): 321.2 (M + H) +; d9H17FN4 required 320.4. X-NMR (CDC12): d 8.54, 7.32 (2d, each 2H, Pirid.), 8.37 (s, 1H, H-6, Pirim.), 7.06, 7.00 (2m, 2H, PhF), 3.68, 2.05 ( 2m, every 4H, 4CH2).

-O- 1-335- (4-Fluorophenyl) -2 -morphine-4- (4-pyridyl) -pyrimidine: MS (z): 337.2 (M + H) +; d9H17FN40 required 336.4. NMR-XH (CDC13): d 8.56, 7.31 (2m, every 2H, Pirid.), 8.40 (s, 1H, H-6, Pirim.), 7.10, 7.03 (2m, every 2H, PhF), 3.94, 3.83 (2m, every 4H, 4CH2).

R Rl1"- O /," ""? N - \ _ / 1-34 2- (3, 5-Dimethylpyrazole) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 346.0 (M + H) +; C20H16FN5 required 345.4. NMR-aH (CDC13): d 8.80 (s, 1H, H-6, Pirim.), 8.60, 7.35 (2m, every 2H, Pirid.), 7.18, 7.08 (2m, every 2H, PhF), 6.08 (s, 1H, Piraz.), 2.70, 2.30 (2s, each 3H, 2CH3). 1-35 5- (4-Fluorophenyl) -4- (4-pyridyl) -2- (3, 5-bis (trif luoromethyl) benzenesulf amo i lo) -pyrimidine: MS (m / z): 542.8 (M + H) +; C23H? 3F7N402S required 542.4. NMR-XH (DMSO-de): d 8.63 (s, 1H, H-6, Pirim.), 8.56 (m, 2H, pyrid.), 8.49, 8.43 (2s, 2H, 1H, Ph (CF3) 2) , 7.26-7.15 (m, 6H, PhF, Pirid.). 1-362- (4-Aminobenzenesulfonyl) -5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 421.8 (M + H) +; C2? H16FN5S required 421.5. NMR-aH (DMSO-d6): d 8.58 (s, 1H, H-6, Pirim.), 8.575 (m, 2H, Pirid.), 7.64, 6.56 (2d, each 2H, PhNH2), 7.28-7.15 ( m, 6H, PhF, Pirid.), 5.99 (s, 2H, NH2). 1-37 2- (2-Dimethylaminoethylthio) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: was prepared according to the general procedure by reacting 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? 9H? 9FN4S required. 354.5. NMR ^ H (CDC13): d 8.59, 7.32 (2m, every 2H, Pirid.), 8.58 (s, 1H, H-6, Pirim.), 7.16, 7.08 (2m, every 2H, PhF), 3.40, 2.76 (2m, every 2H, 2CH2), 2.37 (s, 6H, 2CH3).

Rl = (CH3) 2NCH2CH2S- Example 2 General procedure for the preparation of 2-amino-5- (4-f luorofenyl) -4- (4-pyridyl) -pidimidines 2-N substituted a. 5- (4-Fluorophenyl) -4- (4-pyridyl) -2 (1H) -pyrimidinone The urea (0.67 g, 11.15 mmol) was added to a stirred solution of 0.62 N ethanolic sodium ethanolic (15 ml). An ethanolic solution was added (60 ml) of 3- (dimethylamino) -2- (4-fluorophenyl) -1- (4-pyridinyl) -3-propen-l-one (9.29 mmol) and the mixture was heated to reflux overnight. Evaporated followed by column chromatography (5% methanol / dichloromethane to 100% methanol). The crystals (presumably urea) obtained in the treatment of the resulting product with dichloromethane / methanol were filtered. The filtrate was evaporated and the rest was rechromatographed on a silica gel column (chloroform / methanol / water = 70: 20: 1) to yield the title compound as a yellow foam. MS (m / z): 268.2 (M + H) +; C? 5H10FN30 required. 267.3. NMR-XH (DMSO-dg): d 8.55, 7.24 (2m, every 2H, Pirid.), 8.22 (broad s, 1H, H-6, Pirim.), 7.20-7.10 (m, 4H, PhF). b. 2-Chloro-5- (4-fluoro-phenyl) -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 at reflux for 45 minutes. It was evaporated to dryness at a bath temperature of > 500 ° C. The flask was cooled in a bath with ice and ice water was added. If the pH value was still found to be acidic, then the mixture was neutralized with 5% aqueous ammonium hydroxide. It was extracted with dichloromethane, followed by washing the organic solution with aqueous sodium chloride, drying and evaporation to yield the title compound as a yellow foam which is used without further purification. MS (m / z): 286.1 (M + H) +; C? HX9ClFN3 required 285.7. NMR-aH (CDC13): d 8.68 (s, 1H, H-6, Pirim.), 8.62, 7.42 (2m, every 2H, Pirid.), 7.23-7.10 (m, 4H, PhF). Alternatively, 2-chloro-5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine (MS (m / z): 282 (M + H) +; C? 6H? 2ClN3 required. 281.7) and 2-chloro-4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine (MS (m / z): 336.0 (M) +; C? 6H9ClF3N3 required 335.7) have been synthesized by the same reaction sequence, but starting from 2- (3-methylphenyl) -1- (4-pyridinyl) ethanone (prepared according to: I. Lantos et al., J. Org. Chem. 53, 4223-4227, 1988 ) and 1- (4-pyridinyl) -2- (3-trifluoromethylphenyl) ethanone (prepared according to: P. Sheldrake, Synth Commun. 23 (24), 1967-1971, 1993); and WO 97/12876). Also, thionyl chloride / N, N-dimethylformamide (excess / 3 equivalents, reflux) can be used in place of phosphorus oxychloride. c. General 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, HNR5R21, (0.5-5.5 mmol) are heated at 50-100 ° C for 5-60 minutes (verification with thin layer chromatography). The mixture was applied directly to a column of silica gel which was developed with dichloromethane / methanol or dichloromethane / methanol / concentrated ammonium hydroxide. an alternative procedure using ethanol as a solvent was used in the case of Examples 2-6, 2-11, 2-12, 2-20 and 2-26 as described. The following pyrimidines were prepared according to this procedure using the appropriate amine and the substituted 2-chloropyrimidine. 2-1 2- (2-aminoethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 310.2 (M + H) +; C1 H26FN -HC1 required 309.4 + 36.5. NMR ^ H (CD3OD): d 8.84, 8.10 (2m, every 2H, Pirid.), 8.58 (s, 1H, H-6, Pirim.), 7.28, 7.15 (2m, every 2H, PhF), 3.83 (t , 2H, CH2), 3.27 (t, 2H, CH2). R1 = NH2CH2CH2NH- 2-2 2- (3-aminopropylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 324.0 (M + H) +; Ca8H18FN5-HCl required 323.4 + 36.5. NMR-aH (CD3OD): d 8.85, 8.10 (m, 2H, pyrid.), 8.54 (s, 1H, H-6, pyrim.), 7.27, 7.14 (2m, every 2H, PhF), 3.84, 3.68 ( 2t, each 2H, 2CH2N), 2.18 (m, 2H, CH2). Rl = NH2CH2CH2CH2NH- 2-3 2- (4-Aminobutylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 338.0 (M + H) +; C? 9H20FN5-HCl required. 337.4 + 36.5. NMR-aH (CD3OD): d 8.80, 8.05 (2m, every 2H, Pirid.), 8.50 (s, 1H, H-6, Pirim.), 7.25, 7.14 (2m, every 2H, PhF), 3.58 (t broad, 2H, CH2), 3.02 (broad t, 1H, CH2), 1.80 (m, 4H, 2CH2). Rl = NH2CH2CH2CH2CH2NH- 2-4 2- (2-Dimethylaminoethylamino) -5- (4-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 338.2 (M + H) +; C? 9H20FN5 required 337.4. NMR-2H (CDC13): d 8.57, 7.30 (2m, every 2H, Pirid.), 8.37 (s, 1H, H-6, Pirim.), 7.10, 7.03 (2m, every 2H, PhF), 6.00 (t , 1H, NH), 3.66 (q, 2H, CH2), 2.71 (t, 2H, CH2), 2.41 (s, 6H, 2CH3). R1 = (CH3) 2NCH2CH2NH- 2-5 5- (4'- Fluor or phenyl) -2- (2-f-enyl amino-e-lamino) -4- (4-pyridyl) -pyrimidine: MS (m / z) : 386 (M + H) +; C23H20FN5 required 385.5. NMR-2H (CDC13): d 8.57, 7.28 (m, 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 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 (broad t, 1H, NH), 3.80 (q, 2H, CH2), 3.47 (t, 2H, CH2) . 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 N- (4-fluorophenyl) ethylenediamine (1 ml) in ethanol (1 ml) was heated to reflux for 3 hours. Evaporation was followed by column chromatography (3% methanol / dichloromethane) to give the title compound as a yellowish solid. MS (m / z): 404.2 (M + H) +; C23H19F2N5 required 403.4. NMR-XH (CDC13): 8.60 7.31 (2m, each 2H, Pirid.), 8.40 (s, 1H, H-6, Pirim.), 7.11-7.02 (2m, each 2H, PhF), 6.90, 6.60 (t , dd, every 2H, PhF), 5.62 (t, 1H, NH), 3.82 (q, 2H, CH2), 3.44 (t, 2H, CH2). 2-7 5- (4-Fluorofenyl) -2- (4-methylbenzylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 371.2 (M + H) +; C23H? 9FN4 required 370.4. NMR ^ H (CDC13): d 8.55, 7.34 (2m, every 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 7.30, 7.18 (2d, every 2H, PhMe), 7.08, 7.02 (2m, every 2H, PhF), 5.69 (broad s, 1H, NH), 4.69 (d, 2H, CH2), 2.36 (s, 3H, CH3). 2-8 5- (4-Fluorophenyl) -2- (2- (4-f luorofenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 389.2 (M + H) +; C23HlßF2N4 required 388.4. NMR-XH (CDC13): d 8.57 (m, 2H, Pirid), 8.36 (5, 1H, H-6, Pirim.), 7.32-7.20, 7.12-6.98 (2m, 10H, 2PhF, Pirid.), 5.37 (broad t, 1H, NH), 3.79 (q, 2H, CH2N), 2.97 (t, 2H, CH2). 2-9 2- (2- (4-Chloro phenyl) -ethylamino) -5- (4-f luorofenyl) -4- (4-pyridyl) irimidine: MS (m / z): 405.0 (M + H) +; C23H? 8ClFN4 required. 404.9. NMR-XH (CDC13): d 8.56 (broad s, 2H, Pirid.), 8.34 (s, 1H, H-6, Pirim.), 7.29 (m, d, 4H, Pirid., PhCl), 7.20 (d , 2H, PhCl), 7.08, 7.02 (2m, every 2H, PhF), 5.35 (t, 1H, NH), 3.78 (q, CH2N), 2.96 (t, 2H, CH2). 2-10 2- (2- (4-Bromophenyl) -ethylamino) -5- (4-fl uorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 449.0 (M) +; C23H? 8BrFN4 required. 449.3. NMR-aH (CDC13): d 8.58, 7.47 (m, 2H, pyrid.), 8.37 (s, 1H, H-6, pyrim.), 7.29, 7.17 (2d, every 2H, PhCl), 7.10, 7.02 ( 2d, every 2H, PhF), 5.34 (t, 1H, NH), 3.80 (q, 2H, CH2N), 2.97 (t, 2H, CH2).

Rl =. r-9 '2-H 5- (4-Fluorophenyl) -2- (2- (4-hydroxyphenyl) -ethylamino) -4 (4-pyridyl) pyrimidine: A mixture of 2-chloro-5- (4-fluorophenyl) ) -4- (4-pyridyl) -pyrimidine (61 mg, 0.21 mmol), tyramine hydrochloride (186 mg, 1.01 mmol) and sodium hydrogen carbonate (90 mg, 1.07 mmol) in aqueous ethanol (1 mL) was heated at reflux for 1 hour. Evaporation of the solvent and subsequent column chromatography (5% methanol / dichloromethane) afforded the title compound as a yellow solid. MS (m / z): 387.2 (M + H) +; C23H19FN40 required 386.4. RMN-1 !! (DM? O-d6): d 9.12 (broad s, 1H, OH), 8.54, 7.26 (2m, every 2H, Pirid.), 8.38 (s, 1H, H-6, Pirim.), 7.52 (t, 1H, NH), 7.20-7.10 (m, 4H, PhF), 7.05, 6.69 (2d, every 2H, PhOH), 3. 52 (q, 2 H, CH2N), 2. 7 8 (t, 2 H, CH 2); H 2-12 2- (2- (Aminophenyl) -ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: A solution of 2-chloro-5- (4-fluorophenyl) -4 - (4-pyridyl) -pyrimidine (71 mg, 0.25 mmol) and 2- (4-aminophenyl) ethylamine (0.5 ml, 3.80 mmol) in ethanol (1.5 ml) was heated to reflux for 20 minutes. Evaporation and subsequent chromatography on a silica gel column (2% methanol / dichloromethane) gave the title compound as a yellow syrup. MS (m / z): 386.4 (M + H) +; C23H20FN5 required 385.5. NMR-aH (CDC13): d 8.56, 7.32 (2m, every 2H, Pirid.), 8.35 (s, 1H, H-6 Pirim.), 7.12-6.99 (m, 6H, PhF, PhNH2), 6.68 (d , 2H, PhNH2), 5.37 (t, 1H, NH), 3.75 (q, 2H, CH2N), 2.88 (t, 2H, CH2). 2-13 5- (4-Fluorophenyl) -2- (2- (2-f luorofenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 389.2 (M + H) +; C23H? 8F2N4 required 388.4. NMR-aH (CDC13): 8.57 (m, 2H, Pirid.), 8.35 (5, 1H, H-6, Pirim.), 7.34-7.20, 7. 14-7.00 (2m, 10H, 2PhF, Pirid.), 5.42 (broad t, 1H, NH), 3.82 (q, 2H, CH2N), 3.05 (t, 2H, CH2). 2-14 2- (2- (2-Chloro phenyl) -ethylamino)) -5- (4-f luorofenil) -4- (4-pyridyl) pyrimidine: MS (m / z): 405.0 (M + H) +; C23H? 8ClFN4 required. 404.9. XH NMR (CDC13): d 8.57 (m, 2H, Pyrid.), 8.36 (s, 1H, H-6, Pirim.), 7.40-7.00 (m, 10H, PhF, PhCl2, Pyrid.), 5.44 ( t broad, 1H, NH), 3.84 (q, 2H, CH2N), 3.15 (t, 2H, CH2). 2-15 5- (4-Fluorophenyl) -2- (2- (2-methoxy-enyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 401.2 (M + H) +; C24H2? FN40 required. 400.5 NMR-XH (CDC13): d 8.56, 7.30 (2m, each 2H, Pyrid.), 8.34 (s, 1H, H-6, Pirim.), 7.24, 7.08, 7.02, 6.92 (4m, each 2H, PhF , PhOMe), 5.50 (broad t, 1H, NH), 3.87 (s, 3H, CH3), 3.78 (q, 2H, CH2N), 3.02 (t, 2H, CH2). 2-162- (2- (2,4-Di-chloro-phenyl) -ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) pyrimidine: MS (m / z): 439.0 (M) +; C23H17C12FN4 required 439.3. NMR ^ H (CDC13): 8.56 (s broad, 2H, Pirid.), 8.34 (5, 1H, H-6, Pirim.), 7.37 (s, 1H, PhCl), 7.30 (broad d, 2H, Pirid. ), 7.22-7.15 (m, 2H, PhCl), 7.08, 7.05 (2m, every 2H, PhF), 5.40 (t, 1H, NH), 3.80 (q, 2H, CH2N), 3.10 (t, 2H, CH2 ). 2-17 2- (2- (2,6-Dichlorophenyl) -ethylamino) -5- (4-fl uorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 439.0 (M) +; C23H? 7Cl2FN4 required. 439.3. NMR-XH (CDC13): 8.57 (m, 2H, Pyrid.), 8.36 (s, 1H, H-6, Pirim.), 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, CH2N), 3.38 (t, 2H, CH2). 2-185- (4- Fluorophenyl) -2- (2- (3-methoxy phenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 401.2 (M + H) +; C24H2? FN40 required. 400.5. RMN-1 !! (CDC13): d 8.56 (m, 2H, Pyrid.), 8.34 (s, 1H, H-6, Pirim.), 7.32-7.22, 7.11-6.98, 6.89-6.77 (3m, 10H, PhF, PhOMe, Pyrid .), 5.38 (t, 1H, NH), 3.82 (m, 5H, CH2N, CH2), 2.96 (t, 2H, CH2). 2-19 2- (2- (3-C-phenyl) -ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 405.4 (M + H) +; C23H1BC1FN4 required 404.9. NMR-XH (CDC13): d 8.60 (d, 2H, Pirid.), 8.38 (s, 1H, H-6, Pirim.), 7.32-7.24 (m, 5H, Pirid., PhCl), 7.18 (, 1H, PhCl), 7.11, 7.04 (2m, every 2H, PhF), 5.35 (t, 1H, NH), 3.83 (q, 2H, CH2N), 3.00 (t, 2H, CH2). 2-205- (4-Fluorophenyl) -2- ((2-hydroxy-2-phenyl) -ethylamino) -4- (4-pyridyl) -pyrimidine: A 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 hours. Evaporation and squent chromatography on a silica gel column (4% methanol / dichloromethane) gave the title compound as a yellow foam. MS (m / z): 387.0 (M + H) +; C23H? 8FN40 required. 386.4. RMN-1 !! (CDC13): d 8.58 (d, 2H, pyrid.), 8.38 (s, 1H, H-6, pyrim.), 7.47 (d, 2H, Ph), 7.41 (t, 2H, Ph), 7.34 (t , 1H, Ph), 7.28 (d, 2H, pyrid.), 7.10, 7.02 (2m, 2H, PhF), 5.72 (t, 1H, NH), 5.06 (m CHOH)), 4.02-3.92 (m, 2H , OH, 1CH3), 3.72 (ddd, 1H, 1CH2). 2-21 5- (4-Fluoro-phenyl) -2- (methyl-2- (2-f-phenylethyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 385.0 (M + H) +; C24H2? FN4 required. 384.5. XH NMR (CDC13): d 8.57, 7.35 (2m, each 2H, Pyrid.), 8.40 (s, 1H, H-6, Pirim.), 7.34-7.21 (m, 5H, Ph), 7.10, 7.03 ( 2m, every 2H, PhF), 3.96 (t, 2H, CH2N), 3.23 (s, 3H, CH2), 3.00 (t, 2H, CH2). 2-22 5- (4-Fluoro-phenyl) -2- ((3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 385.2 (M + H) +; C24H2? FN4 required. 384.5. NMR-XH (CDC13): d 8.56 (m, 2H, pyrid.), 8.34 (s, 1H, H-6, pyrim.), 7.34-7.20 (m, 7H, Ph, pyrid.), 7.08, 7.01 ( 2m, every 2H, PhF), 5.38 (t, 1H, NH), 3.58 (q, 2H, CH2N), 2.78 (t, 2H, CH2), 2.03 (m, 2H, CH2).

Rl -cr- '. 2-23 5- (4-Fluorophenyl) -2- ((l-methyl-3-f-enylpropyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 399.0 (M + H) +; C25H23FN4 required 398.5. NMR-aH (CDC13): d 8.56 (m, 2H, Pirid.), 8.32 (s, 1H, H-6, Pirim.), 7.32-7.17 (m, 7H, Pirid., Ph), 7.09-7.02 ( 2m, every 2H, PhF), 5.16 (d, 1H, NH), 4.28 (m, 1H, CH), 2.77 (m, 2H, CH2), 1.94 (m, 2H, CH2), 1.34 (d, 3H, CH3). 2-24 5- (4-Fluorophenyl) -2- ((3-imidazolylpropyl) -amino) -4- (-pyridyl) -pyrimidine: MS (m / z): 375.0 (M + H) +; C21H? 9FN4 required. 374.4. RMN-1 !! (CDC13): d 8.57, 7.26 (2m, every 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 7.56 (s, 1H, Imid.), 7.16-6.96 (m, 6H, PhF, Imid.), 5.38 (broad t, 1H, NH), 4.12 (t, 2H, CH2N), 3.56 (q, 2H, CH2NH) 2.20 (m, 2H, CH2).

Rl 2-255- (4-Fluorophenyl) -2- ((4-f-enyl-n-butyl) -amino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 399.0 (M + H ) +; C25H23FN4 required 398.5. NMR-aH (CDC13): d 8.56 (m, 2H, pyrid.), 8.34 (s, 1H, H-6, pyrim.), 7.33-7.17 (m, 7H, Ph, pyrid.), 7.08, 7.02 ( 2m, every 2H, PhF), 5.33 (broad t, 1H, NH), 3.56 (q, 2H, CH2N), 2.71 (t, 2H, CH2), 1.76 (m, 4H, 2CH2). H 2-26 5- (4-Fluorophenyl) -2- (1-piperazinyl) -4- (4-pyridyl) -pyrimidine: A 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 minutes. Evaporation and subsequent chromatography on a silica gel column (5% methanol / dichloromethane) afforded the title compound as a yellow solid. MS (m / z): 336.2 (M + H) +; C19H18FN5 required 335.4. NMR-'H (CDC13): d 8.54, 7.29 (2m, every 2H, Pirid.), 8.37 (s, 1H, H-6, Pirim.), 7.08, 7.00 (2m, every 2H. PhF), 3.95 ( t, 4H, 2CH3), 3.01 (t, 4H, 2CH2).

/ ^ Rl = N N- 2-27 5- (4-Fluoro-phenyl-2- (1-piperidinyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 335.2 (M + H) +; C20H? 9FN4 required 334.4. NMR-aH (CDC13): d 8.55, 7.30 (2m, every 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 7.08, 7.01 (2m, 2H, PhF), 3.91 (t, 4H, 2CH2N), 1.74, 1.68 (2m, 6H, 3CH2).

Rl -O- 2-28 5- (4-Fluorophenyl) -2- (4-methy1-1-piperazinyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 350.0 (M + H) +; C20H20FN5 required 349.4. NMR-'H (CDC13): d 8.58, 7.32 (2m, every 2H, Pirid.), 8.40 (s, 1H, H-6, Pirim.), 7.10, 7.04 (2m, every 2H, PhF), 4.00 ( t, 4H, 2CH2), 2.57 (t, 4H, 2CH2), 2.42 (s, 3H, CH3).

Rl = H5 • N- 2-29 5- (4-Fluorophenyl) -2- (4-phenyl-1-piperazinyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 412.2 (M + H) +; C25H22FN5 required 411.5. NMR-aH (CDC13): d 8.58 (broad d, 2H, Pirid.), 8.42 (s, 1H, H-6, Pirim.), 7.38-7.30 (, 4H, Pirid., Ph), 7.15-7.00 ( m, 6H, PhF, Ph), 6.94 (t, 1H, Ph), 4.13 (t, 4H, 2CH2), 3.33 (t, 4H, 2CH2). 2-30 5- (4-Fluorophenyl) -2- (2-morpholinoethylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 380.4 (M + H) +; C2? H22FN50 required. 379.4. NMR-'H (CDC13): d 8.58, 7.30 (2m, every 2H, Pirid.), 8.38 (s, 1H, H-6, Pirim.), 7.10, 7.03 (2m, every 2H, PhF), 5.91 ( s broad, 1H, NH), 3.79 (broad s, 4H, 2CH2), 3.66 (broad s, 2H, CH2), 2.71 (broad s, 2H, CH2), 2.59 (broad s, 4H, 2CH2). 2-31 5- (4-Fluorophenyl) -2- (2-piper i diño e tilamino) -4- (4-pyridyl) -pyridine: MS (m / z): 378.2 (M + H) +; C22H24FN5 required 377.5 RMN ^ H (CDC13): d 8.54, 7.27 (2d, every 2H, Pirid.), 8.34 (s, 1H, H-6, Pirim.), 7.06, 7.00 (2m, every 2H, PhF), 6.04 ( broad t, 1H, NH), 3.66 (q, 2H, CH2NH), 2.74 (t, 2H, CH2), 2.61 (broad s, 4H, 2CH2), 1.68 (m, 4H, 2CH2), 1.50 (m, 2H , CH2). 2-32 5- (4-Fluoro-phenyl) -4- (4-pyridyl) -2- (2-pyrrolidinoethylamino) -pyrimidine: MS (m / z): 364.0 (M + H) +; C2? H22FN5 required. 363.4 H-NMR (CDC13): d 8.55, 7.28 (2m, every 2H, Pirid.), 8.36 (s, 1H, H-6, Pirim.), 7.08, 7.02 (2m, every 2H, PhF), 6.28 ( t, 1H, NH), 3.86 (q, 2H, CH2NH), 3.18 (t, 2H, CH2N), 3.10 (broad s, 4H, 2CH2N), 2.02 (broad s, 4H, 2CH2). 2-33 5- (4-Fluorophenyl) -2- (3-morpholinopropylamino) -4- (4-pyridyl) -pyrimidine: MS (m / z): 394.2 (M + H) +; C22H24FN50 required 393.5. X-NMR (CDC13): d 8.54, 7.27 (2m, every 2H, Pirid.), 8.33 (5, 1H, H-6, Pirim.), 7.06, 7.00 (2m every 2H, PhF), 6.00 (t, 1H, NH), 3.76 (t, 4H, 2CH20), 3.60 (q, 2H, CH2NH), 2.52 (t, 2H, CH2N), 2.50 (m, 4H, CH2N), 1.86 (m, 2H, CH2).

R1 = ~ N "N" H 2-34 5- (4-Fluorophenyl) -2- (3- (2-pyrrolidinon-1-yl) -propylamino) -4- (4-pyridyl) -pyridine: MS (m / z): 392.2 (M + H) +; C22H22FN50 required 391.5. NMR-aH (CDC13): d 8.58, 7.30 (m, 2H, Pirid), 8.36 (s, 1H, H-6, Pirim.), 7.10, 7.04 (m, 2H, PhF), 5.88 (t, 1H, NH), 3.56 (q, 2H, CH2NH), 3.48, 3.45 (2t, every 2H, 2CH2), 2.46 (t, 2H, CH2), 2.08 (m, 2H, CH2), 1.90 (m, 2H, CH2) . 2-35 2- (((S) -2-amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyridine hydrochloride: MS (m / z): 400.1 (M + H) +; C24H22FN5 required 399.5 (free base). 2-36 2- (((S) -2-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine-chlorohydrate: The 2-chloro was reacted -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine and the (S) -1, 2-benzylethylenediamine according to General Procedure, Step C (70 ° C for 75 minutes) to give the title compound. MS (m / z 450.4 (M + H) +; C25H22F3N5 required 4449.5 (free base). 2-37 (((S) -2-amino-3-phenylpropyl) -amino) -5- (3-methyl phenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: The 2- chloro-5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine and (S) -1,2-benzylethylenediamine according to the General Procedure, Step C (100 ° C for 20 minutes) to give the composed of the title. MS (m / z): 396.2 (M + H) +; C25H25N5 required 395.5 (free base). 2-382 (((S) -2-N, N-Dimethylamino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: The 2-chloro was reacted -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine and (S) -2-N-dimethylamino-3-phenylpropylamine according to the General Procedure, Step C (100 ° C for 45 minutes ) to give the title compound. MS (m / z): 427.8 (M + H) +; C26H26F? 5 required. 427.5. 2-392- (((S) -2-N-Dimethylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine: The 2-chloro was reacted -5 (3-methylphenyl) -4- (4-pyridyl) -pyrimidine and (S) -2-N, N-dimethyl-amino-3-phenylpropylamine according to the General Procedure, Step C (100 ° C for 30 minutes). minutes) to give the title compound. MS (m / z): 424.2 (M + H) +; C2 H29F? 5 required. 423.6. 2-40 (2- (3-Amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: The 2-chloro-5- ( 4-fluorophenyl) -4- (4-pyridyl) -pyrimidine and 1-phenyl-1,3-propanediamine according to the General Procedure, Step C (100 ° C for 30 minutes) to give the title compound. MS (m / z): 4001. (M + H) +; C24H22F? 5 required. 399.5 (free base). 2-41 ((3-Amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyridine hydrochloride: The 2-chloro-4- ( 4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine and l-phenyl-1,3-propanedimine according to the General Procedure, Step C (100 ° C for 1 hour) to give the title compound. MS (m / z): 450.3 (M + H) +; C2 H22F3N5 required 449.5 (free base). 2-42 ((3-Amino-3- (2-fluorophenyl) propyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: The 2- chloro-4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine and 1- (2-fluorophenyl) -1,3-propanediamine according to the General Procedure, Step C (100 ° C for 30 minutes) to give the title compound. MS (m / z): 468.4 (M + H) +; C25H2? F4N5 required. 467.5 (free base). 2-43 2- ((3-Amino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: The 2-chloro-5- ( 3-methylphenyl) -4- (4-pyridyl) -pyrimidine and 1-phenyl-1,3-propanediamine according to the General Procedure, Step C (100 ° C for 30 minutes) to give the title compound. MS (m / z): 396.1 (M + H) +; C25H25N5 required 395.5 (free base). 2-44 2- ((2-Amino-2-methyl-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: The 2-chloro was reacted -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine and 2-amino-2-methyl-3-phenylpropylane in accordance with the General Procedure, Step C (100 ° C for 30 minutes) for give the title compound. MS (m / z): 410.2 (M + H) +; C26H27N5 required 409.5 (free base).

Rl = "'2-45 2- ((3-Hydroxy-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine: The 2-chloro-5 was reacted - (3-methylphenyl) -4- (4-pyridyl) -pyrimidine and 3-hydroxy-3-phenylpropylamine according to the General Procedure, Step C (100 ° C for 30 minutes) to give the title compound. MS (m / z): 397.2 (M + H) +; C25H24N40 required 396.5. 2-46 ((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 (IR, 2R) -2-methyl-1-phenyl-1,3-propanediamine were reacted according to the procedure General, Step C (50 ° C for 1 hour) to give the title compound. MS (m / z): 464.4 (M + H) +; C26H24F3N5 required 463.5 (free base).

Rl = 2-47 2- (((2S, 3S) -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 (SS, 2S) -2-methyl-1-phenyl-1,3-propanediamine were reacted according to General Procedure, Step C (90 ° C for 45 minutes) to give the title compound. MS (m / z): 464.1 (M + H) +; C26H24F3N5 required 463.5 (free base). 2-48 2- ((S) -3-benzylpiperazinyl) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyridine hydrochloride: The 2-chloro-4- (4-pyridyl) was reacted -5- (3-trifluoromethylphenyl) -pyrimidine and (S) -2-benzylpiperazine according to the General Procedure, Step C (70 ° C for 30 minutes) to give the title compound. MS (m / z): 475.5 (M + H) +; C27H24F3N5 required 476.1 (free base).

Rl -ero 2-49 4- (4-pyridyl) -2- (((S) tetrahydroisoquinol-3-ylmethylene) amino) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: The 2-chloro- 4- (4-pyridyl) -5 (3-trifluoromethylphenyl) -pyrimidine and (S) -tetrahydroisoquinol-3-ylmet-lenamine according to the General Procedure, Step C (50 ° C for 1.5 hours) to give the compound of the title. MS m / z): 462.4 (M + H) +; C26H22F3N5 required 461.5 (free base). 2-50 S- (3-Methylphenyl) -4- (4-pyridyl) -2- (((S) -tetrahydroisoquinol-3-ylmethylene) amino) -pyrimidine: The 2-chloro-5- (3 methylphenyl) -4- (4-pyridyl) -pyrimidine and (S) -tetrahydroisoquinol-3-ylmethyleneamine according to the General Procedure, Step C (100 ° C for 45 minutes) to give the title compound. MS (m / z): 408.2 (M + H) +; C26H25N5 required 407.5 (free base).

Rl -COT- Example 3 General procedure for the preparation of 2-acylamino-5- (4-f-lorofenyl) -4 - (4-pyridyl) pyrimidines Chlorocarbonyl RC (0) C1 (0.57 mmol) was added dropwise to a solution of 2-amino-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine (0.38 mmol) in pyridine (3 ml. ) at bath temperature with ice. It was stirred for 3 hours at room temperature, monitored by thin layer chromatography, drained in ice water, extracted with dichloromethane, dried and evaporated. The crude product was purified by silica gel column chromatography (hexane-acetone) and recrystallized with a suitable solvent such as ethyl acetate. The following compounds were prepared using an appropriate acid chloride according to this procedure: 3-1 2 -Acet amido-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 309.0 (M + H) +; C17H? 3FN40 required. 308. 3. NMR-XH (CDC13): d 8.63 (s, 1H, H-6, Pirim.), 8.60, 7.29 (2m, every 2H, Pirid.), 8.26 (broad s, 1H, NH), 7.14, 7.08. (2m, every 2H, PhF), 2.58 (s, 3H, CH3CO). R = CH3 - 3-2 2-Butyramido-5- (-f luorofenyl) -4- (4-pyridyl) -pyrimidine: MS (m / z): 337.2 (M + H) +; Ca9H? 7FN40 required. 336. 4. NMR-XH (CDC13): d 8.64, (s, 1H, H-6, Pirim.), 8.60, 7.31 (2m, every 2H, Pirid.), 8.17 (broad s, 1H, NH), 7.14, 7.08 (2m, every 2H, PhF), 2.80 (t, 2H, CH2CO), 1.82 (m, 2H, CH2), 1.06 (t, 3H, CH3). R = CH3CH2CH2- 3-3 5- (4-Fluorofenyl) -2-p i is lamido-4- (4-pyridyl) -pyrimidine: MS (m / z): 351.0 (M + H) +; C20H? 9FN O required. 350.4. NMR-aH (CDC13): d 8.69 (s, 1H, H-6, Pirim.), 8.60, 7.35 (2m, every 2H, Pirid.), 8.25 (broad s, 1H, NH), 7.15, 7.08 (2m , every 2H, PhF), 1.4 (s, 9H, 3CH3). R = (CH3) 3C- 3- 2-Benzamido-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: MS Cm / z): 371.0 (M + H) +; C22H15FN40 required 370. 4. NMR-: H (CDC13): d 8.75 (s, 2H, NH, H-6, Pirim.), 8.61, 7.36 (2m, every 2H, pyrid.), 8.00, 7.63, 7.55 (d.t. t, 2H, 1H, 2H, Ph), 7.18, 7.10 (2m, every 2H, PhF). 3-5 5- (4-Fluoro-phenyl) -2-phenylacetamido-4- (4-pyridyl) -pyrimidine: MS (m / z): 385.0 (M + H) +; C23Ha FN0 required 384.4. NMR-aH (CDC13): d 8.66 (s, 1H, H-6, Pirim.), 8.59, 7.28 (2m, every 2H, pyrid.), 8.21 (broad s, 1H, NH), 7.43-7.30 (m , 5H, Ph), 7.14, 7.08 (2m, every 2H, PhF), 4.13 (s, 2H, CH2). 3-6 5- (4-Fluorophenyl) -2-hydrocinnamamido-4- (4-pyridyl) -pyrimidine: MS (m / z): 399.2 (M + H) +; C24Hi9FN40 required 398.4. NMR-: H (CDC13): d 8.60 (s, 1H, H-6, Pirim.), 8.54 (m, 2H, pyrid.), 8.20 (broad s, 1H, NH), 7.31-7.16 (m, 7H , Ph, Pirid.), 7.11, 7.05 (2m, every 2H, PhF), 3.20, 3.09 (2t, every 2H, 2CH2).

EXAMPLE 4 General procedure for the preparation of 5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidones 2- substituted to. 2- (4-fluorophenyl) -3- (4-pyridyl) -acrylic acid A 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 at 150 ° C for 1 h followed by evaporation and co-distillation with water. The resulting material was crystallized in the addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to provide the title compound. MS (m / z): 244.0 (M + H) +; Ca4H10FNO2 required 243.2 NMR-aH (DMS0-d6): d 8.43, 6.98 (2d, each 2H, Pirid.), 7.73 (s, 1H, CH =), 7.21 (d, 4H, PhF). b. 2- (4-Fluorophenyl) -3- (4-pyridyl) -ethyl acrylate: The concentrated sulfuric acid (2.2 ml) was carefully added to a suspension of 2- (4-fluorophenyl) -3- (4-pyridyl) ) -acyclic (6.7 g, 27.5 mmol) in ethanol (120 ml) and the mixture was refluxed for 2 hours. The solvent was evaporated, the rest was taken up in dichloromethane and the organic solution was washed with aqueous sodium hydrogen carbonate and water, followed by drying and evaporation. Flash column chromatography on silica gel (hexane-acetone = 2: 1) afforded the pure title compound. MS (m / z): 271.8 (M + H) +; C? 6H? 4FN02 required. 271.3 NMR-aH (CDC13): 8.44, 6.88 (2m, every 2H, Pirid.), 7.72 (s, 1H, CH =), 7.16, 7.06 (2m, every 2H, PhF), 4.28 (q, 2H, CH2 ), 1.28 (t, 3H, CH3). c. General procedure: A stirred mixture of 2- (4-fluorophenyl) -3- (4-pyridyl) -ethyl acrylate (357 mg, 1.38 mmol), amidine hydrochloride (2.61 mmol) and sodium methoxide (250 mg, 4.62 mmole) in ethanol (5 ml) was heated in a sealed tube at 120 ° C for 3 hours. It was neutralized with 2N hydrochloric acid before evaporation. The residue was taken up in acetic acid (25 ml) and treated with sodium nitrite (670 mg, 9.71 mmol) at 44 ° C for 20 minutes. After evaporation, the resulting product was taken up in dichloromethane and the solution was washed with aqueous sodium hydrogen carbonate and water before drying and evaporation. The product was purified by recrystallization with methanol. If the crude product of nitrite oxidation was soluble in water, as was found for 5- (4-fluorophenyl) -2-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, then the treatment was not made aqueous, but the material obtained in the evaporation was applied to a column of silica gel (5% methanol / dichloromethane) before recrystallization. The following compounds were prepared in accordance using the appropriate amidine hydrochloride: 4-1 5- (4-Fluorophenyl) -2-methyl-1-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 282.2 (M + H) +; C 6H12FN30 required 281.3 X-NMR (DMSO-d6): d 8.46 (m 2 H, Pirid.), 7.2-7.03 (m, 6H, PhF, Pirid.). 2.38 (s, 3H, CH3). Rl = CH3 - 4-2 5- (4-Fluor or phenyl) -2-isopropyl-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 310.0 (M + H) +; d8H16FN30 required 309.4 X-NMR (DMSO-d6): 8.45 (m, 2H, pyrid.), 7. 21-7.03 (m, 6H, PhF, Pirid.), 2.90 (m, 1H, CH (CH3) 2,) 1. 26, 1.24 (2s, each 3H, 2CH3). Rl = (CH3) 2CH- 4-3 2- (2,6-Dichlorobenzyl) -5- (4-f luorofenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 426.0 (M) +; C22H? 4Cl2FN30 required. 426.3 NMR-XH (DMSO-d6): d 8.37 (m, 2H, pyrid.), 7.50 (d, 2H, PhCl2), 7.35 (t, 1H, PhCl2), 7.18-7.08 (m, 4H, PhF), 6.96 (m, 2H, pyrid.), 4.36 (s, 2H, CH2).

Rl β 4-4 5- (4-Fluorophenyl) -2-phenyl -6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 344.2 (M + H) +; C2? H? 4FN30 required. 343.4 NMR-aH (DMSO-d6): d 8.49 (d, 2H, pyrid.), 8.20 (d, 2H, Ph), 7.66-7.50 (m, 3H, pyrid., Ph), 7.32-7.11 ( m, 6H, PhF, Ph).

Rl 4-5 -5s- (4-Fluorophenyl) -2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone: 2- (4-fluorophenyl) -3-oxo-3- Ethyl (4-pyridyl) -propionate (293 mg, 1.02 mmol), the 4-phenylbutanecarboxamidine (315 mg, 1.79 mmol) and the pyridinium p-toluensulfonate (10 mg) were suspended in p-xylene (10 ml). With efficient stirring, the mixture was heated to reflux using an apparatus Dean-Stark with continuous water removal. After 16 hours, the solvent was evaporated and the product was purified by column chromatography on silica gel (3% methanol / dichloromethane) followed by recrystallization of acetone. MS (m / z): 400.3 (M + H) +; C25H22FN30 required 399.5 Rl = Ph (CH2) 4- Example 5 General procedure for the preparation of 5- (4- fl uorophenyl) -6- (4-pyridyl) -2-ti or alkyl -4 (3H) -pyrimidines Step A. 2- (4-Fluorophenyl) -3-oxo-3- (4-pyridyl propionyl ethyl) (According to: Legrand and Lozac'h, Bul l. Soc. Chim. Fr., 79-81 (1955)). A mixture of ethyl 4-fluorophenylacetate (13 g, 71.35 mmol), ethyl isonicotinate (10.7 ml, 71.4 mmol) and sodium spheres (1.64 g, 71.34 mmol) was heated to 90-95 ° C under argon. The mixture was heated to reflux and gradually returned to a solid. After 2.5 hours, the mixture was neutralized with dil acetic acid. with cooling followed by extraction with dichloromethane. The organic solution was washed with water, dried and evaporated. Flash chromatography on a silica gel column (hexane-acetone = 4: 1, 3: 1, 2: 1) afforded the title compound as an oil. MS (m / z): 287.8 (M + H) +; C? 6H? 4FN03 required. 287.3 RMN-1 !! (CDC13), (ketone: enol = 1: 0.33): d 13.50 (s, 0.3H, OH-E), 8.81 (m, 2H, pyrid.-K), 8.48 (m, 0.66 H, pyrid. ), 7.72 (m, 2H, Pirid.-K), 7.38 (m, 2H, PhF-K), 7.14-7.04 (m, 2H, PhF-K, -0.65H, Pyrid.E; -0.65H, PhF -E), 6.96 (t, 0.64H, PhF-E), 5.51 (s, 1H, CH-K), 4.23-4.2- (, CH2-K, E), 1.26 (t, CH3-K, E) . Step B. 5- (4-fluorophenyl) -6- (4-pyridyl) -2-thiouracil: A stirred mixture of ethyl 2- (4-fluorophenyl) -3-oxo-3- (4-pyridyl) -propionate (22.3 g, 77.6 mmole) and thiourea (5.9 g, 77.6 mmole) was reacted at 190 ° C. under argon for 40 minutes. The reaction mixture was allowed to reach room temperature, taken up in acetone and the precipitate was filtered to provide the title compound. MS (m / z): 300.2 (M + H) +; C? 5H10FN3OS required 299.3 NMR-XH (DMSO-de): d 12.74, 12.65 (2s, 2H), 8.51 (m, 2H, Pirid.), 7.26 (m, 2H, Pirid.), 7.09 and 7.03 (2m, every 2H, PhF ).

Alternatively, ethyl 2- (4-fluorophenyl) -3-oxo-3- (4-pyridyl) -propionate (2.87 g, 10 mmol) and thiourea (2.28 g, 30 mmol) were suspended in p-xylene anhydrous (50 ml) with very efficient stirring. The mixture of pyridinium p-toluenesulfonate (100 mg) was added and heated to reflux for 12-16 hours using a Dean-Stark apparatus with continuous water removal (0.2 ml). The reaction mixture was cooled and a dark brown solid was filtered using a Buchner funnel. The collected solid was suspended in acetone (25 ml) and filtered. The product washed with acetone contained a very small amount of thiourea, which was removed by trituration with hot water (20-30 ml). The product was filtered and dried with air.

Step C. General procedure: Arylalkyl bromide (0.36 mmol) was added dropwise to a stirred mixture of 5- (4-fluorophenyl) -6- (4-pyridyl) -2-thiouracil (100 mg, 0.33 mmol) and potassium carbonate (46 mg, 0.33 mmol) in N, N-dimethylformamide (4.6 ml). Stirring was continued for 3 hours followed by evaporation. Flash chromatography on a silica gel column (hexane-acetone = 3: 1, 2: 1, 1: 1) and recrystallization from hot methanol gave the objective compound. The following compounds were obtained using the appropriate arylalkyl bromide according to the above procedure: -1 5- (4-Fluorophenyl) -2- (2-phenylethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 404.2 (M + H) +; C23H18FN3OS required 403.4. NMR-aH (DMSO-d6): d 13.08 (broad s, 0.7H), 8.49 (m, 2H, Pirid.), 7.30-7.06 (m, 11H, Pirid., Ph, PhF), 3.41 (dd, 2H , CH2S), 3.00 (t, 2H, 0H2). -2 5- (-Fluorophenyl) -2- (3-phenylpropyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 418.0 (M + H) +; C24H20FN3OS required 417.5. NMR-XH (DMSO-d6): d 13.10 (broad s, 0.7H), 8.47 (m, 2H, Pirid.), 7.29-7.06 (, 11H, Pirid., Ph, PhF), 3.18 (t, 2H, CH2S), 2.71 (t, 2H, Cii2Ph), 2.03 (m, 2H, CH2). •• -ce 5-3 5- (4- Fluorophenyl) -2- (2-f-enoxyethyl) thio-6- (4-pyridyl-4 (3H) -pyrimidinone: MS (m / z): 420.0 (M + H) +; C23H? 8FN302S required 419.5 NMR-XH (DMSO-d6): d 13.20 (broad s, 0.7H), 8.46 (m, 2H, Pirid.), 7.24-7.07 (m, 8H, Pirid ., PhF, Ph), 6.95 (d, 2H, Ph), 6.92 (t, superimposed, 1H, Ph), 4.30 (t, 2H, CH20), 3.58 (t, 2H, CH2S). -4 5- (4-Fluorofenyl) -2- (2-f-enylamino-ethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z); 419.0 (M + H) +; C23H? 9FN4OS required 418.5. NMR-2H (DMSO-d6): d 13.20 (broad s, 0.8H), 8.48, 7.22 (2m, every 2H, Pirid.), 7.16, 7.10 (2m, every 2H, PhF), 6.89 (t, 2H, Ph), 6.54 (d, 2H, Ph), 6.48 (t, 1H, Ph), 5.90 (broad s, 0.6H, NH), 3.43-3.25 (m, 2CH2).

EXAMPLE 6 General procedure for the preparation of 2-amino-5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinones 2-N substituted 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) and potassium carbonate. (198 mg, 1.43 mmol) in N, N-dimethylformamide (13 ml) at bath temperature with ice. After 40 minutes, 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? 6H? 2F? 3OS required. 313.3. RM? -tE (DMSO-d6): d 13.10 (s broad), 8.47, 7.22 (2m, every 2H, Pirid.), 7.16, 7.10 (2m, every 2H, PhF), 2.56 (s, 3H, CH3) .

Step B. General procedure: A mixture of 5- (4-fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone (100 mg, 0.32 mmol) and an amine HNR5R21 (1 mmol) was heated to 180 ° C. for 2 hours. The resulting product was purified by flash chromatography on a column of silica gel (hexane-acetone or methanol-dichloromethane or dichloromethane-methanol-concentrated ammonium hydroxide) to provide the objective compound. The following compounds were prepared using the procedure outlined above and an appropriate amine: 6-1 2- (2- (2-Chlorophenyl) ethyl-ano) -5- (-fluorophenyl) -6- (-pyridyl) -4 (3H) pyrimidinone: MS (m / z) 421.2 (M + H ) +; C23H18C1FN40 required 420.9. NMR-aH (DMSO-d6): d 11.24 (s broad), 8.44, 7.16 (2m, every 2H, Pirid.), 7.43, 7.38 (2dd, every 1H, PhCl), 7.30, 7.26 (2dt, every 1H, PhCl), 7.10-7.00 (m, 2H, PhF), 6.74 (broad s, 1H, NH), 3.60 (q, 2H, CH2N), 3.03 (t, 2H, CH2). 6-2 5- (4- Fluoro-phenyl) -2- ((3-f-enylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 401.2 (M + H) +; C2 H2? FN40 required 400.5. NMR-XH (DMSO-d6): d 11.16 (s broad), 8.44, 7.14 (2m, each 2H, Pirid.), 7.32-7.01 (m, 9H, Ph, PhF), 6.78 (broad s, NH), 3.36 (q, 2H, CH2N), 2.67 (t, 2H, CH2? H), 1.89 (m, 2H, CH2). 6-3 5- (4-Fluorophenyl) -2- ((1-met il -3-f-enylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone: A reaction time was required from 15 hours to 180 ° C. MS (m / z): 415.0 (M + H) +; C25H23FN40 required 414.5. X-NMR (CDC13): d 8.48 (m, 2H, Pirid.), 7.28-7.08 (m, 9H, Pirid., Ph, PhF), 6.94 (m, 2H, PhF), 5.67 (broad s, 1H, NH), 4.08 (m, 1H, CÍÍCH3), 2.61 (t, 2H, Ctf2Ph), 1.67 (m, 2H, CH2), 1.08 (d, 3H, CH3). - 6-4 5- (4-Fluorofenyl) -2- ((3-imidazolylpropyl) -amino) -6- (4-pyridyl) -4 (3ff) -pyrimidinone: MS (m / z): 391.0 (M + H) +; C2? H19FN60 required. 390.4. NMR-XH (DMSO-d6): d 11.24 (broad s), 8.42, 7.12 (2m, every 2H, Pirid.), 7.62, 7.18 (2s, every 1H, Imid.), 7.08-6.99 (m, 4H, PhF), 6.88 (s, 1H, Imid.), 4.02 (t, 2H, CH2N), 3.28 (superimposed by the water signal, CH2NH), 2.00 (m, 2H, CH2). 6-5 2- (((S) -2-amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: The reaction was made at 170 ° C for 7 hours. MS (m / z): 416.1 (M + H) +; C26H22FN50 required 415.5.

Example 7 5- (4-Fluorophenyl) -2-hydrazino-β- (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 60 min. It was evaporated and the reaction product was recrystallized with hot methanol to provide the title compound. MS (m / z): 298.0 (M + H) +; C? 5H? 2FN50 required. 297.3. NMR ^ H (DMSO-d6): d 8.41, 7.12 (2m, every 2H, pyrid.), 7.05, 7.00 (2m, every 2H, PhF). R1 = NH-NH2 Example 8 General procedure for the preparation of 5-aryl-2,6-dipyridyl - (3H) -pyrimidinones These compounds were prepared according to the literature (Kabbe, supra, German patent No. 1271116 (1968)) as follows: A stirred mixture of ethyl phenylacetate (3.13 mmole), cyanopyridine (6.24 mmole) and sodium methoxide (3.5 mmole) ) in n-butanol (1.2 ml) was heated at 110 ° C for 2 hours. The reaction mixture was concentrated and dissolved in water (4 ml), followed by the addition of saturated, aqueous ammonium chloride (2 ml). The precipitate was filtered and recrystallized with hot methanol. The following compounds were prepared according to this procedure using the appropriate starting materials: 8-1 5-Phenyl-2,6-bis- (4-pyridyl) -4- (3H) pyridinone: MS (m / z): 327.2 (M + H) +; C20H? 4N4O required 326.4. NMR-aH (DMSO-d6): d 8.78, 8.47, 8.13 (3m, - every 2H, Pirid.), 7.40-7.14 (, 7H, Ph, Pirid.). 8-2 5- (4-Fluorophenyl) -2,6-bis- (-pyridyl) -4 (3H) -pyrimidinone: MS (/ z): 345.2 (M + H) +; C20Ha3FN4O required 344.4 RMN-1 !! (DMSO-d6): d 8.80, 8.49, 8.13 (3m, every 2H, Pirid.), 7.40-7.08 (m, 6H, PhF, Pirid.). 8-3 2,5,6-Tris- (4-pyridyl) -4 (3H) -pyrimidinone was prepared according to the general procedure by reacting ethyl 4-pyridylacetate and 4-cyanopyridine in the presence of methoxide of sodium. EM (m / z): 328.2 (M + H) +; C? 9H? 3N50 required. 327.4 NMR-XH (DMSO-de): 8.65, 8.45, 8.35, 8.18, 7.25, 7.13 (6m, every 2H, Pirid.). 8-4 5- (4-Fluorophenyl) -2,6-bis- (3-pyridyl) -4 (3H) -pyrimidinone: MS (m / z): 345.2 (M + H) +; C20H? 3FN4O required 344.4 NMR-aH (DMSO-d6): d 9.34, 8.77, 8.54, 8.48, 7.78, 7.60, 7.34 (7m, 3xlH, 2H, 3xlH, Pirid.), 7.26, 7.15 (2m, every 2H, PhF).

Example 9 4 -Amino-5- (4-fl uorophenyl) -2,6-bi s- (4-pyridinyl) pyrimidine 4-Amino-5- (4-fluorophenyl) -2,6-bis- (4-pyridyl) -pyrimidine was prepared according to the literature (Kabbe, s upra): Sodium methoxide (180 mg, 3.33) was added mmoles) 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 ml). The mixture was stirred for 20 minutes at room temperature before heating at 110 ° C for 1.5 hours. The room temperature was allowed to reach and ethanol (2.5 ml) was added. The precipitate was filtered and recrystallized with acetic acid / water (3.5 / 10 ml) to give the title compound. MS (m / z): 344.2 (M + H) +; C20H? 4FN5 required. 343.4 NMR-aH (DMSO-d6): 8.76, 8.47, 8.22 (3m, every 2H, pyrid.), 7.4-7.16 (m, 6H, PhF, pyrid.).

Example 10 4-Methoxy-5-phenyl-2, 6-bi s- (4-pyridyl) -pyrimidine A mixture of 5-phenyl-2,6-bis- (4-pyridyl) -4 (3H) -pyrimidinone (360 mg, 1.10 mmol) and phosphorus oxychloride (2 ml) was heated to reflux for 1.5 hours. The treatment was done as described for the preparation of 2-chloro-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine. To a solution of the crude 4-chloro-5-phenyl-2,6-bis- (4-pyridyl) -pyrimidine (250 mg, 0.37 mmol) in methanol (5 ml) was added methanolic 0.5 N sodium methoxide (2.45 g. ml, 0.73 mmol) and heated at reflux for 1 hour. After evaporation, the resulting material was partitioned between ethyl acetate and water. The organic solution was washed with water, dried and evaporated. Chromatography of the crude product on a column of silica gel (ethyl acetate) gave the title compound. MS (m / z) 341.2 (M + H) +; C2? H? 6N40 réquer. 340.4'H-NMR (CDC13): 8.82, 8.54, 8.40 (3m, each 2H, Pirid.), 7.40-7.18 (m, 7H, Ph, Pirid.), 4.15 (s, 3H, CH30).

EXAMPLE 11 Process for the preparation of 5- (4-Fl uorophenyl) -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 hour. hour. The treatment was done as described for the preparation of 2-chloro-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine. A portion (290 mg) of the resulting product (495 mg) was purified by flash chromatography. (ethyl acetate, a very small amount of triethylamine) in silica gel. MS (m / z) 363.2 (M + H) +; C20H12C1FN4 required 362.8 NMR-: H (CDC13): d 8.84, 8.60, 8.38, 7.30 (4m, every 2H, Pirid.), 7.22, 7.13 (2m, every 2H, PhF).

Step B 5- (4-Fluoro-phenyl) -2,4-bis- (4-pyridyl) -pyrimidine: A stirred mixture of 4-chloro-5- (4-fluorophenyl) -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 hours. Filtration and evaporation of the solvent was followed by flash chromatography (ethyl acetate) on a silica gel column to provide the title compound. MS (m / z): 329.2 (M + H) +; C20H13FN4 required 328.4. RMN-1 !! (CDC13): d 8.91 (s, 1H, H-6, Pirim.), 8.83, 8.65, 8.40, 7.45 (4m, every 2H, Pirid.), 7.30-7.06 (m, 4H, PhF).

Example 12 Process for the preparation of 2- (((S) -2-N-glycylamino-3-f-enylpropyl) -amino) -4- (4-pyridyl) -5- (3- trif l uoromethyl phenyl) -pyrimidine 12-1 2- (((S) -2-N-glycylamino-3-phenylpropyl) -amino) -4- (pyridyl) -5- (3-trifluoromethylphenyl) pyrimidine hydrochloride: Ethyl chloroformate (86 μl) was added , 0.901 mmol) at bath temperature with ice to a stirred mixture of N- (tert-butoxycarbonyl) glycine (160 mg, 0.911 mmol) and 4-methylmorpholine (110 μL, 1.00 mmol) in tetrahydrofuran (10 mL). After 40 minutes, a solution of 2- (((S) -2-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine (409 mg , 0.911 mmoles) in tetrahydrofuran (15 ml) at bath temperature with ice. Within 1 hour, the mixture was allowed to reach room temperature. It was diluted with dichloromethane, washed with aqueous sodium hydrogen carbonate, followed by drying of the organic solution and evaporation. The resulting material was purified on a column of silica gel (5% methanol / dichloromethane), then dissolved in methanol (2 ml) and 4N hydrogen chloride / dioxane (2 ml) was added. After 1 hour at room temperature, it was evaporated and the rest was taken up in dichloromethane followed by washing with aqueous sodium hydrogen carbonate, drying the organic solution and evaporating. Column chromatography on silica gel (dichloromethane-methanol concentrated ammonium hydroxide = 95: 5: 0; 90: 10: 0.6) gave the title compound as the free base which was converted to the hydrochloride by the addition of chloride of hydrogen 4N / dioxane (85 μl) to its methanolic solution (3 ml) followed by evaporation. MS (m / z): 507.4, (M + H) +; C27H25F3N60 required 506.5 (free base). The following compound was prepared using the above procedure and the appropriate starting materials: 12-2 2- (((S) -2-N-glycylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride EM (m / z) : 543.2, (M + H) +; C27H28? 60 required 453.6 (free base).

Example 13 Process for the preparation of (S) -l, 2-Benzyl-ethylenediamine (S) -1,2-Benzylethylenediamine: The diamine was prepared according to literature (H. Brunner, P. Hankofer, U. Holzinger, B. Treittinger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44 (1990)) by reducing the amine of L-phenylalanine with lithium aluminum hydride. The (R) -enantiomer was prepared in the same manner as the D-phenylalanine amide.

Example 14 Process for the preparation of 2- (((S) -2- Acetamido-3-f-enylpropyl) -amino) -5- (4-fluoro-enyl) -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: A solution of 2- (((S) -2-amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -3-methyl-1-6- (4-pyridyl) -4 (3H) -pyrimidinone (25 mg, 0.058 mmole) and acetic anhydride (200 ml) in methanol (2 ml) was kept at room temperature for 1 hour. Evaporation followed by chromatography of the resulting product on a column of silica gel (10% methanol / dichloromethane) provided the title compound. MS (m / z): 472.3 (M + H) +; C27H26FN502 required 471.5.

Example 15 Process for the preparation of Cl or hydrate of 2- (((S) -2-N-i-sopropylamino-3-f-enylpropyl) -amino) -4- (4-pyridyl) -5- (3- trif l uoromethyl phenyl) -pyrimidine -1 2- (((S) -2-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine hydrochloride: Sodium triacetoxyborohydride was added (184 mg, 0.868 mmol) to a 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 μL, 0.675 mmol) in 1,2-dichloroethane (4 mL). After 16 hours, the reaction was rapidly cooled by the addition of saturated, acidic sodium carbonate, followed by extraction with dichloromethane, drying of the organic solution and evaporation. Silica gel column chromatography (5% methanol / chloroform) gave the title compound as a free base which was converted to the mohohydrochloride by the addition of 6N hydrochloric acid (73 μl) to its methanolic solution (3 ml ) and the subsequent evaporation. MS (m / z): 491.7 (M) +; C28H28F3N5 required 491.6 (free base). The following compounds were prepared using the above procedure and the appropriate starting materials. -2 S) -2-N-cyclohexylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine: MS (m / z): 532.0 (M + H) +; C31H32F3? 5 required. 531.6 (free base). -3 2- (((S) -2-N- isopropylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (-pyridyl) -pyrimidine hydrochloride: MS (m / z) ): 439.1 (M + H) +; C28H3 ?? 5 required 437.6 (free base).

Rl 15-4 2- (((S) -2-N-Butylamino-3-f-enylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: EM ( m / z): 452.1 (M + H) +; C29H33? 5 required 451.6 (free base). -5 2- (((S) -2-N-cyclohexylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z) 478.3 (M + H) +; C3iH35? 5 required. All .1 (free base). -6 5- (4-Fluorophenyl) -2- (((S) -2-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z) ): 442.1 (M + H) +; C27H28F? 5 required. 441.6 (free base).

Rl -c? P 15-7 5- (4-Fluorophenyl) -2- ((3-N-isopropylamino) -3-phenylpropyl) -amino-4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 442.2 (M + H) +; C27H28F? 5 required. 441.6 (free base).

Example 16 Process for the preparation of 2 (((S) -2-amino-3-f-enylpropyl) -amino) -5- (3-chloro-4-fluorofil) -4- (4-pyridyl) hydrochloride -pyrimidine Step A: 4- (4-Pyridyl) -2 (1H) -pyrimidinone: A mixture of 4-acetylpyridine (25 mL, 226.0 mmol) and bis (dimethylamino) methoxymethane (44 mL, 293.8 mmol) was heated to 85 ° C. for 30 minutes followed by evaporation to dryness to recover a solid of 3- (dimethylamino) -1- (4-pyridyl) -3-propen-1-one. His ethanolic solution (200 ml) was transferred into ethanolic sodium ethoxide 1.13 N (200 ml) containing urea (16.3 g, 271 mmol). The mixture was heated to reflux overnight, then cooled down to the temperature of the bath with ice. The precipitate was filtered, 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. More material was obtained from the original reaction filtrate which was concentrated, diluted with a minimal amount of water and washed with dichloromethane. The aqueous solution was neutralized with 6N hydrochloric acid and the precipitate was filtered. MS (m / z): 174.1 (M + H) +; C9H7N30 required 173.2.

Step B: 2-Chloro-4- (4-pyridyl) -pyrimidine: With cooling the ice bath under argon, 4- (pyridyl) -2 (1H) -pyrimidinone (13.45 g, 77.7 mmol) was combined and thienyl chloride (92 ml). N, N-Dimethyl formamide (13.2 ml, 170.5 mmol) was slowly added and the mixture was heated to reflux for 1 hour. It was evaporated and co-styled with toluene. At 0 ° C, water was added to the rest, then 10% ammonium hydroxide until neutral followed by extraction with dichloromethane. The drying of the organic solution was followed by evaporation and the resulting solid was recrystallized with acetone. MS (m / z): 192.1, 194.0 (M + H) +; C9H6C1N3 required 191.6.

Step C: 2- (((S) -2-Amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine: A mixture of 2-chloro-4- (4-pyridyl) -pyrimidine ( 4.5 g, 23.7 mmol) and (S) -l, 2-benzylethylenediamine (8.0 g, 53.3 mmol) was heated at 100 ° C for 25 minutes. Column chromatography on silica gel (dichloromethane-methanol concentrated ammonium hydroxide = 95: 5: 0.4) afforded the title compound. MS (m / z): 306.5 (M + H) +; C? 8H19N5 required. 305.4.

Step D: 2- (((S) -2-Amino-3-phenylpropyl) -amino) -5-bromo-4- (4-pyridyl) -pyrimidine: Bromide (787 μL, 15.28 mmol) was added to a solution with stirring of 2- (((S) -2-amino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine (2.33 g, 7.64 mmol) in chloroform (25 ml). Stirring was continued for 2 days. The mixture was partitioned between dichloromethane and aqueous sodium hydrogen carbonate. The organic solution was washed with brine, dried and evaporated. The resulting product was purified on a column of silica gel (dichloromethane-methanol-concentrated ammonium hydroxide = 92: 8: 0.6). MS (m / z): 384.0, 386.0 (M + H) +; C? 8H18BrN5 required. 384.3.

Step E: 2- (((S) -2-Amino-3-phenylpropyl) amino) -5- (3-chloro-4-fluorophenyl) -4- (4-pyridyl) -pyrimidine: A mixture of 2- ( (2 (S) -amino-3-phenylpropyl) amino) -5-bromo-4- (4-pyridyl) -pyrimidine (204 mg, 0.53 mmol), aqueous 2M sodium carbonate (1.66 ml, 3.32 mmol and 3-pyridine) chlorobenzene-4-fluoroben (103 mg, 0.637 mmol) in toluene (5 ml) was stirred for 10 minutes under argon.The mixture was completely degassed (10 times), before the addition of tetracis (triphenylphosphine) palladium (O) ) (18 mg, 0.016 mmol) After heating at reflux for 1.6 hours, the reaction mixture was diluted with toluene and washed with brine, the organic solution was dried and evaporated, and subsequent column chromatography on silica gel. (dichloromethane-methanol concentrated ammonium hydroxide = 95: 5 04) provided the title compound which was converted to the hydrochloride by the addition of 6N hydrochloric acid (64 μl) to its methan solution. opal (2 ml) followed by evaporation. MS (m / z): 434.1 (M) +; C24H2? ClFN5 required. 433.9 (free base). The following compounds were prepared according to 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) +; C24H22FN5 required 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) +; C27H29N5 required 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) +; C26H26N60 required 438.5 (free base). 16-5 2- (((S) -2-amino-3-phenylpropyl) -amino) -5- (4-chlorophenyl) -4- (4-pyridyl) -pyrimidine hydrochloride: MS (m / z): 416.3 (M + H) +; C24H22C1N5 required 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) +; C26H23N5S required 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) +; C28H25N5 required 431.5 (free base).

Example 17 Procedures for the preparation of (S) -2-Benzylpiperazine (S) -2-Benzylpiperazine: At bath temperature with ice, lithium aluminum hydride (1.6 g, 42.16 mmol) was added in portions to a stirring mixture of (S) -2-benzylpiperazine-3,6-dione. (3.0 g, 14.70 mmol) and tetrahydrofuran (80 ml). After 30 minutes at bath temperature with ice, the mixture was refluxed for 4 hours with stirring. The reaction was rapidly quenched by the addition portion by part of sodium sulfate decahydrate and some methanol until the emission of hydrogen ceased. It was filtered and the solids were washed several times with dichloromethane. The combined filtrates were evaporated to leave a white solid. MS (m / z): 177.1 (M + H) +; CnH? 6N2 required. 176.3.

Example 18 Procedures for the preparation of (S) -2-N, N-Dimeti lami non-3-phenylepropyl amine (S) -2-N, N-Dimethylamino-3-phenylpropylamine: Sodium triacetoxyhydride (13.0 g, 61.3 mmole) was added to a stirring mixture of phenylalanine amide (3.6 g, 21.9 mmol) and 37% solution of formaldehyde (4.4 ml, 58.7 mmol) in 1,2-dichloroethane (77 ml). After stirring for 2 hours, the reaction was quenched by the addition of saturated, aqueous sodium hydrogen carbonate. Then pellets of potassium hydroxide were added followed by extraction with dichloromethane, drying of the organic solution and evaporation. (S) -2-N, N-dimethylamino-3-phenylpropylamide was reduced with lithium-aluminum hydride according to literature (H. Brunner, P. Hankofer, U. Holzinger, B. Treittnger and H. Schoenenberger, Eur. J. Med. Chem. 25, 35-44, (1990)) to provide the title compound.

Example 19 Process for the preparation of 2 (((S) -2-N, N-dimethylamino-3-f-enylpropyl) -amino) -5- (4-fluorofenyl-3-methyl-6- (4-chlorohydrate -pyridyl) -4 (3H) -pyrimidinone Step A. 5- (4-Fluorophenyl) -3-methyl-2-methylsulfonyl-6- (4-pyridyl) - (3H) -pyrimidinone: A mixture of 5- (4-fluorophenyl) -3-methyl-2- methylthio-6- (4-pyridyl) - (3H) -pyrimidinone (400 mg, 1.22 mmol) and Oxone® (potassium peroxymonosulfate, 2.3 g, 3.74 mmol) in methanol (100 mL) and water (45 mL) was stirred for 13 hours. The solvent was concentrated to approximately 50 ml, followed by extraction with dichloromethane, drying the organic solution and evaporation. The resulting white solid was used without 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-hydrochloride 3H) -pyrimidinone: A mixture of crude 5- (4-fluorophenyl) -3-methyl-2-methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (430 mg g, 1.19 mmol) and (S) -2 N, N-dimethyl amino-3-phenylpropylamine (600 ml, -3.4 mmol) was stirred at room temperature for 1 hour and then briefly heated to 50 ° C. Column chromatography on silica gel (3-5% methanol / chloroform) gave the title compound as a free base which was converted to the monohydrochloride by the addition of 4N hydrochloric acid / dioxane (160 mmI, 0.64 mmol) to its methanolic solution (4 ml) and the subsequent evaporation. MS (m / z): 458.0 (M + H) +; C27H28FN50 required 457.5 (free base).

Example 20 5- (4-fluoro-enyl) -6- (4 - (2-acetamido) -pyridyl) -2- ti -alkyl-4 (3H) -pyrimidinones Step A. 2- (4-Fluorophenyl) - Ethyl 3-OXO-3- (4- (2-acetamido) -pyridyl)) -propionate: A solution of 2-chloroisonicotinic acid (25. Og, 0.16 moles) in 65 mL of concentrated ammonium hydroxide was heated to 205 Celcius in a steel pump for 72 hours. After cooling to 23 ° C, the solution was acidified to a pH of 1 using 6N HCl and subsequently filtered to remove the unreacted starting material. The solution was concentrated to a quarter of the original volume (approximately 200 mL) in vacuo and carefully adjusted to a pH of 6 using IN NaOH. After storing the cloudy solution at 0 ° C for 20 hours, the desired 2-aminoisonicotinic acid was filtered. To a suspension of 2-aminoisonicotinic acid in ethanol (600 mL) was added 47.1 mL of 4 N anhydrous HCl in dioxane. After heating to reflux for 20 hours, an additional 47.1 mL of anhydrous 4N HCl in dioxane was added and the reaction was heated to reflux for an additional 20 hours. The concentration with a stream of nitrogen in the hood was followed by the additional concentration in vacuo, the remaining solid was diluted with saturated bicarbonate (200 mL), extracted with ethyl acetate (2 x 200 mL), dried (Na 2 SO 4) . After concentration in vacuo, the desired ethyl 2-aminoisonicotinate was obtained. To a solution of ethyl 2-aminoisonicotinic acid in pyridine (45 mL) at 0 ° C under an argon atmosphere was added dropwise acetyl chloride for 5 minutes. After 2 hours at 0 ° C, the reaction was poured into ice on 300 g, extracted with ethyl acetate (2 x 300 mL), washed with water (2 x 100 mL) followed by brine (2 x 100 mL) and dried (Na 2 SO 4). After concentration in vacuo, the residue was purified by the application of column chromatography (step gradient from ethyl acetate: hexane 1: 4 then ethyl acetate: hexane 1: 1) to give the ethyl 2-acetamidoisonicotinate. To a solution of diisopropylamine (14.15 mL, 101 mmol) and THF (40 mL) at -78 ° C n-butyl lithium (38.1 mL, 95 mmol) was added dropwise over 5 minutes. After 10 minutes, ethyl 4-fluorophenylacetate (17.3 g, 95 mmol) in 40 mL dry THF was added. After 10 minutes, ethyl 2-acetamidoisonicotinate (6.0 g, 29 mmol) in 20 ml of dry THF was added. The reaction was allowed to warm to 23 ° C overnight, and then acetic acid (95 mmol) was added in one portion. The reaction was concentrated in vacuo, then repeatedly divided between saturated bicarbonate (200 ml) and ether (300 ml), the combined bicarbonate layers were neutralized with 10% citric acid and extracted with ethyl acetate (2 x 300 ml. ). The organic layers were dried (Na2SO4), 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: 2- (4-fluorophenyl) -3-oxo-3- (4- (2- acetamido) pyridyl) -propionate (1.3 g, 3.78 mmol) and thiourea (863 mg, 11.3 mmol) were suspended in anhydrous p-xylene (15 ml) with very efficient stirring. To the mixture was added pyridinium p-toluenesulfonate (38 mg) and heated to reflux for 12-16 hours using a Dean-Stark apparatus with continuous water removal (0.1 ml). The reaction mixture was cooled and a dark brown solid was filtered using a Buchner funnel. The collected solid was suspended in acetone (25 ml) and filtered. The product washed with acetone contained a very small amount of thiourea, which was removed by trituration with hot water (20-30 ml). The product was filtered and dried with air followed by azeotropogenization with toluene.

Example 21 Process for the preparation of (S) -2-N-Ethyl amino-3-phenylpropylamine (S) -2-N-Etilamino-3-phenylpropylamine: Acetic anhydride (1.2 ml) was added, 12.7 mmol) was added to a stirring solution of L-phenylalanine amide (1.0 g, 6.10 mmol) in methanol (25 mL). After 1.5 hours at room temperature, it was evaporated followed by drying in an oil pump vacuum. The resulting L-N-ethylphenylalanine amide (6.1 mmol) was reduced with lithium aluminum hydride (570 mg, 15.0 mmol) in tetrahydrofuran (65 mmol) at 55 ° C for 4 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate followed by extraction with dichloromethane, drying and evaporation. Column chromatography on silica gel (chloroform: methanol: triethylamine = 90: 7: 3) gave the amine as a yellowish oil. MS (m / z): 179.1 (M + H) +; CnHlßN2 required 178.3.

Example 22 Process for the preparation of 2-Ami non-2-methyl-3-f-enylpropylamine 2-Amino-2-methyl-3-phenylpropylamine: A solution of commercially available D, La-methyl phenylalanine methyl ester (5.0 g, 25.7 mmoles) in 28% aqueous ammonium hydroxide (50 ml) was maintained at room temperature for 3 days. The white precipitate resulting from the amide of D, L-α-methyl phenylalanine was filtered and dried (2.5 g). This material (2.0 g, 11.22 mmol) was reduced with lithium-aluminum hydride (1.3 g, 34.26 mmol) in boiling tetrahydrofuran for 24 hours. The reaction was rapidly quenched by the addition of sodium sulfate decahydrate at bath temperature with ice. The salts were filtered, followed by evaporation to leave the title compound as an oil. MS (m / z): 165.1 (M + H) +; C? 0H? 6N2 required. 164.2. An alternative preparation was reported by M. Freiberger and R. B. Hasbrouck, J. Am. Chem. 82, 696-698 (1960).

Example 23 Procedures for the preparation of 2-methyl-3-phenylpropyl amine 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 tetrahydrofuran (184 ml) was stirred at room temperature. environment for 5 hours. It was poured into saturated, aqueous sodium sulfate and extracted with dichloromethane followed by drying the organic solution and evaporating to provide the amide as an oil. Other syntheses have been reported, for example Dorno and Fust, Chem. Ber. 87, 984 (1954).

Example 24 Procedures for the preparation of Chlorhydrate - (4-phorophenyl) -3-methyl -2- ((2-methyl-3-f-enylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone - (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 g, 1.45 mmol) and 2-methyl-3-phenylpropylamine (1.5 g, 10.1 mmol) was heated at 50 ° C for 30 minutes. Column chromatography on silica gel (2-5% methanol / dichloromethane; hexane-acetone = 2: 1) provided the title compound. MS (m / z): 429. 4 (M + H) +; C26H25FN40 required 428.5 (free base).

Example 25 Process for the preparation of 1-phenyl-3-propanediamine 1-Phenyl-1,3-propanediamine: 3-phenyl-3-aminopropionic acid (SG Cohen and SY Weinstein, J. AM Chem. Soc. 86, 725-728, 1964) was converted to 1-phenyl-1 , 3-propanediamine as reported in the literature (M. Koji and J. Fujita, Bull, Chem. Soc. Jpn. 55, 1454-1459 (1982)).

Analogously, 1- (2-fluorophenyl) -1,3-propanediamine, 1- (2-methylphenyl) -1,3-propanediamine and 1- (2-chlorophenyl) -1,3-propanediamine have been prepared by using the above procedure and the appropriate starting material.

Example 26 Process for the preparation of 3-Ethyl -5- (4-fl uorophenyl) -2-methyl ti o- 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 to a stirred mixture of (4-fluoro-phenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone (1.8 g, 5.97 mmol) and sodium hydride (60% oily suspension, 320 mg, 8 mmol) in N, N-dimethylformamide (60 ml) at room temperature. Additional ethyl bromide (2 x 600 ml, 2 x 8.03 mmol) was added after 2 and 3.5 hours. After 8 hours, the reaction mixture was neutralized with acetic acid and evaporated. The remainder was taken up in dichloromethane, the organic solution was washed with water, dried and evaporated. Flash chromatography on a silica gel column (hexane-acetone = 3: 1, 2: 1) afforded the title compound as a solid in the second major fraction.

Example 27 Process for the preparation of 3-Ethyl-5- (4-fluorophenyl) -2-methylsulfonyl-6- (4-pyridyl) -4 (3H) • pyrimidinone 3-Ethyl-5- (4-fluorophenyl) -2-methylsulfonyl-6- (4-pyridyl) - (3H) -pyrimidinone: A mixture of 3-ethyl-5- (4-fluorophenyl) -2-methylthio- 6 - (4-pyridyl) -4 (3H) -pyrimidinone (300 mg, 0.88 mmol) and OxoneR (Potassium peroxymonosulfate, 2.54 g, 4.14 mmol) in methanol (71 ml) and water (33 ml) was stirred for 14 hours. The solvent was concentrated to about 35 ml, followed by extraction with dichloromethane, drying and evaporation. The resulting white solid was used without purification in the next step.

Example 28 Process for the preparation of 2- (((S) -2-amino-3-f-enylpropyl) -amino) -3-ethyl-5- (4- f-fluorophenyl) -6- (4-pyridyl) hydrochloride ) -4 (3H) -pyrimidinone 2- (((S) -2-amino-3-phenylpropyl) -amino) -3-ethyl-5- (4-fluoro-phenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: A mixture of 3-ethyl-5- (4-fluorophenyl) -2-methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone (150 mg, 0.44 mmol) and (S) -1,2-benzylethylenediamine (200 ml, -1.3 mmol) was heated at 190 ° C for 4.5 hours. Column chromatography on Iatrobeads® (chloroform: methanol: triethylamine = 90: 7: 3) gave the title compound as a free base which was converted to the crystallization monohydrochloride by the addition of 2N hydrochloric acid (165 ml, 0.33 mmol) ) and methanol (1.5 ml). Filtration provided the title compound. MS (m / z): 444.0 (M + H) +; C26H27FN20 required 443.5 (free base).

EXAMPLE 29 Procedures for the preparation of Cl orhi dra of 3-ethyl-5- (4-fluoro-phenyl) -2- ((2-methyl-3-phenylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone 3-Ethyl-5- (4-fluorophenyl) -2- ((2-methyl-3-phenylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: A mixture of 3- crude ethyl-5- (-fluorophenyl) -2-methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (320 mg g, 0.89 mmol) and 2-methyl-3-phenylpropylamine (600 ml, -4 mmol) was heated at 60 ° C for 2 hours. Column chromatography on silica gel (hexane-acetone = 2: 1; 2-5% methanol / dichloromethane) afforded the title compound. MS (m / z): 443.2 (M + H) +; C27H27FN40 required 442.5.

EXAMPLE 30 Process for the preparation of 3- (2-methyl phenyl) ropolyme amine 3- (2-Methylphenyl) propylamine: Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added to a suspension with stirring of sodium hydride (60% oily suspension, 1.24 g, 31 mmol) in tetrahydrofuran (50 ml) under argon. After 30 minutes, 2-methylbenzaldehyde (3.6 ml, 31.1 mmol) was added and stirring was continued for 1 hour. The reaction was quenched by the addition of water and extracted with dichloromethane followed by drying and evaporation of the organic solution. Column chromatography (hexane: hexane: ethyl acetate = 3: 1) afforded 2- (2-methylphenyl) acrylonitrile as an oil. This material (3.8 g), 10% palladium on carbon (3.8 g) and 12 N hydrochloric acid (11.8 ml, 142 mmol) in methanol (125 ml) were hydrogenated with hydrogen at atmospheric pressure for 2 days. The catalyst was removed by filtration and the solvent was evaporated. The resulting material was divided between dichloromethane and water. The aqueous layer was made basic with 10 N sodium hydroxide and extracted with dichloromethane, followed by drying and evaporation. The resulting material was purified on a column of silica gel (chloroform: methanol: triethylamine = 85: 10: 5) to give the title compound as an oil.

Example 31 Process for the preparation of 2-amino-3- (2-fl uorophenyl) -propylamine Step A. Methyl 2-amino-3- (2-fluorophenyl) propionate: 5 g (27.3 mmol) of (D, L) - (2-fluoro-phenyl) alanine was suspended in 50 ml of methanolic HCl and stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and dried to give a yellow oil. MS (m / z): 198 (M + H) +; C? 0H12FNO2 required 197.2.Step B. 2-Amino-3- (2-fluorophenyl) propione ida: Methyl 2-amino-3- (2-fluorophenyl) propionate was suspended in 50 ml of 30% ammonium hydroxide and stirred at room temperature for 18 hours. The mixture was filtered, washed with cold water and the 2-amino-3- (2-fluorophenyl) propionamide was collected as a white solid. MS (m / z): 183.1 (M + H) +; C9HnFN20 required 182.2.

Step C. 2-Amino-3- (2-fluorophenyl) -propylane: 2-Amino-3- (2-fluorophenyl) propionamide was carefully added to a cold (5 °) mixture of LAH (1.0 g, 26.3 mmoles) and 20 ml of THF under argon. The reaction was then heated to reflux for 10 hours. The reaction was cooled to 5 ° C and carefully treated with Na 2 SO 4 * 10 H 20. The resulting mixture was stirred for 18 hours, then filtered to remove the solids. The filtrate was concentrated in vacuo to give an amber oil. MS (m / z): 169 (M + H) +; C9H13FN2 required 168.19.

Example 32 Procedures for the preparation of (1R, 2R) -2-Methyl-1-phenyl-1,3-propanediamine Step Aj The (2S, 3R, aS) -3- (N-benzy l -Na-methylbenzylamino) -2-methyl-3-phenylpropionate methyl was prepared as reported for the 2R, 3S, aR-enantiomer (S) .G. Davies and I.A.S. Walters, J. Chem. Soc. Perkin Trans. I, 1129-1139 (1994).

Step B: (2S, 3R) -3-amino-2-methyl-3-phenylpropionate methyl: A mixture of (2S, 3R, aS) -3- (N-benzyl-Na-methylbenzylamino) -2-methyl Methyl-3-phenylpropionate (13.0 g, 33.55 mmol) and 10% palladium on carbon (13.0 g) in glacial acetic acid (260 ml) was hydrogenated under a hydrogen balloon for 24 hours. The catalyst was removed by filtration followed by evaporation and co-distillation with toluene to give the title compound as a solid. MS (m / z): 194.2 (M + H) +; CnH15? 02 required. 193.3.

Step C: (2S, 3R) -3-Amino-2-methyl-3-phenylpropionamide: A solution of methyl (2S, 3R) -3-amino-2-methyl-3-phenylpropionate (6.3 g, 33 mmol) in methanolic ammonia 2? (20 ml) and ammonium hydroxide (28-30%, 40 ml) was stirred at room temperature. After 3 days, it was evaporated followed by chromatography on a short column of silica gel (dichloromethane-methanol-concentrated ammonium hydroxide = 93: 7: 0.7, 90: 10: 0.8) to provide the amide as a white solid. MS (m / z): 179.2 (M + H) +; C? 0H14N2O required 178.2.

Step D: (IR, 2R) -2-methyl-1-phenyl-1,3-propanediamine: Lithium aluminum hydride (2.3 g, 60.60 mmol) was added in portions to a stirred solution of (2S, 3R) -3-amino-2-methyl-3-phenylpropionamide (2.6 g, 14. 59 mmole) in tetrahydrofuran (54 ml) at bath temperature with ice. After 45 minutes, the mixture was refluxed for 16 hours. With cooling the bath with ice, the reaction was rapidly cooled by the addition portion by part of sodium sulfate decahydrate and some methanol until the emission of hydrogen ceased. The solids were removed by filtration and washed with dichloromethane. The combined filtrates were evaporated to provide the title compound. MS (m / z): 165.2 (M + H) +; C? 0H? 6N2 required. 164.3.

In an analogous manner, the enantiomer (IS, 2S) -2-methyl-1-phenyl-1,3-propanediamine was prepared from (2R, 3S, aR) -3- (N-benzyl-Na-meth. methyl lbencyl amino) -2-methy1-3-phenylpropionate. MS (m / z): 165.3 (M + H) +; C? 0H16? 2 required. 164.3 Similarly, the enantiomers (IS, 2R) -2-methyl-1-pheny1-1, 3-propanediamine and (IR, 2S) -2-methyl-1-phenyl-1,3-propanediamine can be prepared starting from (2S, 3S, aR) - and - (2R, 3R, aS) -3- (N-benzyl-l-Na-methylbenzylamino) -2-methyl-3-phenylpropionate of tertbutyl (Davies et al., J. Chem Soc. Chem. Commun. 1153-1155, 1993)).

Example 33 Process for the preparation of 5- (4-fl uorophenyl) -2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone - (4-Fluorophenyl) -2- (4-phenylbutyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone: 2- (4-fluorophenyl) -3-oxo-3- (4-pyridyl) ethylpropionate (293 mg, 1.02 mmol), 4-phenylbutanocarboxamidine (315 mg, 1.79 mmol) and pyridinium p-toluenesulfonate (10 mg) were suspended in p-xylene (10 ml). With efficient stirring, the mixture was heated to reflux using a Dean-Stark apparatus with continuous water removal. After 16 hours, the solvent was evaporated and the product was purified by column chromatography on silica gel (3% methanol / dichloromethane) followed by recrystallization of acetone. MS (m / z) 400.3 (M + H) +; C25H22FN30 required 399.5.

EXAMPLE 34 Process for the preparation of 5- (4- f luorofenyl) -2- (N-methyl-N- (2-f-enylethyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone - (4-Fluorophenyl) -2- (N-methyl-N- (2-phenylethyl) amino-6- (4-pyridyl) -4 (3H) -pyrimidinone was prepared using the methods described above. / z): 401.2 (M + H) +, C24H2? FN40 required 400.5.

Example 35 The compounds shown in Tables I-II can be prepared using the procedures of Examples 1-33.

TABLE I TABLE I R1 Example 36 Biological Assays The following assays were used to characterize the ability of the compounds of the invention to inhibit the production of TNF-α and the IL-1-ß. The second assay measured the inhibition of TNF-α and / or IL-1β in mice after oral administration of the test compounds. The third assay, an inhibition assay of glucagon binding in vitro, can be used to characterize the ability of the compounds of the invention to inhibit glucagon binding. The fourth assay, an in vitro assay of the inhibiting activity of the enzyme Cyclooxygenase (COX-1 and COX-2), can be used to characterize the ability of the compounds of the invention to inhibit COX-1 and / or COX-2.

Assay of production of TNF by activated monocytes with lipopolysaccharide A monocyte slaughter The test compounds were evaluated for the ability to inhibit the production of TNF by monocytes activated with bacterial lipopolysaccharide (LPS). Leukocytes from residual, new sources (a byproduct of platelet pheresis) were obtained from a local blood bank and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation in Ficol-Paque Plus (Pharmacia). PBMCs were suspended at 2 x 106 / ml in DMEM supplemented to contain 2% Fetal Bovine Serum (FCS), 10 mM, 0.3 mg / ml glutamate, 100 U / ml penicillin G and 100 mg / ml streptomycin sulfate (full media). The cells were placed in 96 well, flat bottom Falcon culture plates (200 μl / well) and cultured overnight at 37 ° C and 6% C02. The non-adherent cells were removed by washing with 200 μl / well of fresh medium. Wells containing adherent cells (~ 70% monocytes) were refilled with 100 μl of fresh medium.

Preparation of stock solutions of the test compound The test compounds were dissolved in DMZ Stock solutions of the compound were prepared at an initial concentration of 10-50 μM. The stock solutions were initially diluted to 20-200 μM in complete media. Then nine serial dilutions were prepared in two parts of each compound in a complete medium.

Treatment of cells with the test compounds and activation of TNF production with lipopolysaccharide One hundred microliters of each dilution of the test compound was added to microtiter wells containing adherent monocytes and 100 μl of complete medium. The monocytes were cultured with the test compounds for 60 minutes, at which time 25 μl of the complete medium containing 30 ng / ml of E lipopolysaccharide was added. col i K532 to each well. The cells were cultured an additional 4 hours. The supernatants of the culture were then removed and the presence of TNF in the supernatants was quantified using an ELISA.

TNF ELISA Corning 96-well flat-bottom ELISA plates were coated overnight (4 ° C) with 150 μL / well of 3 μg / mL murine anti-human TNF-a Mab ( R & D Systems # MAB210). The wells were then blocked for 1 hour at room temperature with 200 μL / well of CaCl2-free ELISA buffer supplemented to contain 20 mg / ml of BSA (normal ELISA buffer: 20 nM, 150 mM NaCl, 2 mM CaCl2 , 0.15 mM thimerosal, pH 7.4). The plates were washed and refilled with 100 μl of test supernatants (diluted 1: 3) or models. The models consisted of eleven serial dilutions of 1.5 parts of a stock solution of 1 ng / ml of recombinant human TNF (R & amp; amp;; D Systems). The plates were incubated at room temperature for 1 hour on an orbital shaker (300 rpm), washed and refilled with 100 μl / well of 0.5 μg / ml of antihuman, goat TNF-a (R &D systems # AB-210-NA) biotinylated in a ratio of 4: 1. The plates were incubated for 40 minutes, washed and refilled with 100 μl / well of streptavidin conjugated with alkaline phosphatase. (Jackson ImmunoResearch # 016-050-084) at 0.02 μg / ml. Plates were incubated 30 minutes, washed and refilled with 200 μl / well of 1 mg / ml p-nitrophenyl phosphate. After 30 minutes, the plates were read at 405 nm on a Vmax plate reader.

Data Analysis The normal curve data were fitted to a second-order polynomial and the unknown TNF-a concentrations were determined from their OD by solving this equation for the concentration. The TNF concentrations were then plotted against the concentration of the test compound using a second-order polynomial. This equation was then used to calculate the concentration of test compounds causing a 50% reduction in TNF production. It can also be shown that the compounds of the invention inhibit the LPS-induced release of IL-1β, IL-6 and / or IL-8 from monocytes by measuring the concentrations of IL-1β, IL-6 and / or IL-8 by methods well known to those skilled in the art. In a manner similar to the assay described above which involves the LPS-induced release of TNF-α from monocytes, it can also be shown that the compounds of this invention inhibit the LPS-induced release of IL-β, IL-6 and / or IL-8 of monocytes when measuring the concentrations of IL-lß, IL-6 and / or IL-8 by methods well known to those skilled in the art. In this manner, the compounds of the invention can decrease the high levels of TNF-α, IL-1, IL-6 and IL-8. The reduction of elevated levels of these inflammatory cytokines at basic or lower levels is favorable in control, decreased progress and relief of many disease states. All compounds are useful in methods of treating disease states in which TNF-α, IL-β, IL-6 and IL-8 play a role to the full extent of the definition of diseases mediated by TNF-a described herein.

Inhibition of TNF-α production induced by LPS in mice Male DBA / 1LACJ mice were dosed with a vehicle or test compounds in a vehicle (the vehicle consists of 0.5% tragacanth in 0.03 N HCl) 30 minutes before of lipopolysaccharide injection (2 mg / kg, IV). Ninety minutes after the injection of LPS, blood was collected and the serum was analyzed by the ELISA for TNF levels. The following compounds exhibit activities in the monocyte assay (release of TNF induced by LPS) with IC5o values of 20 μM or less: - (4-Fluorophenyl) -2- (4-pyridyl) -4- (4-pyridyl) -pyrimidine - (4-Fluoro-phenyl) -2- (2-methylthiazole-4-yl) -4- (4-pyridyl) -pyrimidine - (4-fluorophenyl) -4- (4-pyridyl) -2- (2-thienyl) -pyrimidine 2- (2-diethylaminoethylamino) -5- (4-fluorophenyl) -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 - (4-Fluorophenyl) -2- (2-methoxy-phenylamino) -4- (4-pridyl) pyrimidine - (4-Fluorophenyl) -2- (2-fluorophenylamino) -4- (4-pridyl) pyrimidine - (4-Fluorophenyl) -2-phenylthiomethyl-4- (4-pyridyl) -pyrimidine 2- (Benzylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2-phenylethylamino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (methyl- (2-phenylethyl) -amino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- ((2-hydroxy-2-phenyl-ethyl) amido) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2- (4-hydroxy phenyl) ethyl-amino) -4- (4-pyridyl) pyrimidine 2- (2- (4-Aminophenyl) ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2- (4-fluorophenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2- (2-fluorophenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine 2- (2- (2-Chlorophenyl) ethyl-amino)) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 2- (2- (4-Chlorophenyl) ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 2- (2- (3-chlorophenyl) ethyl-amino)) -5- (4-fluorophenyl) -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 - (4-Fluorophenyl-2- (2- (2-methoxyphenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl-2- (2- (3-methoxy phenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl-2- ((3-phenylpropyl) amino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- ((1-methy1-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine 2- (((S) -2-Amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2-phenylaminoethylamino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl-2- ((3-imidazolylpropyl) -amino) -4- (4-pyridyl) -pyrimidine 5- (4-Fluorophenyl-2- ((4-phenylbutyl) -amino) -4- ( 4-pyridyl) -pyrimidine - (4-Fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine - (4-Fluorophenyl) -2-morpholino-4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (l-piperazinyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -4- (4-pyridyl) -2- (2-pyrrolidinoethylamino) -pyrimidine - (4-Fluorophenyl) -2- (2-morpholinoethylamino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2-piperidinoethylamino) -4- (4-pyridyl) -pyrimidine - (4-F1-fluorophenyl) -2- (2- (2-pyrrolidinon-1-yl) propyl-amino) -4- (4-pyridyl) -pyrimidine 2- (2,6-Dichlorobenzyl) -5- (4-fluorophenyl) -6- (4-pyridyl) - (3H) -pyrimidinone - (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 > - (4-Fluorophenyl) -2- (2-phenoxyethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone - (4-Fluorophenyl) -2- (2-phenylaminoethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- (2- (2-Chlorophenyl) ethyl-amino) -5- (4-fluorophenyl) -6- (4-pyridyl) -4 (3íf) -pyrimidinone - (4-Fluorophenyl) -2- ((3-phenylpropyl) amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone - (4-Fluorophenyl) -2- ((1-methy1-3-phenylpropyl) -amino) -6- (4-pyridyl) -4 (3H) -pyrimidinone - (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-N, N-Dimethylamino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 2- (((?) - 2 -N, N-Dimethyl-amino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine 2- ((3-Amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -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 - (((2S, 3S) -3-Amino-2-methy1-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine 2- (((2R, 3R) -3-Amino-2-methyl-3-phenylpropyl) -amino) -4- (4-pyridyl) -5- (3-trifluoromethyl-phenyl) -pyrimidine 2- ((S) -3-Benzylpiperazinyl) -4- (4-pyridyl) -5- (3-trifluoromethylphenyl) -pyrimidine 4- (4-pyridyl-2- (((S) -tetra-idroisoquin-3-ylmethylene) ) amino) -5- (3-trifluoromethylphenyl) -pyrimidine - (3-Methylphenyl) -4- (4-pyridyl) -2- (((S) -tetrahydroisoquinol-3-ylmethyl) amino) -pyrimidine 2- (((S) -2-N-Isopropylamine-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-N-Isopropylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine 2- (((S) -2-N-Buti lamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine 2- (((S) -2-N-Cyclohexylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (((S) -2-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine - (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-trifluoromethyl-phenyl) -pyrimidine 2- (((S) -2 - N-Gl icylamino-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 - (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) - 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-flurophenyl) -6- (4-pyridyl) -4 (H) -pyrimidine.

The following compounds exhibit activities in the monocyte assay (release of T? F induced by LPS) with IC50 values of 5 μM or less: 2- (2-Aminoethylamino) -5- (4-fluorophenyl) -4- ( 4-pyridyl) -pyrimidine 2- (2-Aminopropylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 2- (Benzylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 5_ (4-Fluorophenyl) -2- (2-phenylethylamino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (N-methyl-N- (2-phenylethyl) amino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2-hydroxy-2-phenyl-ethyl) amino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2- (4-hydroxy phenyl) ethylamino) -4- (4-pyridyl) -pyrimidine - (4-Fluoro-phenyl) -2- (2- (4-fluorophenyl) ethylamino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2- (2-fluorophenyl) ethylamino) -4- (4-pyridyl) -pyrimidine 2- (2- (2-Chlorophenyl) ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 2- (2- (4-chlorophenyl) ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 2- (2, 4-Dichlorophenyl) ethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (3-phenylpropyl) amino) -4- (4-pyridyl) -pyrimidine 2- ((S) -2-Amino-3-phenylpropyl) ami o-5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2-phenylaminoethylamino) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (3-imidazolylpropyl) amino-4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine - (4-Fluorophenyl) -2- (l-piperazinyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (2-phenylethyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone - (4-Fluorophenyl) -2- (3-phenylpropyl) thio-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- (2- (2-chlorophenyl) ethyl-amino) -5- (4 -fluorophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone - (4-Fluorophenyl) -2- (3-phenylpropyl) amino-6- (4-pyridyl) -4 (3H) -pyrimidinone - (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-N, N-Dimet i lamino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine 2- (((S) - 2-N, N-Dimet i l amino- 3-f eni lpropi l) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine 2- ((3-Amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -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- (((2S, 3S) -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-trifluoromethyl-phenyl) -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 - (3-Methyl phenyl) -4- (4-pyridyl) -2- (((S) -tetrahydroisoquinol-3-ylmethylene) amino) -pyrimidine 2- (((S) -2-N- I sopropi l amino-3-f enylpropy) -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- 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-N-Cyclohexylamino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine - (4-Fluorophenyl) -2- (((S) -2-N-isopropylamino-3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine - (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) -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 invention have anti-inflammatory properties in animal models of inflammation, including foot edema by carrageenan, collagen-induced arthritis and adjuvant arthritis, such as the paw edema model by carrageenan (CA Winter and collaborators Proc. Soc. Exp. Biol. Med. (1962) vol 111, p 544; KF Swingle, in RA Scherrer and MW Whitehouse, Eds., Antiiinflammatory Agents, Chemistry and Pharmacology, Vol. 13-11, Academic, New York , 1974, p.33) and collagen-induced arthritis (DE Trentham et al J. Exp. Med. (1977) vol.146, p 857; S. Courtenay, Nature (New Biol.) (1980), Vo. 283, p 666).

Protection against Glucagon I12S binding with CHO / hGLUR cells The assay is described in WO 97/16442, which is incorporated herein by reference in its entirety. Reagents Reagents can be prepared as follows: (a) preparing new 1M o-phenanthroline (Aldrich) (198.2 mg / ml ethanol); (b) prepare new 0.5M DTT (Sigma); (c) Protease Inhibitor Mixture (1000X); 5 mg of leupeptin, 10 mg of benzamidine, 40 mg of bacitracin and 5 mg of trypsin inhibitor of soy per ml of DMSO and store the aliquots at -20 ° C; (d) 250 μM of human glucagon (Peninsula): solubilize a vial of 0.5 mg in 575 μl of acetic acid 0. ÍN (1 μl produces a final concentration of 1 μM in the assay for non-specific binding) and store in aliquots at -20 ° C; (e) Assay Buffer: 20 mM Tris (pH 7.8), 1 mM DTT and 3 mM o-phenanthroline; (f) Test Buffer with 0.1% BSA (for label dilution only, 0.01% final in the assay): 10 μl of 10% BSA (heat inactivated) and 990 μl of Assay Buffer; (g) Glucagon I125 (NEN, receptor grade, 2200 Ci / mmol): dilute to 50,000 cpm / 25 μl in the assay buffer with BSA (final concentration of approximately 50 pM in the assay). Collection of CHO / hGLUR Cells for Assay 1. Remove media from the confluent flask then rinse once each with PBS (Ca, Mg-free) and Enzyme-free Dissociation Fluid (Specialty Media, Inc.). 2. Add 10 ml of Enzyme-free Dissociation Fluid and keep for approximately 4 minutes at 37 ° C. 3. Gently drain the free cells, crush, take an aliquot for counting and centrifuge the rest for 5 minutes at 1000 rpm. 4. Resuspend one pellet in the Assay Buffer at 75,000 cells per 100 μl. Membrane preparations of CHO / hGLUR cells can be used in place of whole cells in the same volume of the assay. The final protein concentration of a membrane preparation is determined on a per batch basis.

Assay The determination of inhibition of glucagon binding can be carried out by measuring the reduction of the binding of glutagon I 125 in the presence of the compounds of Formula I. The reagents are combined as follows: Compound / 250 μM Glucagon Cells Vehicle Glucagon I125 CHO / hGLUR Union - / 5 μl 25 μl 100 μl Total + 5 μl 25 μl 100 μl Union ic No Spec. - / 5 μl 1 μl 25 μl 100 μl of Compound The mixture is incubated for 60 minutes at 22 ° C on a shaker at 275 rpm. The mixture is filtered on a pre-moistened GF / C filter mat (0.5% polyethylimine (PEI)) using an Innotech Collector or Tomtec Collector with four washes of 20 mM ice-cooled Tris buffer (pH 7.8). The radioactivity in the filters is determined by a gamma-scintillation counter.

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

Enzyme Activity Assay Cyclooxygenase The monocytic human leukemia cell line, THP-1, differentiated by exposure to phorbol esters expresses only COX-1; the human osteosarcoma cell line 143B predominantly expresses COX-2. THP-1 cells are routinely cultured in complete RPMl media supplemented with 10% FBS and human osteosarcoma cells (HOSC) are cultured in minimal, essential media, supplemented with 10% fetal bovine serum (MEM-PBS). 10%); all cell incubations are at 37 ° C in a humid environment containing 5% C02.

COX-1 Assay In preparation for the COX-1 assay, THP-1 cells are grown for confluence, divided 1: 3 in RPMl containing 2% PBS and 10 mM Forbol 12-myristate 13-acetate (TPA), and incubated for 48 hours on a shaker to prevent binding. The cells were pelleted and resuspended in Hank's Damped Saline Solution (HBS) at a concentration of 2.5 x 10 4 cells / mL and placed in 96-well culture plates at a density of 5 x 10 5 cells / mL. The test compounds are diluted in HBS and added to the desired final concentration and the cells are incubated for an additional 4 hours. Arachidonic acid is added to a final concentration of 30 M, the cells are incubated for 20 minutes at 37 ° C, and the enzymatic activity is determined as described below.

COX-2 Assay For the COX-2 assay, subconfluent HOSCs are treated with trypsin and resuspended at 3 x 106 cells / mL in MEM-FBS containing 1 ng of IL-lb of human / mL, place in 96-well tissue culture plates at a density of 3 x 104 cells per well, incubate in a shaker for 1 hour to eventually distribute the cells, followed by an additional 2 hours of static incubation to allow binding. The media is then replaced with MEM containing 2% FBS (MEM-2% FBS) and 1 ng IL-lb human / mL, and the cells are incubated for 18-22 hours. After replacing the media with 190 mL of MEM, 10 mL of the test compound diluted in HBS is added to achieve the desired concentration and the cells are incubated for 4 hours. The supernatants are removed and replaced with MEM containing 30 mM of arachidonic acid, the cells are incubated for 20 minutes at 37 ° C and the enzyme activity is determined as described below.

Determined Activity of COX After incubation with arachidonic acid, the reactions are stopped by the addition of IN HCl, followed by neutralization with IN NaOH and centrifugation to pellet the cell debris. The activity of the enzyme cyclooxygenase in the supernatants of both cells HOSC and THP-1 is determined by measuring the concentration of PGE2 using a commercially available ELISA (Neogen # 404110). A normal PEG2 curve is used for calibration, and COX-1 and COX-2 inhibitors are commercially available as normal controls. Accordingly, the compounds of the invention or a pharmaceutical composition thereof are useful for the prophylaxis and treatment of rheumatoid arthritis; Paget's diseases, osteoporosis; multiple myeloma; uveitis; acute and chronic myelogenous leukemia; destruction of pancreatic ß cells; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress 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 diseases; graft reaction against the host; reperfusion injury of ischemia; atherosclerosis; brain trauma; Alzheimer disease; apoplexy; myocardial infarction; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgias due to infection. HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses (including HSV-1, HSV-2), and herpes zoster, all of which are sensitive to inhibition of TNF-α and / or IL-1 or antagonism of glucagon, will also be positively affected by the compounds and methods of the invention. The compounds of the present invention may also possess analgesic properties and may be useful for the treatment of pain disorders, such as hyperalgesia due to excessive IL-1. The compounds of the present invention can also prevent the production of prostaglandins by inhibiting enzymes in the human arachidonic / prostaglandin acid pathway, including cyclooxygenase (WO 96/03387, incorporated herein by reference in its entirety). Due to their ability to lower TNF-α and IL-1 concentrations or inhibit glucagon binding to their receptor, the compounds of the invention are also useful in searching for tools to study the physiology associated with blocking these effects. The methods of the invention comprise administering an effective dose of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either, to a subject (i.e., an animal, preferably a mammal, more preferably a human) in need of a reduction in the level of TNF-α, IL-1, IL-6 and / or IL-8 levels and / or a reduction in plasma glucose levels and / or that the Subject may be suffering from rheumatoid arthritis; Paget's disease, osteoporosis; multiple myeloma; uveitis; acute and chronic myelogenous leukemia; destruction of pancreatic ß cells; osteoarthritis; rheumatoid spondylitis; gouty arthritis; inflammatory bowel disease; adult respiratory distress 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 diseases; graft reaction against the host; Alzheimer disease; apoplexy; myocardial infarction; reperfusion injury of ischemia; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgia due to infection or that the subject is infected with HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses (including HSV-1, HSV-2) , or herpes zoster. In another aspect, this invention comprises the use of a compound of the invention, or pharmaceutically acceptable salts thereof, in the preparation of a medicament for the treatment either acutely and chronically of a disease state mediated by TNF-a, IL- lß, IL-6 and / or IL-8, including those previously described. Also, the compounds of this invention are useful in the preparation of an analgesic medicament and a medicament for treating pain disorders, such as hyperalgesia. The compounds of the present invention are also useful in the preparation of a medicament for preventing the production of prostaglandins by inhibiting enzymes in the arachidonic acid / prostaglandin pathway of human. Even in another aspect, this invention provides a pharmaceutical composition comprising an effective amount that decreases TNF-a, IL-lβ, IL-6 and / or IL-8 and / or an effective amount that decreases the level of glucose in the plasma of a compound of the invention and a pharmaceutically acceptable carrier or diluent, and if desired other active ingredients. The compounds of the invention are administered by any suitable route, preferably in the form of a pharmaceutical composition adapted for such a route, and in an effective dose for the proposed treatment. Therapeutically effective doses of the compounds of the present invention required to arrest the progress or prevent tissue damage associated with the disease are readily ascertained by one of ordinary skill in the art using standard methods.

For the treatment of diseases mediated by TNF-α, IL-1β, IL-6, and IL-8 and / or hyperglycemia, the compounds of the present invention can be administered orally, parenterally, by inhalation, rectally or topically in unit dose formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein includes, subcutaneously, intravenously, intramuscularly, intrasternally, infusion techniques or intraperitoneally. The dosage regimen for treating diseases mediated by TNF-α, IL-1, IL-6 and IL-8 and / or hyperglycemia with the compounds of this invention and / or compositions of this invention is based on a variety of factors, including the type of disease, the age, weight, sex, medical conditions of the patient, the severity of the condition, the route of administration and the particular compound used. In this way, the dosage regimen can vary widely, but can be determined routinely using standard methods. Dosage levels in the range of about 0.01 mg to 30 mg per kilogram of body weight per day, preferably from about 0.1 mg to 10 mg / kg, more preferably from about 0.25 mg to 1 mg / kg are useful. for all methods of use described herein. The pharmaceutically active compounds of this invention can be processed according to conventional pharmacy methods to produce medicinal agents for administration to patients, including humans and other mammals. For oral administration, the pharmaceutical composition may be in the form of, for example, a capsule, a tablet, a suspension or a liquid. The pharmaceutical composition is preferably made in the form of a unit dose containing a given amount of the active ingredient. For example, they may contain an amount of active ingredient of about 1 to 2000 mg, preferably about 1 to 500 mg, more preferably about 5 to 150 mg. A daily dose, suitable for a human or other mammal can vary widely depending on the condition of the patient and other factors, but, once again, it can be determined using routine methods. The active ingredient can also be administered by injection as a composition with suitable carriers including saline, dextrose or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg / kg of total body weight, preferably from about 0.1 to about 10 mg / kg, and more preferably from about 0.25 mg to 1 mg / kg. . Injectable, sterile injectable preparations, such as aqueous or oleaginous suspensions, can be formulated in accordance with the known using suitable dispersing or wetting agents and suspending agents. The injectable, sterile preparation can also be an injectable, sterile solution or suspension in a non-toxic, parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspension medium. For this purpose any fixed, soft oil, including synthetic mono- or diglycerides, may be employed. In addition, fatty acids such as oleic acid find use in the preparation of injectable solutions.

Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at rectal temperature and will therefore melt in the rectum. and they will release the drug. A topical dose, suitable of the active ingredient of a compound of the invention is 0.1 mg to 150 mg administered one to four, preferably once or twice a day. For topical administration, the active ingredient may comprise from 0.001% to 10% w / w, for example from 1% to 2% by weight of the formulation, although it may comprise as much as 10% w / w, but preferably not more than 5% w / w, and more preferably from 0.1% to 1% of the formulation. Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin (eg, liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear or ear. nose. For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds can be mixed with lactose, sucrose, starch powder, cell esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, alginate of sodium, polyvinyl-pyrrolidine, and / or polyvinyl alcohol, and in tablets or capsules for conventional administration. Alternatively, the compounds of this invention can be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum and / or various buffers. . Other adjuvants and modes of administration are well known in the pharmaceutical art. The carrier or diluent may include a material for delaying time, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art. The pharmaceutical compositions can be prepared in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions or emulsions). The pharmaceutical compositions can be subjected to pharmaceutical, conventional operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers etc. Solid dosage forms for oral administration may include capsules, tablets, pills, poles and granules. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. The tablets and pills can be further prepared with enteric coatings. Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring and perfuming agents. The compounds of the present invention may possess one or more asymmetric carbon atoms and thus are capable of existing in the form of optical isomers as well as in the form of racemic or non-racemic mixtures thereof. The optical isomers can be obtained by resolution of the racemic mixtures according to conventional procedures, for example, by the formation of diastereomeric salts, by treatment with an optically active acid or base. Examples of suitable acids are tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric and camphorsulfonic and then the separation of the mixture of diastereoisomers by crystallization followed by the release of the optically active bases of these salts. A different procedure for the separation of optical isomers involves the use of an optimally selected chiral chromatography column to maximize the separation of the enantiomers. Yet another available method involves the synthesis of diastereoisomeric, covalent molecules by reacting the compounds of the invention with an optically pure acid in an activated form or an optically pure isocyanate. The synthesized diastereomers can be separated by a conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed to provide the enantiomerically pure compound. The optically active compounds of the invention can be obtained in the same way by using active starting materials. These isomers may be in the form of a free acid, a free base, an ester or a salt. The compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Salts include, but are not limited to, the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorrate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecyl sulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate , hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate , thiocyanate, tosylate, mesylate and undecanoate. Also, basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl and butyl chloride, bromides and iodides; dialkyl sulfates similar to dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides similar to benzyl and phenethyl bromides, and others. The water-soluble or oil-dispersible products are obtained in this way. Examples of acids that can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid and such organic acids such as oxalic acid, maleic acid, succinic acid and citric acid. Other examples include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases. While the compounds of the invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more compounds of the invention or other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that occur at the same time or at different times, or the therapeutic agents can be given as an individual composition. The foregoing is only illustrative of the invention and is not intended to limit the invention to the disclosed compounds. Variations and changes that are obvious to one skilled in the art are proposed to be within the scope and nature of the invention which are defined in the appended claims. From the above description, one skilled in the art can easily find out the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following claims is claimed as property.

Claims (31)

RE IVINDI CAC I ONES
1. A compound of the formula or a pharmaceutically acceptable salt thereof, characterized in that R? and R2 are each independently -Z-Y, with the proviso that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of -Z-Y is 0-3; and (2) the total, combined number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R1 and R2 is 0-4; wherein each Z is independently (1) a bond; (2) an alkyl, alkenyl or alkynyl radical optionally substituted by (a) 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo radicals, and (b) 1-2 radicals heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl radicals; (3) a heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl radicals; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl radicals; each Y is independently (1) a hydrogen radical; (2) a halo or nitro radical; (3) a radical of -C (O) -R20 or -C (NR5) -NR5R2 ?; (4) a radical -0R2i, -0-C (0) -R2 ?, -O-C (O) -NR5R21 or -0-C (0) -NR22-S (0) 2-R20; (5) a radical of -SR21, -S (O) -R20, -S (O) 2 -R20, -S (0) 2 -NR5R2 ?, -S (0) 2 -NR22-C (0) - R21, -S (O) 2-NR22-C (O) -OR20 or -S (O) 2-NR22-C (O) -NR5R21; Or (6) a radical of -NR5R2 ?, -NR22-C (O) -R2i, -NR22-C (0) -OR20, -NR22-C (0) -NR5R2 ?, -NR22-C (NR5) - NR5R21, -NR22-S (O) 2-R20 or -NR22-S (O) 2-NR5R2 ?; wherein each R5 is independently (1) hydrogen radicals; (2) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, -S03H or halo radicals; or (3) aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalkyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl radicals; Y wherein each R20 is independently (1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, N- (alkoxycarbonyl) -N- (alkyl) amino, aminocarbonylamino, alkylsulfonylamino radicals , hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkanoyl radicals, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo, alkyl or haloalkyl; (2) a heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl radicals; every R2? it is independently a hydrogen radical or R2o, " each R22 is independently (1) a hydrogen radical; (2) an alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl radicals; with the proviso that when Z is a bond and Y is -NR22-C (O) -NH2, then R22 is another, then R22 is different from an optionally substituted aryl radical; Y R n and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of (1) R 30; (2) halo or cyano radicals; (3) radicals of -C (0) -R30, -C (0) -OR29, -C (O) -NR31R32 or -C (NR31) -NR31R32; (4) radicals of -OR29, -0-C (0) -R29, -O-C (O) -NR3? R32 or -o-c (O) -NR33-S (O) 2-R30; (5) -SR29 radicals, -S (O) -R30, -S (O) 2 -R30, -S (0) 2 -NR31R32, -S (0) 2 -NR33-C (0) -R30, -S (O) 2-NR 33 -C (O) -OR 30 or -S (0) 2-NR 33 -C (0) -NR 31 R 32; or (6) radicals of -NR3? R32, -NR33-C (O) -R29, -NR33-C (0) -OR30, -NR33-C (0) -NR31R32, -NR33-C (NR31) -NR31R32 , -NR33-S (O) 2-R30 or -NR33-S (0) 2-NR31R32; with the proviso that (1) Rp is different from a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of substituted aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of Ru and Ri2 is 0-1; wherein each R30 is independently (1) alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of -NR3? R31, -C02R23, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl radicals; each R29 is independently a hydrogen radical or R30; each R3i and R32 are each independently (1) hydrogen radicals; (2) an alkyl radical optionally substituted by a cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; and wherein each R33 is independently (1) a hydrogen radical; or (2) an alkyl radical optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl radicals; Y with the proviso that (1) when R1 and R12 are the same and are a 5 or 6 member ring having from 1-3 heteroatoms independently selected from N, S and 0, ring to which a benzene ring is optionally fused, R11 is phenyl or naphthyl optionally substituted with halo, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkyl thiol of 1 to 4 carbon atoms, hydroxy, amino, alkylamino of 1 to 4 carbon atoms, or dialkylamino, or R 11 is a 5- or 6-membered ring having from 1-3 heteroatoms independently selected from N, S and 0, ring to which a benzene ring is optionally fused and optionally substituted with alkyl of 1 to 6 carbon atoms. carbon, then R2 is different from OH or NH2; (2) when R2 is H, R11 is phenyl and R12 is phenyl or 4-pyridyl, then R1 is different from H, methyl, or amino, (3) when R2 is H, R11 is 2-methylphenyl and R12 is 2- pyridyl, then R1 is different from n-propyl; and (4) when R11 and R12 are each an optionally substituted phenyl radical, then R1 is different from an optionally substituted 2-pyridyl radical.
2. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that Ra and R2 are each independently -Z-Y, with the proviso that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of -Z-Y is 0-3; and (2) the total, combined number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in Ri and R2 is 0-4; each Z is independently (1) a link; (2) an alkyl radical of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by (a) 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy , alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halo and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 atoms carbon, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (3) a heterocyclyl radical optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1-4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 4 carbon atoms of 1 to 3 halo radicals; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms of carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; each Y is independently (1) a hydrogen radical; (2) a halo or nitro radical; (3) a radical of -C (0) -R20, or -C (NR5) -NR5R2 ?; (4) a radical of -OR21, -0-C (0) -R21, -O-C (O) -NR5R21 or -O-C (O) -NR22-S (O) 2-R20; (5) a radical of -SR2 ?, -S (O) -R20, -S (O) 2 -R20, -S (0) 2 -NR5R2 ?, -S (0) 2 -NR22-C (0) -R2 ?, -S (O) 2-NR22-C (0) -OR20 or -S (O) 2-NR22-C (0) -NR5R2 ?; or (6) a radical of -NR5R2 ?, -NR22-C (O) -R2i, -NR22-C (O) -OR20, -NR22-C (O) -NR5R2 ?, -NR22-C (NR5) - NR5R2 ?, -NR22-S (O) 2 -R20 or -NR22-S (O) 2-NR5R2 ?; each R5 is independently (1) hydrogen radicals; (2) alkyl radicals of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, -S03H or halo; or (3) aryl, heteroaryl, aryl-alkyl radicals of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, heterocyclyl, heterocyclyl-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon or cycloalkyl-3C-8C-alkyl atoms of 1 to 4 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, N- ((alkoxy of 1 to 4 atoms) carbon) carbonyl) -N- (alkyl-1 to 4 carbon atoms) amino, aminocarbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms carbon, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, aryl-alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocyclyl, aryl or optionally substituted heteroaryl radicals by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbon) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl of 1 to 5 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms , alkylsulfonyl of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1-4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (C 1 -C 4 alkoxy) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; each R2X is independently a hydrogen radical or R20; each R22 is independently (1) a hydrogen radical; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1) to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio from 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1 3 halo radicals; or (3) heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 atoms carbon, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; with the proviso that when Z is a bond and Y is -NR22-C (O) -NH2, then R22 is different from an optionally substituted aryl radical; Rn and 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of (1) R30; (2) halo or cyano radicals; (3) radicals of -C (O) -R30, -C (0) -OR29, -C (O) -NR31R32 or -C (NR31) -NR3aR32; (4) radicals of -OR29, -0-C (0) -R29, -O-C (O) -NR31R32 or -O-C (O) -NR33-S (O) 2-R30; (5) radicals of -SR29 / -S (0) -R30, -S (O) 2 -R30, -S (0) 2-NR31R32, -S (0) 2-NR33-C (0) -R30, -S (O) 2-NR33-C (O) -OR30 or -S (0) 2-NR33- C (0) -NR31R32; or (6) radicals of -NR31R32, -NR33-C (O) -R29, -NR33-C (O) -OR30, -NR33-C (O) -NR31R32, -NR33-C (NR31) -NR31R32, - NR33-S (O) 2-R30 or -NR33-S (O) 2-NR31R32; provided that (1) Ru is different from a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of substituted aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of Rp and Ri2 is 0-1; each R30 is independently (1) alkyl radicals of 1 to 4 carbon atoms, alkenyl of 2 to 4 carbon atoms or alkynyl of 2 to 4 carbon atoms optionally substituted by 1-3 radicals of -NR3iR3 ?, -C02R23, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo or arylalkoxy of 1 to 4 carbon atoms , arylalkylthio of 1 to 4 carbon atoms, arylalkylsulfonyl of 1 to 4 carbon atoms, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-) from 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms , alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 atom s of carbon, alkylsulfonyl of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms carbon, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms , hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; each R29 is independently a hydrogen radical or R30; each R3i and R32 are each independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a cycloalkyl radical of 3 to 8 carbon atoms, aryl, heterocyclyl or heteroaryl optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 atoms carbon, 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 4 -alkyl or haloalkyl of 1 to 4 C atoms of 1-3 halo radicals; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical of 3 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 atoms) carbon) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; Y each R33 is independently (1) a hydrogen radical; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a heterocyclyl, aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-) from 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms , alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; Y wherein heterocyclyl is a radical of a saturated, monocyclic or bicyclic heterocyclic ring system having 5-8 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is partially unsaturated or optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is a radical of a monocyclic or bicyclic, aromatic, heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzofused or carbocyclic-fused, saturated, of 3 to 4 carbon atoms.
3. 3. The compound according to claim 2 or a pharmaceutically acceptable salt thereof, characterized in that each Z is independently (1) a link; (2) an alkyl radical of 1 to 8 carbon atoms, alkenyl of 2 to 8 carbon atoms or alkynyl of 2 to 8 carbon atoms optionally substituted by (a) 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or halo and (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 atoms carbon, di- (C 1 -C 4 -alkyl) amino, C 1 -C 5 -alkanoylamino, (C 1 -C 4 -alkoxy) carbonylamino, alkylsulfonylamino with 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of and 1 to 4 carbon atoms of 1-3 halo radicals; (3) a heterocyclyl radical optionally substituted by 1-2 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1-4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl from 1 to 4 carbon atoms of 1-3 halo radicals; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms of carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; each R5 is independently (1) hydrogen radicals; (2) alkyl radicals of 1 to 4 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkynyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, • di- (C 1 -C 4 -alkyl) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms -S03H or halo; or (3) aryl, heteroaryl, aryl-alkyl radicals of 1 to 4 carbon atoms, heteroaryl-alkyl of 1 to 4 carbon atoms, heterocyclyl, heterocyclyl-alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or cycloalkyl-3C-aC-alkyl of 1 to 4 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms, alkenyl of 2 to 5 carbon atoms or alkynyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, N- ((alkoxy of 1 to 4 carbon atoms) carbonyl) -N- (alkyl of 1 to 4 carbon atoms) amino, aminocarbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, aryl-alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl of 1 to 5 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 atom s of carbon, alkylsulfonyl of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (C 1 -C 4 alkoxy) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; every R2? is independently a hydrogen radical or R20; each R30 is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-3 radicals of (a) -NR31R31; (b) C 1 -C 4 alkoxy or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1-3 amino, alkylamino, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino radicals of 1 to 5 atoms of carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl; or (c) hydroxy radicals, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, or phenyl-alkoxy of 1 to 4 carbon atoms, phenyl-alkylthio of 1 to 4 carbon atoms, heterocyclyl , phenyl or heteroaryl optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; (2) haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; each R29 is independently a hydrogen radical or R30; every R3? is independently (1) hydrogen radicals; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1) to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano , alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; Y each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a cycloalkyl radical of 3 to 6 carbon atoms, aryl, heterocyclyl or heteroaryl optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 atoms carbon, di- (C 1 -C 4 -alkyl) amino, C 1 -C 5 -alkanoylamino, (C 1 -C 4 -alkoxy) carbonylamino, alkylsulfonylamino with 1 to 4 carbon atoms, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, cyano, C 1-4 -alkyl or haloalkyl with 1 to 4 C atoms of 1-3 halo radicals; or (3) an aryl, heteroaryl, heterocyclyl or cycloalkyl radical of 3 to 6 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl) of 1 to 4 atoms carbon) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms of 1-3 halo radicals; Y each R33 is independently a hydrogen radical or alkyl of 1 to 4 carbon atoms.
4. 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, characterized in that wherein Ri is -Z-Y, with the proviso that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in Rx is 0-3; Z is (1) a link; (2) an alkyl radical of 1 to 8 carbon atoms or alkenyl of 2 to 8 carbon atoms optionally substituted by (a) 1-3-amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl) (from 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms carbon or halo and (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino , alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 atoms carbon or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; (3) a heterocyclyl radical optionally substituted by 1-2 amino radicals, di (alkyl-1 to 4 carbon atoms) amino, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl radicals of 1 to 4 carbon atoms; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms of carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; And it is (1) a hydrogen radical; (2) a halo radical; (3) a radi cal - C (O) -R20 or -C (NR5) -NR5R2?; (4) a radical of -OR2? , -0-C (0) -R2? , or -O-C (O) -NR5R2?; (5) a radical of -SR2i, -S (O) -R20, -S (O) 2 -R20, or (6) a radical of -NR5R21, -NR22-C (0) -R21, -NR22-C (0) -OR20, -NR22-C (0) -NR5R21, -NR22-C (NR5) -NR5R2? , -NR22-S (0) 2-R20 or -NR22-S (0) 2-NR5R2 ?; each R5 is independently (1) hydrogen radicals; (2) alkyl radicals of 1 to 4 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 4 carbon atoms) amino, hydroxy, alkoxy from 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, -S03H or halo; or (3) phenyl-alkyl radicals of 1 to 2 carbon atoms, heteroaryl-alkyl of 1 to 2 carbon atoms, heterocyclyl-alkyl of 1 to 2 carbon atoms or cycloalkyl-3C-6C-alkyl of 1 to 2 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl- of 1 to 4 carbon atoms) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-) from 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, N- ((alkoxy of 1 to 4 carbon atoms) carbonyl) -N- ( alkyl of 1 to 4 carbon atoms) amino, aminocarbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms , halo or aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, aryl-alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 6 carbon atoms, heterocyclyl, aryl or radicals of heteroaryl optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1) to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl of 1 to 5 carbon atoms, hydroxy, alkoxy from 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; (2) a heterocyclyl radical optionally substituted by 1-2 amino radicals, alkylamino of 1 to 4 carbon atoms, di (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, ( C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (C 1 -C 4 alkoxy) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; every R2? is independently a hydrogen radical or R2o; each R22 is independently (1) a hydrogen radical; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino, di (alkyl-1 to 2 carbon atoms) amino, alkanoylamino radicals of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms carbon or haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; R2 is a radical of hydrogen, alkyl of 1 to 4 carbon atoms, halo, hydroxy, alkoxy of 1 to 4 carbon atoms, haloalkoxy of 1 to 2 carbon atoms of 1-3 halo radicals, thiol, alkylthio of 1 to 4 carbon atoms, aminosulfonyl, alkylaminosulfonyl of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) aminosulfonyl, amino, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 radicals of halo; R n and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of (i) R 30; (2) halo or cyano radicals; (3) radicals of -C (O) -R30, -C (0) -OR29, -C (0) -NR31R32 or -C (NR31) -NR31R32; (4) radicals of -OR29, -SR29, -S (O) -R30, -S (O) 2 -R30, -S (0) 2-NR31R32, -NR31R32, -NR33-C (0) -R29- NR33-C (0) -OR30, with the proviso that (1) Rp is different from a 4-pyridyl, 4-pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and (2) the total number of substituted aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of Rn and Ri2 is 0-1; each R3o is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by (a) amino, alkylamino radicals of 1 to 4 carbon atoms or di- (alkyl-1 to 4 carbon atoms) Not me; (b) hydroxy, alkoxy of 1 to 4 carbon atoms, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl) of 1 to 4 atoms carbon) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (2) haloalkyl of 1 to 2 carbon atoms of 1-3 halo radicals; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, carbon, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; each R29 is independently a hydrogen radical or R30; every R3? is independently hydrogen or alkyl radicals of 1 to 4 carbon atoms; Y each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or radicals of trifluoromethyl; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 atoms carbon, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; Y each R33 is independently a hydrogen or methyl radical; and wherein heterocyclyl is a radical of a monocyclic, saturated, heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is a radical of a monocyclic, aromatic, heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or carbocyclic -fused, saturated, of 3 to 4 carbon atoms.
5. 5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, characterized in that Z is (1) a link; (2) an alkyl radical of 1 to 4 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by (a) 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino , alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or halo and (b) 1-2 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl- of 1 to 2 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (3) a heterocyclyl radical optionally substituted by 1-2 amino, di (alkyl-1 to 2 carbon atoms) amino, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy radicals from 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or alkyl radicals of 1 to 4 carbon atoms; or (4) an aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy 1-4) carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; each R5 is independently (1) a hydrogen radical; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or halo; or (3) phenyl-alkyl radicals of 1 to 2 carbon atoms, heteroaryl-alkyl of 1 to 2 carbon atoms, heterocyclyl-alkyl of 1 to 2 carbon atoms or cycloalkyl-3C-6C-alkyl of 1 to 2 carbon atoms optionally substituted by 1-3 amino radicals, di- (alkyl- of 1 to 2 carbon atoms) amino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, methoxy, methylthio, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; each R22 is independently a hydrogen radical or alkyl of 1 to 4 carbon atoms; Ru is an aryl radical and R12 is a heteroaryl radical wherein the aryl or heteroaryl radicals are optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; (3) radicals of -C (O) -R30, -C (0) -OR29, -C (0) -NR31R32 or -C (NR3?) -NR3? R32; or (4) radicals of -OR29, -SR29, -S- (0) -R30, -S (0) 2 -R30, -S (0) 2-NR31R32, -NR31R32, -NR33-C (0) - R29; with the proviso that the total number of substituted aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of Rp and Ri2 is 0-1; each R30 is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, di- (alkyl- of 1 to 2 carbon atoms) amino, acetamido, hydroxy, alkoxy of 1 to 2 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (2) a trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, di (alkyl-1 to 2 carbon atoms) amino, acetamido, hydroxy, alkoxy of 1 to 2 carbon atoms, halo, alkyl 1 to 4 carbon atoms or trifluoromethyl radicals; each R29 is independently a hydrogen radical 0 R30; Y each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms or an alkyl radical of 1 to 2 carbon atoms substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino radicals, di (alkyl-1) to 2 carbon atoms) amino, acetamido, hydroxy, alkoxy of 1 to 2 carbon atoms, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 amino, di (alkyl-1 to 2 carbon atoms) amino, acetamido, hydroxy, alkoxy of 1 to 2 carbon atoms, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; Y wherein heterocyclyl is a radical of a monocyclic, saturated, heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is a radical of a monocyclic, aromatic, heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused.
6. 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, characterized in that wherein R1 is -Z-Y, with the proviso that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in Ri is 0-2; Z is (1) a link; (2) an alkyl radical of 1 to 4 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by (a) 1-3 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms or halo and (b) 1-2 aryl or heteroaryl radicals optionally substituted by 1 -2 amino radicals, di- (alkyl- of 1 to 2 carbon atoms) amino, acetamido, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; or (3) aryl or heteroaryl radical optionally substituted by 1-3 amino radicals, di (alkyl-1 to 2 carbon atoms) amino, acetamido, (alkoxy of 1 to 4 carbon atoms) carbonylamino, hydroxy, alkoxy 1 to 2 carbon atoms, alkylthio having 1 to 2 carbon atoms, cyano, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; And it is (1) a hydrogen radical; (2) a radical of -C (O) -R20; (3) a radical of -OR21, -SR2i, -S (O) -R20, -S (O) 2 -R20 or (4) a radical of -NR5R2 ?, -NR22-C (O) -R2i, - NR22-C (0) -OR20, -NR22-C (0) -NR5R21, -NR22-S (O) 2 -R20 or -NR22-S (O) 2-NR5R2 ?; each R5 is independently (1) a hydrogen radical; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-3 halo radicals; or (3) phenyl-alkyl radicals of 1 to 2 carbon atoms or heteroaryl-alkyl of 1 to 2 carbon atoms optionally substituted by 1-3 amino, dimethylamino, hydroxy, methoxy, methylthio, methyl radicals 0 trifluoromethyl radicals; each R20 is independently (1) alkyl radicals of 1 to 8 carbon atoms or alkenyl of 2 to 5 carbon atoms optionally substituted by 1-3 amino, alkylamino radicals of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonylamino, N- ((alkoxy of 1 to 4 carbon atoms) carbonyl) -N- (alkyl-1 to 4 carbon atoms) amino, aminocarbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or aryl-alkoxy of 1 to 4 carbon atoms, aryl-alkylthio of 1 to 4 carbon atoms, aryl-alkylsulfonyl of 1 to 4 carbon atoms, cycloalkyl from 3 to 6 carbon atoms, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl of 1 to 4 carbon atoms) amino, alkanoylamino from 1 to 5 carbon atoms, (C 1 -C 4 alkoxy) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, alkanoyl 1 5 carbon atoms, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or haloalkyl of 1 to 2 carbon atoms of 1-3 radicals of halo; (2) a heterocyclyl radical optionally substituted by 1-2 amino radicals, di (C 1 -C 4) alkyl amino, (C 1 -C 4 alkoxy) carbonylamino, hydroxy, alkoxy 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino, acetamido, (alkoxy of 1 to 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, (alkoxy of 1 to 4 carbon atoms) carbonyl, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; every R2? it is independently a hydrogen radical or R2o, " R2 is a radical of hydrogen, alkyl of 1 to 4 carbon atoms, halo, hydroxy, alkoxy of 1 to 4 carbon atoms, trifluoromethoxy, thiol, alkylthio of 1 to 4 carbon atoms, amino, alkylamino of 1 to 4 atoms carbon, di- (C 1 -C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino or trifluoromethyl; Ru is an aryl radical and R12 is a heteroaryl radical, wherein the aryl or heteroaryl radicals are optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; or (3) radicals of -C (O) -NR31R32, OR29, -SR29, -S (O) -R30, -S (O) 2 -R30, -S (0) 2 -NR3? R32, -NR31R32 or -NR33-C (O) -R29; with the proviso that the total number of substituted aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of Rp and R? 2 is 0-1; each R30 is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or radicals of trifluoromethyl; (2) a trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or trifluoromethyl radicals; each R29 is independently a hydrogen radical or R30; every R3? is independently hydrogen, methyl or ethyl radicals; Y each R32 is independently (1) hydrogen radicals; (2) an alkyl radical of 1 to 4 carbon atoms or an alkyl radical of 1 to 2 carbon atoms substituted by a phenyl or heteroaryl radical optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy radicals, methoxy, methyl, or trifluoromethyl radicals; or (3) a phenyl or heteroaryl radical optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, methoxy, methyl radicals or trifluoromethyl radicals.
7. 7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, characterized in that Ru is an aryl radical optionally substituted by 1-2 radicals of (1) R30; (2) halo or cyano radicals; or (3) radicals of -C (O) -NR3? R32 -OR29, -SR29, -S (O) -R30, -S (O) 2 -R30, -S (0) 2 -NR3? R32, - NR3? R32 or -NR33-C (O) -R29; Y R 12 is a heteroaryl radical optionally substituted by 1-2 radicals of (1) R 30; (2) halo or cyano radicals; or (3) radicals of -C (O) -NR3? R32, -OR29, -SR29, NR3aR32 or NR33-C (0) -OR29; with the proviso that the total number of substituted aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each of Rn and R? 2 is 0-1; R3o is independently (1) an alkyl radical of 1 to 4 carbon atoms optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or radicals of trifluoromethyl; (2) a trifluoromethyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-3 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or trifluoromethyl radicals; R29 is an aryl or heteroaryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl radicals or trifluoromethyl radicals; Y R32 is independently (1) a hydrogen radical or alkyl of 1 to 4 carbon atoms; or (2) a phenyl or heteroaryl radical optionally substituted by a 1-2 amino, dimethylamino, acetamido, hydroxy, methoxy, methyl radicals or trifluoromethyl radicals.
8. 8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, characterized in that wherein Ri is -Z-Y, with the proviso that (1) the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in Ri is 0-1; Z is (1) a link; (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-2 amino radicals, di- (alkyl-1 to 2 carbon atoms) amino, (carbonamino-1-alkoxy) carbonylamino , hydroxy, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, halo or aryl or heteroaryl optionally substituted by 1-2 hydroxy radicals, alkoxy of 1 to 2 carbon atoms, alkylthio of 1 to 2 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; each R 5 is independently a hydrogen radical or alkyl of 1 to 4 carbon atoms; each R2o is independently (1) alkyl radicals of 1 to 8 carbon atoms optionally substituted by 1-3 amino radicals, alkylamino of 1 to 4 carbon atoms, di- (alkyl-1 to 4 carbon atoms) amino , C 1 -C 5 -alkanoylamino, (C 1 -C 4 -alkoxy) carbonylamino, N- (C 1-4 -alkoxy) carbonyl) -N- (C 1-4 -alkyl) amino, aminocarbonylamino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, alkylsulfinyl of 1 to 4 carbon atoms, alkylsulfonyl of 1 to 4 carbon atoms, halo or cycloalkyl of 3 to 6 carbon, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-2 amino radicals, di- (alkyl-1 to 4 carbon atoms) amino, alkanoylamino of 1 to 5 carbon atoms, (1-alkoxy) 4 carbon atoms) carbonylamino, alkylsulfonylamino of 1 to 4 carbon atoms, hydroxy, alkoxy of 1 to 4 carbons ono, alkylthio of 1 to 4 carbon atoms, halo, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; (2) a heterocyclyl radical optionally substituted by 1-2 hydroxy radicals, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms or alkyl of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (C 1 -C 4 alkoxy) carbonyl, amino, alkylamino of 1 to 4 carbon atoms, di (C 1 -C 4 alkyl) amino, hydroxy, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, cyano, halo, azido, alkyl of 1 to 4 carbon atoms or trifluoromethyl radicals; every R2? is independently a hydrogen radical or R20 R 2 is a radical of hydrogen, methyl, ethyl, fluoro, chloro, hydroxy, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, acetylamino or trifluoromethyl; Ru is an aryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl radicals or trifluoromethyl radicals; Ri2 is a heteroaryl radical optionally substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl radicals, or trifluoromethyl radicals;
9. 9. The compound according to claim 8, or a pharmaceutically acceptable salt thereof, characterized in that Z is (1) a link; or (2) an alkyl radical of 1 to 4 carbon atoms optionally substituted by 1-2 amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio radicals or halo radicals; And it is (1) a hydrogen radical; (2) a radical -C (O) -R20; (3) a radical of -OR2 ?, -SR2X, -S (O) -R20, -S (O) 2 -R20 or (4) a radical of -NR5R21, -NR22-C (O) -R2 ?, or -NR22-S (O) 2-OR20; R5 is a hydrogen radical; each R20 is independently (1) alkyl radicals of 1 to 6 carbon atoms optionally substituted by 1-3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N- ((t-butoxy) carbonyl) -N- (methyl) radicals amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or cycloalkyl of 5 to 6 carbon atoms, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, acetamino radicals , hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; (2) a heterocyclyl radical optionally substituted by 1-2 hydroxy or alkyl radicals of 1 to 4 carbon atoms; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl radicals or trifluoromethyl radicals; every R2? is independently a hydrogen radical or R20; each R22 is independently a hydrogen or methyl radical; Ru is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; R 2 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4-pyrimidinyl radical optionally substituted by an amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl radical or trifluoromethyl radicals.
10. 10. The compound according to claim 9 or a pharmaceutically acceptable salt thereof, characterized in that Y is (1) a radical of -C (O) -R20; (2) a radical of -OR2 ?, -SR2i, -S (O) -R20, -S (O) 2 -R20 or (3) a radical of -NRR2 ?, -NR22-C (O) -R2a, or -NR22-C (O) 2-OR20; each R20 is independently (1) alkyl radicals of 1 to 6 carbon atoms optionally substituted by 1-3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N- ((t-butoxy) carbonyl) -N- (methyl) radicals amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or cycloalkyl of 5 to 6 carbon atoms, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, acetamino radicals , hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; (2) a heterocyclyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl radicals or trifluoromethyl radicals; Y each R2i is independently a hydrogen radical or R20.
11. 11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, characterized in that Y is a radical of -0R2 ?, -SR2i or -NR5R2?, - each R20 is independently (1) alkyl radicals of 1 to 6 carbon atoms optionally substituted by 1-3 amino, methylamino, dimethylamino, hydroxy or phenyl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl radicals or trifluoromethyl radicals; (2) a heterocyclyl radical; or (3) aryl or heteroaryl radicals optionally substituted by 1-2 amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl radicals or trifluoromethyl radicals; every R2? is independently a hydrogen radical or R20; Ru is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl radicals or trifluoromethyl radicals; Y R 12 is a 4-pyridyl radical optionally substituted by an amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl radical or trifluoromethyl radicals.
12. 12. The compound according to claim 1, characterized in that it is: 5- (4-Fluorophenyl) -2- (4-pyridyl) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2- (2-methylthiazol-4-yl) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -4- (4-pyridyl) -2- (2-thienyl) -pyrimidine, 2- (2-Diethylaminoethylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2-Aminobutylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2,6-Dichlorobenzyl) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2,6-Dichloro-phenylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2,6-Dimethylphenylamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2- (2-methoxy-phenylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-fluorophenyl) -2- (4-fluorophenylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2-phenylthiomethyl-4- (4-pyridinyl) -pyrimidine, 2- (2- (4-Aminophenyl) ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2- (2-Chlorophenyl) ethyl-amino)) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine,o. 2- (2- (4-Chlorophenyl) ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (2- (3-Chloro-phenyl) -ethyl-amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 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-Fl orophenyl) -2- (2- (3-methoxy phenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2 - ((1-methy1) -3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl-2- ((4-phenyl-butyl) -amino) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2-morpholino-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, 2- (4-Fluorophenyl) -2- (3- (2-pyrrolidinon-1-yl) propylamino) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2- (2-phenoxyethyl) thio-6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-Fluorophenyl) -2- (2-phenylaminoethyl) thio-6- (4-pyridyl) -4-hydroxy-pyrimidine, 2- (2-Aminoetilamino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- (3-Aminoethylamino) -5- (4-fluorophenyl) -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- (N-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) ethyl) -amino-4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2- (2- (4-fluorophenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2- (2- (2-fluorophenyl) ethyl-amino) -4- (4-pyridyl) -pyrimidine, 5- (4-Fluorophenyl) -2- ((3-phenylpropyl) -amino) -4- (4-pyridyl) -pyrimidine, 2- ((2 (S) -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-imidazolylpropi1) -amino) -4- (4-pyridyl) -pyrimidine, 5- (-Fluorophenyl) -4- (4-pyridyl) -2-pyrrolidino-pyrimidine, 5- (4-Fluorophenyl) -2- (1-piperazinyl) -4- (4-pyridyl) -pyrimidine, 2- (2,6-Dichlorobenzyl) -5- (4-fluorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-Fluorophenyl) -2- (2-phenylethyl) thio-6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-Fluorophenyl) -2- (3-phenylpropyl) thio-6- (4-pyridyl) -4-hydroxy-pyrimidine, 2- (2- (2-Chlorophenyl) ethyl-amino) -5- (4-fluorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-Fluorophenyl) -2- ((3-phenylpropyl) amino) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 5- (4-Fluorophenyl) -2- ((1-methy1-3-phenylpropyl) -amino) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 2- (2- (2-chlorophenyl) ethyl- amino) -5- (-fluorophenyl) -6- (4-pyridyl) -4-hydroxy-pyrimidine, 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-N, N-Dimethyl-amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -4- (4-pyridyl) -pyrimidine, 2- ((S) -2-N, N-Dimet i l amino-3-phenylpropyl) -amino) -5- (3-methylphenyl) -4- (4-pyridyl) -pyrimidine, 2- ((3-Amino-3-phenylpropyl) -amino) -5- (4-fluorophenyl) -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- (((2S, 3S) -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-ylmethylene) amino) -5- (3-trifluoromethylphenyl) -pyrimidine, 5- (3-Methyl phenyl) -4- (4-pyridyl) -2- (((S) -tetrahydroisoquinol-3-ylmethylene) amino) -pyrimidine, 2- (((S) -2-N-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-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- N-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, or 2- (((S) -2-Amino-3-phenylpropyl) -amino) -5- (4-flurophenyl) -6- (4-pyridyl) -4 (3H) -pyrimidine or a pharmaceutically acceptable salt thereof .
13. 13. A pharmaceutical composition, characterized in that it comprises a compound according to claims 1 to 12 and a pharmaceutically acceptable carrier.
14. 14. A method of prophylaxis or treatment of inflammation, characterized in that it comprises administering an effective amount of a compound according to claims 1 to 12.
15. 15. A method of prophylaxis or treatment of inflammation, characterized in that it comprises administering an effective amount of a composition according to claim 13.
16. 16. A method of prophylaxis or treatment of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute or chronic myelogenous leukemia, destruction of pancreatic ß cells, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, respiratory distress syndrome adult (ARD?), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter syndrome, type I and type II diabetes, bone resorption diseases , graft-versus-host reaction, Alzheimer's disease, stroke, myocardial infarction, reperfusion injury from ischemia, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever and myalgia due to infection with HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses or zoster rpes in a mammal, characterized in that it comprises administering an effective amount of a compound according to claims 1-12.
17. 17. A method of prophylaxis or treatment of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute or chronic myelogenous leukemia, destruction of pancreatic ß cells, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, respiratory distress syndrome adult (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 diseases, graft-versus-host reaction, Alzheimer's disease, stroke, myocardial infarction, reperfusion injury from ischemia, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever and myalgias due to infection by HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses or her pes zoster in a mammal, characterized in that it comprises administering an effective amount of a composition according to claim 13.
18. 18. A method for decreasing plasma concentrations of either or both of TNF-α and IL-1, characterized in that it comprises administering an effective amount of a compound according to claims 1-12.
19. 19. A method for decreasing plasma concentrations of either or both of TNF-α and IL-1, characterized in that it comprises administering an effective amount of a composition according to claim 13.
20. 20. A method for decreasing plasma concentrations of either or both of IL-6 and IL-8, characterized in that it comprises administering an effective amount of a compound according to claims 1-12.
21. 21. A method for decreasing plasma concentrations of either or both of IL-6 and IL-8, characterized in that it comprises administering an effective amount of a composition according to claim 13.
22. 22. A method of prophylaxis or treatment of diabetes disease in a mammal, characterized in that it comprises administering an effective amount of a compound according to claims 1 to 12 to produce a glucagon antagonist effect.
23. 23. A method of prophylaxis or treatment of diabetes disease in a mammal, characterized in that it comprises administering an effective amount of a pharmaceutical composition according to claim 13 to produce a glucagon antagonist effect.
24. 24. A method of prophylaxis or treatment of a pain disorder in a mammal, characterized in that it comprises administering an effective amount of a compound according to claims 1 to 12.
25. 25. A method of prophylaxis or treatment of a pain disorder in a mammal, characterized in that it comprises administering an effective amount of a pharmaceutical composition according to claim 13.
26. 26. A method for decreasing the production of prostaglandins in a mammal, characterized in that it comprises administering an effective amount of a compound according to claims 1 to 12.
27. 27. A method for decreasing the production of prostaglandins in a mammal, characterized in that it comprises administering an effective amount of a pharmaceutical composition according to claim 13.
28. 28. A method for decreasing the activity of the enzyme cyclooxygenase in a mammal, characterized in that it comprises administering an effective amount of a compound according to claims 1 to 12.
29. 29. The method according to claim 28, characterized in that the enzyme cyclooxygenase is COX-2.
30. 30. A method for decreasing the activity of the enzyme cyclooxygenase in a mammal, characterized in that it comprises administering an effective amount of a pharmaceutical composition according to claim 13.
31. 31. The method according to claim 30, characterized in that the enzyme cyclooxygenase is COX-2.