MXPA06008169A - Substituted heterocyclic compounds and methods of use - Google Patents

Abstract

The present invention relates to pyrimidinones and pyridones and derivatives thereof, and pharmaceutically acceptable salts thereof. Also included is a method of treatment of inflammation, rheumatoid arthritis, Pagets disease, osteoporosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreaticßcell destruction, 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 diabetes, type II diabetes, bone resorption diseases, graft vs. host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, the herpes viruses or herpes zoster infection in a mammal comprising administering an effective amount a compound as described above.

Description

SUBSTITUTE HETEROCICLES COMPOUNDS AND METHODS OF USE THEREOF FIELD OF THE INVENTION The present invention comprises a new class of compounds useful in the treatment of diseases, such as diseases mediated by TNF-α, IL-β, 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 processes useful in the preparation of such compounds.

BACKGROUND OF THE INVENTION Interleukin 1 (Ll) and Tumor Necrosis Factor a (TNF-a) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli (e.g., lipopolysaccharide). - LPS) or external cellular stress (for example, osmotic shock and peroxide). Elevated levels of TNF-a and / or IL-1 over baseline levels have been implicated in mediation or Ref .: 174524 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 rejection; "Ischemic reperfusion injury, atherosclerosis, brain trauma, multiple sclerosis, cerebral malaria, sepsis, septic shock, toxic shock syndrome, fever, and myalgia due to infection, HIV-1, HIV-2, HIV-3, cytomegalovirus ( CMV), influenza, adenovirus, herpes viruses (including HSV-1, HSV-2), and herpes zoster are also exacerbated by TNF-a, TNF-a has been reported to play a role in cranial trauma, stroke, and ischemia, for example, in animal models of cranial trauma (rat), TNF-a levels increased in the bruised hemisphere (Shohami et al., J. Cereb.-Blooá flow Metab., 14, 615 (1994)) In a rat model of ischemia, where the middle cerebral artery was occluded, TNF-a mRNA levels increased (Feurstein et al., Neurosci, Lett, 164, 125 (1993)). TNF-a in rat cortex has been reported as a promoter of significant accumulation of neutrophils in capillaries and adherence in b small blood vessels. TNF-a promotes the infiltration of other cytokines (IL-lß, IL-6), and also chemokines, which promote the infiltration of neutrophils within the infarct area (Feurstein, Stroke 25, - 1481 (1994)). TNF-a has also been implicated in playing a role in type II diabetes (Endocrinol 130, 4352, 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 the monoliths induced high levels of HIV expression in a clone of chronically infected T cells (Clouse et al., J., Immunol., 142, 431 (1989)). Lahdevirta et al., Am. " Med. 85, 289 (1988)) discussed the role of TNF-a in the HIV-associated conditions of muscle generation cachexia. TNF-a is upstream in the inflammation cascade of the cytokine. As a result, elevated levels of TNF-α can lead to elevated levels of other inflammatory and pro-inflammatory cytokines, such as IL-1, IL-6, and IL-8. Elevated levels of IL-1 above baseline levels have been implicated in the mediation or exacerbation of a disease status number, 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; damage by ischemic reperfusion; atherosclerosis; brain trauma; multiple sclerosis; sepsis; septic shock; and septic shock syndrome. Viruses sensitive to inhibition by TNF-α, eg, HIV-1, HIV-2, HIV-3, are also affected by IL-1. TNF-a and IL-1 seem 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 the pancreatic β cell frequently accompanies type I diabetes. Functional abnormalities of pancreatic β cells may appear in patients with type II diabetes. Type II diabetes is characterized by functional resistance to insulin. In addition, type II diabetes is also often accompanied by elevated levels of plasma glucagon and increased rates of hepatic glucose production. Glucagon is a regulatory hormone that attenuates the inhibition of hepatic gluconeogenesis by insulin. Glucagon receptors have been found in the liver, kidney and adipose tissue, thus, glucagon antagonists are useful for attenuating plasma glucose levels (WO 97/16442, incorporated by reference herein, in Through the antagonism of glucagon receptors, it is thought that insulin response capacity in the liver will improve, thereby decreasing gluconeogenesis and decreasing the speed of production of glucose. Hepatic In models of rheumatoid arthritis in animals, multiple intra-articular injections of IL-1 have led to an acute and destructive form of arthritis (Chandrasekhar et al., Clinical Immunol Immunopathol 55, 382 (1990)). using cultured rheumatoid synovial cells, IL-1 is a more potent inducer of stromelysin than TNF-a (Firestein, Am. J. Pathol, 140, 1309 (1992).) At local injection sites, it has been Observed migration of neutrophils, lymphocytes and monoliths. The emigration is attributed to the induction of chemokines (for example, IL-8), and to the • upregulation of the. adhesion molecules (Dinarello, Eur. Cytokíne Netw., 5, 517-531 (1994)). IL-1 also seems to play in the promotion of certain viral life cycles. For example, increased expression of HIV, induced by the cytokine in a chronically infected macrophage line, has been associated with a selective concomitant increase in IL-1 production (Folks et al., J. Immunol. 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, IL-1 and T? F-a induce synoviocytes and chondrocytes to produce collagenase and neutral proteases, which leads to tissue destruction within the arthritic joints. In an arthritis model (collagen-induced (CIA) in rats and mice), intra-articular administration of T? Fa either before or after the induction of CIA led to an accelerated onset of arthritis and a further course severe disease (Brahn et al., Lymphokine Cytokine Res. 11, 253 (1992); Cooper, Clin. Exp. Immunol. 898, 244 (1992)). TL-8 has been implicated in the exacerbation and / or promotion of many disease states in which massive infiltration of neutrophils within sites of inflammation or damage (eg, ischemia) is mediated by the chemotactic nature of IL-8. , including, but not limited to, the following: asthma, inflammatory bowel disease, psoriasis, adult respiratory distress syndrome, cardiac and renal damage, thrombosis and glomerulonephritis. In addition to the effect of chemotaxis on neutrophils, IL-8 also has the ability to activate neutrophils. In this way, the reduction in IL-8 levels can lead to decreased neutrophil infiltration. Several procedures have been undertaken to block the effect of TNF-a. One procedure involves the use of soluble receptors for TNF-a (for example, TNFR-55 or TNFR-75), efficacy has been demonstrated in animal models of disease states mediated by TNF-a. A second method to neutralize TNF-α using a monoclonal antibody specific for TNF-α, cA2, has shown an improvement in the swollen joint count in a human phase II trial of rheumatoid arthritis (Feldmann et al., Immunological Reviews, pp. 195: 223 (1995)). These procedures block the effects of TNF-a and IL-1 either by protein sequestration or receptor antagonism. U.S. Patent No. 5,100,897 incorporated by reference herein, in its entirety discloses pyrimidinone compounds useful as angiotensin II antagonists wherein one of the nitinogen atoms of the pyrimidinone ring is' substituted with a phenylmethyl radical. or substituted phenylethyl. U.S. Patent No. 5,162,325 incorporated by reference herein, in its entirety discloses pyrimidinone compounds useful as angiotensin II antagonists wherein one of the nitrogen atoms of the pyrimidinone ring is substituted with a phenylmethyl radical. . European Patent No. 481448 incorporated herein by reference, in its entirety discloses pyrimidinone compounds useful as angiotensin II antagonists wherein one of the nitrogen atoms of the pyrimidine ring is substituted with a phenyl, phenylmethyl or phenethyl radical . Canadian Patent No. 2,020,370 discloses pyrimidinone compounds useful as an angiotensin II antagonist, wherein one of the nitrogen atoms of the pyrimidinone ring is substituted with a substituted diphenylaliphatic hydrocarbon radical.

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 others. disorders, such as pain and diabetes In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation.As a consequence, the invention also comprises the 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 the intermediates and processes useful for the preparation of the compounds of the invention The compounds of the invention are represented by the following general structures: wherein R1, R2, R3, R4, R5, R6, J and X are as defined herein. The foregoing merely summarizes certain aspects of the invention, and is not intended or should be construed as limiting the invention in any way.All patents and other publications cited herein are incorporated herein by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION According to the present invention, the compounds of the formula are provided: or a pharmaceutically acceptable salt or hydrate thereof, wherein J is = 0, = S, -CHN02, = N-CN, = CHS02Rb NS02Rb or = NHRb; X is independently, in each case, N or CR3; R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) R, -C (= 0) OR, -C ( = 0) NRaR, C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -0C (= 0) NRRa '0C (= 0) N (Ra) S (= 0) 2Rb, -0 ( alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) ORa, -SRa, 5 -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0 ) 2NRaRa, S (= 0) 2N (Ra) rC (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRaRa , -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, "- N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NR (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 atoms) carbon) 0Ra; R 2 is alkyl of 1 to 8 carbon atoms substituted with 0, 1, or 3 substituents selected from haloalkyl of 1 to 4 carbon atoms, halo, oxo, cyano, nitro, -C (= 0) Rb, - C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0R, -0C (= 0) Rb, 5 0C (= 0) NRaRa '-0C (= 0 ) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl) from 2 to 6 carbon atoms) 0Ra, -SR, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0 ) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, - N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, 0 N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N ( Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRR or -NRa (C2-C6 alkyl) 0Ra; and further substituted with 0, 1 or 2 substituents selected from Rg, -C (= 0) Rg, -C (= 0) 0R3, C (= 0) NRaRg, -C (= NRa) NRaRg, -OR9, -0C (= 0) R9, -0C (= 0) NRaRg, -5 0C (= 0) N (Ra) S (= 0) 2Rg, -0 (alkyl of 2 to 6 carbon atoms) NRRg, -O (alkyl) from 2 to 6 carbon atoms) 0Rg, -SR3, -S (= 0) Rg, -S (= 0) 2Rg, -S (= 0) 2NRaRg, -NRaRg, -N (Ra) C (= 0) ~ Rg, N (Ra) C (= 0) ORg, -N (Ra) C (= 0) NRaRg, -C (= 0) Re, -C (= 0) ORe, -C (= 0) NRaRe, -C (= NR ') NRaRe, -0Re, -OC (= 0) Re, -0C (= 0) NRaRe, 0C (= 0) N (Ra) S (= 0) 2Re, -O (2-alkyl) to 6 carbon atoms) NRaRe, 0 (C2-C6 alkyl) 0Re, -SRe, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRaRe, - NRaRe, -N (Ra) C (= 0) Re, and -N (Ra) C (= 0) NRaRe and -N (Ra) C (= 0) NRaRe; R3 is selected from H, Re, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C ( = 0) Rb, -0C (= 0) NRaRa '"-0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0R, -SR, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, • -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRRa, N (Ra) C ( = NR) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NR (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; Rd is independently, in each case it is H, Rd, Re R9; R7 is independently, in each case it is H, Rd, Re Rg; m is 2 or 3; Ra is independently, in each case it is H or Rb; Rb is independently, in each case is phenyl, benzyl or alkyl of 1 to 6 carbon atoms, phenyl, benzyl and alkyl of 1 to 6 carbon atoms are substituted with 0, 1, 2 or 3 substituents selected from halo , alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 3 carbon atoms, -O (alkyl of 1 to 4 carbon atoms), -NH 2, -NH (alkyl of 1 to 4 carbon atoms), - N (C 1-4 alkyl) (alkyl of 1 to 4 carbon atoms); Rd is independently, in each case, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C ( = 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, - -OC (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, - O (C2-C6 alkyl) NRaRa, -O (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (R) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa , -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) RaR or -NRa (alkyl of 2 to 6 carbon atoms) ) ORa; Re is independently, in the case of alkyl of 1 to 6 carbon atoms substituted with 0, 1, 2 or 3 substituents independently selected from Rd, and further substituted with 0 or 1 substituents selected from R9, and Rg is independently, in each case a 6, 7 or 7-membered bicyclic monocyclic ring of 6, 7, 8, 9, 10 or 11 members saturated, partially saturated or unsaturated, containing 0, 1, 2, 3 or 4 selected atoms of nitrogen, oxygen and sulfur , wherein the carbon atoms of the ring are substituted with 0, 1 or 2 oxo groups and the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 atoms carbon, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -0C (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) carbon) ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S. (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa,. N (Ra) C (= NRa) NRaR, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NR (alkyl of 2 to 6 carbon atoms) NRaRa or - NRa (C2-C6 alkyl) 0Ra; In yet another embodiment, in conjunction with the preceding and following embodiments, R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen and, sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= O) 0Rb , -C (= 0) NRaRa, C (= NRa) NRRa, -0Ra, -0C (= O) Rb, -OC (= 0) NRaRa 'OC (= 0) N (Ra) S (= 0) 2Rb , -O (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, _.- SRa, -S (= 0) Rb, -S (= 0) 2Rb , -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (R) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRRa, N (Ra) C (= NRa) NRRa, -N (R) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaR, -NR (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2) to 6 carbon atoms) 0Ra; In yet another embodiment, in conjunction with the above and following embodiments, R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen 'sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -0Ra, -0C (= 0) Rb, SRa, -S ( = 0) Rb, -S (= 0) 2Rb, NRaR and -N (Ra) C (= 0) Rb. In yet another embodiment, in conjunction with the above and following embodiments, Rx is a saturated or unsaturated 5 or 6 membered ring containing 0, 1, 2 or 3 atoms selected from nitrogen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. In yet another embodiment, in conjunction with the above and following embodiments, R1 is a saturated or unsaturated 6-membered ring containing 0, 1, 2 or 3 atoms selected from nitrogen and sulfur, where "the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo., in conjunction with the previous and following modalities,. R1 is phenyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo In a further embodiment, together with the preceding and following embodiments R1 is pyridinyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo In yet another embodiment, in conjunction with the above and following embodiments. R1 is pyrimidinyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo In another embodiment, in conjunction with the above and following embodiments.

R1 is a 5-membered saturated or unsaturated ring containing 1 or 2 atoms selected from nitrogen, oxygen or sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. In yet another embodiment, in conjunction with the foregoing and following embodiments, R 2 is alkyl of 1 to 8 carbon atoms substituted with 0, 1, 2 or 3 substituents selected from haloalkyl of 1 to 2 carbon atoms, halo, oxo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0R, -C (= 0) NRaR, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, "-0C (= 0) NRaR '-OC (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) ORa , -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NR) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, - NRa (C2-C6 alkyl) NRaRa or -NRa (C2-C6 alkyl) 0Ra; and further substituted with 0, 1 or 2 substituents selected from R9, -C (= 0) Rg, - C (= 0) 0Rg, C (= 0) NRaR9, -C (= NRa) NRaRg, -OR9, -0C (= 0) R9, -0C (= 0) NRaRg, 0C (= 0) N (Ra) S (= 0) 2R9, -O (alkyl of 2 to 6 carbon atoms) NRaRg , -O (alkyl of 2 to 6 carbon atoms) OR9, -SRg, -S (= 0) R9, -S (= 0) 2Rg, -S (= 0) 2NRaR9, -NRaRg, -N (Ra) C (= 0) Rg, - N (Ra) C (= 0) 0R9, -N (Ra) C (= 0) NRaRg, -C (= 0) Re, -C (= 0) 0Re, C (= 0) NRRe, -C (= NRa) NRaRe, -0Re, -OC (= 0) Re, -OC (= 0) NRaRe, 0C (= Ce) N (Ra) S (= 0) 2Re, -O ( alkyl of 2 to 6 carbon atoms) NRRe, O (alkyl of 2 to 6 carbon atoms) 0Re, -SRe, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRaRe , -NRaRe, -N (Ra) C (= 6.) Re, and -N (R) C (= 0) NRaRe and -N (Ra) C (= 0) NRaRe; In yet another embodiment, in conjunction with the above and following embodiments, R2 is alkyl of 1 to 8 carbon atoms substituted with 0, 1, 2 or 3 substituents selected from haloalkyl of 1 to 2 carbon atoms, halo, oxo, cyano , nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, OC (= 0 ) NRaRa '-0C (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) ORa, -SRa , -S (= 0) R, -S (= 0) 2Rb, ~ S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaR, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, - N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl) from 2 to 6 carbon atoms) NRaRa or -NR (C2-C6 alkyl) 0Ra; and further substituted with R9. In yet another embodiment, in conjunction with the above and following embodiments, R 2 is alkyl of 1 to 8 carbon atoms substituted with 1, 2 or 3 substituents selected from haloalkyl of 1 to 2 carbon atoms, halo, cyano, nitro, - C (= 0) Rb, C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, "-0Ra, -0C (= 0) Rb, OC (= 0) NRaRa '- OC (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRRa, S (= 0) 2N (Ra) C (= 0) Rb, ~ S (= 0) 2N (Ra) C (= 0) ) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, "- N (R) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N ( R) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2) to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0R; and further substituted with Rg. In yet another embodiment, in conjunction with the above and following embodiments, R2 is alkyl of 1 to 8 carbon atoms substituted with Rg. In yet another embodiment, in conjunction with the foregoing and following embodiments, R 2 is alkylphenyl of 1 to 6 carbon atoms, wherein the phenyl group has 0, 1, 2 or 3 substituents selected from alkyl of 1 to 8 haloalkyl carbon atoms from 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, - 0C (= 0) Rb, -0C (= 0) NRaRa '-0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl) from 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0 ) Rb, -S (= 0) 2N (Ra) C (= 0) ORb, S (= 0) 2N (Ra) C (= 0) NRaR, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N ( Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; In yet another embodiment, in conjunction with the above and following embodiments, R3 is selected from Re, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb , C (= 0) NRaRa, -C-. { = NRa) NRRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa '0C (= 0) N (R) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) carbon) NRaRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NR) NRRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; In yet another embodiment, in conjunction with the preceding and following embodiments, R3 is H. In other embodiments, in conjunction with the preceding and following embodiments, J is = 0 or = S. In yet another embodiment, in conjunction with any of the preceding and following embodiments, J is = CHN02 or = CHS02Rb. In yet another embodiment, in conjunction with any of the preceding and following embodiments, J is = N-CN, = NS02Rb or = NR. Yet another aspect of the invention relates to compounds having the structure: or a pharmaceutically acceptable salt or hydrate thereof, wherein J is = 0, = S, -CHN02, "= N-CN, = CHS02Rb NS02Rb or = NHRb, X is independently, in each case, N or CR3; R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 atoms , carbon, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRRa, C (= NRa) NRRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2R, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, - O (C2-C6 alkyl) ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) ORb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= - NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) RRa or -NRa (alkyl of 2 to 6 atoms) carbon) 0Ra; wherein R1 is not thiazole, imidazole or p'irazole; R2 is alkyl of 2 to 8 carbon atoms substituted with 0, 1, 2 or 3 substituents selected from haloalkyl of 1 to 2 carbon atoms, halo, oxo, cyano, nitro, -C (= 0) Rb, -C ( = 0) 0Rb, -C (= 0) NRaR, -C (= NRa) NRaR, -0R, -0C (= 0) Rb, 0C (= 0) NRRa '-0C (= 0) N (Ra) S (= p) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaR, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0 ) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N ( Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) ) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaR or -NRa (alkyl) from 2 to 6 carbon atoms) 0R; and further substituted with 0, 1 or 2 substituents selected from Rg, -C (= 0) Rg, -C (= 0) 0Rg, C (= 0) NRaRg, -C (= NRa) NRaRg, -0Rg, -0C (= 0) Rg, -0C (= 0) NRaRg, 0C (= 0) N (Ra) S (= 0) 2Rg, -O (alkyl of 2 to 6 carbon atoms) NRaRg, -0 (alkyl of 2) to 6 carbon atoms) 0Rg, -SRg, -S (= 0) Rg, -S (= 0) 2Rg, -S (= 0) 2NRaRg, -NRaRg, -N (Ra) C (= 0) Rg, N (Ra) C (= 0) 0Rg, -N (Ra) C (= 0) NRaRg, -C (= 0) Re, -C (= 0) 0Re, C (= 0) NRaRe, -C (= NRa) NRaRe, -0Re, -0C (= 0) Re, -0C (= 0) NRaRe, 0C (= 0) N (Ra) S (= 0) 2Re, -0 (alkyl of 2 to 6 carbon atoms ) NRaRe, 0 (alkyl of 2 to 6 carbon atoms) 0Re, -SRe, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRaRe, -NRaRe, -N (Ra ) C (= 0) Re, y - N (Ra) C (= 0) NRaRe and -N (Ra) C (= 0) NRaRe; R3 is independently, in each case, selected from hydrogen, Re, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) ) NRaRa, -C (= NRa) NRaR, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl) from 2 to 6 carbon atoms) NRaRa, -O (C2-C6 alkyl) 0R, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa , S (= 0) 2N (R) C (= 0) Rb, S (= 0) 2N (R) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, - NRaR, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa,. N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to- 6. carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; R4 is H, Re or Rg; R5 is H, Re or R9; R6 is independently, in each case, selected from 'H, Rd, Re or Rg, R7 is independently, in each case, selected from H, Rd, Re or Rg, Ra is independently, in each case, selected from H or Rb; Rb is independently, in each case _ is phenyl, benzyl or alkyl of 1 to 6 carbon atoms, phenyl, benzyl and alkyl of 1 to 6 carbon atoms are substituted with 0, 1, 2 or 3 substituents. selected from halo, alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 3 carbon atoms, -O (alkyl of 1 to 4 carbon atoms), -NH2, -NH (alkyl of 1 to 4 carbon atoms) ), -N (alkyl of 1 to 4 carbon atoms) (alkyl of 1 to 4 carbon atoms); Rd is independently, in each case, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, '-0Ra, -OC (= 0) Rb,. -OC (= 0) NRaR '0C (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) ORb, S (= 0) 2N (Ra) C (= 0) NRRa, -NRaRa, N (Ra) C (= 0) Rb, ~ N (Ra) C (= 0) ) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NR (C2-C6 alkyl) NRaRa or -NR (C2-C6 alkyl) 0Ra; Re is independently, in the case of alkyl of 1 to 6 carbon atoms substituted with 0, 1, 2 or 3 substituents independently selected from Rd, and further substituted with 0 or 1 substituents selected from Rg, and Rg is independently, at each case a 6, 7 or 7 membered bicyclic 6, 7, 8, 9, 10 or 11 membered monocyclic ring saturated, partially saturated or unsaturated, containing 0, 1, 2, 3 or 4 atoms selected from nitrogen, oxygen and sulfur , where; the carbon atoms of the ring are substituted with 0, 1 or 2 oxo groups and the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms , halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, - C (= 0) NRRa, -C (= NRa) NRaRa, -0Ra, --OC (= 0) Rb , -0C (= 0) NRaRa 'OC (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms ) 0Ra, -SR, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) ) 2N (R) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (R) C (= 0) R, -N (Ra) C (= 0) 0Rb, -N (R) C (= 0) NRaRa, N (R) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRRa , -NRa (C2-C6 alkyl) NRaRa or -NRa (C2-C6 alkyl) 0Ra; In yet another embodiment, in conjunction with the preceding and following embodiments, R1 is phenoyl, furanyl, pyrrolyl , oxazole or triazole, any of which is substituted with 0, 1, 2 or 3 substituents selected s of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRR, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa '-0C (= 0) N (Ra) S (= 0) 2Rb, -0 (2-alkyl) to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) R, -S (= 0) 2Rb, -S (= 0) 2NRaR, S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa , N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRRa,. - N (R) C (= NRa) NRaR, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; where R1. It is not thiazole, imidazole or pyrazole. In yet another embodiment, in conjunction with the foregoing and following embodiments, R1 is a saturated or unsaturated 6-membered ring containing 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa '-0C (= 0) N (Ra) S (= 0) 2Rb, -0 (C2-C6 alkyl) NRaRa, -O (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S ( = 0) 2NRR, S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (R) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaR, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa ) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 atoms) carbon) 0R; In yet another embodiment, in conjunction with the above and following embodiments, R1 is a 6-membered unsaturated ring containing 1, 2 or 3 nitrogen atoms, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRRa, -0Ra, - OC (= 0) Rb, -OC (= 0) NRaR '-0C (= 0) N (R) S (= 0) 2Rb, -0 (2 to 6 alkyl) carbon atoms) NRRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, - -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S ( = 0) 2N (R) C (= 0) Rb ", -S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRRa, -NRaRa , -N (Ra) C (= 0) R, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NR) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra_) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; In another modality more, -in conjunction with the modalities, previous and following, R1 is phenyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, C (= NRa) NRaRa, -0R, -0C (= 0) Rb, -0C (= 0) NRRa '0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, -SR, -S (= 0) Rb, -S (= 0 ) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N ( Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (R) ) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (R) S (= 0) 2NRRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl) of 2 to 6 carbon atoms) 0Ra; In yet another embodiment, in conjunction with the above and following embodiments, R 1 is phenyl substituted with 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro , -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -0C (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaR, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRRa, SC = P) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) ) 0Rb, S (= 0) 2N (Ra) C (= 0) NRRa, -NRaRa, N (Ra) C (= 0) Rb, -N (R) C (= 0) 0Rb, -N (Ra) C (= 0) NRRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) s "(= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa '(alkyl of 2 to 6 carbon atoms) 0Ra; In yet another embodiment, together with the above and following embodiments, R 1 is phenyl, pyridinyl or pyrimidinyl, all of which are substituted with 0, 1 or 2 substituents selected from halo, alkyl of 1 to 3 carbon atoms, and CF3. In yet another embodiment, in conjunction with the preceding and following embodiments, R 1 is phenyl, pyridinyl or pyrimidinyl. In yet another embodiment, in conjunction with the preceding and following embodiments, R1 is phenyl. In yet another embodiment, in conjunction with the above and following embodiments, R2 is alkyl of 2 to 8 carbon atoms. In yet another embodiment, in conjunction with the above and following embodiments, R2 is alkyl of 2 to 8 carbon atoms substituted with Rg. In yet another embodiment, in conjunction with the foregoing and following embodiments, R2 is alkyl of 2 to 8 carbon atoms substituted with 1, 2 or 3 substituents selected from haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRRa, C (= NRa) NRaR, -ORa, -OC (= 0) Rb, -OC (= 0) NRaR ' 0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl-- of 2 to 6 carbon atoms) 0Ra, -SRa, - S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C ( = 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N ( Ra) C (= 0) NRaRa, N (R) C (= NRa) NRRa, -N (Ra) S (= 0) 2Rb, -N (R) S (= 0) 2NRaRa, -NRa (alkyl of 2) to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; additionally substituted with R9. In yet another embodiment, in conjunction with the above and following embodiments, R2 is alkyl of 2 to 8 carbon atoms substituted with phenyl, the phenyl is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 8 carbon atoms. carbon, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NR) NRaRa, ~ 0R, -0C (= 0) Rb, -OC (= 0) NRaRa 'OC (= 0) N (R) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) ORa, -SR, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, "S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, - N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; In another embodiment, together with the above modalities and following, R2 is alkyl of 2 to 8 carbon atoms substituted with 1, 2 or 3 their substituents selected from haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, C (= NRa) NRaRa, - 0R, -0C (= 0) Rb, -0C (= 0) NRRa '0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C ( = 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa,. -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, - N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) RRa or -NRa (alkyl of 2 to 6 carbon atoms) 0R; and further substituted with, the phenyl is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0 ) Rb, -C (= 0) 0Rb, - C (= 0) NRaR, -C (= NR) NRaRa, -0Ra, -OC (= 0) Rb, -OC (= 0) NRaRa 'OC (= 0 ) N (R) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, ~ -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= O) NRaRa, -NRaRa, N (R) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb ,. -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; In yet another embodiment, in conjunction with the above and following embodiments, R3 is selected from Re, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb , -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaR '0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, - S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S - (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa,. -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N ( Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0R; In yet another embodiment, in conjunction with the preceding and following embodiments, R3 is hydrogen.

In yet another embodiment, in conjunction with any of the preceding and following embodiments, J is = 0 or = S. In yet another embodiment, in conjunction with any of the above and following embodiments, J is = CHN02 or = CHS02Rb. In yet another embodiment, as a whole "- with any of the foregoing and following embodiments, J is = N-CN, = NS02Rb or = NRb -" Yet another aspect of the invention relates to a pharmaceutical composition comprising a compound of conformity with any of the above modalities and a pharmaceutically acceptable carrier. Yet another aspect of the invention relates to a method of prophylaxis or treatment of inflammation, which comprises administering an effective amount of a compound according to any of the foregoing modalities. Yet another aspect of the invention relates to a method of prophylaxis or treatment of 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 rejection; ischemic damage by reperfusion; 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 infection or herpes zoster in a mammal, which comprises administering an effective amount of a compound in accordance with" any of the previous modalities. Yet another aspect of the invention relates to a method for decreasing the plasma concentrations of one or both of TNF-α and IL-1, which comprises administering an effective amount of a compound according to any of the above embodiments. Yet another aspect of the invention relates to a method for decreasing the plasma concentrations of one or both of IL-6 and IL-8, which comprises administering an effective amount of a compound according to any of the foregoing modalities. Yet another aspect of the invention relates to a method of prophylaxis or treatment of diabetes in a mammal comprising administering to it an effective amount of a compound in accordance with any of the above embodiments to produce a glucagon antagonist effect. Yet another aspect of the invention relates to a method of prophylaxis or treatment of a pain disorder of a mammal comprising administering to it an effective amount of a compound in accordance with any of the foregoing embodiments. Another aspect of the invention relates to a method of decreasing the production of prostaglandins in a mammal comprising administering to it an effective amount of a compound in accordance with any of the foregoing modalities. Yet another aspect of the invention relates to a method for decreasing the activity of the enzyme cyclooxygenase in a mammal comprising administering to it an effective amount of a compound according to any of the above embodiments. AND? Yet another modality, the enzyme cyclooxygenase is COX-2. Yet another aspect of the invention relates to a method for decreasing the activity of the enzyme cyclooxygenase in a mammal, which comprises administering an effective amount of the aforementioned pharmaceutical composition. In yet another embodiment, the enzyme cyclooxygenase is COX-2. Still another aspect of the invention relates to the manufacture of a medicament comprising a compound according to any of the above embodiments. Yet another aspect of the invention relates to the manufacture of a medicament for the treatment of inflammation, comprising an effective amount of a compound according to any of the above modalities. Yet another aspect of the invention relates to the manufacture of a medicament for the treatment of 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 rejection; ischemic damage by reperfusion; 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 infection or herpes zoster in a mammal that comprises administering an effective amount of a compound according to any of the above modalities. The compounds of this invention can generally have several asymmetric centers and are typically described in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diastereomers. The specification and claims contain the list of species using the language of "selected from ... and ..." and "is ... or ..." (sometimes referred to as Markush groups). When this language is used in this application, unless stated otherwise, it is understood that it includes the group as a whole, or any simple members thereof or any subgroups thereof. The use of this language is purely for brevity and is not understood in any way to limit the elimination of individual elements or subgroups as necessary. Unless otherwise specified, the following definitions apply to the terms found in the specification and claims: "aryl" means a phenyl or naphthyl radical, wherein the phenyl may be fused with a cycloalkyl bond of 3; to 4 carbon atoms. "Benzo group", alone or in combination means a bivalent radical "C4H4 =, a representation of which is - CH = CH-CH = CH-, which when linked to another ring neighbor, form a benzene ring - for example, tetrahydronaphthalene, indole and the like .. '"Alkyl of a to β carbon atoms" means an alkyl group comprising a minimum number of a and a maximum of β carbon atoms in a branched, cyclic or linear relationship or any combination of the three, where a and b represent integers The alkyl groups described in this section may also contain one or two double or triple bonds The examples of alkyl of 1 to 6 carbon atoms include, but are not limited to the following: "Halo" or "halogen" means the halogen atoms selected from fluorine, chlorine, bromine and iodine. "Haloalkyl of a to β carbon atoms" means an alkyl group, as described above, wherein any number - at least one - of the hydrogen atoms bonded to the alkyl chain are replaced by fluorine, chlorine, bromine or iodine . "Heterocycle" means a ring comprising at least one carbon atom and at least one other atom selected from nitrogen, oxygen and sulfur. Examples of heterocycles that can be found in the claims include, but are not limited to, the following: "Pharmaceutically acceptable salt" means a salt prepared by conventional means, and are well known to those skilled in the art. "Pharmacologically acceptable salts" include the 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, mandéli.co acid, and the like. When the compounds of the invention include an acidic functional group such as a carboxylic group, then pharmaceutically acceptable cation pairs, suitable for the carboxyl group, are well known to those skilled in the art, and include the alkali metal, alkaline earth metal cations , ammonium, quaternary ammonium and the like. For additional examples of "pharmacologically acceptable salts" see infra and see Berge et al., J. Pharm. Sci. 66: 1 (1977). "Exiting groups" refers in general to groups easily displaceable by a nucleophile, such as an amine, a thiol or a nucleophilic 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, tosylated 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 carboxyl, amino, hydroxyl, mercapto and the like, from undergoing unwanted reactions, such as nucleophilic substitution, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino 0 protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl, and cycloalkenylalkyl! substituted, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-5-methylbenzyl, trifly and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxyl, nitro, acylamino, acyl, and the like, and salts, such as like the phosphonium and ammonium salts. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-phenylfluorenyl), phenanthrenyl, durenyl and -like groups. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl radicals preferably have 6 to 10 carbon atoms, including, but not limited to, cyclohexenylmethyl and the like. Suitable acyl, alkoxycarbonyl and araleoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, -butyryl, acetyl, trifluoroacetyl, tricycloacetyl, phthaloyl, and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can 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 linked, for example, 1,2-bis (methylene) benzene, phthalimidyl, succymidyl, maleimidyl and the like, and wherein these heterocyclic groups may further include attached aryl and cycloalkyl rings. 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 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 carboxyl, hydroxyl, and mercapto groups. For example, aralkyl groups. Alkyl groups are also suitable groups to protect the hydroxyl and mercapto groups, such as tert-butyl. The silyl protecting groups are silyl atoms optionally substituted with one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, tri-ethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and diphenylmethylsilyl. Silylation of the amino groups provides the mono- or di-silylamino groups. The silylation of the aminoalcohol compounds can lead to a N, N, O-trisilyl derivative. The removal of the silyl functional group from a silyl ether functional group is easily achieved by treatment with, for example, a metal hydroxide or an 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, phenyldi-ethylsilyl chloride, diphenylmethylsilyl chloride and their products in combination with imidazole or DMF. The methods for silylating the amines and removing the silyl protecting groups are well known to those skilled in the art. The methods of preparing these amine derivatives from the corresponding amino acids, amino acid amides or amino acid esters, are also well known to those skilled in the art of organic chemistry including the chemistry of amino acids / amino acid esters or aminoalcohol. The protecting groups are removed under conditions that 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 and mixtures thereof. A t-butoxycarbonyl protecting group can be removed using an inorganic or organic acid, such as hydrochloric acid or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride.The resulting amine salt can be easily neutralized to producing the free amine The carboxyl 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. that the compounds of the invention may contain groups that may exist in tautomeric forms, such as the groups a cyclic and acyclic midin and guanidine, heteroatom substituted heteroaryl groups (Y '= 0, S, NR) and the like, which are illustrated in the following examples: and although only one form is named, described, visualized and / or claimed here, it is intended that all tautomeric forms are inherently included in such a name, description, display and / or claim. Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active and inactive compound that is chemically modified through 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 suitability and techniques involved in the in vitro administration of the 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 Designo 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. , pivaloyloxymethyl). The amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by the esterases releasing in vivo 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 as N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). The hydroxyl groups have been masked as esters and ethers. European Patent EP 039,051 (Sloan and Little, 11/4/81) describe the prodrugs of Mannich base hydroxamic acid, their preparation and use. "Cytokine" means a secreted protein that affects the functions of other cells, particularly since these refer to the modulation of interactions between the cells of the immune system or the cells involved in the inflammatory response. Examples of cytokines include, but are not limited to, interln 1 (IL-1), preferably IL-1β, interln 6 (IL-6), interln 8 (IL-8), and TNF, preferably TNF-a (factor of tumor necrosis 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 that induces "the release of another cytokine. For example, a disease state in which IL-1 plays a major role, but in which the production or action of IL-1 is a result of TNF, could be considered as mediated by TNF. The invention can be synthesized according to one or more of the following methods It should be noted that general procedures are shown relating 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 with respect to a group is (S), or (R). They have a stereochemistry (for example (R)) can often be used to produce those that have opposite stereochemistry (for example (S)) using well-known methods, for example, by inversion.

Reaction Scheme A: Pd (OAc) 2 Toluene BINAP "NaOtBu Example 1: Tetrahydro-pyrimidin-2-ylidenamine hydrochloride: A suspension of 1,3-diaminopropane (74 g, 1 mol) and guanidine hydrochloride (76 g, 0.8 mol) was heated to 140 ° C while stirring for 20 hours. The reaction temperature dropped to 100 ° C and 100 ml of isopropyl alcohol were added. At room temperature the resulting solid was collected by filtration and the solid was washed with diethyl ether. It dried in the air all night. White powder M + l = 100. 3- (3,4-Dimethyl-phenyl) -3-oxo-propionic acid methyl ester: To a stirred solution of 3,4-dimethylacetophenone (1.0 g, 6.8 mmol) in _10 ml of tetrahydrofuran at 0 ° C under a nitrogen atmosphere was added potassium hexamethyldisilazide (1.46 g, 6.8 mmol). The resulting suspension was stirred for 10 minutes and dimethyl carbonate (0.58 mL, 6.8 mmol) was added. The reaction was stirred for 16 hours by warming to room temperature and then it was emptied onto ice (50 ml) / hydrochloric acid (5 ml). The product was extracted with 50 ml of ethyl acetate and the organic material was washed with saturated sodium chloride and then dried over magnesium sulfate. The product was isolated as an amber oil after removal of the solvent in vacuo. M + l = 207. 2- (3,4-dimethyl-phenyl) -6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-ji-one: A suspension of 3- (3,4) methyl ester -dimethyl-phenyl) -3 -oxo-propionic acid (1.2 g, 5.8 mmol), tetrahydro-pyrimidin-2-ylidene-mina hydrochloride (0.78 g, 5.8 mmol), and potassium carbonate (0.80 g, 5.8 mmol) in 20 ml of ethanol was heated to reflux for 4 hours. 5 ml of water was added to the reaction at room temperature and the tan solid was collected by filtration. M + l = 256. 2- (3, 4-dimethyl-phenyl) -9- (2-methylsulfanyl-pyrimidin-4-yl) -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: Una suspension of 2- (3,4-dimethyl-phenyl) -6, 7-, 8,9-tetrahydro-pyrimido [1,2-a > ] pyrimidin-4-one (400 mg, 1.6 mmol), 4-chloro-2-methylthiopyrimidinone (0.24 mL, 2.0 mmol), palladium acetate (11 mg, 0.05 mmol), bis (diphenylphosphino) -1, 1 '- binaphthyl (37 mg, 0.05 mmol), and sodium tert -butoxide (192 mg, 2.0 mmol) was heated to reflux in 6 ml of toluene under a nitrogen atmosphere overnight. The reaction was diluted with 550 ml of ethyl acetate and the organic materials were washed with saturated ammonium chloride. The solvents were removed in vacuo, and the resulting pale yellow solids were washed with ethanol / diethyl ether (1:10, 2 L). M + l = 380. 2- (3, 4-dimethyl-phenyl) -9- (2-methanesulfonyl-pyrimidin-4-yl) -6,7,8-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: A a stirred solution of 2- (3,4-dimethyl-phenyl) -9- (2-methylsulfanyl-pyrimidin-4-yl) -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one (260 mg, 0.69 mmol) in 2 ml of acetonitrile and 2 ml of trifluoroacetic acid at 0 ° C under a nitrogen atmosphere, urea hydrogen peroxide was added (129 mg, 1.37 mmol) and trifluoroacetic anhydride (0.20 ml, 1. 4- mmol). After 30 minutes, the solvents were removed in vacuo, and the residue was partitioned between 50 mL of dichloromethane and 10 mL of 5% sodium carbonate. The organic material was dried over magnesium sulfate, then concentrated to a solid in vacuo. M + l = 412. 2- (3, 4-dimethyl-phenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,8-tetrahydro-pyrimido [1, 2 -a] pyrimidin-4-one: "A suspension of 2- (3,4-dimethylphenyl) -9- (2-methanesulfonyl-pyrimidin-4-yl) -6,7,8,9-tetrahydro-pyrimido [ 1; 2-a] pyrimidin-4-one (150 mg, 0.36 mmol) and S- (-) -a-methylbenzylamine (1.3 ml, 10 mmol) was heated at 90 ° C in 1 ml of dioxane for 5 hours. The reaction was concentrated in vacuo and purified on silica The resulting yellow solid was washed with methanol / diethyl ether (1:10, 2 mL) M + l = 453. XH NMR (CDC13) d (3H, 1.58 ppm) , t (2H, 2.11 ppm), s (6H, 2.29 ppm), m (1H, 3.99 ppm), m (1H, 4.11 ppm), m (1H, 4.11), m (1H, 5.08 ppm), m ( 1H, 5.40 rpm), s (1H, 6.56 ppm), d (1H, 7.18 ppm), m (2H, 7.23 ppm), t (2H, 7.33 ppm), d (2H, 7.38 ppm), dd (1H, 7.62 ppm), s (1H, 7.67 ppm), d (1H, 8.13 ppm) The examples in the following table were prepared using the above method, but substituting 3, 4-dlmethylacetophenone with methyl appropriate ketone.

Method to HPLC A: Luna C185 mm 100 x 4.6 mm; flow rate 1.0 ml with gradient of 0 minutes 5% - > 9 minutes 95% - > 9.5 min 95% - > 10 min '5%. Solvent A: water (0.1% TFA); Solvent B: -acetonitrile (0.1% TFA). Reaction Scheme B: UHP ACN / TFAA TFA H2 Pd / C Example 14 9- (2-methylsulfanyl-pyrimidin-4-yl) -3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: A a stirred solution of 9- (2-methylsulfanyl-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (500 mg, 1.42 mmol) in 10 m of dichloromethane at 0 ° C. in nitrogen atmosphere, nitronium tetrafluoroborate in a 0.5 M solution (7 ml, 3.55 mmol) was added. The external cooling was 0 removed and the reaction was warmed to room temperature, while stirring for 1 hour. The reaction was washed with 5% sodium bicarbonate and saturated ammonium chloride. The organic material was concentrated in vacuo and the orange solid was isolated after purification on silica. M + l = 397. 9- (2-methanesulfonyl-pyrimidin-4-yl) -3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: To a stirred solution of 9- (2-methylsulfanyl-pyrimidin-4-yl) -3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (235 mg, 0.59 mmol) in 2 ml of acetonitrile and 2 ml of trifluoroacetic acid at 0 ° C under a nitrogen atmosphere was added urea hydrogen peroxide (113 mg, 1.2 mmol) and trifluoroacetic anhydride (0.17 ml, 1.2 mmol). After 30 minutes the solvents were removed in vacuo, the residue was partitioned between 50 ml of dichloromethane and 10 ml of 5% sodium hydrogen carbonate. The organic material was dried over magnesium sulfate, then concentrated to a solid in vacuo. M + l = 429. 3 - . 3 - . 3-Nitro-9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one: A solution of 9 - (2-methanesulfonyl-pyrimidin-4-yl) -3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (220 mg, 0.51 mmol ) and phenylethylamine (Q.13 ml, 1.0 mmol) in 2 ml of dichloromethane was heated at 80 ° C for .1 hour. The purification residue on silica, and the final product was isolated as a white solid. M + l = 470. 3-amino-9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: A suspension of 3 -nitro-9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (40 mg, 0.09 mmol ) in 10 ml of methanol was stirred with palladium 105 on 5 mg of carbon, under a hydrogen atmosphere for 4 hours. The reaction mixture was filtered through Celite, and the final product was isolated as a white solid after removal of the solvent in vacuo. M + l = 440 1 H NMR (CDC13) t (2H, 2.20 ppm), t (2H, 2.91 ppm), dd (2H, 3.67 ppm), s (2H, 4.07 ppm), m (4H, 4.15 ppm), s (1H, 5.10 ppm), d (1H) , 7.17 ppm), m (3H, 7.24 ppm), m (2H, 7.31 ppm), m (1H, 7.36 ppm), t (2H, 7.46 ppm), d (2H, 7.79 ppm), d (1H, 8.03 ppm). 3-amino-9- [2 - [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl] -2-phenyl-6,7,8,9-tetrahydro-pyrimido [ 1,2- a] pyrimidin-4-one: To a solution of 9-. { 2- [2- (3-Azidomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl] -3-nitro-2-phenyl-6,7,8,9-tetrahydro-pyrimido [1_, 2 α] pyrimidin-4-one (61 mg, 0.11 mmol) in 1 ml of methanol was added securely 10 mg of palladium on carbon (1 Q%) and stirred under an atmosphere of hydrogen distributed by a balloon. After 2 hours, the reaction was filtered through a pad of Celite and the solvent was removed under reduced pressure. The product was purified on silica. M + 1 = 483 NMR XH (CDC13) d (3H, 1.19 ppm), (2H, 2.20 ppm), dd (1H, 2.76 ppm), dd 2.96 ppm), s (2H, 3.84 ppm), m (6H, 4.08 ppm), q (1H, 4.30 ppm), d (1H, 4.95 ppm), m (4H, 7.13 ppm), t (1H, 7.28 ppm), t (1H, 7.36 ppm), t (2H, 7.45 ppm) ), d (2H, 7.80 ppm), d (1H, 8.03 ppm). The examples in the following table were prepared using the above methods, as indicated, using the appropriately substituted oxopropionic acid derivative of reaction scheme A and the appropriate amine to replace phenethylamine, if desired: Reaction Scheme C: Diagram of Reaction D: Scheme-Reaction E: Example 19 l-bromo-3- (2-nitro-propenyl) -benzene: A suspension of 3-bromo-benzaldehyde (2.5 g, 13.5 mmol), ammonium acetate (1.09 g, 14.2 mmol) and 250 ml of nitroethane, it heated to reflux all night. The solvent was removed in vacuo, and then the residue was removed between ethyl acetate and saturated sodium chloride. The concentrated organic material was purified on silica and isolated as a yellow oil.

NMR aH (CDC13) s (3H, 2.44 ppm), m (2H, 7.35 ppm), m (2H, 7.55 ppm) s (1H, 8.00 ppm). [2- (3-Bromo-phenyl) -1-methyl-ethyl] -carbamic acid tert-butyl ester. To a stirred solution of lithium aluminum hydride (24 ml of 1 M in tetrahydrofuran (THF) 24 mmol) at 0 ° C under a nitrogen atmosphere was used sulfuric acid (0.61 mL, 12.0 mmol) in 10 mL of tetrahydrofuran dropwise. Then, a solution of l-bromo-3- (2-nitro-propenyl) -benzene (1.17 g, 4.8 mmol) in THF was added dropwise by means of an addition funnel. The reaction was warmed to room temperature overnight. The reaction was cooled to 0 ° C, and a saturated solution of potassium tartrate and sodium tetrahydrate was added dropwise to the reaction. Once a cake was formed, the organic phase was reduced to a vacuum oil.

This residue was then dissolved in dichloromethane and dried over magnesium sulfate. Di-tert-butyldicarbonate was added (1.05 g, 4.8 mmol) and the solution was stirred overnight at room temperature. The reaction was reduced to an oil under vacuum and isolated as a white solid after purification on silica M + I = 314/316. [2- (3-Cyano-phenyl) -1-methyl-ethyl] -carbamic acid tert-butyl ester: [2- (3-bromo-phenyl)] -butyl ester was added to a sealed pressure tube. ) -1-methyl-ethyl] -carbamic acid (1.23 g, 3.9 mmol), sodium cyanide (250 mg, 5.1 mmol), potassium iodide (130 mg, 0.8 mmol), NN '-dimethylethylenediamine (0.41 mL, 3.9 mmol). ), and 6 ml of toluene. This suspension was then purged with nitrogen before adding copper iodide (150 mg, 0.8 mmol). The reaction mixture was heated at 130 ° C for 16 hours, while stirring. The reaction was partitioned between ethyl acetate and 30% aqueous ammonia. The organic material was washed with saturated ammonium chloride, then dried over magnesium sulfate. The reaction was reduced to a vacuum oil, and isolated as a white solid after purification on silica. M + l = 261. 3- (2-Amino-propyl) -benzonitrile: A "solution of [2- (3-cyano-phenyl) -1-methyl-ethyl] -carbamic acid-tert-butyl ester (180 mg, 0.69 mmol) in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid was stirred for 15 minutes at room temperature, the solvents were removed in vacuo, and the residue was partitioned between dichloromethane and sodium hydroxide IN.The organic material was dried over magnesium sulfate and reduced to vacuum oil, M + l = 161.

Ter-butyl acid ester. { 2- [3- (benzhydrylidene-amino) phenyl] -l-methyl-ethyl} -carbamic: A suspension of [2- (3-bromo-phenyl) -1-methyl-ethyl] -carbamic acid tert-butyl ester (750 mg, 2.39 mmol), benzophenone-imine (0.44 2.63 mmol), ter-butyl ester. Sodium butoxide (298 mg, 3.1 mmol), bis (diphenylphosphonium) -1, 1'-biphenyl (45 mg, 0.07 mmol), palladium acetate (16 mg, 0.07 mmol), and 7.5 mL of toluene was heated to reflux for 3 hours while stirring under a nitrogen atmosphere.The reaction was diluted with ester and the organic materials were washed with water and saturated sodium chloride.The product was isolated as a yellow viscous oil after purification on silica, M + l = 415. " 3- (2-Amino-propyl) -phenylamine: A solution of - tert.-butyl ester. { 2- [3- (benzhydrylidene-amino) -phenyl] -1-methyl-ethyl} Carbamic acid (200 mg, 0.48 mmol) in 5 ml of dichloromethane and 5 ml of trifluoroacetic acid was stirred for 45 minutes at room temperature. The solvents were removed in vacuo and the residue was suspended in 5N hydrochloric acid at 60 ° C for 20 minutes. The two-phase system was washed with ether and the organic materials were discarded. The pH of the aqueous layer was then adjusted to 14 with ION sodium hydroxide. The aqueous material was then washed three times with 10 ml of dichloromethane. The combined organic materials were dried over magnesium sulfate, and the product was isolated on an amber film after removal of the solvent in vacuo. M + l = 151. 3- (2-Nitro-propenyl) -benzoic acid methyl ester: To a 25O ml round bottom flask was added 3-formyl-benzoic acid methyl ester (2.20 g, 13.4 mmol), ammonium acetate (1.03) g, 13.4 mmol), and 60 ml of nitroethane. The mixture was heated to reflux under a nitrogen atmosphere while stirring for 1.5 hours. The solvent was removed in vacuo and then the residue was partitioned between 100 ml of ethyl acetate and 5% sodium bicarbonate. The organic material was washed with saturated sodium chloride, dried with magnesium sulfate, then concentrated to a vacuum oil. The product was purified on silica and isolated as a yellow solid. RMN ^? (CDC13) s (3H, 2.47 ppm), s (3H, 3.96 ppb), t (1H, 7.55 ppm), d (2H, 7.61 ppm) m (3H, 8.09 ppm). [3- (2-amino-propyl) -phenyl] -methanol: To a stirred suspension of lithium aluminum hydride (90 ml of 1M in tetrahydrofuran (THF), 90 mmol) at 0 ° C under a nitrogen atmosphere a solution of the 3- (2-nitro-propenyl) -benzoic acid methyl ester (2.03 g, 9.2 mmol) in THF was added dropwise by means of an addition funnel over the course of 75 minutes. The reaction was warmed to room temperature overnight, cooled to 0 ° C, and then a saturated solution of potassium sodium tartrate tetrahydrate was added dropwise to the reaction. Once a cake was formed, the organic phase was removed and reduced to an oil under vacuum. This residue was then dissolved- in dichloromethane and dried over magnesium sulfate. The product was purified on silica and isolated as a colorless oil. M + l = 166. 9-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: A mixture of 9- (2-methanesulfonyl-pyrimidin-4-yl) -2-phenyl -6,7,8,8-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (344 mg, 0.90 mmol), [3- (2-amino-propyl) "-phenyl] -methanol (371 mg, 2.25 mmol), and 8 m of N-methylmorpholine was heated at 100 ° C for 20 hours.The reaction was diluted with 15 ml of dichloromethane and 40 ml of ethyl acetate, washed three times with 50 ml of water, and then with 10 ml of saturated sodium chloride, the organic mass was dried over magnesium sulfate and then concentrated to a vacuum oil.The product was purified on silica and isolated as a white solid. . 9-. { 2- [2- (3-Azidomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimidol [1,2-a] pyrimidin-4-one: To a stirred mixture of 9-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino) -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (230 mg, 0.49 mmol), 1,8-diazabicyclo [5.4.0] undec-7- ene (0.13 ml, 0.88 mmol), and 12 ml of tetrahydrofuran at 0 ° C under a nitrogen atmosphere, diphenylphosphoryl azide (0.19 mL, 0.88 mmol) was added. The mixture was stirred overnight by heating to room temperature. The solvent was removed in vacuo and the product isolated as a solid, white after purification on silica. M + l = 494. 9-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamine) -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: To a vessel filled with nitrogen containing a stirred solution of 9-. { 2- [2- (3-Azidomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimidol [1,2-a] pyrimidin-4-one (190 mg, 0.39 mmol) in 25 mL of methanol was added 10% palladium on carbon (20%). mg). The mixture was stirred under a hydrogen atmosphere. After 2 hours, the reaction was filtered through a pad of Celite and the solvent removed in vacuo. The residue was purified on silica and isolated as a white solid. M + 1 = 468. XH NMR (CDC13) d (3H, 1.21 ppm), q (2H, 2.22 ppm), dd (1H, 2.77 ppm), dd (1H, 2.98 ppm), s (2H, 3.85 ppm) , m (4H, 4.12 ppm), q (1H, 4.30 ppm), d (4.96 ppm), s (1H, 6.60 ppm), d (1H, 7.0 ppm), d (2H, 7.18 ppm), d (1H , 7.21 ppm), m (1H, 7.27 ppm), m (3H, 7.44 ppm), m (2H, 7.90 ppm), d (1H, 8.17 ppm). 9-. { 2- [2- (3-isopropylamino-methyl) -phenyl] -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimidol [1,2- a] pyrimidin-4-one: To a solution of 9-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimidol [1,2-a] pyrimidin-4-one (79 mg, 0.17 mmol) and acetone (0.015 mL, 0.21 mmol) was stirred for 10 minutes before of adding sodium borohydride (108 mg, 3.4 mmol). After 10 minutes, the solvent was removed in vacuo and the residue was diluted between 10 ml of dichloromethane and saturated sodium chloride. The product was isolated as a white solid after purification on silica. M + l = 509- Resolution of the R / S enantiomers: 9-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimidol [1,2, -a] pyrimidin-4-one and 9-. { 2- [2- (3-aminomethyl-phenyl) -1 (R) -methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimidol [1,2-a] pyrimidin-4-one: a mixture. of 9-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6, 7, 8, 9-tetrahydro-pyrimidol [1, 2, -a] pyrimidin-4-one was separated by means of chiral HPLC using a column CHIRALPAK AS (10 μm 20 x 250 mm) and eluting with 0.2% diethylamine in methanol / carbon dioxide (35:65) at 50 ml / minute (120 bar). The S-enantiomer was then confirmed by comparing the retention times on the previous column to that of 9-. { 2- [2- (3-aminomethyl-phenyl) -1 (S) -methyl-ethylamino] -pyrimidin-4-yl} Synthetic -2-phenyl-6,7,8,9-tetrahydro-pyrimidol [1,2, -a] pyrimidin-4-one, using reaction schemes E and F.

Reaction Scheme F: diisoproyl azodicarboxylate (3-bromobenzyloxy) -tert-butyldimethylsilane: A solution of 3-bromobenzyl alcohol (7.1 g, 38 mmol) and tert-butyldimethylsilyl chloride (5.7 g, 38 mmol) in 40 ml of N, N-dimethylformamide was stirred at room temperature. environment for 5 hours. 40 ml of water were added and the mixture was extracted with hexanes. The combined extracts were washed with 10% aqueous hydrochloric acid, saturated sodium bicarbonate, saturated sodium chloride, and dried over magnesium sulfate. The desired product was isolated after concentration and purification by chromatography on silica gel (hexanes). AH NMR (CDC13) 7.48 (s, 1H), 7.34 (m, - "- 1H), 7.24 (m, 2H), 4.72 (s, 2H), 0.95 (s, 9H), 0.11 (s, 6H). 1- [3- (tert-butyldimethylsilyloxymethyl) phenyl] -propan-2-ol: A A stirred solution of (3-bromobenzyloxy) -tert-butyldimethylsilane (7.0 g, 24 mmol) in 100 ml of tetrahydrofuran under an atmosphere of nitrogen, magnesium chips (0.73 g, 30 mmol) and an iodine crystal were added. The mixture was refluxed for 1 hour, cooled to 0 ° C and copper (I) iodide (4.57 g, 24 mmol) was added. After stirring at 0 ° C for 5 minutes, (R) - (+) - propylene oxide was added and the mixture was stirred for 2 hours. A mixture of ammonium chloride and ammonium hydroxide (5: 1, 100 mL) was added, the biphasic mixture was stirred vigorously until the copper salts dissolved, and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the organic extracts were dried over magnesium sulfate and purified by flash column chromatography (ethyl acetate / hexanes). 0 XR NMR (CDCI3) 7.28 1H), 7.22 (m, 1H), 7.17 (s, 1H), 7.10 (d, 1H), 4.73 (s, 2H), 4.00 1H), 2.77 (d, 1H), 2.70 (d, 1H), 1.60 (s, 1H), 1.24 (d, 3H), 0.94 (s, 9H), 0.10 (s, 6H). [3- (2-azidopropyl) -benzyloxy] -ter-butyldimethylsilane: To a stirred solution of 1- [3- (tert-butyldimethylsilyloxymethyl) -phenyl] -propan-2-ol (130 mg, 0.46 mmol) in 1.5. mL of THF under a nitrogen atmosphere at 0 ° C was added diisopropyl azodicarboxylate (140 mg, 0.7 mmol), triphenylphosphine (180 mg, 0.7 mmol), and diphenylphosphoryl azide (190 mg, 0.7 mmol) and the mixture was stirred at RT. 0 ° C for 15 minutes. The mixture was diluted with dichloromethane, washed with water, brine, dried over magnesium sulfate and purified by flash column chromatography (ethyl acetate / hexanes). 2 H NMR (CDCl 3) 7.27 (m, 1H), 7.2 (m, 1H), 7.16 (s, 1H), 7.08 (m, 1H), 4.74 (s, 2H), 3.65 (m, 1H), 2.82 (dd) , 1 HOUR) . 2.73 (dd, 1.25 (d, 3H), 0.94 (s, '9H), 0.10 (s, 6H). 2- [3- (tert-Butyldimethylsilyloxymethyl) -phenyl] -1-methyl-ethylamine: To a stirred solution of [3- (2-azidopropyl) -benzyloxy] -ter-butyldimethylsilane (100 mg, 0.33 mmol). in 1 ml of THF and 0.3 ml of water at 0 ° C, triphenylphosphine (128 mg, 0.5 mmol) was added and the solution was stirred with warming to room temperature overnight. The mixture was concentrated in vacuo and purified by flash column chromatography (NH3-MeOH / CH2Cl). M + l = 280. [3-2-aminopropyl) -phenyl] -methanol: - To a stirred solution of 2- [3- (tert-Butyldimethylsilyloxymethyl) -phenyl] -1-methyl-ethylamine (730 mg, 2.6 mmol) in 2 ml of tetrahydrofuran was added 3.1 mmol of tetrabutylammonium fluoride and the mixture was stirred at room temperature for 2 hours. The solvent was removed in vacuo and the product was obtained after flash column chromatography (NH3-MeOH / CH2Cl2). XH NMR (CDC13) 7.30- (m, 1H), 7.26 (m, 1H), 7.19 (s, 1H), 7.10 (d, 1H), 4.67 (s, 2H), 3.61 (m, 1H), 2.71 ( d, 1H), 2.51 (d, 1H), 1.67 s broad, 3H), 1.12 (d, 3H). The examples in the following table were prepared using the above methods, as indicated, using the suitably substituted oxopropyl acid derivative of reaction scheme A and the appropriate amine to replace phenethylamine, if desired: Reaction Scheme G: Reaction Scheme H: Example 50 (5-Bromo-pyrimidin-2-yl) -bis-carbamic acid tert-butyl ester: A suspension of 5-bromo-pyrimidin-2-ylamine (10.2 g, 58.6 mmol), di-tert-butyldicarbonate (28.1 g, 129 mmol), and 100 ml of pyridine was heated at 70 ° C overnight while stirring under a nitrogen atmosphere. The solvent was removed in vacuo, then the residue was partitioned between diethyl ether and 5% potassium diacid phosphate. The organic phase was washed with saturated ammonium chloride and then dried over magnesium sulfate. The Partial evaporation of the ether in vacuo yielded a white solid which was then collected by filtration. M + l = 374/376. 3- (2-bis-tert-butoxycarbonylamino-pyrimidin-5-yl) -acrylic acid tert-butyl ester: A mixture of (5-bromo-pyrimidin-2-yl) -bis-carbamic acid tert-butyl ester (5.0 g, 13.4 mmol), tert-butylacrylate (3.9 mL, 26.7 mmol), potassium acetate (3.9 g, 40.2 mmol), tetrabutylammonium bromide (4.3 g, 13.4 mmol) -,. Palladium acetate (150 mg, 0.7 mmol), and 50 ml of N, N'-dimethylformamide was stirred at 70 ° C for 1 hour. The solvent was removed in vacuo, and the residue was partitioned between 200 ml of ether and water. The organic phase was further washed with water and saturated ammonium chloride, then dried over magnesium sulfate. The product was isolated as a yellow solid after purification on silica. M + l = 422.

Salt of 3- (2-amino-1,4,5,6-tetrahydro-pyrimidin-5-yl) -propionic acid ethyl ester hydrochloride: A solution of 3- (2-bis-) -butyl tert-butyl ester tert-butoxycarbonylamino-pyrimidin-5-yl) -acrylic acid (3.0 g, 7.1 mmol) in 20 ml of dichloromethane and 50 ml of trifluoroacetic acid was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the resulting solid was suspended in 2M hydrochloric acid in 25 ml of diethyl ether and 75 ml of ethanol. Palladium hydroxide on carbon (20%) was added to the flask filled with nitrogen, and stirred for 3 days under a hydrogen atmosphere distributed via a balloon. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated to an amber oil under vacuum. M + l = 200. 3- [6-Oxo-l- (2-phenethylamino-pyrimidin-4-yl) -8- phenyl-1, 3,4,6-tetrahydro-2H-pyrimido [1,2-a] pyrimidin-3-acid] il] -propionic: A solution of 3- [6-oxo-1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 3,4,6-tetrahydro-2H-pyrimidoic acid ethyl ester. [1,2-a] pyrimidin-3-yl] -propionic acid (240 mg, 0.46 mmol), 10% aqueous lithium hydroxide (0.2 ml), and 5 ml of tetrahydrofuran was heated to 50 ° C. The reaction was divided between 50 ml of dichloromethane and 5% of sodium dihydrogen phosphate. The organic phase was dried over magnesium sulfate, then concentrated to a white solid in vacuo. M + l = 497.

Benzyl acid ester. { 2- [6-oxo-l- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-l, 3,4,6-tetrahydro-2H-pyrimido [1,2-a] pyrimidin-3-yl ] -ethyl} -Carbamic: A suspension of 3- [6-oxo-l- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 3,4,6-tetrahydro-2H-pyrimido [1, 2 -] a] pyrimidin-3-yl] -propionic acid (218 mg, 0.44 mmol), diphenylphosphoryl azide (0.095 mL, 0.44 mmol), N-N '-diisopropylethylamine (0.077 mL, 0.44 mmol), and 5 mL of toluene was heated to reflux for 1 hour. Benzyl alcohol (0.091, 0.88 mmol) was added to the reaction and heating was continued at reflux for an additional 6 hours. After removal of the solvent in vacuo, the product was isolated as a white solid after purification on silica. M + l = 602. 7- (2-amino-ethyl) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine-4- ona: A solution of the benzyl ester of the acid. { 2- [6-oxo-l- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1,3,4,6-tetrahydro-2H-pyrimido [1,2-a] pyrimidin-3-yl) ] -ethyl} Carbamic acid (100 mg, 0.17 mmol), 5 ml of dichloromethane and 15 ml of methanol was added 10% of palladium on carbon (5 mg) and stirred at room temperature under a hydrogen atmosphere overnight. The reaction was filtered through a pad of Celite, and the solvent was removed in vacuo to give a white solid. M + l = 468. 7- (2-isopropylamino-ethyl) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidine-4- ona: To a solution of 7- (2-amino-ethyl) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2] α-pyrimidin-4-one (70 mg, 0.15 mmol), 0.02 ml of acetone, 0.5 ml of dichloromethane and 0.5 ml of methanol was added sodium triacetoxyborohydride (3.8 mg, 0.18 mmol). The reaction was stirred for 2 hours at room temperature. The solvents were removed in vacuo. The residue was partitioned between dichloromethane and "5% sodium bicarbonate." The organic phase was purified on silica to give a white solid, M + 1 = 510. RMN ^ H (CDC13) d (6H, 1.17 ppm), m ( 2H, 1.68 ppm), m (1H, 2.32 ppm), m (3H, 2.78 ppm), t (2H, 2.94 ppm), m (1H, 3. 55 ppm), dd (2H, 3.70 ppm), d (1H, 4.40 ppm), dd (1H, 4.53 ppm), m (1H, 5.10 ppm), s (1H, 6.60 ppm), m (3H, 7.24 ppm) ), m (2H, 7.32 ppm), m (3H, 7.44 ppm), m (2H, 7.90 ppm) d (1H, 8.18 ppm).

The examples in the following table were prepared using the above methods, as indicated, using the appropriate substituted alkene to replace the tert-butylacrylate, if desired: Reaction Scheme I: Example 59 4,5-Dihydro-1H-imidazole-2-ylamino-hydroiodic acid: A suspension of 2-methylsulfanyl-4,5-dihydro-1H-imidazole-hydroiodic acid (3.0 g, 12.3 mmol) and 2 M ammonia in 20 ml of methanol was heated at 90 ° C in a sealed tube overnight. The solvents were removed in vacuo to provide a white solid. M + l = 86.

Method of HPLC A: 5-95% acetonitrile (0.1% trifluoroacetic acid) in 10 minutes at 1 ml / minute on Agilent zorbax Exlipse XDB C-8 (4.16 x 150 mm 5 μm) Method of CLAR B: 5-95 % acetonitrile (0.1% trifluoroacetic acid) in 14 minutes at 1 ml / minute on Luna C-18 (4.6 x 150 mm 5 μm).

Reaction Scheme J: For the generic structure: Example 60 2-amino-3-methyl-6-phenyl-3H-pyrimidin-4-one: A mixture of potassium hydroxide (1.22 g, 22 mmol), methyl iodide (6.85 g, 48 mmol), and 2- amino-6-phenyl-3H-pyrimidin-4-one (2.62 g, 14 mmol) in 130 ml of ethanol was stirred at room temperature in a 250 ml round bottom flask with stopper for 3 days. An additional 6.85 g of methyl iodide (48 mmol) was added and stirring was continued for 1 day. The solvent was removed in vacuo and the residue was dissolved in 35 ml of water, heated to 50 ° C, and 1 N HCl was added dropwise until the solid dissolved completely. The solution was cooled to room temperature, basified with saturated NaHCO 3, and the resulting white solid was filtered and dried in vacuo. M + l: 202. 3-Methyl-2- (2-methylsulfanyl-pyrimidin-4-ylamino) -6-phenyl-3H-pyrimidin-4-one. A mixture of 2-amino-3-methyl-6-phenyl-3H-pyrimidin-4-one (500 mg, 2.5 mmol), NaOtBu (286 mg, 3 mmol), 4-chloro-2-thiomethylpyrimidine (477 mg , 3 mmol), (2'-dicyclohexylphosphanyl-biphenyl-2-yl) -dimethylamine (98 mg, 0. 24 mmol), and Pd2 (dba) 3 (113 mg, 0.12 mmol) in 12 ml of toluene was heated at 110 ° C for 5 hours, cooled to room temperature and diluted with 12 ml of saturated ammonium chloride. The layers were separated and the aqueous layer was extracted with 20 ml of ethyl acetate once and with 20 ml of methylene chloride once. The combined organic extracts were concentrated to less than 5 ml and the resulting off-white solid was collected by filtration to give the product. M + l: 326. 2- (2-methanesulfinyl-pyrimidin-4-ylamino) -3-methyl-6-phenyl-3H-pyrimidin-4-one. 'M-CPBA (91 mg, 0.5 mmol) was added to a solution of 3-methyl-2- (2-methylsulfanyl-pyrimidin-4-ylamino) -6-phenyl-3H-pyrimidin-4-one (115 mg, 0.35 mmol) in 2 ml of methylene chloride and the mixture was stirred at room temperature for 15 minutes, then quenched. with saturated NaHCO 3. The layers were separated and the aqueous layer was extracted with methylene chloride twice. The organic extracts - combined were dried over magnesium sulfate, filtered and concentrated in vacuo. This material was combined with the material obtained from a second reaction on 472 mg of the initial material. The combined material was purified by column chromatography to give the product. M + l: 342. 2- . { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-ylamino} -3-methyl-6-phenyl-3H-pyrimidin-4-one. A mixture of [3- (2-amino-propyl) -phenyl] -methanol (300 mg, 1.8 mmol) and the 2- (2-methanesulfinyl-pyrimidin-4-ylamino) -3-methyl-6-phenyl- 3H-pyrimidin-4-one (300 mg, 0.9 mmol) - in 8 ml of NMP was heated at 100 ° C for 16 hours. The reaction was cooled to room temperature and ethyl acetate was added. The mixture was then washed with water three times, with brine once, dried over magnesium sulfate, filtered, concentrated in vacuo, and purified by TLC on a preparative scale to give the product. M + l: 443. 2- . { 2- [2- (3-Azidomethyl-phenyl) -1-ethylamino] -pyrimidin-4-ylamino} 3-methyl-6-phenyl-3H-pyrimidin-4-one. A mixture of diphenylphosphoryl azide (237 mg, 0.86 mmol), 1,8-diazabicyclo [5.4.0] undec-7-ene (130 mg, 0.86 mmol), and 2-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-ylamino} 3-methyl-6-phenyl-3H-pyrimidin-4-one (190 mg, 0.43 mmol) in 3.5 mL of THF was stirred at 35 ° C for 17.5 hours. The mixture was cooled to room temperature, diluted with water and extracted with methylene chloride three times. The combined extracts were dried over magnesium sulfate, filtered, concentrated in vacuo and purified by column chromatography to give the product. M + l: 468. 2- . { - [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-ylamino} 3-methyl-6-phenyl-3H-pyrimidin-4-one. A powder mixture of Zn ° (60 mg, 0.9 mmol), ammonium chloride (49 mg, 0.9 mmol), and 2-. { 2- [2- (3-Azidomethyl-phenyl) -1-ethylamino] -pyrimidin-4-ylamino} 3-methyl-6-phenyl-3H-pyrimidin-4-one (216 mg, 0.46 mmol) in a mixture of 2 ml of water and 2 ml of ethanol was heated to reflux for 2 hours, and cooled to room temperature . The mixture was partitioned between water and chloroform / lPA 4: 1, the layers separated and the aqueous layer extracted with chloroform / IPA 4: 1 three times. The extracts were dried over magnesium sulfate, filtered, concentrated and purified by TLC on a preparative scale (30 mg, 15%). X H NMR (400 MHz, CDC13): 8~14 (d, J4, 1H), 7.68 (s, 2H), 7.53 (m, 1H), 7.45 (m, 2H), 7.19 (m, 1H), 7.13 (d, J 16, 1H), 7.-04 (s, 1H), 6.95 (s, 1H), 6.40 (s broad, 1H), 6.10 (s broad, 1H), 4.62 (s broad, 1H), 4.18 _ (s broad, 1H), 3.78 (.S-, 2H), 3.61 (s, 3H), '2.74 (s broad, 2H) -, - 1.11 (d, J 6, 3H). M + l: 442.

Example 61 1- (2- { 2- [4- (1-Amino-ethyl) -phenyl] -ethylamino}. Pyrimidin-4-yl) -8-phenyl-1, 2,3,6- tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: Reaction Scheme K: 1- (4-Bromo-phenyl) -ethyl] -carbamic acid tert-butyl ester: A mixture of 1- (4-bromo-phenyl) -ethylamine (7.0 g, 35 mmo-1), di-ter- butylcarbonate (35 ml, 1.0 M in THF), and triethylamine (4.9 ml, 35 mmol) in 140 ml of THF was stirred at room temperature for 17 hours. The mixture was washed with saturated ammonium chloride, with brine, dried over magnesium sulfate and concentrated to give a white solid as the desired product. M + l = 300.

Ethyl 3- [4- (1-tert-butoxycarbonylamino-ethyl) -phenyl] -acrylic acid ester: To a mixture of [1- (4-bromo-phenyl) -ethyl] -carbamic acid-tert-butyl ester ( 3.0 g, 10 mmol), tris (dibenzylideneacetone) dipalladium (0.55 g, 0.6 mmol), and N-methyldicyclohexylamine (2.1 ml, 10 mmol) was purged with nitrogen, followed by the addition of 20 ml of 1,4-dioxane and tri-tert-butylphosphine (0.24 g, 1.2 mmol). The mixture was again purged with nitrogen and ethyl acrylate (2.16 ml, 20 mmol) was added. The mixture was heated to 80 ° C for 30 minutes, emptied into 100 ml of water and extracted with 150 ml of ethyl acetate. The organic layer was separated, washed again with water, dried over magnesium sulfate, concentrated and chromatographed on silica gel using hexanes / ethyl acetate 2: 1 to give a light brown oil. M + l = 320 Ethyl 3- [4- (1-tert-butoxycarbonylamino-ethyl) -phenyl] -propionic acid ethyl ester: Through a mixture of 3- [4- (1-tert-butoxycarbonylamino-ethyl) -phenyl acid ethyl ester ] -acrylic (0.22 g, 0.69 mmol) and palladium hydroxide on carbon (100 mg) in 10 ml of ethanol, hydrogen was bubbled through a balloon for 17 hours. The mixture was filtered through celite and concentrated to give an off white solid. M + l = 322. 3- [4- (tert-Butoxycarbonylamino-ethyl) -phenyl] -propionic acid: The mixture of 3- [4- (l-tert-butoxycarbonylamino-ethyl) -phenyl] -propionic acid ethyl ester (8.69 g, 27 mmol) and 1 N sodium hydroxide (135 ml, 135 mmol) in 50 ml of methanol was heated to reflux for 1 hour, brought to room temperature and concentrated. The residue obtained was dissolved in 50 ml of ethyl acetate and the mixture was acidified to pH 6-5 with 1 N hydrochloric acid. The organic phase was separated and concentrated to give an off white solid. M + l = 294.

Ter-butyl acid ester. { 1- [4- (2-Azidocarbonyl-ethyl) -phenyl] -ethyl} -carbamic: To a mixture of 3- [4- (1-tert-butoxycarbonylamino-ethyl) -phenyl] -propionic acid (1.0 g, 3.4 mmol) in 10 mL of THF at 0 ° C, triethylamine (0.8 mL) was added. ). After 30 minutes', ethyl chloroformate was added dropwise. The mixture was stirred at 0 ° C for 1 hour and then sodium azide (0.24 g, "3.74 mmol) in 2 ml of water was added dropwise. The ice bath was removed and the mixture was stirred at room temperature for 1.5 hours. The mixture was diluted with 100 ml of ethyl acetate, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give a white solid. M + l = 319.

Ter-butyl ester of acid. { 1- [4- (2-Benzyloxycarbonylamino-ethyl) -phenyl] -ethyl} Carbamic: The mixture of the ter-butyl ester of acid. { 1- [4- (2- 'azidocarbonyl-ethyl) -phenyl] -ethyl} Carbamic acid (2.2 g, 6.92 mmol) and benzyl alcohol 1.0 ml 10.4 mmol) in 20 ml of toluene was heated at 105 ° C for 17 hours. The mixture was brought to room temperature and a white solid was ground which corresponded to the desired product. This solid was filtered, washed with toluene and dried under high vacuum. M + l = 399.

Ter-butyl acid ester. { 1- [4- (2-Amino-ethyl) -phenyl] -ethyl} -carbamic: The mixture of the ter-butyl ester of acid. { 1- [4- (2-Benzyloxycarbonylamino-ethyl) -phenyl] -ethyl} Carbamic acid (0.80 g, 2.0 mmol), 1,4-cyclohexadiene (0.96 ml, 10 mmol) and palladium on carbon (100 mg) in 20 ml of ethanol, and 5 ml of methanol was heated to reflux for 2 hours and dried. led to room temperature. The mixture was filtered through celite and concentrated to provide a white solid. M + l = 265".

Reaction Scheme L: [1- (4-. {2- 2- [4- (4-Oxo-8-phenyl-3,4-dihydro-2H, 6H-pyrimido [1,2-a] pyrimidin-1-tert-butyl ester] -yl) -pyrimidin-2-ylamino] ethyl.}. -phenyl) -ethyl] -carbamic acid: The mixture of 1- (2-methanesulfonyl-pyrimidin-4-yl) -8-phenyl-i, 2, 3 , 6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (0.20 g, 053 mmol) and the tert-butyl ester of the acid. { 1- [4- (2-Amino-ethyl) phenyl] -ethyl} Carbamic acid (0.304 g, 0.79 mmol) in 6 ml of dioxane: 1-methyl-2-pyrrolidinone 1: 1 was heated at 100 ° C for 17 hours. The mixture was partitioned between 10 ml of water and 20 ml of ethyl acetate. The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-4% methanol / methylene chloride to give a solid. White. M + l = 568. 1- (2- { 2- [4- (1-amlno-ethyl) -phenyl] -ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro- pirimido [1, 2- a] pyrimidin-4-on: The mixture of the ter-butyl ester of the acid [1- (4-. {2- 2- [4- (4-oxo-8-phenyl-3, 4- dihydro-2H, 6H-pyrimido [1,2-a] pyrimidin-1-yl) -pyrimidin-2-ylamino] ethyl]} - phenyl) -ethyl] -carbamic acid (0.24 -g, 0.42 mmol) and acid Trifluoroacetic acid (0.7 ml, 20 mmol) in 5 ml of dichloromethane was stirred at room temperature for 1.5 hours. The mixture was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, concentrated and chromatographed on silica gel using 0 to 8% 2M NH3, methanol / methylene chloride to give a white solid. M + l = 468. RMNXH (DMSO) d (3H, 1.21 ppm), m (2H, 2.15 ppm), t (2H, 2.83 ppm), d (1H, 3.18 ppm), b (2H, 3.49 ppm), m (6H, 4.13 ppm) ), s (1H, 6.62 ppm), d (2H, 7.09 ppm), d (2H, 7.16 ppm), d (2H, 7.27 ppm), m (3H, 7.46 ppm), dd (2H, 7.96 ppm), b (1H, 8.18 ppm).

Example 62 1- (2- {2 [4- (1-isopropylamino-ethyl) -phenyl] -ethylamino}. Pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro - pirimido [1,2-a] pyrimidin-one Reaction Scheme M: 1- (2- {2 [4- (1-isopropylamino-ethyl) -phenyl] -ethylamino}. Pyrimidin-4-yl) -8-phenyl-1,3,3,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: The mixture of l- (2- {2- [4- (1-amino-ethyl) -phenyl] -ethylamino} -pyrimidin-4- il) -8-phenyl-1, 2, 3, 6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (70 mg, 0.15 mmol), sodium triacetoxyborohydride (0.13 g, 0.60 mmol), ml of acetone and 0.5 ml of acetic acid in 10 ml of methanol was stirred at room temperature for 17 hours. The mixture was concentrated and the residue was dissolved in 50 ml of methylene chloride, washed with saturated sodium bicarbonate, with brine, dried over magnesium sulfate and concentrated to give a white solid. M + l = 510. X H NMR (DMSO) dd (6H, 0.92 ppm), d (3H, 1.19 ppm), m (2H, 2.14 ppm), m (1H, 2.44 ppm), t (2H, 2.82 ppm), b (2H, 3.48) ppm), m (1H, 3.77 ppm), m (4H, 4.03 ppm), s (1H, 6.62 ppm), d (2H, 7.08 ppm), d (2H, 7.16 ppm), d (2H, 7.24 ppm) , m (3H, 7.46 ppm), dd (2H, 7.96 ppm), b (1H, 8.18 ppm).

Example 63 1-. { 2- [2- (4-aminomethyl-phenyl) -1-methyl-ethylamino] pyrimidin-4-yl} -8-phenyl-1, 2,3,6-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one Reaction Scheme N: 4- (2-Nitro-propenyl) -benzoic acid methyl ester: The mixture of 4-formyl-benzoic acid methyl ester (20.1 g, 122.4 mmol), ammonium acetate (9.4 g, 122. 4 mmol) in 200 ml of nitroethane was heated to reflux by 2. 5 hours. The mixture was brought to room temperature and concentrated. The residue was partitioned between 200 ml of water and 500 ml of ethyl acetate. The organic layer was separated, washed with saturated sodium bicarbonate, with brine, dried over magnesium sulfate, concentrated and chromatographed on silica gel using hexanes / ethyl acetate 6: 1 to give a yellow solid. M + l = 222. [4- (2-Amino-propyl-phenyl] -methanol: The suspension of lithium aluminum hydride (11 g, 277 mmol) in 200 mL of THF was brought to 0 ° C, followed by the slow addition of the methyl ester. - 4- (2-nitro-propenyl) -benzoic acid (12.25 g), 55.4 mmol) in 100 ml of THF. Once the addition was complete, the mixture was stirred at 0 ° C for 15 minutes and brought to room temperature and stirred for 17 hours. The mixture was brought to G ° C and quenched with solid sodium sulfate decahydrate, until bubbling stopped. The suspension was filtered and the filtrate was concentrated and the yellow oil obtained was chromatographed on silica gel using 0 to 8% NH3 2M methanol / methylene chloride. M + l = 166. l-. { 2- [2- (4-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: 1- (2-methanesulfonyl-pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro-pyrimidin [1,2-a] pyrimidin-4-one (1.1 g 2.9 mmol) and [4- (2-amino-propyl) -phenyl] -methanol (0.96 g, 5.8 mmol ) in dioxane: 1-methyl-2-pyrrolidinone 1: 1 (16 ml) was heated at 100 ° C for 20 hours. The mixture was partitioned between 30 ml of water and 60 ml of ethyl acetate. The organic phase was separated, washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate and dried. chromatographed on silica gel using 0 to 8% 2M NH3 methanol / methylene chloride to give a white solid. M + l = 469. NMR E (CDC13) d (3H, 1.21 ppm), s (1H, 1.79 ppm), m (2H, 2.22 ppm), m (1H, 2.79 ppm), m (1H, 2.98 ppm), m (4H, 4.11 ppm), m (1H, 4.13 ppm), b (3H, 4.68 ppm), s (1H, 6.60 ppm), d (2H, 7.21 ppm), d (3H, 7.29 ppm), m (3H, 7.44 ppm) , dd (2H, 7.91 ppm), d (1H, 8.17 ppm). 1- . { 2- [2- (4-Azidomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-l, 2,3,6-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one: The mixture of 1-. { 2- [2- (4-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2, 3,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (0.11 g, 0.24 mmol) and 1,8-diaza-bicyclo [5.4.0] undec- 7-ene (47 μl, 0.312 mmol) in 5 ml of tetrahydrofuran was brought to 0 ° C followed by the addition of diphenylphosphoryl azide (68 μl, 0.312 mmol). The mixture was removed from the ice bath and stirred at room temperature for 17 hours. The mixture was concentrated and chromatographed on silica gel using 0 to 8% NH3 2M methanol / methylene chloride to give a white solid. M + l = 494. 1- . { 2- [2- (4-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-l, 2,3,6-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one: The mixture of 1-. { 2- [2- (4-Azidomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,6-tetrahydro-pyrimido [1,2, -a] pyrimidin-4-one, 1,4-cyclohexadiene (80 μl, 0.80 mmol) and 100 mg of palladium on carbon in 10 ml of ethyl acetate was heated to reflux for 3 hours and brought to room temperature. The mixture was filtered through celite and concentrated to give a white solid. M + l = 468. NMR X H d (3 H, 1.22 ppm), m (2 H, 2.23 ppm), m (1 H, 2.76 ppm), m (1 H, 2.98 ppm), s (2 H, 3.84 ppm), m (4 H, 4.11 ppm), m (1H, - 4.31 ppm), d (1H, 4.95 ppm), s (1H, 6.60 ppm), d (2H, 7.21 ppm), d (3H, 7.23 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.18 ppm).

EXAMPLE 64 1- (2- { 2- [4- (2-Amino-propyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2, 3,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one Reaction scheme O 4- . { 2- [4- (4-oxo-8-phenyl-3,4-dihydro-2H, 6H-pyrimido [1,2- a] pyrimidin-1-yl) -pyrimidin-2-ylamino] -propyl} - Benzaldehyde: The mixture of 1-. { 2- [2- (4-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (0.38 g, 0.81 mmol) and manganese dioxide (3.5 g, -40.5 mmol) in dichloromethane were added. stirred at room temperature for 3 hours. The mixture was filtered and concentrated to give a white solid. M + l = 467. 1- (2-. {1-methyl-2- [4- (2-nitro-propenyl) -phenyl] -ethylamino} - pyrimidin-4-yl) -8-phenyl-1, 2,3, 4,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: The mixture of 4- (2- [4- (4-oxo-8-phenyl-3,4-dihydro-2H, 6H- pyrimido [1, 2-a] pyrimidin-1-yl) -pyrimidin-2-ylamino] -propyl-.}. -benzaldehyde (35 mg, 0.08 mmol), ammonium acetate (10 mg, 0.16 mmol) in 5 ml The nitroethane was heated to reflux for 4 hours, the mixture was brought to room temperature and concentrated, the residue was dissolved in 20 ml of ethyl acetate, washed with water, with saturated sodium bicarbonate solution, with brine, dried over magnesium sulfate and concentrated, M + l = 524. 1- (2- { 2- [4- (2-amino-propyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3, 6-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one: Through a mixture of 1- (2. {1-l-methyl-2- [4- (2-nitro-propenyl) -phenyl] -ethylamino}. -. pyrimidin-4-yl ") -8-phenyl-1, 2,3,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (10 mg, 0.02 mmol) and palladium on c.arbon (catalytic) methane! Hydrogen was bubbled through a balloon for 17 hours.The mixture was filtered through celite, concentrated and subjected to chromatography on silica gel using 0 to 4% methanol / methylene chloride to give an off-white solid M + l = 496. XH NMR (CDC13) d (3H, 1.28 ppm), d (3H, 1.79 ppm), m (1H, 1.86 ppm), m (2H, 2.22 ppm), (1H, 2.80 ppm), m (1H, -2.94 ppm), (3H, 3.75 ppm), m (4H, 4.15 ppm), m (1H, 4.30 ppm), s (1H, 6.60 ppm), d (3H , 7.15 ppm), d (2H, 7.22 ppm), m (3H, -_ 7:44 ppm), dd (2H, 7.91 ppm), d (1H, 8.17 ppm).

Example 65 1- (2- { 2- [3- (1-amino-1-methyl-ethyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -8-phenyl- 1, 2,3, 6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one Reaction Scheme P; 2- (3-bromo-phenyl) -propan-2-ol: The methyl ester of 3-bromo-benzoic acid (1.0 g, 4.7 mmol) in 10 ml of tetrahydrofuran was brought to -78 ° C, followed by the addition of methylmagnesium bromide (7.7 ml, 10.81 mmol) and warmed to room temperature and stirred for 17 hours. The mixture was poured into saturated ammonium chloride and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over magnesium sulfate and chromatographed on silica gel using 0 to 4% methanol / dichloromethane to provide a colorless oil.

N- [1- (3-bromo-phenyl) -1-methyl-ethyl] -2-chloroacetamide: To a mixture of 2- (3-bromo-phenyl) -propan-2-ol (0.76 g, 3.6 mmol) and 7 ml of chloro-acetonitrile were added 0.6 ml of acetic acid and the resulting mixture was cooled to 0 ° C. 0.6 ml of concentrated sulfuric acid was added dropwise and the mixture was brought to room temperature and stirred for 17 hours. The mixture was poured into 10 ml of ice water and extracted with ethyl acetate. The extracts were combined, dried over magnesium sulfate and concentrated to give a white solid. M + l = 291. 1- (3-bromo-phenyl) -1-methyl-ethylamine: The mixture of N- [1- (3-bromo-phenyl) -1-methyl-ethyl] -2-chloroacetamide (1.0 g, 3.5 mmol), thiourea (0.32 g, 4.2 mmol), 1.5 ml of acetic acid in 7 ml of ethanol was heated to reflux for 10 hours and brought to room temperature. Water was added to the mixture until a pritate formed which was filtered. The filtrate was basified to pH 7-8 with 15% sodium hydroxide. The product was extracted with ethyl acetate and concentrated to give a yellow solid. M + l = 214. 3- [3- (1-Amino-1-methyl-ethyl) -phenyl] -2-methyl-acrylic acid methyl ester: The mixture of l- (3-bromo-phenyl) -1-methyl-ethylamine (0.74) g, 3.5 mmol), tris (dibenzylideneacetone) dipalladium (0.19 g, 0.21 mmol), and N-methyldicyclohexylamine (10 mmol) was purged with nitrogen followed by the addition of 7 ml of 1,4-dioxane and tri-tert-butylphosphine (85 mg, 0.42 mmol). The mixture was again purged with nitrogen and ethyl acetate (0.75 mL, 7.0 mmol). The mixture was heated at 80 ° C for 1 hour, brought to room temperature, poured into 50 ml of water and extracted with 100 ml of ethyl acetate. The organic layer was separated, washed again with water, dried over magnesium sulfate, concentrated and chromatographed on silica gel using 0-4% methanol / methylene chloride to give a yellow oil. 3- [3- (1-Amino-1-methyl-ethyl) -phenyl] -2-methyl-propionic acid methyl ester: The mixture of 3- [3- (1-amino-1-methyl) methyl ester ethyl) -phenyl] -2-methyl-acrylic (2.0 g, 8.6 mmol), magnesium (0.63 g, 25.8 mmol) in methanol was heated to reflux for 3 hours until the initial material was consumed. The mixture was brought to room temperature, filtered and the filtrate was concentrated.

The obtained residue was washed with saturated ammonium chloride, with brine, dried over magnesium sulfate and concentrated. 3- [3- (1-tert-Butythoxycarbonylamino-1-methyl-ethyl) -phenyl] -2-methyl-propionic acid methyl ester: To a mixture of 3- [3- (1-amino-1-methyl-3-methyl) methyl ester 1-methyl-ethyl) -phenyl] -2-methyl-propionic acid (1.17 g, 5.0 mmol) in THF was added 1 ml of triethylamine and stirred at room temperature for 15 minutes, followed by the addition of (Boc) 20 and dimethylaminopropylamine (cat.). The resulting mixture was stirred at room temperature for 17 hours. The mixture was poured into 200 ml of ethyl acetate and washed with saturated ammonium chloride, brine, dried over magnesium sulfate and chromatographed on silica gel using 0 to 4% methanol / dichloromethane and 7% NH3 2M methanol / methylene chloride to provide a yellow oil. M + l = 336. 3- [3-1-tert-Butoxycarbonylamino-l-methyl-ethyl) -phenyl] -2-methyl-propionic acid: A mixture of 3- [3- (1-tert-butoxycarbonylamino-1-methyl) methyl ester -ethyl) -phenyl] -2-methyl-propionic acid (430 mg, 1.3 mmol) and 1 N sodium hydroxide (6.5 ml, 6.5 mmol) in 10 ml of methanol was heated to reflux for 48 hours. The mixture was brought to room temperature and concentrated. The residue was dissolved in 20 ml of dichloromethane and acidified to pH about 5 using 10% KHS04. The organic phase was separated and concentrated. M + l = 322.

Ter-butyl acid ester. { l- [3- (2-Azidocarbonyl-propyl) -phenyl] -1-methyl-ethyl} -carbamic: To a stirred solution of 3- [3-1-tert-butoxycarbonylamino-l-methyl-ethyl) -phenyl] -2-methyl-propionic acid (0.33 g, 1.03 mmol) in 5 ml - of THF at 0 ° C was added -trietylamine (0.29 ml, 2.06 mmol). After 40 minutes, 0.11 ml was added dropwise - of chloroformate. The mixture was stirred at 0 ° C for 1.5 hours and then, sodium azide (73 mg, 1.13 mmol in 0.5 ml of water) was added dropwise, the mixture was brought to room temperature and stirred for an additional 1.5 hours. The resulting mixture was diluted with 20 ml of ethyl acetate, washed with saturated sodium bicarbonate, with brine, dried over magnesium sulfate and concentrated to give a yellow oil.

Ter-butyl acid ester. { l- [3- (2-Benzyloxycarbonylamino-propyl) -phenyl] -1-methyl-ethyl} - Carbamic: The mixture of the ter-butyl ester of acid. { l- [3- (2-Azidocarbonyl-propyl) -phenyl] -1-methyl-ethyl} Carbamic acid (0.34 g, 0.98 mmol) and benzyl alcohol (0.15 ml, 1.5 mmol) in 2 ml of toluene was heated at 105 ° C for 17 hours. The mixture was brought to room temperature, concentrated and chromatographed on silica gel using 0-4% methanol / methylene chloride to give a light yellow solid.

"Tertiary butyl ether". { l- [3- (2-Amino-propyl) -phenyl] -1-methyl-ethyl} -carbamic: To a mixture of tert-butyl ester of acid. { l- [3- (2-Benzyloxycarbonylamino-propyl) - "phenyl] -1-methyl-ethyl} -carbamic acid (0.28 g, 0.65 mmol), 1,4-cyclohexadiene (0.31 mL, 3.25 mmol) and Pd / C (cat.) In methanol was heated to reflux for 17 hours The mixture was filtered through celite and concentrated to give a light yellow oil M + l = 293. [1-Methyl-l- (3- (2- [4- (4-oxo-8-phenyl-3,4-dihydro-2H, 6H-pyrimido [1,2-a] pyrimidin) tert-butyl ester -1-yl) -pyrimidin-2-ylamino] -propyl.} - phenyl) -ethyl] -carbamic acid: To a mixture of the ter-butyl ester of the acid-. {L- [3- (2-amino- propyl) -phenyl] -l-methyl-ethyl.}. -carbamic acid (0.19 g, 0.65 mmol) and 1- (2-methanesulfonyl-pyrimidin-4-yl) -8-phenyl-1, 2, 3, 6- Tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (0.26 g, 0.72 mmol) in 2 ml of NMP was heated at 100 ° C for 17 hours.The mixture was drained in 15 ml of water and extracted with ethyl acetate The organic extracts were combined, washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and chromatographed on silica gel using 0-4% methanol / methylene chloride to give a light yellow oil, M + l = 596. 1- (2- { 2- [3- (1-amino-1-methyl-ethyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: To a mixture of the tert-butyl ester of acid [1-methyl-1- (3-. {2- 2- 4- (4-oxo-8-phenyl-3,4-dihydro-2H, 6H-pyrimido [1,2-a] pyrimidin-1-yl) -pyrimidin-2-ylamino] -propyl.} - phenyl) -ethyl ] -carbamic acid (0.25 g, 0.42 mmol) and 1 ml of trifluoroacetic acid in 2 ml of dichloromethane was stirred at room temperature for 30 minutes. The mixture was washed with saturated sodium bicarbonate, with brine, dried over magnesium sulfate and purified by chromatography on silica gel using 0-8% 2N NH3 methanol / methylene chloride. M + l = 496. XH NMR (CDC13) d (3H, 1. 23 ppm), s. (6H, 1.47 ppm), m (2H, 2.21 ppm), m (1H, 2.82 ppm), m (1H, 2.98 ppm), s (1H, 3.48 ppm), m (4H, 4.12 ppm), m (1H, 4.35 ppm), d (1H, 4.95 ppm), s (1H, 6.60 ppm), d (1H, 7.09 ppm), d (1H, 7.21 ppm), m (2H, 7.36 ppm), m (3H , 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.16 ppm).

Reaction Scheme Q: For the general structure Example 66 7-hydroxy-2-phenyl-9- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine -4-ona 2-imino-hexahydro-pyrimidin-5-ol hydrochloride: A mixture of 2-hydroxy-l, 3-diaminopropane (9.80 g, 108 mmol) and guanidine hydrochloride (10.4 g, 108 mmol) in a 100 ml round bottom flask was heated to 140 ° C under a nitrogen atmosphere. 5 hours. The reaction mixture, while under vigorous stirring, was allowed to cool to 100 ° C whereupon a mixture of 5 ml of iPrOH and 5 ml of CH 3 CN was added, resulting in the formation of a suspension. After cooling to room temperature, the mixture was filtered and the solid was washed with additional CH.CN '(30 ml in total). The solid was subsequently dried under vacuum to yield a white solid XH NMR (400 MHz, D20): 4.21 (m, 1H), 3.34 (dt, J 15.2, 2.8, 2H), 3.22 (dt, J 15.2, 2.8 ). 7-hydroxy-2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: In a 250 ml round bottom flask with a stir bar, one was heated mixture of 3-oxo-3-phenyl-propionic acid ethyl ester (15 g, 78 mmol), potassium carbonate (11.0 g, 80 mmol) and 2-imino-hexahydro-pyrimidin-5-ol hydrochloride (11.8 g) , 78 mmol) in 150 ml of ethanol at 90 ° C under nitrogen atmosphere overnight. After 17 hours, the mixture was cooled to room temperature, and filtered. The mother liquor was concentrated until obtaining a mud that was then diluted with water. The resulting suspension was filtered and the solid was washed first with methanol, then with a mixture of ethyl acetate-methanol (21: 1) to give the first batch of the product. The solid residue of the crude reaction was washed first with water (3 x 10 ml), then with methanol, and finally with a mixture of ethyl acetate-methanol (2: 1) to produce a second batch of the product. The combined products were air-dried to provide a white solid. NMR "? (400 MHz, DMSOs): 7.94 (m, 2H9, 7.44 (bt, J 3.2, 0.5 H), 6.10 (s, 1H), 5.35 (d, J 3.2, 0.5_H), 4.22 (m, 1H), 4.12 (d, J 14, 1H), 3.54 (dd, J 14 2.0, 1H), 3.39 (d, J 12.4, 1H), 3.18 (m, 1H), M + l: 244. 7- (tert-butyl-dimethyl-silanyloxy) -9- (2-methylsulfanyl-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine- 4-one: 7- (tert-butyl-dimethyl-silanyloxy) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one: A mixture of alcohol (1.0 g, 4.1 mmol), TBDMSCl (1.3 g, 6.1 mmol) and imidazole (0.80 g, 12 mmol) in 9 ml of DMF was stirred at room temperature. After 5 hours, the reaction mixture was diluted with 50 ml of ethyl acetate. The organic phase was washed with 3 portions of 20 ml of water, dried over sodium sulfate and concentrated to a solid. M + 1: 358. In a -150 ml round bottom flask with a stir bar, 4-chloro-2-methylsulfanyl-pyrimidine (1.0 g, 9.3 mmol) and 7- (tert-butyl-dimethyl- silanyloxy) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (1.0 g, 2.8 mmol) in 12 ml of PhMe and 3 ml of dioxane under the atmosphere of nitrogen. Subsequently, BINAP (0.18 g, 0.28 mmol), Pd (OAc) 2 (0.063 g, 0.28 mmol), and NaOtBu (.54 g, 5.6 mmol) were added. The mixture was heated to 110 ° C with vigorous stirring for 4 hours. After it was cooled to room temperature, the mixture was diluted with 50 ml of ethyl acetate, and the resulting mixture was washed with water, saturated ammonium chloride, and dried with sodium sulfate. The organic layer was concentrated and the residue was purified on silica with hexanes / ethyl acetate (1: 1). The product was further purified by trituration with hexanes-ethyl acetate (2: 1) to give a white solid. X H NMR (400 MHz, CDC13): 8.37 (d, J 4, 1 H), 7.91 (m, 2 H), 7.71 (d, J 4, 1 H), 7.46 (m, 3 H), 6.67 (s, 1 H), 4.52 (m, 1H), 4.35 (dt, 2H), 4.0 (dd, 1H), 3.85 (dd, 1H), 2.58 (s, 3H), 0.79 (s, 9H), 0.11 (s, 3H), 0.07 (s, 3H). M + l: 482. 7- (tert-butyl-dimethyl-silanyloxy) -9- (2-methanesulfonyl-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine- 4-one: To a suspension of urea-water (120 mg, 1.27 mmol) in 2.0 ml of MeCN, cooled to 0 ° C, trifluoroacetic anhydride (0.18 ml, 1.27 mmol) was added slowly. After 5 minutes, the cold solution was added to a solution of 7- (tert-butyl-dimethylsilanyloxy) -9- (2-methylsulfanyl-pyrimidin-4-yl) -2-phenyl-6,7,8, 9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (0.3 g, 0.62 mmol) in 2.0 ml of DCM at 0 ° C. The resulting mixture was stirred at room temperature for 3 hours and quenched with carbonate, aqueous sodium acid The mixture was then extracted with 3 portions of DCM and the organic layer was dried over sodium sulfate to give a white solid after evaporation This material was used directly for the next step: M + l: 498, 514. 7- (tert-butyl-dimethyl-silanyloxy) -2-phenyl-9- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one •. A mixture of 7- (tert-butyl-dimethyl-silanyloxy) -9- (2-methanesulfonyl-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one, prepared from the last step (0.6 mmol) and (S) -1-phenylethylamine (1.0 ml, 7.8 mmol) in 6 ml of dioxane was heated at 110 ° C for 17 hours. The brown solution was cooled to room temperature and diluted with 10 ml of ethyl acetate. The mixture was washed with 2 portions of water, dried over sodium sulfate, and concentrated to an oil. Purification on silica (0-1% NH3 2 N-methanol in DCM) gave the crude product as a white solid. M + l: 555. 7-hydroxy-2-phenyl-9- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine- 4- ona: A solution of 7- (tert-butyl-dimethyl-silanyloxy) -2-phenyl-9- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9- Tetrahydro-pyrimido [1,2-a] pyrimidin-4-one (20 mg) in 3 ml of methanol-1 ml of DCM was treated with 1.5 ml of concentrated HCl. After the mixture was stirred at room temperature by After 16 hours, it was neutralized with aqueous sodium hydrogen carbonate and then extracted with 3 portions of DCM The organic layer was dried over sodium sulfate and concentrated to a solid which was purified on silica (1-3%). NH3 2N-methanol in DCM) to give the product as a white solid.1H NMR (400 MHz, DMSO-d6): 8.12 (d, J 5.6, 1H), 7.94 (m, 2H), 7.70 (m, 1H, NH), 7.44 (m, 3H), 7.32 (t, J 7.2, 2H), 19 (m, 1H), 708 (d, J 5.6, 1H), 5.50 (ds, 1H, OH), 5.01 ( m, 1H), 4.39 (b, 1H), 4.22 (bt, 1.5H), 3.89 (d, J 4.8, 1H), 3.68 ( m, 0.5H), 3.3 (b, 1H), 1.45 (d, J 7.2, 3H). M + l: 441.

Example 67 8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one Step A. 4-Cyano-3-phenyl-but-3-enoic acid ethyl ester. A 250 ml round bottom flask equipped with a large stir bar was charged with the 3-oxo-3-phenyl-propionic acid ethyl ester (48 g, 0.25 mol), 80 ml of benzene, cyanoacetic acid ( 23 g, 0.27 mol), ammonium acetate (4- g, 0.05 mol), and acetic acid (7.5 ml, 0.13 mol) subsequently The total heterogeneous yellow mixture was equipped with a condenser and a Dean-Stark trap and The mixture was heated to reflux for 96 hours.The whole mixture was cooled to room temperature and emptied into a separatory funnel containing 100 ml of water.The organic layer was collected and the aqueous layer was extracted with 2 50 ml portions of acetate. The combined organic phases were then dried over sodium sulfate, followed by filtration and concentration to give the crude cyanamide as a brown syrup, which was purified by vacuum distillation to give the desired product as a pale yellow oil. B. 8-phenyl-1, 2, 3, 4-tetrahydro-pi [1, 2-a] pyrimidin-6-one. A 50 ml round bottom flask equipped with a stir bar was charged with the crude cyanamide product (2.15 g, 0.01 mol), 1,3-diaminopropane (0.84 ml, 0.01 mol) and 5 ml of 1,2-dichlorobenzene subsequently. The complete solution was equipped with a cooling condenser with air and heated to 160 ° C overnight. The resulting solution was concentrated and the crude material was passed through a short path of the SiO2 column by elution with hexanes, DCM and 1% methanol in DCM subsequently. The fraction containing the product was collected and concentrated, followed by washing with ethyl acetate to obtain the desired pyridone product as a yellow solid. MS m / e 227 (M + H) +.

Example 68 7-phenyl-2,3-dihydro-lH-imidazo [1,2-a] pyridin-5-one. The ethyl ester of 4-cyano-3-phenyl-but-3-enoic acid (crude, 9.37 g, 0.043 mol), ethylenediamine (about 3 ml, 0.043 mol) was mixed in 20 ml of dichlorobenzene and heated to 160 °. C all night. The resulting suspension was cooled to room temperature, filtered and the filtered cake was washed with ethyl acetate and finally dried to give the title compound as a brown yellow solid. MS m / e 213 (M + H) +.

Example 69 1- (2-methylsulfanyl-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. To a mixture of 8-phenyl-1,3-, 4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (1.86 g, 8.23 mmol), sodium tert-butoxide 1.6 g, 16 mmol), BINAP (0.15 g, 0.207 mmol), and Pd (OAc) 2 (55 mg, 0.2 mmol) were added "20 ml of toluene and 4-chloro-2-methylthiopyrimidine (1.5 ml, 12 mmol). After purging with nitrogen for 10 minutes, the entire mixture was heated to 70 ° C for 3 hours before being cooled to room temperature The resulting material was diluted with saturated aqueous ammonium chloride, with water and DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated.Column chromatographic purification (3% methanol in DCM) of the crude residue afforded the title compound. title as a yellow solid MS m / e 351 (M + H) +.

Example 70 1- (2-methylsulfanyl-pyrimidin-4-yl) -7-phenyl-2,3-dihydro-lH-imidazo [1,2-a] pyridin-5-one. Following the procedure described for the synthesis of 1- (2-methylsulfanyl-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydropyrido [1,2-a] irimidin-6-one , but using 7-phenyl-2,3-dihydro-1H-imidazo [1,2-a] pyridin-5-one (1 g, 4.7 mmol), sodium tert -butoxide (1.26 g, 13.16 mmol), BINAP (0.43 g, 0.7 mmol), Pd (0Ac) 2 (0.16 g, 0.7 mmol), 20 ml of toluene and "4-chloro-2-methylthiopyrimidine- (0.66 ml, 0.56 mmol) .The title compound was isolated. as a yellow solid, MS m / e 337 (M + H) +.

Example 71" 1- (2-Chloro-5-methyl-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the procedure described above and using 8-phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (0.48 g, 2.13 mmol), sodium tert-butoxide (0.41 g) g, 4.26 mmol), BINAP (66 mg, 0.11 mmol), Pd (0Ac) 2 (24 mg, 0.11 mmol), 5 mL of toluene and 2,4-dichloro-5-methylpyrimidine (0.37 mL, 3.19 mmol). The title compound was isolated (120 mg) as a yellow solid, together with the remaining initial material. MS m / e 353 (M + H) +.

Example 72 1- (6-chloro-pyrimidin-4-yl) -8-phenyl-1,2,4,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. To a stirred mixture of 1,8-phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (0.23 g, 1.0 mmol), 4,6-dichloropyrimidine (0.23) g, 1.53 mmol) in 3 ml of DMF was added an excess amount of sodium hydride at 0 ° C. Y. The resulting suspension was stirred for 1.5 hours at the same temperature before being poured on ice and extracted with DCM (2 times). The combined organic layers were washed with water, brine and dried over sodium sulfate. Concentration, followed by washing the residue with isopropyl alcohol afforded the title compound as a yellow solid. MS m / e 339 (M + H) +.

Example 73 1- (6-chloro-pyrazin-2-yl) -7-phenyl-2,3-dihydro-lH-imidazo [1,2-a] pyridin-5-one. "Following the procedure described in the synthesis of 1- (2-methylsulfanyl-pyrimidin-4-yl) -7-phenyl-2, 3-dihydro-1H-imidazo [1, 2-a] pyridin-5-one, but using 2,6-dichloropyrimidine as the coupling component, 7-phenyl-2,3-dihydro-lH-imidazo [1, 2-a] pyridin-5-one (0.5 g, 2.4 mmol) was converted to title product as a pale yellow solid, MS m / e 325 (M + H) +.

Example 74 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. To a solution of 1- (2-methylsulfanyl-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (1.46 g, 4.17 mmol) in 10 ml of DCM was slowly added m-CPBA (1.23 g, 70%, 5.01 mmol) at 0 ° C and the resulting suspension was stirred at the same temperature for 1 hour before being quenched with water and sodium bicarbonate. saturated sodium. The organic layer was collected and the aqueous layer was extracted with DCM. Then the combined organic phases were washed with 1 N sodium hydroxide, with brine and dried over sodium sulfate. Filtration followed by concentration produced a yellow foam of the desired corresponding sulfoxide, which was used directly without further purification. The crude sulfoxidó (0.14 g, 0.394 mmol) and the phenylethylamine (0.15 ml, 1.18 mmol) in 2 ml of NMP was heated at 100 ° C for 4 hours.After it was concentrated, the pale brown residue was diluted with alcohol isopropyl (or ethyl acetate) and the precipitate was collected as the title compound MS m / e 424 (M + H) +.

Example 75 l-. { 2- [2- (2-Chloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-l, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure described for the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidine-6- Ona, the sulfoxide (0.22 g, 0.6 mmol) was displaced with 2- (2-chlorophenyl) ethylamine (0.25 mL, 1.8 mmol) to give the title compound as a yellow solid. MS m / 458 (M + H) +.

Example 76 l-. { 2- [2- (2,6-dichloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-l, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the written compound for the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2, 3, 4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one , the sulfoxide (0.1 g, 0.27 mmol) was displaced with 2- (2,6-dichlorophenyl) ethylamine (0.16 g, 0.82 mmol) to give the title compound as a yellow solid MS m / e 492 (M + H) +.

Example 77 1- . { 2- [2- (2,4-dichloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure in the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one , the sulfoxide (0.11 g, 0.3 mmol) was displaced with 2- (2,4-dichlorophenyl) ethylamine (0.14 mL, 0.9 mmol) to give the title compound as a yellow solid. MS m / e 492 (M + H) +.

Example 78 8-phenyl-1- [2- (SS) -phenyl-ethylamino) -pyrimidin-4-yl] -1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure described for the synthesis of l- (2-phenethylamino-? Irimidin-4-yl) -8-phenyl-l, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6 -one, the sulfoxide (0.12 g, 0.34 mmol) was displaced with (S) - (-) -a-methylbenzylamine (0.21 mL, 1.03 mmol) to give the title compound as a yellow solid. MS m / e 424 (M + H) +.

Example 79 8-phenyl-l- [2- (2S) -phenyl-propylamino) -pyrimidin-4-yl] -1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure in the synthesis of l- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-l, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one , the sulfoxide (0.16 g, 0.44 mol) was displaced with the (S) - (-) - β-methylbenz-ylamine (0.6 ml, 1.09 mmol) to give the title compound as a yellow solid. MS m / e 438 (M + H) +.

Example 80 l-. { 2- [(SS) - (4-methoxy-phenyl) ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure described for the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidine-6- Ona, the sulfoxide (0.34 g, 0.93 mmol) was displaced with (S) -1- (4-methoxy-phenyl) -ethylamine (0.4 g, 279 mmol) to give the title compound as a light yellow solid. MS m / e 454 (M + H) +.

Example 81 l-. { 2- (S) - [1- (3-bromo-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-l, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure described for the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2, 3, 4-tetrahydro-pyrido [1,2-a] pyrimidine-6- Ona, the sulfoxide (0.152 g, 0.42 mmol) was displaced with (S) -1- (3-bromo-phenyl) -ethylamine (0.42 g, 2.79 mmol) to give the title compound as a light yellow solid. MS m / e 502 (M + H) +.

Example 82 8-phenyl-1-. { 2- (S) - [1- (3-piperazin-l-yl-phenyl) -ethylamino] -pyrimidin-4-yl-l, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidine -6-ona. Following a Pd-catalyzed amination procedure, similar, described in the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1, 2] -a] pyrimidin-6-one, l-. { 2- (S) - [1- (3-bromo-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (0.21 g, 0.42 mmol) was reacted with piperazine (54 mg, 0.63 mmol) to -dar the title compound as a light yellow solid. MS m / e 508 (M + H) +.

Example 83 l-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure described for the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidine-6- Ona, the sulfoxide (0.29 g, 0.83 mmol) was displaced with [3- (2-amino-propyl) -phenyl] -methanol (0.3 g, 1.66 mmol) to give the title compound as a light yellow solid. MS m / e 468 (M + H) +.

Example 84 l-. { 2- [2- (3-aminomethyl-7-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-l, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. To a stirred solution of the l-. { 2- [2- (3-hydroxymethyl-pentyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (0.22 g, 4.7 mmol) in 5 ml of THF was added DBU (0.14 g, 9.4 mmol) and then diphenylphosphoryl azide (0.26 g, 9.4 mmol) and the resulting solution was stirred at room temperature overnight. The resulting mixture was diluted with DCM and water subsequently, and the separated organic layer was washed with saturated sodium bicarbonate and brine. The elimination of the solvent provided the crude azide, which was reduced under hydrogenation conditions (H2 Pd / C, ethanol, room temperature, 4 hours). Filtration followed by concentration gave the crude amine which was purified by flash column chromatography (5% methanol in DCM) to give the title compound as a yellow solid. MS m / e 467 (M + H) +.

Example 85 1- (6-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. To a stirred mixture of 1- (6-chloro-pyrimidin-4-yl) -8-phenyl-1, 2, 3, 4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (0.158) mg, 0.47 mmol) and excess potassium carbonate in 3 ml of DMF, phenylethylamine (0.15 ml, 1.2 mmol) was added. "The entire reaction vessel was irradiated under microwave conditions at 150 ° C for 10 minutes. which was diluted with water and ethyl acetate, the organic layer was collected and the aqueous layer was extracted with ethyl acetate.The complete organic layers were washed with water, with brine and dried over sodium sulfate. gave the crude residue, which was washed with ethyl acetate / ether to give the title compound as a light yellow solid MS m / e 424 (M + H) +.

Example 86 l-. { 6- [2- (2-Chloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one. Following the same procedure described for the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2, 3, 4-tetrahydro-pyrido [1,2-a] pyrimidine-6- ona, l- (6-chloro-pyrimidin-4-yl) -8-phenyl-1,2,4,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one (0.136 g, 0.40 mmol ) was reacted with 2- (2-chlorophenyl) ethylamine (0.17 ml, 1.2 mmol) to give the title compound as a yellow solid. MS m / e 458 (M + H) +. - Example 87 1- (2-phenethylamino-pyrimidin-4-yl) -7-phenyl-2,3-dihydro-1H-imidazo [1,2-a] pyridin-5-one. To a solution of 1- (2-methylsulfanyl-pyrimidin-4-yl) -7-phenyl-2,3-dihydro-lH-imidazo [1, 2-a] pyridin-5-one (2.0 g, 5.95 mmol ) in a 4: 1 mixture of acetonitrile / trifluoroacetic acid (25 ml) was added urea-hydrogen peroxide (1.5 equivalent) followed by the slow addition of 1.5 equivalents of trifluoroacetic anhydride at 0 ° C, and the resulting suspension was stirred at the same temperature for 1 hour before being warmed to room temperature, and stirred for another 2 hours. At this point, 0.5 more equivalents of hydrogen urea-peroxide and trifluoroacetic anhydride were added to consume all the initial material remaining. After it was concentrated, the crude material was divided between water and chloroform, and the separated organic layer was washed with 5% sodium acid carbonate, with brine, and the solvent was removed to produce the sulfoxide / sulfone mixture as a whitish solid, which was used without purification. To a stirred solution of crude sulfoxide / sulfone (0.25 g, 0.69 mmol) in 5 ml of NMP was added phenethylamine (0.1376 g) and the resulting mixture was heated at 130 ° C overnight. After it was cooled, the reaction mixture was diluted with water and DCM, the organic layer was collected and the aqueous layer was extracted with DCM. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to provide the crude material, which was subjected to a preparative thin layer chromatographic purification to provide the title compound as a pale yellow solid. . MS m / e 410 (M + H) +.

Example 88 l-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -7-phenyl-2, 3-dihydro-lH-imidazo [1, 2-a] pyridin-5-one. Following the same procedure described for the synthesis of 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1,2,3-tetrahydro-pyrido [1,2-a] pyrimidin-6-one , the sulfoxide / sulfone (0.4 g) was displaced with [3- (2-amino-propyl) phenyl] -methanol (1.2 equivalents) to give the title compound as a light yellow solid. MS m / e 454 (M + H) +.

Example 89 1- (6-phenethylamino-pyrazin-2-yl) -7-phenyl-2,3-dihydro-lH-imidazo [1,2-a] pyridin-5-one. To a mixture of 1- (6-chloro-pyrazin-2-yl) -7-phenyl-2,3-dihydro-lH-imidazo [1,2- a] pyridin-5-one (85"mg, 0.26 mmol), sodium tert-butoxide (70 mg, 2.8 equivalents), BINAP (24 mg, 15% equiv.), and Pd (0Ac) 2 (9 mg, 15% _ equiv.) Were added 5 ml of toluene and phenethylamine (39 μl, 1.2 equiv.). After it was purged with nitrogen for 10 minutes, the entire mixture was heated to 70 ° C for 3 hours before being cooled to room temperature. The resulting material was filtered through Celite and the filtered cake was washed with DCM / methanol (98: 2) and the filtrates were concentrated. The residual material was purified by preparative thin layer chromatography (2% methanol in DCM) to provide the title compound as a pale yellow solid. MS m / e 410 (M + H) +.

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 IL-1β. The second assay can be used to measure the inhibition of TNF-α and / or IL-1β in mice after oral administration of the test compounds. The third assay, an in vitro glucagon binding inhibition assay, 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. The fifth assay, an inhibition assay of Raf-kinase, can be used to characterize the compounds of the invention to inhibit the phosphorylation of MEK by activated Raf-kinase.

TNF production assay of monocytes activated by lipopolysaccharide Isolation of monocytes The test compounds were evaluated in vi tro for the ability to inhibit TNF production by monocytes activated with bacterial lipopolysaccharide (LPS). Fresh residual source leukocytes (a byproduct of plaquetoferesis) were obtained from a local blood bank, and peripheral blood mononuclear cells (PBMCs) were isolated by density gradient centrifugation on Ficol-Paque Plus (Pharmacia). The PBMCs were suspended at 2 x 10s / ml in DMEM supplemented to contain 2% FCS, 10 mM, 0.3 mg / ml glutamate, 100 U / ml penicillin G and 100 mg / ml streptomycin sulfate. (complete medium). The cells were seeded in plates in 96-well flat bottom culture plates, Falcon (200 μl / well) and cultured overnight at 37 ° C and 6% C02. The cells . non-adherent were removed by washing with 200 μl / well of fresh medium. The wells containing the adherent cells (approximately 70% monocytes) were replenished with 100 μl of fresh medium. Z ' Preparation of the reserve solutions of the test compound The test compounds were dissolved in DMZ.

The stock solutions of the compound were prepared at an initial concentration of 10-50 μM. The reservations were Initial dilutions were at 20-200 μM in complete medium. Nine serial dilutions at 50 percent of each compound were then prepared in complete medium.

Treatment of the cells with the test compounds and activation of TNF production with lipopolysaccharide One hundred microliters of each dilution of the test compound were 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 medium was added to each well. complete study containing 30 ng / ml of lipopolysaccharide from E. coli K532. The cells were cultured an additional 4 hours. The culture supernatants were then removed and the presence of TNF in the supernatants was quantified using an ELISA assay. _ TNF ELISA 96-well flat-bottom ELISA plates Corning High Binding were coated overnight (4 ° C) with 150 μl / well of the murine anti-human TNF-α monoclonal antibody, a 3 μg / ml (R & D Systems # MAB210) The wells were then blocked for 1 hour at room temperature with 200 μl / well of the calcium chloride-free ELISA buffer, supplemented to contain 20 mg / ml of BSA ( ELISA standard buffer: 20 mM, 150 mM sodium chloride, 2 mM calcium chloride, 0.15 mM thimerosal, pH 7.4) The plates were washed and replenished with 100 μl of the test supernatants (diluted 1: 3) or the The standards consisted of eleven serial dilutions at 1.5 from a stock of 1 ng / ml recombinant human TNF.

(R &D Systems). The plates were incubated at room temperature for 1 hour in an orbital shaker (300 rpm), washed and replenished with 100 μl / well of goat anti-human TNF-α antibody at 0.5 μg / ml (R & D Systems # AB- 210-NA) biotinylated at a 4: 1 ratio. The plates were incubated for 40 minutes, washed and replenished with 100 μl / well of streptavidin conjugated to alkaline phosphatase (Jackson ImmunoResearch # 016-050-084) at 0.02 μg / ml. The plates were incubated 30 minutes, washed and replenished with 200 μl / well of p-nitrophenyl phosphate at 1 mg / ml. After 30 minutes, the plates were read at 405 nm on a Vmax plate reader.

Data analysis The data of the standard curve were adjusted to "a polynomial of second order and the - unknown concentrations of TNF-a were determined from an optical density (OD) by solving this equation for the concentration. of TNF were then plotted versus the concentration of the test compound using a second-order polynomial.This equation was then used to calculate the concentration of test compounds that cause a 50% reduction in TNF production. The invention may also show that they inhibit the release of IL-1β, IL-6 and / or IL-8, induced by LPS, from monocytes by measuring the concentrations of IL-1β, IL-6 and / or IL -8 by methods known to those skilled in the art In a manner similar to the assay described above involving the release of TNF-α induced by LPS from monocytes, The compounds of this invention can also show that they inhibit the release of II-lß, IL-6 and / or IL-8-induced LPS from monocytes, by measuring the concentrations of IL-lß, IL -6 and / or IL-8 by methods well known to those skilled in the art. In this way, 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 to basal levels or below is favorable in control, delayed progression, and relief of many disease states. All compounds are useful in methods for treating disease states in which TNF-α, IL-lβ, IL-6 and IL-8 play a role to the full extent of the definition of TNF-α-mediated diseases described in the present.

Assay of production of TNF by THP1 cells activated by lipopolysaccharide THP1 cells are resuspended in fresh THP1 medium (RPMI 1640, 10% FBS inactivated by heat, 1XPGS, 1XNEAA, plus 30 μM of ßME) at a concentration of 106 / ml . One hundred microliters of the cells per well are seeded in a polystyrene 96-well tissue culture plate. One microgram per ml of bacterial LPS is prepared in the THP1 medium and transferred to the wells. The test compounds are dissolved in 100% DMSO and serially diluted 3 times in a 96-well polypropylene microtiter plate (drug plate). The Hl control and LO control wells contain only "DMSO." One microliter of the test compound from the drug plate, followed by 10 μl of LPS is transferred to the cell plate.The treated cells are induced to synthesize and secrete TNF- at 37 ° C for 3 hours Forty microliters of conditioned medium are transferred to a 96-well polypropylene plate containing 110 μl of ECL buffer (50 mM Tris-HCl pH 8.0, 100 mM NaCl, 0.05% Tween 20, 0.05% NaN3 and 1% FBS) supplemented with monoclonal antibody MAB610 0.44 nM (R & D Systems), ruthenylated AF210NA antibody 0.34 nM (R & D Systems) and 44 μg / ml of Dynabeadas M280 sheep anti-mouse ( Dynal) After a 2-hour incubation at room temperature with shaking, the reaction is read on the ECL Instrument M8 (IGEN Inc.) Low voltage is applied to the ruthenylated TNF-α immune complexes, which in the presence of of TPA (the active compound in Origlo), gives as resulting in a cyclic redox reaction that generates light at 620 nM. The amount of TNF-α secreted in the presence of the compound, compared to that in the presence of the DMSO vehicle alone (control Hl) is calculated using the formula:% control (POC) = (average cpd-LO) / (average HL-LO) average) x 100. The data (consisting of POC and the inhibitor concentrator in μM) are adjusted to a 4-parameter equation (y = A + ((B- A) / (l + ((x / C) * D)) ), where A is the minimum value (POC), B is the maximum value (POC), C is the value x (concentration cpd) at the point of inflection and D is the factor of the slope) using an algorithm of non-linear regression of Levenburg-Marquardt. The following compounds show activities in the THP1 cell assay (release of TNF induced by LPS) with ICS0 values of 20 μM or less: 1- (2- { 2- [3- (1-amino-1-methyl-ethyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro-pyrido [1,2- a] pyrimidin-4-one; '1- (2- { 2- [4- (1-amino-ethyl) -phenyl] -ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro pyrido [1,2- a] pyrimidin-4-one, -1- (2- {2- [4- (1-isopropylamino-ethyl) -phenyl] -ethylamino} - pyrimidin-4-yl ) -8-phenyl-1, 2,3,6-tetrahydro-pyrido [1,2- a] pyrimidin-4-one; 1- (2- { 2- [4- (2-Amino-propyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3, 6-tetrahydro-pyrido [1,2- a] pyrimidin-4-one; 1- (2-phenethylamino-pyrimidin-4-yl) -7-phenyl-2,3-dihydro-1H-imidazo [1, 2-a] pyridin-5-one; 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydropyrido [1,2-a] pyrimidin-6-one; 1- (6-phenethylamino-pyrazin-2-yl) -7-phenyl-2,3-dihydro-1H- -imidazo [1, 2-a] pyridin-5-one; 1- (6-phenethylamino-pyrimidin-4-yl) -8-phenyl-1, 2,3,4-tetrahydropyrido [1,2-a] pyrimidin-6-one; l-. { 2- (S) - [1- (3-bromo-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; 1- . { 2- [(1S) - (4-methoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; 1- . { 2- [2- (2,4-dichloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; l-. { 2- [2- (2,6-dichloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; 1- [2- [2- (2-Chloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; l-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-on; l-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [l, 2-a] pyrimidin-6-one; l-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -7-phenyl-2, 3-dihydro-lH-imidazo [1,2-a] pyridin-5-one; - l - [2- [2- (4-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,6-tetrahydro-pyrido [1,2-a] pyrimidin- "4-one; 1-. {6- [2- (2-chloro-phenyl) -ethylamino] -pyrimidin-4-yl.}. 8-phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; 2- (2-fluorophenyl) -9- [2 - (1- (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 2- (2-trifluoromethylphenyl) ) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one; - (3,4-dichlorophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,8-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 2- (3, 4-dimethyl-phenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8, 9-tetrahydro -pyrimido [1,2- a] pyrimidin-4-one; 2- (3-aminophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7, 8, 9-tetrahydro-pyrimido [1, 2a] pyrimidin-4-one; 2- (3-dimethylaminophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6 , 7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one; 2- (3-ethylphenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 2- (3-nitrophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one, 2- (4-fluorophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one; 2- (4-methoxyphenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,8-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one; 2- (4-pyridyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 2- (phenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4 -one; 2- (tert-butyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8-tetrahydro-pyrimido [1,2- a] pyrimidine- 4-one; 2- . { - [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-ylamino} 3-methyl-6-phenyl-3H-pyrimidin-4-one; 3-amino-9-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 3-amino-9-. { 2- [ethyl-2- (2-chlorophenyl)] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 3-amino-9-. { 2- [ethyl-2-phenyl] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 3-methyl-9-. { 2- [1- (S) -phenylethyl] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 3-nitro-9-. { 2- [ethyl-2-phenyl] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 7- (2-isopropylamino-ethyl) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine-4- ona; - (ethyl-2-amino (-N-benzyl)) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2 -a] ] pyrimidin-4-one; - (ethyl-2-amino) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [l, 2-a] pyrimidine-4- ona; - (ethyl-2-carbamic acid benzyl ester) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - (acid-propionic) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one "; - (propionic acid ethyl ester) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; -hydroxy-2-phenyl-9- [2- (1-phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine-4- ona; -phenyl-l- [2- (1S) -phenyl-ethylamino) -pyrimidin-4-yl] -1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; phenyl-1- [2- (2S) -phenyl-propylamino) -pyrimidin-4-yl] -1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; -phenyl-l-. { 2- (S) - [1- (3-piperazin-1-yl-phenyl) -ethylamino] -pyrimidin-4-yl} -l, 2, 3, 4-tetrahydro-pyrido [1,2- a] pyrimidin-6-one; 9- (2-. {2- (2-hydroxyethyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one; 9- (2-. {2- (benzyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine-4 -one; 9- (2-. {2- (ethyl-1 (S) -isopropyl-2-ol) amino.} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro- pyrimido [1,2- a] pyrimidin-4-one; 9- (2-. {2- (ethyl-1 (S) methyl-2- (3-methylaminophenyl)) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,8 -tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-1 (S) -methyl-2-ol) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro- pyrimido [1,2-a] pyrimidin-4-one; - (2- {2- (ethyl-1 (S) methyl-2-phenyl) amino} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [ 1,2-a] pyrimidin-4-one; - (2- {2- (ethyl-l-amido-2-phenyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one; - (2- {2- (ethyl-l-methyl-2- (3-aminophenyl)) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro- pyrimido [1,2- a] pyrimidin-4-one; - (2- {2- (ethyl-l-methyl-2- (3-cyanophenyl)) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro- pyrimido [1,2- a] pyrimidin-4-one; - (2-. {2- (Ethyl-l-methyl-2- (3-methylalcoholphenyl)) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,8-tetrahydro- pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (Ethyl-l-methyl-2- (3-methylaminophenyl)) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,8-tetrahydro pyrimido [1,2- a] irimidin-4-one; 9- (2'-. {2- (ethyl-2- (2-chlorophenyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one, -9- (2- {2- (ethyl-2- (2-methoxyphenyl)) amino} - pyrimidin-4-yl) -2- phenyl- , 7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2- (3,4-dimethylphenyl)) amino}. -pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2 - (4-hydroxyphenyl)) amino.} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - (2 ~. {2- (ethyl-2- (4-methoxyphenyl)) amino} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; - (2- {2- (ethyl-2- (4-methylphenyl)} amino} - pyrimidin-4-yl) -2- phenyl- 6, 7,8, 9 -tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one; - (2- (2- (ethyl-2-aminophenyl) amine.} - pyrimidin-4-yl) -2-phenyl-6,7 , 8, 9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - (2- {2- (ethyl-2-keto-2-phenyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-methoxy) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-morpholino) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-phenoxy) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2- a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-phenyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8! tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-phenyl-2-ol) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one; 9- (2-. {2- (propyl-1-phenyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; - (2- {2- (propyl-2 (S) -amino-2-phenyl) amino} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one; - (2- {2- (propyl-2, 2-dimethyl-3-dimethylamino) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [ 1,2-a] pyrimidin-4-one; - (2- {2- (propyl-2-methyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - (2- {2- (propyl-3-phenyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - (2- { 2- [3- (isopropylamino-methyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro - pyrimido [1,2-a] pyrimidin-4-one; 9- (2- { 2-amino.}. -pyrimidin-4-yl) -2-phenyl-6-, 7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - 9- { 2- [2- (3-aminomethyl-phenyl) -1 (R) -methyl-ethylamino] -pyrimidin-4-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one; and 9-. { 2- [2- (3-aminomethyl-phenyl) -1 (S) -methyl-ethylamino] -pyrimidin-yl} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one.

Inhibition of TNF-α production in mice induced by LPS Male DBA / lLACJ mice are dosed with the vehicle or test compounds in a vehicle (the vehicle consists of 0.5% tragacanth in 0.03 N HCL) 30 minutes before the injection of lipopolysaccharide (2 mg / Kg, IV). Ninety minutes after the injection of LPS, the blood is collected and the serum is analyzed by ELISA for TNF-a levels. The compounds of the invention can be shown to have anti-inflammatory properties in animal models of inflammation, including carrageenan foot edema, collagen-induced arthritis and arthritis by adjuvant, such as the paw edema model by carrageenan (CA inter et. Proc. Soc. Exp. Biol. Med. (1962) Vol. 111, pp. 544; K.F. Swingle, in R.A. Scherrer and M.W. Whitehouse, Eds., Anti- Inflammatory Agents, Chemistry and Pharmacology, Vol. 13-11, Academic, New York, 1974, p. 33) and collagen-induced arthritis (D.E. Trentham et al J. Exp. Med. (1977) Vol. 146, p.857; J. S. Courtenay, Nature (New Biol.) (1980), Vol. 283, Selection of 125I-Glucagon Link with CHO / hGLUR Cells The assay is described in W097 / 16442, which is incorporated by reference herein in its entirety.

Reagents The reagents can be prepared as follows: (a) prepare fresh 1M o-phenanthroline (Aldrich) (198.2 mg / ml ethanol); (b) prepare fresh 0.5 M DTT (Sigma); (c) Mixture of Protease Inhibitor (1000X): 5 mg of leupeptin, 10 mg of benzamidine, 40 mg of bacitracin and 5 mg of soybean trypsin inhibitor per ml of DMSO, and aliquots are stored at -20 ° C; (d) 250 μM human glucagon (Peninsula): solubilize the 0.5 mg vial in 575 μl 0.1 N acetic acid (1 μl produced a final concentration of 1 μM in the assay for the non-specific binding) and aliquots are stored -20 ° C; (e) Test Buffer: 20 mM Tris (pH 7.8), 1 mM DTT and 3 mM o-phenanthroline; "(f) Test Buffer with 0.1% BSA (for marker dilution only, 0.01% final in the test): 10 μl of 10% BSA (heat inactivated) and 900 μl of Test Buffer; ) 125 I-Glucagon (NEN, receptor grade, 2200 Gi / mmol): dilute to 50,000 cpm / 25 μl in the assay buffer with BSA (final concentration of approximately 50 pM in the assay).

Harvesting the CHO / hGLUR Cells for Assay 1. Remove the medium from the confluent flask and then rinse once each with PBS (calcium and magnesium 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 tap the free cells, crush, take an aliquot for counting and centrifuge the rest for 5 minutes at 1000 rpm. 4. Resuspend the button in Test Damper to 75,000 cells per 100 μl. The membrane preparations of CHO / hGLUR cells can be used in place of the whole cells in the same assay volume. The final protein concentration of a membrane preparation is determined on a batch basis.

Assay The determination of the glucagon binding inhibition can be carried out by measuring the reduction of 125 I-glucagon that binds in the presence of the compounds of Formula I. The reagents are combined as follows: Compound / Glucagon 125 Cells Vehicle 250 μM Glucagon CHO / hGLUR Total Link ~ / 5 μl 25 μl 100 μl + Compound 5 μl / - 25 μl 100 μl Link No - / 5 μl 1 μl 25 μl 100 μl Specific 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 mesh (0.5% polyethylimine (PEI) using an Innotech Harvester or a Tomtec Harvester with four washes of ice-cold 20 mM Tris buffer (pH 7.8). The filters are determined by a gamma scintillation counter In this way, the compounds of the invention can also show inhibition of glucagon binding to glucagon receptors.

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

COX-1 Assay In the preparation for the COX-1 assay, THP-1 cells are developed to confluence, divided 1: 3 in RPMI containing 2% FBS and 12-phorbol 12-myristate acetate 10 mM (TPA), and incubated for 48 hours on a shaker to prevent adhesion. The cells are concentrated and resuspended in Hank's Damped Saline Solution (HBS) at a concentration of 2.5 x 10 6 cells / ml and placed in a 96-well culture plate 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 mM, cells were incubated for 20 minutes at 37 ° C, and enzyme activity is determined as described below.

COX-2 Assay For the COX-2 assay, the subconfluent HOSCs are trypsinized and resuspended at 3 x 10 cells / ml in MEM-FBS containing 1 ng of human IL-lb / ml, seeded in tissue culture plates from 96 wells at a density of 3 x 104 cells per well, incubate in a shaker for 1 hour to evenly distribute the cells, followed by a static incubation for an additional 2 hours, to allow adherence. The medium is then replaced with MEM containing 2% FBS (MEM-2% FBS) and 1 ng human IL-lb / ml, and the cells were incubated for 18 to 22 hours. After replacing the medium with 190 ml of MEM, 10 ml of the test compound diluted in HBS are 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 arachidonic acid, the cells were incubated for 20 minutes at 37 ° C, and the enzymatic activity is determined as described below.

Determination of COX Activity After incubation with arachidonic acid, the reactions are stopped by the addition of IN HCl, followed by neutralization with 1 N sodium hydroxide and centrifugation to concentrate the cellular waste. The activity of the cyclooxygenase enzyme in the supernatants of HOSC and THP-1 cells is determined by measuring the concentration of PGE2 using a commercially available ELISA assay (Neogen # 404110). A standard curve of PGE2 is used for calibration, and commercially available COX-1 and COX-2 inhibitors are included as "standard" controls.

Raf Kinase Assay Raf in vi tro kinase activity is measured by the degree of phosphorylation of the MEK substrate (Map kinase / ERK kinase) by the activated Raf kinase, as described in British Patent GB-1,238,959 (incorporated by reference in the present in its entirety). The phosphorylated MEK is trapped on a filter and the incorporation of the radiolabelled phosphate is quantified by scintillation counting.

MATERIALS: Activated Raf is produced by triple transfection of Sf9 cells with baculoviruses expressing Raf labeled with the "Glu-Glu" epitope, val12-H-Ras, and Lck. The "Glu-Glu" epitope, Glu-Try-Met-Pro-Met-Glu, was fused to the carboxyl terminus of full-length c-Raf. Catalytically inactive MEK "_ (K97A mutation) is produced in Sf9 cells transfected with a baculovirus expressing K97A MEK1 labeled with the" Glu-Glu "epitope at the" c "end.The anti-" Glu-Glu "antibody was purified from the developed cells as described in: Grussenmeyer, et al., Proceedings of the National Academy of Science, E.U.A. p. 7952-7954, 1985. Column cushion: 20 mM Tris pH 8, 100 mM sodium chloride, 1 mM EDTA, 2.5 mM EGTA, 10 mM MgCl 2, 2 mM DTT, 0.4 M AEBSF, 0.1% n-octylglucopyranoside, acid okadeic 1 nM, and 10 μg / ml each of benzamidine, leupeptin, pepstatin and aprotinin. 5x reaction buffer: 125 mM HEPES pH = 8, 25 mM MgCl2, 55 mM EDTA, 5 mM Na3V0_, 100 μg / ml BSA. Enzyme dilution buffer: 25 mM HEPES pH 8, 1 mM EDTA, 1 mM Na3V04, 400 μg / ml BSA. Detention solution: 100 mM EDTA, 80 mM sodium pyrophosphate. Filter plates: Multipolar Millipore # SE3M078E3, Immobilon-P (PVDF). ' METHODS: Protein purification: Sf9 cells were infected with baculovirus and developed as described in Williams, et al., Proceedings of the National Academy of Science, E.U.A. p. 2922-2926, 1992. All subsequent steps were performed on ice or at 4 ° C. The cells were concentrated and used by sonication in column cushion. The used ones were centrifuged to 17,000 x g for 20 minutes, followed by a filtration of 0.22 μm. The proteins labeled in the epitope were purified by chromatography on the affinity column GammaBind Plus' a "to which the antibody was coupled "Glu Glu" . The proteins were loaded on the column, followed by sequential washings with two column volumes of the column buffer, and eluted with 50 μg / ml of Glu-Tyr-Met-Pro-Met-Glu in column buffer. Raf kinase assay: The test compounds were evaluated using ten serial dilutions to one third, starting at 10-100 μM. 10 μl of the test or control inhibitor, dissolved in 10% DMSO, were added to the assay plate, followed by the addition of 30 μl of the mixture containing 10 μl of 5 x reaction buffer, 33 P-? - 1 mM ATP (20 μCi / ml), 0.5 μl of MEK (2.5 mg / ml), 1 μl of 50 mM β-mercaptoethanol. The reaction was initiated by the addition of 10 μl of enzyme dilution buffer containing 1 mM DTT and an amount of "activated Raf, which produces linear kinetics over the course" of the reaction time. The reaction was mixed and incubated at room temperature for 90 minutes and stopped by the addition of 50 μl of stop solution. Aliquots of 90 μl of this stopped solution were transferred onto GFP-30 cellulose microtiter filter plates (Polyfiltronics), the filter plates were washed in four well volumes of 5% phosphoric acid, allowed to dry, and then dried. replenished with 25 μl of scintillation cocktail. The plates were counted for the 33P gamma emission using a TopCount Cylindrical Reader. 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 and other agents. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are administered at the same time or at different times, or the therapeutic agents can be administered as a simple composition. The foregoing is merely illustrative of the invention and is not intended to limit the invention to the disclosed compounds. It is intended that variations and changes that are obvious to a person of skill in the art are within the scope and nature of the invention, which is. defined in the appended claims. From the above description, a person skilled in the art can easily harbor 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 the various uses and conditions. For the treatment of diseases mediated by TNF-a, IL-lß, IL-6 and IL-8, cancer and / or hyperglycemia, the compounds of the present invention can be administered orally, parenterally, by inhalation spray, rectally or topically, in unit dose formulations containing conventional pharmaceutically acceptable carriers, adjuvants and vehicles. The term "parenteral" as used herein, includes subcutaneous, intravenous, intramuscular, intras.ternal, infusion techniques or intraperitoneally. The treatment of the diseases and disorders herein is intended to also include the prophylactic administration of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject (for example, an animal, preferably a mammal, most preferably a human) that is believed to be in need of preventive treatment, such as, for example, pain, inflammation and the like. The dosage regimen for treating a disease mediated by TNF-a, IL-1, IL-6 and IL-8, cancer, and / or hyperglycemia with the compounds of this invention and / or the compositions of this invention, is based on a variety of factors, including the type of disease, age, weight, sex, medical condition of the patient, the severity of the condition, the route of administration, and the compound particularly employed. Thus, 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 / k, 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 liquid. The pharmaceutical composition is preferably made in the form of a unit dose containing a given amount of the active ingredient. For example, these 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 suitable daily dose 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 preparations, such as sterile injectable aqueous or oleaginous suspensions, can be formulated according to known methods using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable 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 can be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, fixed sterile oils are conventionally employed as a solvent or suspending medium. For this purpose, any soft fixed oil can be used, including mono- or diglycerides -synthetic. In addition, fatty acids such as oleic acid find use in the preparation of injectables. 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. They are solid at ordinary temperatures but liquid at the rectal temperature, and will therefore melt in the rectum and release the drug. A suitable topical dose 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 can comprise from 0.001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it can comprise as much as 10% w / w, but preferably no more of 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 (for example, liniments, lotions, ointments, creams or pastes) and drops suitable for administration to the eye, to the ear, or the nose. For administration, the compounds of this invention are ordinarily combined with one or more adjuvants suitable for the indicated route of administration.The compounds can be mixed with lactose, sucrose, powdered starch, alkanoic acid cellulose esters, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, sodium alginate, polyvinyl-pyrrolidine and / or polyvinyl alcohol, and formed into 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 material of delay in time, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art. The pharmaceutical compositions may be constituted in a solid form (including granules, powders or suppositories) or in a liquid form (e.g., solutions, suspensions or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical 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, powders and granules. In such solid dose 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, dosage forms may also comprise buffering agents. Tablets and pills can be additionally 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 flavoring agents.

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.

Claims (23)

2. Having described the invention as above, the contents of the following claims are claimed as property:
3. A compound of the formula or a pharmaceutically acceptable salt or hydrate thereof, characterized in that: J is = 0, = S, -CHN02, = N-CN, = CHS02Rb NS02Rb or = NHRb; X is independently, in each case, N or CR3; R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from the group consisting of 1- to 4 carbon atoms haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa '-0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to' 6 atoms carbon) NRaRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -. -S (= 0) 2Rb, - -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) ) NRa-Ra, ~ N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NR (alkyl of 2 to 6 atoms carbon) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; R 2 is alkyl of 1 to 8 carbon atoms substituted with 0, 1, or 3 substituents selected from haloalkyl of 1 to 2 carbon atoms, halo, oxo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, 0C (= O) NRaRa '-0C (= 0) N (Ra) S ( = 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra ) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRRa, N (Ra) C (= NRa) NRaRa, -N (R) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaR-a or -NRa ( alkyl of 2 to 6 carbon atoms) 0Ra; and further substituted with 0, 1 or 2 substituents selected from Rg, -C (= 0) Rg, -C (= 0) 0R3, C (= 0) NRRg, -C (= NRa) NRaR9, -OR9, -0C (= 0) Rg, -0C (= 0) NRaRg, 0C (= 0) N (Ra) S (= 0) 2R3, -0 (alkyl of 2 to 6 carbon atoms) NRaRg, -0 (alkyl of 2) to 6 carbon atoms) 0Rg, -SRg, -S (= 0) Rg, -S (= 0) 2R9, -S (= 0) 2NRaRg, -NRaRg, -N (Ra) C (= 0) Rg, N (Ra) C (= 0) 0R9, -N (Ra) C (= 0) NRRg, -C (= 0) Re, -C (= 0) 0Re, C (= 0) NRaRe, -C (= NRa) NRaRe, -0Re, -OC (= 0) Re, -OC (= 0) NRaRe, OC (= 0) N (Ra) S (= 0) 2Re, -O (alkyl of 2 -'6 atoms carbon) NRaRe, O (C2-C6 alkyl) 0Re, -SRe, -S (= 0) Re, -S (= 0) 2Re, -S (= 0) 2NRRe, -NRaRe, -N (Ra) C (= 0) Re, and - N (Ra) C (= 0) NRaRe and -N (Ra) C (= 0) NRaRe; R3 is selected from H, Re, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C ( = NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of "2 to 6 atoms carbon) NRR, -0 (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) R, -S (= 0) 2Rb, -S (= 0) 2NRaRa, - S (= 0) 2N (R) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0R, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N ( Ra) C (= 0) Rb, -N (Ra) C (= 0) 0R, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRRa, -NRa (alkyl of 2 to 6 carbon atoms) NRR or -NR (alkyl of 2 to 6 carbon atoms) 0Ra; R6 is independently, in each case it is H, Rd, Re
4. R9; R7 is independently, in each case it is H, Rd, Re or Rg; m- is 2 or 3; R is independently, in each case it is H or Rb; Rb is independently, in each case is phenyl, benzyl or alkyl of 1 to 6 carbon atoms, phenyl, benzyl and alkyl of 1 to 6 carbon atoms are substituted with 0, 1, 2 or 3 substituents selected from halo , alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 3 carbon atoms, -O (alkyl of 1 to 4 carbon atoms), -NH2, -NH (alkyl of 1 to 4 carbon atoms), -N (alkyl of 1 to 4 carbon atoms) (alkyl of 1 to 4 carbon atoms); R.R.sub.d is independently, in each case, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, ~ C (= 0) NRaRa, -C (= NRa) NRRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaR 'OC (= 0) N (R) S (= 0) 2Rb,. - -O (C2-C6 alkyl) NRaRa, -O (C2-C6 alkyl) ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRaRa, -NRaR, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa ) NRaRa, -N (R) S (= 0) 2Rb, -N (R) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 atoms) carbon) 0Ra; Re is independently, in the case of alkyl of 1 to 6 carbon atoms substituted with 0, 1, 2 or 3 substituents independently selected from Rd, and further substituted with 0 or 1 substituents selected from R9, and R9 is independently, in each case a monocyclic ring of 5 6 or 7 bicyclic members of 6, 7, 8, 9 ,. 10 or 11 members saturated, partially saturated or unsaturated, containing 0, 1, 2, 3 or 4 atoms selected from nitrogen, oxygen and sulfur, wherein the ring carbon atoms are substituted with 0, 1 or 2 oxo groups and the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -0R, -0C (= 0) Rb, -OC (= 0) NRaRa '- 0C (= 0) N (Ra ) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRRa, -O (alkyl of 2 to 6 carbon atoms) ORa, -SRa, -S (= 0) Rb, -S ( = 0) 2Rb,. -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0R, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa,. N (R) C (= 0) Rb, '-N (Ra) C (= 0) 0Rb, -N (Rá) C (= 0) NRaRa, - N (Ra) C (= NRa) NRaRa, -N (R) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaR or -NRa (alkyl of 2 to 6 carbon atoms) 0R. 2. A compound according to claim 1, characterized in that R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen and sulfur, wherein the ring is substituted with 0 , 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. 3. A compound according to claim 1, characterized in that R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. 4. A compound according to claim 1, characterized in that R1 is phenyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo.
5. 5. A compound according to claim 1, characterized in that R1 is thiophenyl, furanyl, pyrrolyl, oxazole or triazole, any of which is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms , haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra , -0C (= 0) Rb, -OC (= 0) NRaRa '-OC (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C ( = 0) Rb, -S (= 0) 2N (Ra) C (= 0) ORb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaR, -N (Ra) S (= 0) 2Rb, - N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; wherein R1 is not thiazole, imidazole or pyrazole.
6. 6. A compound according to claim 1, characterized in that R1 is saturated or unsaturated 6-membered ring containing 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from 'alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaR '-OC (= 0) N (Ra) S (= 0) 2Rb, -O (C2-C6 alkyl) NRaRa, -0 (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0 ) 2NRaR, S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaR, N (Ra) C (= NRa) NRaRa , -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRR, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms ) 0Ra;
7. 7. A compound according to claim 1, characterized in that R1 is a 6-membered unsaturated ring containing 1, 2 or 3 nitrogen atoms, wherein the ring is substituted with 0, 1, 2 or 3 substituents. selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa '-OC (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2) to 6 carbon atoms) NRaRa, -0 (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa , -N (Ra) C (= 0) Rb, -N (R) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaR, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRR, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra;
8. 8. A compound according to claim 1, characterized in that R1 is phenyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano , nitro, -C (= 0) Rb, -C (= 0) 0Rb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) R, -0C (= 0) NRaRa '- 0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, - SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra ) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa ( alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra;
9. 9. A compound according to claim 1, characterized in that R1 is phenyl substituted with 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaR, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, - S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C ( = 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaR, N (Ra) C (= a) Rb, -N (Ra) C (= 0) 0Rb, -N- (Ra) C (= 0) NRaRa, N (Ra) C _ (= NRa ') NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl) from 2 to 6 carbon atoms) NR a R or -NR a (C 2 -C 6 alkyl) 0 R a;
10. 10. A compound according to claim 1, characterized in that R1 is phenyl, pyridinyl or pyrimidinyl, all of which are substituted with 0, 1 or 2 substituents selected from halo, alkyl of 1 to 3 carbon atoms, - and CF3.
11. 11. A compound "according to claim 1, characterized in that R1 is phenyl, pyridinyl or pyrimidinyl
12. 12. A compound according to claim 1, characterized in that R1 pyridinyl substituted with 0, 1, 2 or 3 substituents selected from alkyl from 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo
13. 13. A compound according to claim 1, characterized in that R 1 is pyrimidinyl substituted with 0, 1, 2 or 3 substituents selected from the group consisting of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo.
14. 14. A compound according to claim 1, characterized in that R1 is a 5-membered saturated or unsaturated ring containing 1.2 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 selected substituents of alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo,
15. 15. A compound of the formula or a pharmaceutically acceptable salt or hydrate thereof, characterized in that J is = 0, = S, -CHN02, = N-CN, = CHS02Rb NS02Rb or = NHR; X is independently, in each case, N or CR3; R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, C (= NRa) NRRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa 'OC (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, - O (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N CRa) C ( = 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb , -N (Ra) C _ (= 0) 0Rb, -N (R) C (= 0) NRRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to "6 carbon atoms) NRaR or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; R2 is alkyl of 2 to 8 carbon atoms substituted with 0, 1, 2 or 3 substituents selected from haloalkyl of 1 to 2 carbon atoms, halo, oxo, cyano, ni tro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRR, -C (= NR) NRaRa, -0Ra, -0C (= 0) Rb, 0C (= 0) NRaRa '-0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S. (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, - N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRRa, -NRa (alkyl) 2 to 6 carbon atoms) NRaRa or -NRa (C2-C6 alkyl) 0Ra; and further substituted with 0, 1 or 2 substituents selected from R9, -C (= 0) R9, -C (= 0) 0Rg, C (= 0) NRaR9, -C (= NRa) NRaRg, -0Rg, - 0C (= 0) R9, -0C (= 0) NRaRg, -0C (= 0) N (R) S (= 0) 2R9, -0 (alkyl of 2 to 6 carbon atoms) NRaRg, -O ( alkyl of 2 to 6 carbon atoms) OR9, -SR3, -S (= 0) Rg, -S (= 0) 2Rg, -S (= 0) 2NRRg, -NRaRg, -N (Ra) C (= 0 ) R9, N (Ra) C (= 0) 0R9, -N (Ra) C (= 0) NRaRg, '-C (= 0) Re, -C (= 0) 0Re, C (= 0) NRaRe, -C (= NRa) NRaRe, -0Re,, -OC (= 0) Re, -OC (= 0) NRaRe, OC (= 0) N (Ra) S (= 0) 2Re, -O (2-alkyl) to 6 carbon atoms) NRaRe, O (alkyl of 2 to 6 carbon atoms) 0Re, -SRe, -S (= 0) Re, -S (= 0) 2Re, - -S (= 0) 2NRaRe, - NRRe, -N (R) C (= 0) Re, and -N (Ra) C (- = 0) NRaRe and -N (Ra) C (= 0) NRaRe; R3. is selected from H, Re, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRRa '0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms ) NRRa, -O (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (R) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0 ) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (C2-C6 alkyl) NRaRa or -NRa (C2-C6 alkyl) 0Ra; R4 is H, Re or Rg, R5 is H, Re or R9, R6 is independently, in each case it is H, Rd, Re R9; R7 is independently, in each case it is H, Rd, Re or Rg; Ra is independently, in each case it is H or Rb; Rb is independently, in each case is phenyl, benzyl or alkyl of 1 to 6 carbon atoms, phenyl, benzyl and alkyl of 1 to 6 carbon atoms are substituted with 0, 1, 2 or 3 substituents selected from halo , alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 3 carbon atoms, -O (alkyl of 1 to 4 carbon atoms), -NH2, -NH (alkyl of 1 to 4 carbon atoms), -N (alkyl of 1 to 4 carbon atoms) (alkyl of 1 to 4 carbon atoms); Rd is independently, in each case, alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C ( = 0) NRaRa, -C (= NRa) NRRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -0 (C2-C6 alkyl) NRaRa, -0 (C2-C6 alkyl) 0Ra, -SR, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0 ) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (R) C (= 0) NRaRa , -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl of 2 to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra; Re is independently, in the case of alkyl of 1 to 6 carbon atoms substituted with 0, 1, 2 or 3 substituents independently selected from Rd, and further substituted with 0 or 1 substituents selected from R9, and Rg is independently, in each case a 6, 7 or 7 membered monocyclic ring of 6, 7, 8, 9, 10 or 11 members saturated, partially saturated or unsaturated, containing 0, 1, 2, 3 or 4 atoms selected from nitrogen, oxygen and sulfur, wherein the carbon atoms of the ring are substituted with 0, 1 or 2 oxo groups and the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 8 carbon atoms, haloalkyl of 1 to 4 carbon atoms carbon, halo, cyano, nitro, -C (= 0) .Rb, -C (= 0) ORb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -OR, -0C (= 0) Rb, -OC (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -0 (alkyl of 2 to 6 carbon atoms) carbon) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N ( Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C ( = 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (C2-C6 alkyl) NRaR or -NRa (C2-C6 alkyl) 0R;
16. 16. A compound according to claim 15, characterized in that R1 is a saturated or unsaturated ring of 5 or 6 members containing 0, 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo.
17. 17. A compound according to claim 15, characterized in that R1 is phenyl substituted with "0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. A compound according to claim 15, characterized in that R1 is thiophenyl, furanyl, pyrrolyl, oxazole or triazole, any of which is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa '-OC (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of - 2 to 6 carbon atoms) NRRa, - O (C2-C6 alkyl) ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRRa, N (Ra) C (= 0) ) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (C2-C6 alkyl) NRaRa or -NRa (C2-C6 alkyl) 0Ra; wherein R1 is not thiazole, imidazole or pyrazole. 19. A compound according to claim 15, characterized in that R1 is a saturated or unsaturated 6-membered ring containing 1, 2 or 3 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRR, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -OC (= 0) NRaR '-OC (= 0) N (Ra) S (= 0) 2Rb, -O (C2-C6 alkyl) NRaRa, -0 (C2-C6 alkyl) 0Ra, - SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (R) C (= 0) Rb, - S (= 0) 2N (Ra) C (= G) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) ) 0Rb, -N (Ra) C (= 0) NRRa, N (R) C (= NR) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRRa, -NRa (C2-C6 alkyl) NRaR or -NRa (C2-C6 alkyl) 0R. 20. A compound according to claim 15, characterized in that R1 is a saturated or unsaturated 6-membered ring containing 1, 2 or 3 atoms wherein the ring substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa ) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa '-0C (= 0) N (Ra) S (= 0) 2Rb, -0 (alkyl of 2 to 6 carbon atoms ) NRaRa, -0 (C2-C6 alkyl) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0R, -N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaR, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NR (C2-C6 alkyl) NRRa or -NRa (C2-C6 alkyl) 0Ra. 21. A compound according to claim 15, characterized in that R1 is phenyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -QRa, -OC (= 0) Rb, -OC (= 0 ) NRaRa '- OC (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) OR, -SRa , -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, - N (Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl) 2 to 6 carbon atoms) NRaRa or -NRa (C2-C6 alkyl) 0Ra. 22. A compound according to claim 15, characterized in that R1 is phenyl substituted with 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa '0C (= 0) N (Ra) S (= 0) 2Rb, -O (alkyl of 2 to 6 carbon atoms) NRaRa, -O (alkyl of 2 to 6 carbon atoms) 0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, S (= 0) 2N (Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) 0Rb, S (= 0) 2N (Ra) C (= 0) NRaRa, '-NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N ( Ra) C (= 0) NRaRa, N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRa (alkyl 2) to 6 carbon atoms) NRaRa or -NRa (alkyl of 2 to 6 carbon atoms) 0Ra. • 23. A compound according to claim 15, characterized in that R1 is phenyl, pyridinyl or pyrimidinyl, all of which are substituted with 0, 1 or 2 substituents selected from halo, alkyl of 1 to 3 carbon atoms, and CF3. 2 . A compound according to claim 15, characterized in that R1 is phenyl, pyridinyl or pyrimidinyl. 25. A compound according to claim 15, characterized in that R1 is pyridinyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. 26. A compound according to claim 15, characterized in that R1- is pyridinyl substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. 27. A compound according to claim 15, characterized in that R1 is a saturated or unsaturated 5-membered ring containing 1 or 2 atoms selected from nitrogen, oxygen and sulfur, wherein the ring is substituted with 0, 1, 2 or 3 substituents selected from alkyl of 1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms and halo. 28. A compound characterized in that it is selected from: l- (2- {2- [3- (1-amino-1-methyl-ethyl) -phenyl] -1-methyl-ethylamino} - pyrimidin-4 -il) -8-phenyl-l, 2,3, 6-tetrahydro-pyrido [1,2- a] pyrimidin-4-one; 1- (2- { 2- [4- (1-Amino-ethyl) -phenyl] -ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro- pyrido [1,2- a] pyrimidin-4-one; 1- (2- { 2- [4- (1-isopropylamino-ethyl) -phenyl] -ethylamino.} - pyrimidin-4-yl) -8-phenyl-1, 2,3,6-tetrahydro- pyrido [1,2- a] pyrimidin-4-one, -1- (2- {2- [4- (2-amino-propyl) -phenyl] -1-methyl-ethylamino} - pyrimidine- 4-yl) -8-phenyl-1, 2,3,6-tetrahydro-pyrido [1,2-a] pyrimidin-4-one, -1- (2-phenethylamino-pyrimidin-4-yl) -7- phenyl-2,3-dihydro-lH-imidazo [1,2-a] pyridin-5-one; 1- (2-phenethylamino-pyrimidin-4-yl) -8-phenyl-1,2,3,4-tetrahydropyrido [1,2-a] pyrimidin-6-one; 1- (6-phenethylamino-pyrazin-2-yl) -7-phenyl-2,3-dihydro-1H-imidazo [1, 2-a] pyridin-5-one; 1- (6-phenethylamino-pyrimidin-4-yl) -8-phenyl-1,2,3,4-tetrahydropyrido [1,2-a] pyrimidin-6-one; l-. { 2- (S) - [1- (3-bromo-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; l-. { 2- [(SS) - (4-methoxy-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; l-. { 2- [2- (2,4-dichloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; l-. { 2- [2- (2,6-dichloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8- phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; 1- [2- [2- (2-Chloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; l-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,4-tetrahydro-pyrido [1,2-a] pyrimidine-. 6-one; l-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-l, 2,3,4-tetrahydro-pyrido [1,2- a] pyrimidin-6-one; l-. { 2- [2- (3-hydroxymethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -7-phenyl-2, 3-dihydro-lH-imidazo [1,2-a] pyridin-5-one; 1- [2- [2- (4-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-yl} -8-phenyl-1, 2,3,6-tetrahydro-pyrido [1,2-a] pyrimidin-4-one; 1- . { 6- [2- (2-Chloro-phenyl) -ethylamino] -pyrimidin-4-yl} -8-phenyl-1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; - (2-fluorophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,8-tetrahydro-pyrimido [1,2-a] pyrimidine- 4-one; 2- (2-trifluoromethylphenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidine -4-one; 2- (3,4-dichlorophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 2- (3, 4-dimethyl-phenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,8-tetrahydro-pyrimido [1,2 -a] pyrimidin-4-one; 2- (3-aminophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1, 2a] pyrimidin-4 -one; 2- (3-dimethylaminophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidine -4-one; 2- (3-Ethylphenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine - -one; 2- (3-nitrophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one; 2- (4-fluorophenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,8-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one; 2- (4-methoxyphenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8-tetrahydro-pyrimido [1,2-a] pyrimidine- 4-one; 2- (4-pyridyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one; 2- (phenyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4 -one; 2- (tert-butyl) -9- [2- (1 (S) -phenyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine -4-one; 2- . { - [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4-ylamino} -3-methyl-6-phenyl-3H-pyrimidin-4-one; 3-amino-9-. { 2- [2- (3-aminomethyl-phenyl) -1-methyl-ethylamino] -pyrimidin-4"-yl.} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2- a] pyrimidin-4-one; 3-amino-9-. {2- [ethyl-2- (2-chlorophenyl)] -pyrimidin-4-yl.} -2-phenyl-6, 7, .8 , 9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 3-amino-9-. {2- 2- [ethyl-2-phenyl] -pyrimidin-4-yl.} -2-phenyl -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 3-methyl-9-. {2- 2- [1- (S) -phenylethyl] -pyrimidin-4- il.) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 3-nitro-9-. {2- 2- [ethyl-2-phenyl] ] -pyrimidin-4-yl.} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 7- (2-isopropylamino-ethyl) -9 - (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - (ethyl-2-amino (N -benzyl)) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - (ethyl -2-amino) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one; - (Benzyl ester of ethyl-2-carbamic acid) -9- (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 7- (propionic acid) -9- (2-phenethylamino-pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 7- (propionic acid ethyl ester) -9 ~. (2-phenethylamino-pyrimidin-4-yl) -2-phenyl-6,7,8,8-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 7-hydroxy-2-phenyl-9- [2- (1-f-enyl-ethylamino) -pyrimidin-4-yl] -6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4 -one; 8-phenyl-l- [2- (SS) -phenyl-ethylamino) -pyrimidin-4-yl] -1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; 8-phenyl-l- [2- (2S) -f-enyl-propylamino) -pyrimidin-4-yl] -1,2,3,4-tetrahydro-pyrido [1,2-a] pyrimidin-6-one; 8-phenyl-1-. { 2- (S) - [1- (3-piperazin-l-yl-f-enyl) -ethylamino] -pyrimidin-4-yl} -l, 2,3,4-tetrahydro-pyrido [1,2- a] pyrimidin-6-one; - (2- {2- (2-hydroxyethyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8-tetrahydro-pyrimido [1,2-a] pyrimidine- 4-one; - (2- {2- (benzyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidine- 4- ona; - (2- {2- (ethyl-1 (S) -isopropyl-2-ol) amino} -pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-one; - (2- {2- (ethyl-1 (S) methyl-2- (3-methylaminophenyl)) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,8- tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-1 (S) -methyl-2-ol) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro- pyrimido [1,2-a] pyrimidin-4-one; 9-_ (2-. {2- (ethyl-1 (S) methy1-2-phenyl) amino.} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro -pyrimido [1,2-a] pyrimidin-4-one; 9- (2- {2- (ethyl-l-amido-2-phenyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one; 9- (2-. {2- (Ethyl-l-methyl-2- (3-aminophenyl)) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro -pyrimido [1,2- a] pyrimidin-4-one; 9- (2-. {2- (ethyl-l-methyl-2- (3-cyanophenyl)) amino}. Pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro -pyrimido [1,2- a] pyrimidin-4-one; 9- (2-. {2- (ethyl-l-methyl-2- (3-methylalcoholphenyl)) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro - pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-l-methyl-2- (3-methylaminophenyl)) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro -pyrimido [1,2- a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2- (2-chlorophenyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-one; - (2- {2- (ethyl-2- (2-methoxyphenyl)) amino} - pyrimidin-4-yl) -2- phenyl-6,7 8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (Ethyl-2- (3, 4-dimethylphenyl)) amino.} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2-a] pyrimidin-4-on, 9- (2-. {2- (ethyl-2- (4-hydroxyphenyl)) amino}. Pyrimidin-4-yl) -2-phenyl -6, 7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one; 9- (2-. {2- (Ethyl-2- (4-methoxyphenyl)) amino.} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [ 1,2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2- (4-methylphenyl)) amino.} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one; 9- (2- {2- (ethyl-2-aminophenyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2- {2- (ethyl-2-keto-2-phenyl) amino} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-methoxy) amino ..} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1, 2 a] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-morpholino) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-phenoxy) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-phenyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2-. {2- (ethyl-2-phenyl-2-ol) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1 , 2-a] pyrimidin-4-one; 9- (2-. {2- (propyl-1-phenyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2- { 2r (propyl-2 (S) -amino-2-phenyl) amino.} - pyrimidin-4-yl) -2- phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2-. {2- (propyl-2, 2-dimethyl-3-dimethylamino) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one; 9- (2-. {2- (propyl-2-methyl) amino.} - pyrimidin-4-yl) -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2-a ] pyrimidin-4-one; 9- (2-. {2- (propyl-3-phenyl) amino.} - pyrimidin-4-yl) -2-phenyl- "6,7,8,9-tetrahydro-pyrimido [1, 2- a] pyrimidin-4-one; 9- (2 -. {2- 2- [3- (isopropylamino-methyl) -phenyl] -1-methyl-ethylamino.} - pyrimidin-4-yl) -2-phenyl- 6, 7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; 9- (2. {2-amino.} - pyrimidin-4-yl) -2-phenyl- 6, 7,8,9-tetrahydro-pyrimido [1,2-a] pyrimidin-4-one; - { 2- [2- (3-aminomethyl-phenyl) -1 (R) -methyl-ethylamino] -pyrimidin-4-yl.} -2-phenyl-6,7,8,9-tetrahydro-pyrimido [1,2- a] pyrimidin-4-one; and -. {2- [2- (3 -aminomethyl-phenyl) -1 (S) -methyl-ethylamino] -pyrimidin-4-yl.} -2-phenyl-6,7,8,8-tetrahydro-pyrimido [1,2- a] pyrimidine-4 -one 29. A pharmaceutical composition, characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier 30. A pharmaceutical composition, characterized in that it comprises a compound according to claim 15, and a carrier Acceptically acceptable. 31. Use of a medicament for treating inflammation, the medicament comprises an effective amount of a compound according to claim 1. 32. Use of a medicament for the treatment of inflammation, the medicament comprises an effective amount of a compound according to claim 15. 33. Use of a compound according to claim 1 for the manufacture of a medicament, for the treatment of inflammation. 34. Use of a compound according to any of claims 1-28 for the manufacture of a medicament for the treatment of inflammation. 35. Use of a medication for the 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; adult respiratory distress syndrome (ARDS); 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 rejection Alzheimer's disease, stroke, myocardial infarction; ischemic damage by reperfusion; atherosclerosis; brain trauma; multiple sclerosis; cerebral malaria; sepsis; septic shock; toxic shock syndrome; fever, and myalgia due to infection by HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes virus or herpes zoster, in a mammal, the drug comprises an effective amount of a Composite according to any of claims 1-28.