MXPA05006367A

MXPA05006367A - Method of using aminocyanopyridine compounds as mitogen activated protein kinase-activated protein kinase-2 inhibitors.

Info

Publication number: MXPA05006367A
Application number: MXPA05006367A
Authority: MX
Inventors: Emily J Reinhard
Original assignee: Pharmacia Corp
Priority date: 2002-12-12
Filing date: 2003-12-09
Publication date: 2005-08-29
Also published as: AU2003296414A1; CA2508780A1; JP2006512338A; AU2003296414A8; BR0317183A; EP1569645A2; WO2004054505A3; WO2004054505A2

Abstract

A method is described for inhibiting mitogen activated protein kinase-activated protein kinase-2 in a subject in need of such inhibition, where the method involves administering to the subject an anminocyanopyridine MK-2 inhibiting compound, or a pharmaceutically acceptable salt thereof.

Description

METHOD OF USE OF AMINOCIANOPIRIDINE COMPOUNDS AS INHIBITORS OF PROTEIN-ACTIVATED KINASE-2 PROTEIN INHIBITORS ACTIVATED BY MITOGEN CROSS REFERENCE FOR PATENTS AND APPLICATIONS RELATED PATENTS This application claims the benefit of Provisional Application No. 60 / 432,807, filed on December 12, 2002, which is incorporated herein by reference in its entirety. This application relates to co-pending and commonly assigned applications having the titles "Method of making tricyclic aminocyanopyridine compounds" (and having Provisional Application Serial No. 60 / 432,738), "Tricyclic aminocyanidridene inhibitors of protein-activated protein kinase 2" mitogen-activated kinase "(and having Provisional Application Serial No. 60 / 432,844), and" Protein kinase 2 activated amino acid kinase inhibitor inhibitors by mitogen-activated protein kinase "(and having Provisional Application Serial number 60 / 432,843) , each of which was presented on the same date as the present application.

BACKGROUND OF THE INVENTION Field of the Invention: The present invention relates to a method of inhibiting activated protein kinase 2 mitogen activated protein kinase (MAPKAP kinase-2, or MK-2) in a subject in need of such inhibition, and also for the prevention and treatment of diseases or disorders mediated by TNFa by the administration of an MK-2 inhibitor. (2) Description of Related Art: Protein mitogen activated kinases (MAPKs) are members of conserved signal transduction pathways that activate transcription factors, translation factors and other targeting molecules in response to a variety of extracellular signals. MAPKs are activated by phosphorylation in a portion of dual phosphorylation with the Thr-X-Tyr sequence by activated mitogen protein kinase (MAPKK) kinases. In higher eukaryotes, the physiological role of MAPK signaling has been correlated with cellular events such as proliferation, oncogenesis, development and differentiation. Accordingly, the ability to regulate signal transduction by means of these trajectories can lead to the development of preventive therapies and treatments for human diseases associated with MAPK signaling, such as inflammatory diseases, autoimmune diseases and cancer. In mammalian cells, three parallel MAPK trajectories have been described. The trajectory of better characterization leads to the activation of the regulated extracellular signal kinase (ERK). Less well understood are the signal transduction pathways that lead to the activation of the terminal kinase N cJun (JNK) and p38 MAPL. See, for example, Davis, Trends Biochem. Sci. 19: 470-473 (1994); Cano, and collaborators, Trends Biochem. Sci. 20: 117-122 (1995). The p38 MAPK trajectory is potentially activated by a variety of cellular stresses and aggressions. These cell stresses and aggressions include thermal shock, UV irradiation, inflammatory cytokines (such as TNF and IL-1), tunicamycin, chemotherapeutic drugs (ie, cisplatin), anisomycin, sorbitol / hyperosmolarity, gamma irradiation, sodium arsenite, and ischemia. . See, Ono, K. and collaborators, Cellular Signaling 12, 1-13 (2000). Activation of the p38 pathway is involved in (1) the production of proinflammatory cytokines, such as TNF-a; (2) induction of enzymes, such as Cox-2; (3) expression of an intracellular enzyme, such as ¡NOS, which plays an important role in the regulation of oxidation; (4) induction of adherent proteins, such as VCAM-1 and many other inflammatory-related molecules. In addition, the p38 pathway functions as a regulator in the proliferation and differentiation of cells of the immune system. See, Ono, K., and collaborators, Id. In 7.

The p38 kinase is a kinase in the 5 'direction of activated protein kinase 2 mitogen protein kinase 2 (MAPKAP kinase-2 or MK-2). (See, Freshney, N. W., et al., J. Cell, 78: 1039-1049 (1994)). MK-2 is a protein that appears to be predominantly regulated by p38 in cells. In fact, MK-2 was the first p38a substrate to be identified. For example, in vitro phosphorylation of MK-2 by p38a activates MK-2. The substrates on which MK-2 acts, in turn, include heat shock protein 27, lymphocyte-specific protein 1 (LAP1), the protein that binds the cAMP response element (CREB), ATF1, serum response factor (SRF), and tyrosine hydroxylase. The MK-2 substrate that has been best characterized is the small heat shock protein 27 (hsp27). The role of the p38 pathway in diseases related to inflammation has been studied in several animal models. The imidazole pyridinyl compound SB203580 has been shown to be a specific inhibitor of p38 in vivo, and has also been shown to inhibit the activation of MK-2 (see, Rouse, J., et al., Cell, 78: 1027-1037 (1994)).; Cuenda, A., and collaborators, Biochem. J., 333: 11-15 (1998)), in addition to a MAP kinase homologue called reactivation kinase (RK). (See, Cuenda, A., et al., FEBS Lett., 364 (2): 229-233 (1995)). Inhibition of p38 by SB203580 can reduce mortality in a murine model of endotoxin-induced shock and inhibit the development of arthritis induced by mouse collagen and rat adjuvant arthritis. See, for example, Badger, A. M. et al., J.

Pharmacol Exp. Ther., 279: 1453-1461 (1996). Another p38 inhibitor that has been used in an animal model that is believed to be more potent than SB203580 in its inhibitory effect on p38 is SB 220025. A recent animal study has determined that SB 220025 causes a dose-dependent decrease Significant in the vascular density of granulomas in laboratory rats. (See Jackson, J. R., et al., J. Pharmacol. Exp. Ther., 284: 687-692 (1998)). The results of these animal studies indicated that p38, or components of the p38 pathway, may be useful therapeutic targets for the prevention or treatment of inflammatory disease. Due to this integral role in the signaling path of p38, the MK-2 has been used as a monitor for measuring the level of activation in the path. Due to its location in the current 3 'in the trajectory, relative to p38, MK-2 has been measured as a more convenient, although indirect, method of evaluating the activation of p38. However, until now, research efforts that explore therapeutic strategies associated with the modulation of these trajectories have focused mainly on the inhibition of p38 kinase. Several compounds that inhibit the activation of p38 kinase have been described in US Patent No. 6,046,208, 6,251, 914, and 6,335,340. These compounds have been suggested to be useful for the treatment of diseases mediated with CSBP / RK / p38 kinase. Commercial efforts to apply the p38 inhibitors have centered around two p38 inhibitors, the pyridinylimidazole inhibitor SKF 86002, and the inhibitor 2,4,5 triaryl imidazole SB203580. See, Lee, J. C, et al., Immunopharmacology 47, 185-192 (2000). Compounds that have a similar structure have also been investigated as potential p38 inhibitors. In fact, the role of the MSP p38 kinase in various disease states has been clarified through the use of inhibitors. Kotlyarov, A. et al., In Nat. Cell Biol., 1 (2): 94-97 (1999) induced a targeted mutation in a mouse MK-2 gene, which results in mice deficient in MK-2. It was shown that mice lacking MK-2 possessed an increased resistance to stress and survived the endotoxic shock induced by LPS better than MK-2 + mice. The authors concluded that MK-2 was an essential component in the inflammatory response that regulates the biosynthesis of TNFa at a post-transcriptional level. More recently, Lehner, MD, et al., In J. Immunol., 168 (9): 4667-4673 (2002), reports that mice deficient in MK-2 showed increased susceptibility to infection of Listeria monocytogenes, and concludes that MK-2 plays an essential role in the defense of the host against intracellular bacteria, probably by regulating the production of TNF and IFN-gamma required for activation of antibacterial effector mechanisms. The location of MK-2 in the signaling path of p38 at a point that is in the 3 'direction of p38 offers the potential that MK-2 can act as a focal point for path modulation without affecting as many substrates as it could regulation of an enzyme further downstream in the signaling cascade such as MAP kinase p338. Accordingly, it would be useful to provide compounds and methods that can serve to modulate the activity of MK-2 in particular, to act as inhibitors of MK-2 activity. Such compounds and methods may be useful for the provision of similar benefits for p38 MAP kinase inhibitors, whose benefits include the prevention and treatment of diseases and disorders that are mediated by TNFa. It would be even more useful to provide MK-2 inhibitors that have improved potency and reduce undesirable side effects relative to p38 inhibitors.

BRIEF DESCRIPTION OF THE INVENTION Briefly therefore, the present invention is directed to a novel method of mitogen-activated protein kinase-activated protein kinase-2 in a subject in need of such inhibition thereof, the method comprising administering to the subject an aminocypyridine-inhibiting compound MK -2, or a pharmaceutically acceptable salt thereof, the compound has the structure: Wherein: R1 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carboxy, Ci-C4 alkyl, aryl C1-C4 alkyl, amino, amino C1-C4 alkyl, alkoxy CrC4, C1-C4 alkylamino, C1-C4 alkyl, di- (C-C4 alkyl) amino, Ci-C4 alkyl, CiC alkyl-Ci-C4 alkyl, hydroxyCiC4 alkyl) and arylC1- C4 alkylcarbonyl; R 2 is selected from the group consisting of-H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, amino, C 1 -C 4 amino, C 1 -C 4 alkylamino, aryl, heteroaryl, heterocyclyl, carboxy, carboxyC 1 alkyl -C4, C 1 -C 4 alkoxy, hydroxy, hydroxy C 1 -C 4 alkyl, hydroxy C 4 alkyl alkylamino, hydroxy C 1 -C 4 alkoxy, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkylamino, amino alkylamino C 1 -C4, aryl C1-C4 alkyl, C1-C4 alkylamino C1-C4 alkyl, dialkylamino C4 alkyl, C1-C4 alkyl, C1-C4 alkyl Ci-C4 alkyl, carboxy C1-C4 alkyl, arylC1-C4 alkylcarbonyl, phthaiamine CiC-4 alkyl, halo, carbamyl, Ci-alkyl, C1-C4 alkoxyarylamino, C1- C10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, cycloalkyl mono- and bicyclic can be optionally substituted with one or more of the groups selected from halogen, hydroxy, C1-C4 alkoxy, aryloxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkyl, carboxy, carbamyl, C1-C4 alkoxycarbonyl, alkoxycarbonyl C 1-C4 C1-C4 alkoxy, carboxy alkoxy amino CrC-4, alkylamino Ci-C4 > di-C 1 -C 4 alkylamino, N-C 1 -C 4 alkyl-N-cyano C 1 -C 4 alkylamino, nitro, C 1 -C 4 alkylcarbonylamino, cyano, halo C 1 -C 4 alkyl, di-halo C 1 -C 4 alkyl, tri-halo C 1 alkyl C4, hydroxy alkoxy Ci-C4, haloalkoxy C-1-C4, tri-haloalkoxy C1-C4, R3 is selected from the group consisting of-H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, C-1-C4 amino, amino, aryl, wherein the aryl group can optionally be substituted with one or more groups selected from halogen, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkyl, carboxy, C 1 -C 4 alkoxycarbonyl, C 1 -C 4 alkoxycarboxy, amino, di-alkylamino dC 4, N-C 1 -C 4 alkyl -N-cyano C1-C4 alkylamino, nitro, alkycarbonylamino Gj-C4, cyano, halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo CrC4 alkyl) halo C1-C4 alkoxy, di-halo alkoxy C1-C4, tri-halo C1-C4 alkoxy, and wherein the groups R2 and R3 are such that they optionally join to form a ring system selected from: R 4 is selected from the group consisting of-H, Ci-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl) hydroxy, C1-C4 alkylthio, C1-C4 alkoxy, Ci-C4 alkoxycarbonyl, mercapto, N-imidazoylphenyl, C 1 -C 4 isoalkyl, aminofluorobenzhydryl, aryl and heteroaryl, wherein the aryl and heteroaryl groups may optionally be substituted with one or more groups selected from halogen, hydroxy, alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, alkylisulfinyl C1-C4, cartoxy, carbamyl, C 1 -C 4 akoxycarbonyl, carboxy C 1 -C 4 alkyl, carboxy C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino, N-C 1 -C 4 alkyl-N-cyano alkylamino C C 4, nitro, C1-C4 aicylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo C- | -C4 alkyl, halo C4 alkoxy, di-halo C1-C4 alkoxy, tri-halo alkoxy C1-C4 wherein the groups R3 and R4 are such that they optionally join to form a ring system selected from: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of -H, and Ci-C5 alkyl; and wherein the groups R1 and R5 optionally join to form a piperidyl ring or oxazinyl ring; p6 p7 8 p9 p10 p11 p12 p13 p14 p15 p16 p17 p18 p19 D20 p26 p27 p28 p29 p30 p31 p32 D33 p34 p35 p36 p37 R21, R22, R23, R24, R25, p43 p44 p45 p46 p47 p48 p49 p49 D50 p51 p52 p53 p54 R38, R39, R40, R4 \ R42, r \, G? R55,? 60? 61? 62? 63 s64? 65? 66? 67? 68? 69? 70? 71 R56, R57, R58, R59,? ,? , G \, G,? ,? , R72, R73, R74, R75, and R76, each is optionally presented and are each independently selected from the group consisting of -H, C4 alkyl, C2-C4 alkenyl, C2-C4 alkyl, C1-C4 isoalkyl, amino, nitro, hydroxy, C1-C4 alkoxy, C1-C4 alkenoxy, oxo, carboxy, halo, halo C-C4 alkyl, dihalo C 1 -C 4 alkyl, trihalo C 1 -C 4 alkyl, cyano, cyano C 1 -C 4 alkyl , dicyano C1-C4 alkyl, halophenyl, hydroxy C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkoxy, - (CH2) -0- (C6H4) -0- (CH3), carboxy C1-C4 alkoxy, alkylcarboxy C1- C4 C1-C4 alkoxy, C 1 -C 4 alkoxyamino, C 1 -C 4 alkylamino, C 1 -C 4 dialkylamino, C 1 -C 4 trialkylamino, C 1 -C 4 alkoxy, C 1 -C 4 diamino alkoxy, C 1 -C 4 alkylamino C 1 -C 4 alkoxy, C 1 -C 4 dialkylamino C 1 -C 4 alkoxy, cyano C 1 -C 4 alkoxy C 1 -C 4 alkyl, - (CH 2) -0- (CF 2) -CHF 2, C 1 -C 4 alkoxy C 1 -C 4 alkyl, phenyl, benzyl, benzoyl, aryl, N-morpholinyl, morpholinyl C 1 -C 4 alkoxy , pyrrolidyl C1-C4 alkoxy, N-pyrrolidyl C4 alkoxy, C4 alkylcarboxy, carboxy C 1 -C 4 alkyl ester, pyridyl C 1 -C 4 alkyl, pyridyl alkoxy CrC 4 COO-CH 2 -CH 3; and wherein R and R are such that they optionally join to form a ring system selected from the type of: The invention is also directed to a novel method of activated mitogen-activated protein kinase-2 protein kinase in a subject in need of such inhibition, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, the compound has the structure: wherein: G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R4 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is-H or Ci-C4 alkyl; R \ R2, R35, R36, R37, R38, R39, and R40 are each independently selected from the group consisting of hydrogen, hydroxy, amino, halo, nitro, branched or unbranched C-1-C6 alkyl, C2- alkenyl C6, C2-C6 alkynyl, Ci-C6 alkoxy) hydroxy C6 alkyl, hydroxy alkoxy C] -C6, alkoxy C1-C6 alkoxy C- | -C6, alkoxy C1-C6 alkyl C1-C6, alkenoxy C2-C6 , branched or unbranched Ci-C6 amino alkyl, diamino alkyl C-2-C6, alkylamino C-pCe C 1 -C 6 alkyl, C 1 -C 6 alkylamino, di- (C 6 alkyl) amino, C 1 -C 4 alkoxyarylamino, C 1 -C 4 alkoxyalkylamino, C 6 alkoxy amino, di- (alkylamino) C1-C4, C2-C5 alkoxy, di- (Ci-C6 alkyl) amino C1-C6 alkyl, C6 alkylamino Ci-C6 alkoxy, halo C1-C6 alkoxy, dihalo alkoxy C ^ Ce, trihalo alkoxy C Ce, cyano C1-C6 alkyl, dicyan Ci-C6 alkyl, cyano C1-C6 alkoxy, dicyan Ci-C6 alkoxy, carbamyl C1-C4 alkoxy, heterocyclyl C4 alkoxy, heteroaryl C1-C4 alkoxy, sulfo, sulfamyl, alkylaminosulfonyl C C4 , C 1 -C 4 hydroxy alkylaminosuifonyl, di- (C 1 -C 4 alkyl) aminosulfonyl, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfinyl, aryl, aryl C 1 -C 6 alkyl, heterocyclyl C 1 -C 6 alkyl, heteroaryl C 1 -C 6 alkyl, C6, heterocyclyl alkoxy heteroaryl C6 alkoxy, aryl alkoxy Cr Cs, wherein the aryl ring may be substituted or unsubstituted and if substituted, the substituent group is selected from one or more of the groups consisting of C1-C6 alkyl, halo, ami no, and substituted or unsubstituted C 3 -C 6 alkoxy C 3 -C 6 cycloalkyl, C 3 -C 6 heterocyclyl, and if substituted, the substituent group is selected from one or more of the group consisting of Ci-C 6 alkyl, C 6 alkoxy , halo, amino, and wherein the C3-C6 heterocyclyl ring contains O, S, or N, Ci-C6 alkoxycarbonyl, Ci-Ce alkoxy branched or unbranched and carboxy, carboxy alkoxy CrC6, carboxy C1-C6 alkyl, hydroxy alkoxycarbonyl Ci -C4, Ci-C4 alkoxycarbonyl, wherein R38 and R39 are such that they optionally join to form a ring system of the type selected from In preferred embodiments, R is other than cyano. The present invention is also directed to a novel method of activated mitogen-activated protein kinase-2 protein kinase in a subject in need of such inhibition, the method comprising administering to the subject a compound, or a pharmaceutically acceptable salt thereof, the Composite has the structure: wherein: G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R and R are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is-H or -CH3; R1 is selected from the group consisting of hydrogen, ethyl, dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl; R2 is selected from the group consisting of hydrogen, hydroxyethyl, propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl, phenylmethyl, dimethylaminoethyl, phthalaminomethyl, butyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl; R35 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl. R36 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl; R37 is selected from the group consisting of hydrogen, hydroxy, methoxy, bromo, and 2-pyridomethyl; R38 is selected from the group consisting of hydrogen, hydroxy, methoxy, arrimo, carboxy, diaminoethoxy, bromine, propoxy, isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro, pyridylmethyl, and fluoro; R39 is selected from the group consisting of hydrogen, hydroxy, methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy, morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy, dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and isobutylcarboxymethoxy, where the R and R groups can be attached to forming a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl, hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy, dimethylaminoethoxy, carboxy, bromine, and pyrridylmethyl. The present invention is also directed to a novel method for preventing or treating a disease or disorder mediated by TNF in a subject in need of such prevention or treatment, the method comprising administering to a subject an effective amount of an inhibitory compound MK-1 of aminocianopyridine. Among the various advantages that are found to be achieved by the present invention, therefore, may be pointed out the arrangement of a method that can serve to modulate the activity of MK-2, in particular, to inhibit the activity of MK-2 and the disposition of a method for the prevention and treatment of diseases and disorders that are mediated by TNFa.beef.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a graph showing the thickness of the leg as a function of time from day 0 to day 7 for MK2 (+ / +) and Mk2 (- / -) mice, which have received serum injection; and Figure 2 is a bar chart showing the thickness of the paw 7 days after injection for normal mice, MK2 (+ / +) mice receiving serum, MK2 (- / -) mice receiving serum and MK2 mice. (+ / +) that receive serum and anti-TNF antibody.

DETAILED DESCRIPTION OF THE PREFERRED MODALITIES According to the pnt invention it has been discovered that certain aminocyanopyridine compounds can inhibit the activity of MAPKAP kinase 2. Many of these compounds show their inhibitory effect at low concentrations, which have IC50 values of MK-2 inhibition in vitro less than 1.0 μ ?, and with some that have IC50 values of less than about 0.5 μ? t? and even as low as about 0.2 μ ?. In this manner, these compounds can be potent and effective drugs for use in methods for preventing or treating diseases or disorders that are mediated by TNFoc. For example, they can be used for the prevention or treatment of arthritis.

Aminocyanopyridine compounds that are useful in the current method include those having the structure shown in formula I: wherein: R1 is selected from the group consisting of-H, C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, carboxy C1-C4 alkyl, aryl C4 alkyl, amino, Ci-C4 amino alkyl, Ci-alkoxy C4, C1-C4 alkylamino, C4 alkyl, di- (Ci-C4 alkyl) amino C1-C4 alkyl, Ci-C4 alkyl Ci-C4 alkyl) idroxy C1-C4 alkyl, and aryl C4 alkylcarbonyl; R 2 is selected from the group consisting of -H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, amino, C 1 -C 4 amino, Cr C 4 alkylamino, aryl, heteroaryl, heterocyclyl, carboxy, carboxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy hydroxy, hydroxy C 1 -C 4 alkyl, hydroxy C 1 -C 4 alkylamino, hydroxy C 1 alkoxy, C 1 -C 4 alkoxy C 1 -C 4 alkyl, C 1 -C 4 alkoxy C 1 -C 4 alkylamino, amino C 1 -C 4 alkylamino, aryl C 1 -C 4 alkyl, C 1 -C 4 alkylamino C 1 -C 4 alkyl, dialkylamino C 1 -C 4 C 1 -C 4 alkyl, C 1 -C 4 alkyl C 1 -C 4 alkyl, carboxy C 4 alkyl, aryl C 1 -C 4 alkylcarbonyl, phthalamine C 1 -C 4 alkyl, halo, carbamyl, C 4 alkylthio, C 1 -C 4 alkoxyarylamino, C 1 -C 10 mono- and bicyclic cycloalkyl, wherein aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl can be optionally substituted with one or more of the selected groups of halogen, hydroxy, Ci-C4 alkoxy, aryloxy, C2-C4 alkenyloxy, C2-C4 alkynyloxy, C1-C4 alkyl, carboxy, carbamyl, Ci-C4 alkoxycarbonyl, alkoxycarbonyl C 1-C4 C1-C4 alkoxy, carboxy alkoxy C1-C4 amino, C1-C4 alkylamino, di-C1-C4 alkylamino, N-C1-C4 alkyl-N-dano C1-C4 alkylamino, nitro, alkylcarbonylamino Cr C4, cyano, halo C 1 -C 4 alkyl, di-halo C 1 -C 4 alkyl, tri-halo C 4 alkyl, hydroxy C 1 -C 4 alkoxy, halo C 1 -C 4 alkoxy, tri-halo C 1 -C 4 alkoxy; R3 is selected from the group consisting of -H, Ci-C6 alkyl, C2-C6 alkeniio, C2-C6 alkynyl, cyano, amino C1-C4 alkyl, amino, aryl, wherein the aryl group can optionally be substituted with one or more groups selected from halogen, hydroxy, C1-C4 alkoxy, CiC ^ alkyl, carboxy, C1-C4 alkoxycarbonyl, carboxy C1-C4 alkoxy, amino, di-C1-C4 alkylamino, N-C4 alkyl-N-cyano C1-C4 alkylamino, nitro, C4 alkylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo Ci-C4 alkyl) halo C4 alkoxy, di-halo C 1 -C 4 alkoxy, tri-halo C1-C4 alkoxy, and Where the groups R2 and R3 are such that they optionally join to form a ring system selected from: As shown above, the ring substituted groups that join to form additional ring structuadjacent to the substituted ring can be described with reference to the chemical formulas shown on the wavy lines to indicate that a partial molecule is shown. In these formulas, the wavy lines are cut through the ring to which the substituents are attached (in this case, the pyridine ring of the formula I), instead of crossing the bond joining the substituted group to the ring. Accordingly, the partial ring shown is the ring to which the substituent groups are shown to be bound in the general formula. R 4 is selected from the group consisting of-H, C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, hydroxy, C 1 -C 4 alkylthio, C 1 -C 4 alkoxy, CrC 4 alkoxycarboxy, mercapto, N-imidazoylphenyl, isoalkyl C1-C-4, aminofluorobenzhydryl, aryl and heteroaryl, wherein the aryl and heteroaryl groups may optionally be substituted with one or more groups selected from halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, C1-C4 alkylthio, alkylsulfonyl C1-C4, C 1 -C 4 alkylsulfinyl, cartoxy, carbamyl, alkoxycarbonyl CrC 4, carboxy C 1 -C 4 alkyl) carboxy C 4 alkoxy, amino, di C 1-4 alkylamino, N-C 1 -C 4 alkyl-N-cyano alkylamino Ci-C, nitro, C1-C4 alkylcarbonylamino, cyano, haloC1 alkyl, di-halo Ci-C4 alkyl, tri-halo C1-C4 alkyl, halo C1-C4 alkoxy, di-halo C1-C4 alkoxy, tri-halo C1-C4 alkoxy wherein the groups R3 and R4 are such that they optionally join to form a ring system selected from: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of-H, and C1-C5 alkyl; and wherein the groups R1 and R5 can be joined to form a piperidyl ring or an oxazinyl ring; R6, R7, RE5, R9, R10, R11,, R12, R13, R14, R15, R16, R17, R18, R19, R20 R21, R22 > R23,, R24, R25, R26, R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37; R38, R39, R40,, R41, R42, R43, R44, R45, R46, R47, R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, R58 R59 R60, R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R7, R, R, R and R each are optionally presented and are each independently selected from the group consisting of -H, Ci-C4 alkyl, C2-C4 alkenyl, C2-C alkynyl, C1-C4 isoalkyl, amino, nitro, hydroxy, Ci-C4 alkoxy, C1-C4 alkenoxy, oxo, carboxy, halo, halo C1-C4 alkyl, dihalo Ci-C4 alkyl, trihalo Ci-C4 alkyl, cyano, cyano Ci-C4 alkyl, diciano C1-C4 alkyl, halophenyl, hydroxy alkoxy C- | -C4, alkoxy CrC alkoxy C1-C4 , - (CH2) -0- (C6H4) -0- (CH3), carboxy C1-C4 alkoxy, C1-C4 alkylcarboxy C1-C4 alkoxy, C1-C4 alkoxyamino, C4 alkylamino, C1-C4 dialkylamino, trialkylamino C4 , C 1 -C 4 alkoxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylamino C 1 -C 4 alkoxy, C 1 -C 4 dialkylamino C 1 -C 4 alkoxy, C 1 -C 4 alkoxy C 1 -C 4 alkyl- (CH 2) -0- ( CF2 CHF2, tetra-C 1 -C 4 alkoxy C 1 -C 4 alkyl, phenyl, benzyl, benzoyl, aryl, N-morphonyl, morphonyl C 1 -C 4 alkoxy, pyrrolidyl C 1 -C 4 alkoxy, N-pyrrolidil C 1 -C 4 alkoxy, Ci-C 4 alkylcarboxy, carboxy C 1 -C 4 alkyl ester, pyridyl C 1 -C alkyl, pyridyl C 1 -C 4 alkoxy, COO-CH 2 CH 3; and wherein R38 and R39 are such that they optionally join to form a ring system selected from the type of: In a preferred embodiment, when R2 is heteroaryl, R3 is other than cyano. It is also preferred that at least one of R1, R2, R3, R4, and R5 is other than hydrogen. In another embodiment, when R1, R3 and R5 are hydrogen: R2 is other than alkenyl, alkyl, alkynyl, aryl, arylalkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, heterocycloalkylcarbonyl, (NZiZ2) alkyl, or -RARB; wherein Z-i and Z2 are each independently selected from the group consisting of hydrogen, alkoxycarbonyl, alkyl, alkylcarbonyl, benzyl, benzyloxycarbonyl, and formyl; RA is selected from the group consisting of aryl and arylalkyl; RB is selected from the group consisting of aryl, arylalkoxy, arylalkyl, aryloxy, heterocycle, and heterocycloalkyl; and R4 is other than alkenyl, alkoxyalkynyl, alkyl, alkynyl, cycloalkyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, or -RC DRE; wherein Rc is selected from the group consisting of aryl, arylalkyl, heterocycle and heterocycloalkyl; RD is selected from the group consisting of aryl, arylalkoxy, arylalkoxy imino, arylalkyl, aryloxy, heterocycle, heterocycloalkoxy, heterocycloalkyl, heterocyclecarbonyl, heterocycle, heterocycle, heterocycle, heterocycle, heterocycle, and heterocycle; and RE is absent or selected from the group consisting of aryl, arylalkoxy, arylalkoxyimino, arylalkyl, aryloxy, heterocycle, heterocyclealkoxy, heterocycloalkyl, heterocyclecarbonyl, heterocycle, heterocycle, heterocycle, heterocycle, heterocycle, and heterocycle. As used herein, the term "alkyl" alone or in combination, means an acyclic, linear or branched alkyl radical, which, unless otherwise indicated, preferably contains from 1 to about 10 carbon atoms and more preferably contains from 1 to about 6 carbon atoms. The "alkyl" also embraces cyclic alkyl radicals containing from 3 to about 7 carbon atoms, preferably from 3 to 5 carbon atoms. The alkyl radicals can be optionally substituted with groups as defined below. Examples of such alkyl radicals include, methyl, ethyl, chloroethyl, hydroxyethyl, n-propyl, isopropyl, n-butyl, cyanobutyl, isobutyl, sec-butyl, tert-butyl, pentyl, aminopentyl, iso-amyl, hexyl, octyl, and similar.

The term "alkenyl" refers to an unsaturated acyclic hydrocarbon radical, linear or branched so as to contain at least one double bond. Unless indicated otherwise, such radicals preferably contain from 2 to about 6 carbon atoms, preferably from 2 to about 4 carbon atoms, more preferably from 2 to about 3 carbon atoms. The alkenyl radicals can optionally be substituted with groups as defined below. Examples of suitable alkenyl radicals include propenyl, 2-chloropropylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, 3- hydroxyhexen-1-yl, hepten-1-yl, octen-1-yl, and the like. The term "alkynyl" refers to an unsaturated hydrocarbon radical, linear or branched so as to contain at least one or more triple bonds, such radicals preferably contain from 2 to about 6 carbon atoms, more preferably from 2 to about of 3 carbon atoms. The alkynyl radicals can optionally be substituted with groups as described below. Examples of suitable alkynyl radicals include the ethynyl, proinyl, hydroxypropyl, butyne-1-yl, butyne-2-yl, pentyne-1-yl, pentyne-2-yl, 4-methoxypentin-2-yl, 3-methylbutyne radicals. -1-yl, hexyl-1-yl, hexin-2-yl, hexin-3-yl, 3,3-dimethylbutyn-1-yl and the like. The term "alkoxy" includes linear or branched oxy containing radicals, each of which has, unless otherwise indicated, alkyl portions of 1 to about 6 carbon atoms, preferably 1 to about 4 carbon atoms. carbon atoms, such as the methoxy, ethoxy, propoxy, isopropoxy, isobutoxy radicals and the like. The term "alkoxyalkyl" also embraces alkyl radicals having one or more alkoxy radicals that are linked to the alkyl radical, that is, to form monoalkoxyalkyl and dialkoxyalkyl radicals. Examples of such radicals include methoxyalkyls, ethoxyalkyls, propoxyalkyls, isopropoxyalkyls, butoxyalkyls, tert-butoxyalkyls, and the like. The "alkoxy" radicals may also be substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide the "haloalkoxy" radicals. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, fluoropropoxy, and the like. The term "alkylthio" embraces radicals containing a linear or branched alkyl radical, preferably, unless otherwise indicated, from 1 to about 6 carbon atoms, they are linked to a divalent sulfur atom. An example of "lower alkylthio" is methylthio (CH3-S-). The term "alkylthioalkyl" embraces alkylthio radicals, which are linked in an alkyl group. An example of such radicals is methylthiomethyl. The term "halo" means radicals comprising halogens, such as fluorine, chlorine, bromine, or iodine. The term "heterocyclyl" means a mono- or multi-ring saturated or unsaturated carbocycle wherein one or more carbon atoms are replaced by N, S, P, or O. These include, for example, structures such as: where Z, Z1, Z2, or Z3 is C, S, P, O, or N, with the proviso that one of Z, Z1, Z2, or Z3 is other than carbon, but it is not O u S when it is linked to another atom Z by a double bond or when it is linked to another atom O or S. In addition, the optional substituents are understood to bind to Z, Z1, Z2, or Z3 only when each is C. The term "heterocycle" it also includes fully saturated ring structures, such as piperazinyl, dioxanyl, tetrahydrofuranyl, oxiranyl, aziridinyl, morpholinyl, pyrrolidinyl, piperidinyl, thiazolidinyl, and others. The term "heteroaryl" means a completely unsaturated heterocycle which may include, but is not limited to, furyl, tenyl, pyrryl, imidazolyl, pyrazolyl, pyridyl, thiazolyl, quinolinyl, isoquinolinyl, benzothienyl, and indolyl. Either, "heterocyclyl" or "heteroaryl," the binding point of the molecule of interest may be the heteroatom or elsewhere within the ring. The term "cycloalkyl" means a mono- or multi-ring carbocycle wherein each ring contains 3 to about 7 carbon atoms, preferably 3 to about 6 carbon atoms, and more preferably 3 to about 5 carbon atoms. carbon. Examples include radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. The term "cycloalkyl" further encompasses spiro systems wherein the cycloalkyl ring is an atom in the carbon ring in common with the 7-membered heterocyclic ring of the benzothiepine. The term "oxo" means a double bond oxygen. The term "aryl" means a fully unsaturated mono- or multi-ring carbocycle, including but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl. The amino-cyanopyridine compounds present inhibit the activity of the MK-2 enzyme. When the target compound inhibits MK-2, it means that the enzymatic activity of MK-2 is lower in the presence of a compound that is under the same conditions in the absence of such a compound. A method that expresses the potency of a compound as an MK-2 inhibitor to measure the "IC5o" value of the compound. The IC5o value of an MK-2 inhibitor is the concentration of the compound that is required to decrease the enzymatic activity MK-2 by half. Accordingly, a compound having a lower IC50 value is considered to be a more potent inhibitor having a higher IC5o value. As used herein, the aminocyanopyridine compounds that inhibit MK-2 may be referred to as inhibitors of aminocyanopyridine MK-2, or inhibitory compounds of aminocyanopyridine MK-2 or inhibitory agents MK-2. Examples of aminocyanopyridine compounds that are suitable for use as MK-2 inhibitors in the present invention are shown in table 1.

TABLE I: Aminocyanopyridine MK-2 inhibitors Notes: a: The aminocyanopyridine compound can be shown with a solvent, such as, for example, trifluoroacetate, with which it can form a salt. Both forms of salts and acids of the aminocyanopyridine compound are included in the present invention. b: The names of the compound are generated by the ACD / Name software. In another embodiment, the method of the present invention encompasses administration to the subject of an aminocyanopyridine compound having the structure as shown in formula I, wherein: R 1 is selected from the group consisting of -H, methyl, ethyl, propyl, butyl, - (ChyCOOH, phenyl, pyridyl, dimethylaminoethyl, methoxyethyl, tetramethylaminoethyl, carboxymethyl, and phenylacetyl; R 2 is selected from the group consisting of -H, methyl, ethyl, propyl, butyl, amino, phenyl, methoxy, carboxy, carboxymethyl, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, phthalaminate, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl, 1,3-isodiazoyl, 1, 3, 4-triazoyl, methoxyphenyl, -S (CH3), tetramethylaminoethyl, acetylaminophenyl, methoxyphenylamino, carboxyphenyl, carboxy-3-isopyrryl, cyanophenyl, cyclopropyl, phenoxyphenyl, pyridyl, dihydroxybromophenyl, difl uoromethoxyphenyl, trifluoromethylphenium, trifluoromethylphiuorophenium, hydroxyphenyl, methylaminomethyl, methylaminoethyl, thiofyl, pyrryl, aminomethyl, R3 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyano, aminomethyl, phenyl, fluorophenyl, and amino; wherein the groups R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, hydroxy, furyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenium, methoxyphenyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl , pyrryl, N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl, mercapto, N-isoimidazoylphenyl, isopropyl, amino, hydroxynaphthyl, thiazoyl, carboxymethylphenyl, trifluoromethylphenyl, methylphenyl, cyanophenyl, dimethylphenyl, fluorobenzhydryl, methoxyfuryl, aminosulfonylphenyl, D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of -H, and C1-C5 alkyl; and wherein the groups R1 and R5 can be joined to form a piperidyl ring; R6, R7, R8, R9,, R10, R11,, R12, R13, R14, R5, R6, R7, R18, R19, R20 R21, R22, R23, D24 P25 D26 R27, R28, R29, R30, R31, R32, R33, R34, R35, R36, R37; R38, R39, R40, p41 p42 D43 R44, R45, R46, R47 > R48, R49, R50, R51, R52, R53, R54, R55, R56, R57, D58 D59 p60 R61, R62, R63, R64, R65, R66, R67, R68, R69, R70, R71, R, R, R, R, and R are each optionally present (e.g. these may be present when required to balance the valence of the atom to which they are shown as a link) and are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, isobutyl, amino, nitro, hydroxy, methoxy, ethoxy, propoxy, 2-propenoxy, oxo, carboxy, bromo, chloro, fluoro, trifluoromethyl, chloromethyl, hydroxymethyl, dicyanomethyl, 2-fluorophenyl, 3-fluorophenyl, hydroxyethoxy, ethoxyethoxy, - (CH2) -0- (C6H4) -0- (CH3)) carboxymethoxy, isopropylcarboxymethoxy, isobutylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, dimethylaminoethoxy, cyanomethoxymethyl, 2-propenoxymethyl, methoxy methyl, isopropoxymethyl, ethoxymethyl, - (CH2) -0- (CF2) -CHF2, isobutoxymethyl , benzoyl, phenyl, N-morphonyl, morphonyl ethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, oxo, ethylcarboxy, carboxyme ethyl-ethyl ester, pyridylmethyl, 4-pyridylmethoxy, 2-pyridylmethyl, and -COO-CH 2 -CH 3; and wherein R and R are such that they optionally join to form a ring system selected from the group type consisting of: In another embodiment, the present method can be practiced by administration of an aminocyanopyridine compound that provides an IC50 of less than about 200 μ ?, in an in vitro assay of the activity of the MK-2 inhibitor. Examples of such compounds comprise the compound shown in formula I, wherein: R1 is selected from the group consisting of -H, methyl, ethyl, - (CH2) COOH, and phenyl; R 2 is selected from the group consisting of -H, methyl, ethyl, amino, phenyl, methoxy, carboxy, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, furyl , carbamylpyrryl, methyl-1,3-isodiazoyl, 1,3-isodiazoyl, 1,4-triazoyl, methoxyphenyl, -S (CH3), acetylaminophenyl, methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl, phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl , trifluoromethylphenyl, trifluoromethylfluorophenyl, hydroxyphenyl, R3 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyano, and aminomethyl; wherein the groups R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, hydroxy, furyl, indolyl, methylfuryl, methylimidazolium, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrryl , N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl, N-isoimidazoylphenyl, amino, hydroxynaphthyl, thiazoyl, carboxymethylphenyl, aminosulfonylphenyl, and D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of -H, and C-i-C5 alkyl; p6 p7 p8 D9 p10 D11 p12 p13 p14 D15 p16 p17 p18 D19 D20 ?? , G? ,? , G, G, G \, G, G? , G, G \, G \,? , G \, G \, G,? 31? 32? 33? 34? 35 R36? 37? 38? 39? 40? 41? 42? 43? 44? 45? 46? 71 G \,? ,? , G, ?? , G, G, G, G? ,, G, G,, G \, G \, G \, G, R72, R73, R74, R75, and R76 are each optionally present (such as, when required to balance the valence of the atom to which they are shown as a link) and are each independently selected from the group consisting of -H, methyl , ethyl, butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, chloro, fluoro, trifluoromethyl, chloromethyl, hydroxymethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy, - (CH2) -0- (C6H4 ) -0- (CH3), carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, cyanomethoxymethyl, methoxymethyl, isopropoxymethyl, ethoxymethyl, - (CH2) -0- (CF2) -CHF2, isobutoxymethyl, phenyl, morphonyl ethoxy, pyrrolidylethoxy, N -pyrrolidylethoxy, and pyridylmethyl, and wherein R38 and R39 are such that they optionally join to form a ring system selected from the group type consisting of: In another embodiment, the present method can be practiced by the administration of an aminocyanopyridine compound that provides an IC50 of less than about 100 μ ?, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula I, wherein: R1 is selected from the group consisting of -H, methyl, and ethyl; R 2 is selected from the group consisting of -H, methyl, amino, phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl -1, 3-isodiazoyl, 1,3-isodiazoyl, 1,4-triazoyl, methoxyphenyl, -S (CH3), acetylaminophenyl, methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl, phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl, and R3 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, and cyano; wherein the groups R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, hydroxy, furyl, indolyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrryl , N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl, amino, and aminosulfonylphenyl; wherein the groups R3 and R4 are such that optionally to form a ring system selected from: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is -H; D6 p7 p8 p9 p10 19 p20? ,? , G? ,, G,,? , R35, R36, R37, R38, R39, R40, R41, R42, R71, R72, R73, R74, R75, and R76 are each optionally present (such as, when required to balance the valence of the atom to which they are shown) as a bond) and are each independently selected from the group consisting of -H, methyl, ethyl, butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, fluoro, trifluoromethyl, chloromethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy, - (CH2) -0- (C6H4) -0- (CH3), carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, phenyl, morphonyl ethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, and pyridylmethyl, and wherein R38 and R39 are such that they optionally join to form a ring system consisting of: In another embodiment, the present method can be practiced by the administration of an aminocyanopyridine compound that provides an IC50 of less than about 50 μ, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula I, wherein: R1 is selected from the group consisting of -H, methyl, and ethyl; R 2 is selected from the group consisting of -H, methyl, amino, phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl -1,3-isodiazoyl, 1,3-isodiazoyl, 1,4-triazoyl, methoxyphenyl, -S (CHs), acetylaminophenyl, methoxyphenylamino, carboxyphenyl, and R3 is selected from the group consisting of -H, methyl, ethyl, propyl, and isopropyl; wherein the groups R2 and R3 are such that they optionally join to form a ring system comprising: R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, furyl, indolyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrrhoyl, N methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, and aminosulfonylphenyl; wherein the groups R3 and R4 are such that they optionally join to form a ring system selected from: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is -H; D6 p7 p8 r9 p10 R, R, R, R, R, and R / b are each optionally present (such as, when required to balance the valence of the atom to which they are shown as a link) and are each independently selected of the group consisting of -H, methyl, ethyl, butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, fluoro, trifluoromethyl, chloromethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy, carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, morphoniloytoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, and pyridylmethyl, and wherein R38 and R39 are such that they optionally join to form a ring system consisting of: In another embodiment, the present method can be practiced by the administration of an aminocyanopyridine compound that provides an IC50 of at least about 20 μ ?, in an in vitro assay of NK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula I, wherein: R1 is -H; R2 is selected from the group consisting of amino, phenyl, fluorophenyl, difluorophenyl, furyl, carbamilpirrilo, methyl-1,3-isodiazoilo, 1, 3-isodiazoilo, 1, 3,4-triazolyl, methoxyphenyl, acetylaminophenyl, methoxyphenylamino, and carboxyphenyl; R3 is selected from the group consisting of -H, methyl, ethyl, and propyl; R 4 is selected from the group consisting of methyl, ethyl, propyl, furyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dihydroxyborophenyl, and aminosulfonylphenyl; wherein the groups R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is -H; R, R, R, R, Rfi > , and R / 0 are each optionally present (such as, when required to balance the valence of the atom to which they are shown as a link) and are each independently selected from the group consisting of -H, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, fluoro, trifluoromethyl, chloromethyl, dicianometilo, hydroxyethoxy, ethoxyethoxy, carboxymethoxy, isopropilcarboximetoxi, methylamino, dimethylamino, aminoethoxy, diaminoetoxi, morfoniletoxi, pirrolidiletoxi, and pyridylmethyl, and wherein R38 and R39 are such that they optionally join to form a ring system consisting of: In one embodiment of this invention, the present method can be practiced by the administration of a tricyclic aminocyanopyridine compound having the structure shown in formula II: II wherein: G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R4 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is-H or C4 alkyl; each of R1, R2, R35, R36, R37, R38, R39, and R40 is independently selected from the group consisting of hydrogen, hydroxy, amino, halo, nitro, branched or unbranched C1-C6 alkyl, C2-C6 alkeniio , C2-C5 alkynyl, alkoxy Ci-C6 alkyl, hydroxy alkyl Ci-C6 alkyl, hydroxy alkoxy Ci-C6 alkyl, C1-C6 alkoxy C1-C5, C1-C6 alkoxy C1-C6 alkenoxy C C6 alkylamino Ci-C6 branched or unbranched, diamino C2-C6 alkyl, Ci-C6 alkylamino Ci-C6 alkyl, Ci-C6 alkylamino, di- (Cr C6 alkyl) amino, Ci-C4 alkoxyarylamino, Ci-C alkoxyalkylamino, Ci-C6 alkoxy amino) di- (alkylamino CrC, C2-C6 alkoxy di- (Ci-C6 alkyl) amino Ci-C6 alkyl, Ci-C6 alkylamino Ci-C6 alkoxy, halo Ci-C6 alkoxy, dihalo Ci-C6 alkoxy, trihalo Ci-C6 alkoxy , cyano Ci-C6, dicyano alkyl CRC6, cyano substituted C C6 dicyano C1-C6 alkoxy, carbamoyl C1-C4 alkoxy, heterocyclyl C1-C4 alkoxy, heteroaryl C1-C4 alkoxy, sulfo, sulfamyl, alkylaminosulfonyl CRC4, hydroxy alkylaminosulfonyl C1 -C4, di- (alky the Ci-C4) alkylaminosulfonyl, C1-C4 alkylthio, alkylsulfonyl Ci-c4l alkylsulfinyl Ci-C4 alkyl, aryl, aryl C C6, C1-C6 heterocyclyl, alkyl Ci-C6 heteroaryl, heterocyclyl alkoxy Ci-C6 alkyl, heteroaryl substituted C ^ -CQ, aryl alkoxy C-6, where the aryl ring may be substituted or unsubstituted and if substituted, the substituted group is selected from one or more of the groups consisting of CrC6 alkyl, halo, amino, and alkoxy C1-C6, substituted or unsubstituted C3-C6 cyclyl, C3-C6 heterocyclyl, and if substituted, the substituted group is selected from one or more of the groups consisting of C1-C6 alkyl, Ci-C6 alkoxy, halo, amino, and where the C3-C6 heterocyclyl ring containing O, S, or N, C1-C6 alkoxy Ci-C6 branched or unbranched, and carboxy, alkoxy Ci-C6 alkyl, carboxy CRC6 alkyl, hydroxy alkoxycarbonyl Cr C4, alkoxycarbonyl C1-C4, where R38 and R39 are such that they optionally join to form a ring system selected from the ti. po And where the terms "alkyl, alkenyl, alkenyl, alkoxy, alkoxyalkyl, haloalkoxy, halo, alkylthio, alkylthioalkyl, heterocyclyl, cyclyl, aryl, heteroaryl, cycloaryl, and oxo" have the same meaning as described above. The tricyclic aminocyanopyridine compounds that are useful in the present invention include benzonaphthridines, pyridochromans, and pyridothiochromans.

Examples of tricyclic aminocyanopyridine compounds that are useful as MK-2 inhibitors in the present method were shown in Table II: Table 2: Inhibitors of tricyclic aminocyanopyridine MK-2 cture a Compound name b MK-2 Prom. IC50 (uM) 2,4-diamino-7-bromo-5H-15.1 chromene [2,3-b] pyridine-3-carbonitrile 2-amino-7,8-dimethoxy-4-15.6 (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile 0. 32 X 0 2,4-d-amino-7-hydroxy-5H-17.4 thiochromeno [2,3-b] pyridine-3-carbonitrile 2,4-diamino-7- (dimethylamino) - 17.6 5H-chromene [2,3-b] pyridine-3-carbonitrile Notes: a: The aminocyanopyridine compound can be shown with a solvent, such as, for example, trifluoroacetate, with which it can form a salt. Both forms of salts and acids of the aminocyanopyridine compound are included in the present invention. b: The names of the compound are generated by the software ACD / Name. In another embodiment, the present method can be practiced by the administration of aminocyanopyridine compounds comprising the compound shown in formula II, wherein: G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R41 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is -H or C-C4 alkyl; R1 is selected from the group consisting of hydrogen, branched or unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy, carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl, alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl, monocyclyl, bicyclyl, polycyclyl, and heterocyclyl; R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl; R35 is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituents, if any, comprise halo moieties; R36 is selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cyclyl, wherein the substituents, if any, comprise halo moieties; R37 is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkyl, arylalkyl, or alkylaryl; R38 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, alkenyl, aikinyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkylaryl, or arylamino; R39 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclic alkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkyl carboxyalkoxy; wherein the R38 and R39 groups can be joined to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclyloalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl. In another embodiment, the present method can be practiced by the administration of an aminocyanopyridine compound comprising the compound shown in formula II, wherein: G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R41 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is-H or -CH3; R1 is selected from the group consisting of hydrogen, ethyl, dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl; R 2 is selected from the group consisting of hydrogen, hydroxyethyl, propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl, phenylmethyl, dimethylaminoethyl, phthalaminomethyl, butyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl; R35 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluoropheni, phenyl, and 3-fluorophenyl. R36 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl; R37 is selected from the group consisting of hydrogen, hydroxy, methoxy, bromo, and 2-pyridomethyl; R38 is selected from the group consisting of hydrogen, hydroxy, methoxy, amino, carboxy, diaminoethoxy, bromine, propoxy, isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro, pyridylmethyl, and fluoro; R39 is selected from the group consisting of hydrogen, hydroxy, methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy, morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy, dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and isobutylcarboxymethoxy, where groups R38 and R39 optionally are linked to form a 6-membered heterocyclic ring; and R is selected from the group consisting of hydrogen, hydroxy, fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl, hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy, dimethylaminoethoxy, carboxy, bromine, and pyrridylmethyl. In another embodiment, the present method can be practiced by the administration of an aminocyanopyridine compound that provides an IC50 of less than about 200 μ, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula II, wherein: G is selected from the group consisting of -O- and -S-; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -O-, R41 and R42 are absent; R1 is selected from the group consisting of hydrogen, and C1-C2 alkyl; R 2 is selected from the group consisting of hydrogen, C 3 alkyl, hydroxy C 1 -C 2 alkyl, C 1 -C 2 alkoxyphenyl, C 1 -C 2 alkoxy C 1 -C 2 alkyl, C 1 -C 2 amino alkyl, Ci-C 2 phenyl alkyl, and dialkylamino C1-C2 Ci-C2 alkyl; R35 and R36 are each independently selected from the group consisting of hydrogen, dicyano C1-C2 alkyl, and halophenyl; R37 is selected from the group consisting of hydrogen, and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, C1-C3 alkoxy, amino, nitro, carboxy, diamino alkoxy Ci-C2, halo, propenoxy, iso alkylcarboxi C-i-C2 alkoxy C3-C4, dialkylamino CrC2, and phenyl; R39 is selected from the group consisting of hydrogen, hydroxy, C1-C3 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy Ci-C2 alkoxy, amino alkoxy Cr C2, morpholino C2 alkoxy, carboxyl alkoxy CrC2, pyrrolidyl alkoxy C C2, dialkylamino Ci-C2 alkoxy C- | -C2, pyrrolidyl Ci-C2 alkyl, C3-C4 isoalkylcarboxyCi-C2 alkoxy, and 2-propenoxy, where groups R38 and R39 optionally join to form a heterocyclic ring of 6 members; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, Ci-C2 alkyl, Ci-C2 alkoxy, nitro, amino, pyrrolidyl C- | -C2 alkoxy, carboxy Ci-C2 alkoxy, hydroxy Ci-C2 alkoxy, and amino C 1 -C 2 alkoxy. In another embodiment, the present method can be practiced by the administration of an aminocyanopyridine compound that provides an IC50 of less than about 100 μ ?, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula II, wherein: G is selected from the group consisting of -O- and -S-; when G is sulfur, R41 and R42 are optionally absent, or are oxo; when G is -O-, R41 and R42 are absent; R1 is hydrogen; R 2 is selected from the group consisting of hydrogen, C 3 alkyl, hydroxy C 1 -C 2 alkyl, C 1 -C 2 alkoxyphenyl, C 1 -C 2 alkoxy C 1 -C 2 alkyl, C 1 -C 2 amino alkyl, C 1 -C 2 alkyl phenyl 2, and C 1 -C 2 dialkylamino C 1 -C 2 alkyl; R35 and R36 are each independently selected from the group consisting of hydrogen, and dicyan alkyl CrC2. R37 is selected from the group consisting of hydrogen, and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, Ci-C2 alkoxy, amino, carboxy, nitro, diamino C1-C2 alkoxy, halo, 2-propenoxy, C3-C4 isoalkylcarboxy, C1-C2 alkoxy, dialkylamino Ci-C2, and phenyl; R39 is selected from the group consisting of hydrogen, hydroxy, C1-C2 alkoxy, hydroxy alkoxy Ci-C2, alkoxy CrC2 alkoxy C1-C2, amino alkoxy Cr C2, morpholino alkoxy C1-C2, carboxyl alkoxy C1-C2, pyrrolidyl alkoxy C1 -C 2, dialkylamino C 2 C 2 alkoxy C 1, pyrrolidyl C 1 -C 2 alkyl isoalkylcarboxy C 3 -C 4 alkoxy C 1 -C 2 alkoxy, and 2-propenoxy; wherein the groups R38 and R39 optionally join to form a 6-membered heterocyclic ring and R40 is selected from the group consisting of hydrogen, hydroxy, halo, C1-C2 alkoxy, nitro, amino, pyrrolidyl C1-C2 alkoxy, and carboxy CrC2 alkoxy. In another embodiment, the present method can be practiced by the administration of an aminocyanopyridine compound that provides an IC50 of less than about 50 μ ?, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula II, wherein: G is selected from the group consisting of -O- and -S-; when G is sulfur, R4 and R42 are optionally absent, or are oxo; when G is -O-, R41 and R42 are absent; R is hydrogen; R 2 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, hydroxy C 1 -C 2 alkyl, C 1 -C 2 alkoxyphenyl, C 1 -C 2 alkoxy C 1 -C 2 alkyl, C 1 -C 2 amino alkyl, and C 1 -C 2 phenyl alkyl; R35 and R3S are each independently selected from the group consisting of hydrogen, and dicyan Ci-C2 alkyl. R37 is selected from the group consisting of hydrogen, and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, C ^ -Cz alkoxy, amino, carboxy, C2 diamino alkoxy, halo, 2-propenoxy, C3-C4 isoalkylcarboxyCi-C2 alkoxy, and dialkyl amino CrC2; R39 is selected from the group consisting of hydrogen, hydroxy, C1-C2 alkoxy, hydroxy alkoxy Ci-C2, alkoxy Ci-C2 alkoxy C1-C2, amino alkoxy Ci-C2, morpholino alkoxy Ci-C2, carboxyl alkoxy Ci-C2, pyrrolidyl C1-C2 alkoxy dialkylamino CrC2 C1-C2 alkoxy, pyrrolidyl C2 alkyl, C3-C3 isoalkylcarboxy, CrC2 alkoxy, and 2-propenoxy; wherein groups R38 and R39 optionally join to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, Ci-C2 alkoxy, nitro, amino, and pyrrolidyl Ci-C2 alkoxy. In another embodiment, the present method can be practiced by administration of an aminocyanopyridine compound that provides an IC5o of less than about 20 μ ?, in an in vitro assay of MK-2 inhibitory activity. Examples of such compounds comprise the compound shown in formula II, wherein: G is selected from the group consisting of -O- and -S-; when G is sulfur, R4 and R42 are optionally absent, or are oxo; when G is -O-, R4 and R42 are absent; R1 is hydrogen; R 2 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, hydroxy C 1 -C 2 alkyl, C 1 -C 2 alkoxyphenyl, C 1 -C 2 alkoxy C 1 -C 2 alkyl, and C 1 -C 2 alkyl amino; R35 and R36 are each independently selected from the group consisting of hydrogen, and dicyanoethyl; R37 is selected from the group consisting of hydrogen, and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, C 1 -C 2 alkoxy, amino, carboxy, C 1 -C 2 diamino alkoxy, halo, 2-propenoxy, C 3 -C 4 isoalkylcarboxy C 1 -C 2 alkoxy, and C 2 4 dialkylamino; R39 is selected from the group consisting of hydrogen, hydroxy, alkoxy CrC2, hydroxy alkoxy Ci-C2, alkoxy Ci-C2 alkoxy C1-C2, amino alkoxy C-1-C2, morpholino alkoxy C1-C2, carboxyl alkoxy Ci-C2, pyrrolidyl Ci-C2 alkoxy, dialkylamino C C2 alkoxy Ci-C2, pyrrolidyl Ci-C2 alkyl, isoalkylcarboxi C3-C4 C1-C2 alkoxy, and 2-propenoxy; wherein groups R38 and R39 optionally join to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, methoxy, nitro, and amino. Examples of aminocypyridine MK-2 inhibitor compounds that can be used herein include the present method, without limitation, the following: 2-amino-4- (2-fluorophenyl) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6,7-dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonitrile , 2-amino-4- (2,3-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 8-amino-6- (2- furyl) -4,5-dihydro-1H-pyrazoo [4,3-h] quinoline-7-carbonitrile, 2-amino-3-cyano-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-8-carboxylic acid, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] -1H-pyrrole-2-carboxamide, 2-amino-4-phenyl-6,8 -dihydro-5H-pyrazoIo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (2-furyl) -4- (1-methyl-1H-imidazol-4-yl) nicoylinitrile , 8-amino-6- (2-furyl) -4,5-dihydro-1 H -pyrazolo [4,3-h] quinoline-7-carbonitrile, 2-amino-4- (2-furyl) -8- hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2,6-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (4-hydroxyphenyl) -4- (1 H -imidazol-5-yl) nicotinonitrile, 2-amino-4- (2-phorophenyl) -6- (2-furyl Nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (2-fluoryl) -5.6- (2-fluorophenyl) -5,6- dihydrobenzo [h] quinoline-3-carbonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzoic acid, 2-amino-6- (2-furyl) -4 - (1 H-imidazol-5-yl) nicotinonitrile, 2-amino-4- (2-furyl) -6- (1 H -pyrazol-3-yl) nicotinonitrile, 2-amino-3-cyano-4- ( 4H-1, 2,4-triazol-3-yl) -5,6-dihydrobenzo [h] quinoline-8-carboxylic acid, 2-amino-6- (3-hydroxyphenyl) -4- (1 H-imidazole-5 -yl) nicotinonitrile, 2-amino-6- (2-furyl) -4- (1H-imidazoI-4-yl) nicotinonitrile, 2-amino-4- (2,4-difluorophenyl) -6,7-dihydro- 5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 4,6-diamino-2- (trifluoromethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino- 4- (2-furyl) -6,8-dihydro-5H-pyrrolo [3,4-h] quinoline-3-carbonitrile, 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridine] -2-yl] benzoic, 2-amino-4- (2-f) uryl) -5,6-dihydro-1, 8-phenanthroline-3-carbonitrile J 2-amino-6- (3,4-dihydroxyphenyl) -4- (2-fluorophenyl) nicotinonitrile, 2-amino-4- (1 - methyl-1 H-imidazol-4-N) -6-phenylnicotinonitrile, 2-amino-4- (2-furyl) -6- (1H-pyrazol-3-yl) nicotinonitrile, 4- [6-amino-5 -cyano-4- (1 H-imidazol-5-yl) pyridin-2-yl] benzoic acid, 2-amino-4- (3-fluorophenyl) -6,8-dihydro-5H-pyrazolo [3,4-h3-quinoline] -3-carbonitrile, 2-amino-6- (3,4-dihydroxypheni) -4- (2-fluorophenyl) nicot! Nitrile, N-. { 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] phenyl} Methansulfonamide, 2-amino-4- (2-furyl) -6,7-dihydro-5H-pyrroIo [2,3-h] quinoline-3-carbonitrile, 2-amino-4- (1H-imidazole) 5-I) -6-phenylnicotonnonitrile, 2-amino-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile1 2-amino-4- (1H-imidazole-5) -yl) -6- (4-methoxyphenyl) nicotinonitrile, 2-amino-6- (3-chlorophenyl) -4- (1 H-imidazol-5-yl) nicotinonitrile, 2-amino-4- (2-furyl) -6- (1H-pyrazol-4-yl) nicotinonitrile, 2-amino-4- (4-methoxyphenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2- amino-4- (2,5-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (4-fluorophenyl) -6,8- dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (4H-1, 2,4-triazol-3-yl) -5,6-dihydrobenzo [h] quinoline- 3- carbonitrile, 4,6-diamino-2- (chloromethyl) -2,3-dihydro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (1H-) midazol-4-yl) -6-phenyleotinonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridn-2-yl] benzenesulfonic acid, 4- [6 -amino-5-cyano-4- (2-furyl) pyridin-2-yl] phenol boronic, 2-amino-6- (4-methoxyphenyl) -4- (4H-1, 2,4-triazol-3-yl) nicotunomyl, 2-amino-4- (2-fluorophenyl) -6- (3-furyl) nicotonitrile, 2-amino-6- (2-furyl) -4- (methylthio) nicotonitrile, 2-amino- 4- (2-fluorophenyl) -6- (3-hydroxyphenyl) nicotinonitrile, 8-amino-6- (2-furyl) -4,5-dihydro-2H-pyrazolo [4,3-h ] quinoline-7-carbonitrile, 2-amino-4- (2-bromophenyl) -6- (2-furyl) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (4-hydroxy-phenyl) -nicotinonitrile, 2-amino-4-phenyI-6-thien-2-ylnicotinonitrile, 2-amino-4- (3-methoxyphenyl) -6,7-dihydro-5H-pyrazoium [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -7-methyl-6,7- Hydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-fluorophenyl) -6- (1 H -pyrrol-2-yl) n-trichonitrile, 2-amino-4- (2-furyl) -5-methyl-6,8-dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2 -furyl) -6- (1-methyl-1 H-pyrrol-3-yl) nicotinonitrile, 3-amino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile, N- [4- (2- amine-3-cyano-6,7-dihydro-5H-p-azozo [3,4-h] quinolin-4-yl) phenyl] acetamide, 6-amino-4 - [(4-methoxyphen l) amino] -2- (trifluoromethyl) -2,3-dihydro [2,3-b] pyridine-5-carbonitrile, 4- [6-amino-5-cyano- 4- (2-furyl) pyridin-2-yl] -N- (tert-butyl) benzenesulfonamide, 4,6-diamino-2-ethyl-2,3-dihydrofuro [2,3-b] pyridine -5-carbonitrile, 6-amino-4- (2-furyl) -2,4'-bipridine-5-carbonyltryl, 2,4-diamino-6- (methylthio) nicotinonitrile, acid 3- (2-amino-3-cyano-6,7-dihydro-5H-pyrazoo [3,4-h] quinolin-4-yl) benzoic acid, 2-amino-6- (4-chlorophenyl) -4 - (H-imidazol-5-yl) nicotinnonyl, 2-amino-4- (1,3-benzodioxol-4-yl) -6,7-dihydro-5H-pyrazolo [3 , 4-h] quinoline-3-carbonitrile, 4,6-diamino-2-methyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile! 2-amino-4- (1 H-imidazol-5-yl) -6- [4- (methylsulfonyl) phenyl] n-trichonitrile, 2,4-diammonoquinoline-3-carbonitrile , 2,8-diamino-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-aminono-4,6-di (2-furyl) n-trinonitrile, 4,6-diamino-2-butyl-2,3-dihydro [2,3-b] ] pyridine-5-carbonitrile, ethyl 4- [6-amino-5-cyano-4- (1 H-imidazol-5-yl) pyridn-2-yl] benzoate, 2,4-diamino-6-methoxynicotinonitrile, 2-amino-4-methylnicotinonitrile, 2-amino-4- (4-cyanophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3 carbonitrile, 2-amino-4-cyclopropyl-6-methylnicotinonitrile, 2-amino-4- (2-furn) -6- (1-methyl-1H-p! rrol-2-! l) nicotinonitriio, 2-amino- 4- (2-chlorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (2-furyl) -4- (4-phenoxyphenyl) nicotinonitrile , 2-amino-4-pyridin-3-yl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6-. { [2- (4-chlorophenyl) -2-oxoethyl] thio} -4- (2-furyl) pyridine-3) 5-dicarbonitrile, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] phenylboronic acid, 2 -amino-6- (3-chlorophenyl) -4- (1 H -imidazol-4-yl) nicotinonitrile, 4- (6-amino-5-cyano-4-phenylpyridin-2-yl) -N- (tert- butyl) benzenesulfonamide, 2-amino-4-methoxynicotinonitrile, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] benzoic acid, 4,6-diamino-2 - [(4 -methoxyphenoxy) methyl] -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-fluorophenyl) -6- (4-methoxyphenyl) nicotinonitrile, 4- [6- amine-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] -N- (tert-butyl) benzenesulfonamide, (2,4-diamino-3-cyano- 5 H -chromene [2,3-b] pyridin-9-yl) oxy] acetic acid, 3-pyridinecarbonitrile, 2-amino-4-methylim 2-amino-6- (2-furyl) nicotinonitrile, 2-amino-4 - (2-furyl) -6- (3-hydroxyphenyl) nicotinonitrile, 4- [6-amino-5-cyano-4- (2-furii) pyridin-2-yl] benzamide J 2-amino-4- (2- furyl) -7-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6- (1 H -indol-3-yl) nicotinonitrile, 2 -amino-4-pirin-4 -yl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (3-fluorophenyl) -6- (4-hydroxyphenyl) nicotinonitrile1 -amino-4- [2- (difluoromethoxyl) phenyl] -6,7-dihydro-5H-pyrazoo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6- thien-3-ylnicotinonitrile, 2-amino-4- (3-fluorophenyl) -6- (4-methoxyphenyl) nicotinonitrile, 2- [2-amino-3-cyano-6- (2-furyl) pyridine) 4-yl] phenylboronic acid, 2,4-diamino-6-propylpyridine-3,5-dicarbonitrile, 4,6-d-amino-2 - [(prop-2-ynyloxy) methyl] -2,3 -dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4,6-diamino-2- (hydroxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino -6- (2-furyl) -4- [4- (trifluoromethyl) phenyl] nicotinonitrile, S-amino ^ -methylthienoP ^ -bjpyridine-e-carbonitrile, 2-amino-4- (2-furyl) -5,5 -dimeti-6,8-dithy-5H-pyrrazolo [3,4-h] quinoline-3-carbonyl, N- [3-cyano-4- (2-fluorophenyl) - 6- (2-furyl) pyridin-2-yl] glycine, 2 - [(allyloxy) methyl] -4,6-diamino-2,3-dihydrofuro [2,3- b] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6-methyl- 5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 4,6-diamino-2- (methoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino- 4- (2-furyl) -6- (1 H -indoI-3-yl) nicotinonitrile, 2-amino-4- (2-funl) -6- [4- (1H-imidazol-1-yl) phenyl] nicotinonitrile, 2-amino-4- (2-furyl) -6- (4-hydroxy-phenyl) nicotinonitrile, 2-amino-4- (2-furyl) -5,6,7,8-tetrahydro -5,8-methanoquinoline-3-carbonitrile, 4,6-diamino-2- (εpropoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 3- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] phenylboronic acid, 4,6-diamino-2- (ethoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (4-bromophenyl) -6- (2-furyl) nicotinonitrile, 4,6-diamino-2 - [(1,1, 2,2-tetrafluoroethoxy) methyl] - 2,3-dihydrofuro [2,3-b] pyridine-5-carbonitriyl, 2-amino-4- [2-luoro-4- (trifluoromethyl) phenyl] -6- (2-furyl) nicotinonitrile, 2-amino-4- (2-methoxyphenyl) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-fluorophenyl) -5-methyl- 6,8-dihydro-5H-pyrazolo [3J4-h] quinoline-3-carbonitrile, 3,6-d-amino-4-ethyl-1 H-pyrazolo [3,4-b] pyridine-5-carbonitrile It, 6-amino-4- (2-furyl) -2,2'-bipyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6- (8-hydroxy-1-naphthyl) nicotinonitrile , 4- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) benzoic acid, 2-amino-6- (3,4-dichlorophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-4- (2-furyl) -6- (10H-phenothiazin-2-N) nicotinonitrile, sodium 2-amino-3-cyano-4-quinolinecarboxylate, -anilino-4- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile, 2-amino-4- (3-fluorophenyl) -6- (2-furyl) nicotinonitrile, 2-amino-4- ( 4-fluorophenyl) -6- (2-furyl) nicotinonitrile >; 4,6-diamino-2- (tert-butoxymethyl) -2 > 3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6- (1,3-thiazoI-2-yl) nicotinonitrile, 4- (2-fluorophenyl) -6- (2-furyl) -2-piperidin-1-N-nicotinonitrile, 2-amino-6- (4-chlorophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-6- (4-hydroxyl) Phenyl) -4- (2-methoxyphenyl) n-phenyl-1-trichloride, 2-amino-6- (2-furyl) -4- (2-hydroxyphenyl) nicotinonitrile, 3- (2 methyl-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinoyl-4-yl) benzoate, 2-amino-4- (2-chlorophenyl) -6- (5-methyl-2-furyl) n-trinonitrile, 3,6-diamino-2-benzoyltin [2,3-b] pyridine-5-carbonitrile, methyl 4- [ 6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzoate, 2-aminonicotinonitrile, 2-amino-4- (2-furyl) -8-. { [2- (trimethylene) ethoxy] meth} -6,8-Hydro-5H-párazoI [3,4-h] quinoline-3-carboriitrile, 3-amino-5H-pyrid [4,3-b] ndol-4- carbonitrile, 2- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) benzoic acid, 2-amino-6- (4-methoxyphenyl) - 4-phenylnicotinonitrile, 2-amino-4- (2-furyl) -5) 6,7,8-tetrahydroquinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6-isobutylnicotinonitrile, 2- amine-6-benzyl-4- (2-furyl) nicotinonitrile, 2-amino-4- (2-furyl) -6-methyl-5-phenylnotronic acid, 2-am No-4- (2-furyl) -6- [4- (1-trifluoromethoxy) phenyl] nitrotonitrile, 2-amino-4- (2-furyl) -6-propyl-5,6,7 , 8-tetrahydro-1, 6-naphthyridine-3-carbonitrile, 2-amino-4- (2-furyl) benzo [h] quinoline-3-carbonitrile, 2-amino-6- (4-methoxyphenyl) -4-thien-2-ylnicotinonitrile, 2-amino-4- (2-fluorophenyl) -6-tetrahydrofuran-2-ylnicotinitrile, 6-amino-5-cyano-4- (2 -furyl) ethyl pyridine-2-carboxylate, 2-amino-4- (2-furyl) -9-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- ( 2-furyl) -8-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonit ryl, 2-amino-4- (2-furyl) -8,9-dimethoxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -7-methoxy- 5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -7,9-dimethyl-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] ethyl benzoate, 2-amino-6- (3-bromophenyl) -4- (2- furil) nicotinonitrile, 2-amino-4- (2-furyl) -6- [4- (trifluoromethyl) phenyl] nicotinonitrile, 2-amino-4- (2-furyl) -6- [3- (trifluoromethyl) phenyl] nicotinonitrile, 2-amino-4- (2-furyl) -6- [4- (methylsulfonyl) pheny] nicotinonitrile, 4,6-diamino-2- (phenoxymethyl) -2,3- dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4,6-diamino-3-phenyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4,6-diamino-3- vinyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonyltrio, 2-amino-4- (2-fluorophenyl) -5-methyl-6,8-dihydro-5H- prazrazolo [3,4 h] quinoline-3-carbonitrile, 3-amino-1-methyl-5,6,7,8-tetrahydroquinoline-4-carbonitrile, 2-amino -4- (2-fluorophenyl) -5,5-dimethyl-6,8-dihydro-5H-pyrrazolo [3 , 4-h] quinoline-3-carbonyltryl, 2-amino-4- (2-fluorophenyl) -6- (3-hydroxy-phenyl) nicotonitrile, 2-amino-4- [2- (difluoromethoxy) phenyl] -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2- (bicyclamine) -4- (2-fluorophenyl) -6- ( 2-furyl) n¡cotonnonitrile, 2-amino-4- (2-furyl) -6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2- b) pyridine-3-carbonitrile, 2-amino-4- (2-furyl) -5H-indene [1,2-b] pyridine-3-carbonitrile, 3- amino-1- methyl-5,6,7,8-tetrahydro-1,3-quinoline-4-carbonyltryl, 2-amino-4- (2-fluorophenyl) -6- (3-hydroxyphenyl) nicotinonitrile , 2-amino-4- (2-thienyl) -5,6,7,8-tetrahydro-3-quinolinecarbonitrile, 2-amino-4- (3-fluorophenyl) -5,6,7,8 -tetrahydro-3-quinolinecarbonitrile, 2- (1-pperidinyl) -6- (2-thienyl) -4- (trifluoromethyl) n-phenylnitrile, 2- (dimethylamino) -6- (2-t-phenyl) ) -4- (trifluoromethyl) nicotinnonitrile, 3- quinolinecarbonitrile, 2-amino-4-methyl- or 2-amino-4-methyl-3-quinoxycarbonitrile, 2-amino-4- (4-methoxy-phenyl) -6- (2-t-phenyl) n-trinonitrile, 2-amino-6-ci Clopropyl-4- (2-methoxy-phenyl) n-phenyl-nitrile, 2-amino-4- (2-fluorophenyl) -6-phenyl-nicotinonitrile, (4bS, 8aR) -2,4-diam No-4b, 5,6,7,8,8a-hexahydro [1] benzofuro [2,3-b] pyridine-3-carbonitrile, 2-amino-4- (2- fluorophenyl) -5,5-dimethyl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -5-phen L-6,8-dhydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonyltryl, 3-amino-1, 6-dimethyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4-carbonitrile, S-amino-I J-dimethyl-S.ej. S-tetrahydro-y-naphthine-2-carbonyl, 2-amino-4- (2-fluorophenyl) -5-phenyl-6,8-dhydro-5H-pyrazolo [3,4-h] quinoline-3 -carbonitrile, 2-amino-4- (2-fluorophenyl) -5-phenyI-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, , 6-d-amino-2- (morpholin-4-methyl) -2,3-dihydrofuro [2,3-b] pyridin-5-carbonitrile, (4,6-d-amino-5) Ethyl-2-oxo-2,3-dihydro-1 H -pyrrolo [2,3-b] pyridin-1-yl) acetate, 2-amino-4- (2-methoxyphenyl) ) -6- (5-methyl-2-furyl) nicotinonitrile, 2-amino-6-methyl-4- (4-nitrophenol) nicotinone, 2-amino-4- (3,4 -d-methoxyphenol) -6- (5-methyl-2-furyl) nicotonitrile, 2,4-diamno-6 - [(4-methoxyphenyl) thio] nicotinonitrile, 4,6- diamino-2- (phenoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4,6-d-amino-3-phenyl-2,3- dihydrofuran [2,3-b] pyridine-5-carbontrotyl, 4,6-d-amino-2 - [(2-meth1-phenoxy) methyl] -2,3-dihydrofuro [2,3-b] ] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6- (4-methoxyphenyl) n-phenyl-n-triyl, 2-amino-4- (3-fluorophenyl) -5,6-dihydro-benzo [h] quinoline-3 -carbonitrile, 2-amino-4- (4-methoxyphenyl) -6,7-dihydro-5H-cyclopenta [b] pyridine-3-carbonitrile, 2-amino-9-ethyl-9H -pyrid [2,3-b] indoIe-3-carbonyltrio, 2-amino-6-isobutyl-4- (4-methylphenyl) nicotonitrile, 1- (2-furyl) - 3 - [(3-hydroxypropyl) amino] -5,6,7,8-tetrahydroisoquinoline-4-carbonitrile, 2-azepane-1-yl-6- (4-phlorophenol) -4-phenyl cotinontrile, 2-amino-6-tert-butyl-4- (4-methylphenyl) nicotinnonitrile, 2-amino-4- (4-bromophenyl) -6-methylnicotinone, 2-amino -4-thien-2-yl-5,6,7,8,9,10-hexahydrocycloocta [b] pyridine-3-carbonitrile, 2-amino-4- (4-chlorophenyl) -6,7,8,9 -tetrahydro-5H-cyclohepta [b] pyridine-3-carbonitrile, 2- (allylammon) -5-amino-7- (4-bromophenyl) thieno [3,2-b] pyridine-3,6-dicarbonitrile, 2-amino-4-pyridin-3-yl-5,6l7,8,9,10-hexahydro-cyclooxy [b] pyridione-3-carbonitrile, 2 -amino-4- (4-bromophenyl) -6-tert-butylnicotinonitrile, l ^ -furi-S-morfol in ^ -il-S.ej.S-tetrahydroisoquinoline ^ -carbonitrile, 2-amino-4- (4-rnethylphenyl) -6,7-dihydro-5H-cyclopentany [b] pyridine-3-carbonitrile, 2-amino- 7,7-dimethyl-7,8-dihydro-5H-pyran [4,3-b] pyridine-3-carbonitrile, 2-amino-6-isobutyl-4- (4-methoxyphenyl) nicotinonitrile, 4J6-diamino-2 -oxo-1-phenyl-2,3-dihydro-1 H -pyrrolo [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-methoxyphenyl) -5,6-dimethylinotinonitrile, 2- (dimethylamino) -4- (2-fluorophenyl) -6- (2-furyl) nicotinonitriio, 2- (dimethylamino) -4- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile, 4- (2 -fluorophenyl) -6- (2-furyl) -2- (methylamino) nicotinonitrile, 4- (2-fluorophenyl) -6- (2-furyl) -2-morpholin-4-ylnicotinonitrile, tert-butyl N- [3 -cyano-4- (2-fluorophenyl) -6- (2-furyl) pyridin-2-yl] glycinate, 2- (Ethylamino) -4- (2-phlorophenyl) -6- (2-furyl) nicotinonitrile, ethyl 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] benzoate , 2-amino-6- (2-fluorophenyl) -4- (3-furyl) nicotinonitrile, 6-amino-4- (2-fluorophenyl) -2,2, -bipyridine-5-carbonitrile, 2-amino-4- (2-fluorophenyl) -6-thien-2-ylnicotinonitrile, 6-amino-5-cyano-4- (2-fluorophenyl) pyridine-2-carboxylic acid ethyl ester, 2-amino-6- (2-furyl) -4 phenyl-nicotinonitrile, 2-amino-3-cyano-4- (2-furyl) -5,6,7,8-tetrahydroquinoline-6-carboxylic acid, 2-amino-4- (2- furyl) -6- (4-hydroxyphenyl) -5-methyl-nicotinonitrile, 2-arnino-4- (2-furyl) -6- (4-methoxy-phenyl) -5-methyl-trichloride , 2-amino-6- (4-fluorophenyl) -4- (2-furyl) -5-methynicotinonitrile, 2-amino-4- (2-furyl) -5,6-diphenyl-nicotinonyl, 2-am No-4- (2-furyl) -5-methyl-6-phenolnicotinonitrile, 2-amino-6- (3,4-dylmethyl) -4- (2-furyl) nicotinone tr, 2-amino-6- (4-fluorophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-4- (3-fluorophenyl) -6- (3- hydroxyphenyl) nicotinonitrile, 6-amino-4- (3-fluorophenyl) -2,4'-bipyridine-5-carbonitrile, 6-amino-4- (2-fluorophenyl) -2,4'-bipyridine- 5-carbonyl, 2-amino-4-butyl-6-methyl otithonitrile, 2-amino-6-methyl-4-propylnicotonitrile, 2-amino-4-ethyl-6-methylnicotinonitrile, 2-amino-4,6-dimethylnicotinonitrile, 2-amino-4- [2 - (hexyloxy) phenyl] -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonomethyl, 2-amino-4- [2- (beta-D-glucopyranosyloxy) ) phenyl] -6,7-dihydro-5H-pyrrazol [3,4-h] quinoline-3-carbonitrile, 4- [2- (allyloxy) phenyl] -2-amino -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, [2- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] ] quinolin-4- l) phenoxy] methyl acetate, 2-amino-4- (2-ethoxyphenyl) -6,7-dihydro-5H-pyrrazolo [3,4-h] quinoline- 3-carbonitrile, ethyl 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] -1H-pyrrole-2-carboxylate, 2-amino -6-methylnicotinonitrile, 2-amino-6- (4-cyanophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-6- (4-fluorobenzyl) -4- (2-furyl) nicotinonitrile, 2-amino -5- (4-fluorophenyl) -4- (2-furyl) -6-methylnicotinonitrile, 2-amino-4- (2-furyl) -6- (4-methoxyphenyl) nicotinonitrile, 2-amino-4- (2-methylphenyl) -5,6,7,8-tetrahydroquinoline-3-c arbonitrile, 2-amino-4- (4-methoxyphenyl) -5,6,7,8-tetrahydroquinoline-3-carbonitrile, 2-amino-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitri 2-amino-6- (4-methoxyphenyl) -4- (2-methylphenyl) n-trinonitrile, 2-amino-4,6-bs (4-methoxyphenyl) nicotonitrile, 2-amino -4- (3-chlorophenyl) -6- (4-methoxyphenyl) nicotinonitrile, 2-amino-4- (2-chlorophenyl) -6- (4-methoxyphenyl) n-phenyl-nitronium, 2-amino-4- ( 2-furyl) -5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile, 2-amino-4- (2-furyl) -6- (4-methylphenol) nichotonitrile, 2-amino-4- (2-furyl) -6-phenolnicotinonitrile, 6-amino-4- (2-furyl) -2,3'-bipyridine-5-carbonyltryl, 2-amino-6 - (1,3-benzodioxol-5-yl) -4- (2-furyl) nicotinonitrile, 2-amino-4-isoquinolin-4-yl-6- (4-rethoxyphenyl) nicotonitrile, -amino-4- (1-benzothien-3-yl) -6- (4-methoxy-phenyl) n-trichnonitrile, 2-amino-6- (4-methoxyphenyl) -4-thien-3 ilnicotonnonitrile, 2-amino-4- (3-furyl) -6- (4-methoxy-phenyl) nicotonomethyl, 2-amino-6- (4-methoxyphenyl) -4- (1H- pyrrol-2-yl) nicotinonitrile, 2-amino-4- (2-fur) 1) -6- (1H-pyrroyl-2-yl) n-phenyl-nitrile, 2'-amino-6, - (4-methoxyphenyl) -3,4'-bipyridine-3'- carbonitrile, 2-amino-4- [2- (trifluoromethoxy) phenyl] -6,7-dhydro-5H-pyrazolo [3,4-h] quinol-3-carbonyltr lo, 2-amino-4- (2-furyl) -5H-thiochromeno [4,3-b] pyridine-3-carbonitrile, 2-amino-4. { 4 - [(2-Cyanoethyl) (methyl) amino] phenyl} -6,7-dihydro-5H-pyrazole [3,4-h] quinoline-3-carbonitrile, 2-amino-4- [2- (2-hydroxyethoxy) phenyl] -6,7-dihydro-5H-pyrazolo [ 3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-methylphenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino- 4- [4- (dimethylamino) phenyl] -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (1H-indol-7-yl) -6 , 7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 4- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinoline- 4-yl) methyl benzoate, 2- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) methyl benzoate, [2- ( 2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) phenoxy] acetic acid, 2-amino-6-phenylnicotinonitrile, 2-amino-6-cyclohexyl-nicotinonitrile, 2-amino-4- (2-furyl) -6- (1-trityl-H-pyrazol-4-yl) nicotinonitrile-2-amino -4- (2-fluorophenyl) -6- (4-hydroxy-phenyl) nicotinonitrile, 2,4-diamino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonomethyl, 2-amino-7,8-dihydroxy-4 - [(2-hydroxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile , 2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-4- (ethylamino) -7,8-dihydroxy -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9 -fluoro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4 -diamino-8- (2-hydroxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 8,10-diamino-2,3-dihydro-11 H- [1 , 4] dioxin [2 \ 3 ': 6,7] chromene [2,3- b] pyridine-9-carbonitrile, 2,4,7-triamino-5H-chromene [2,3-b] pyridine-3-carbonitrile 2,4-d-amino-5H-chromene [2,3 -b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromene [2,3-b] pyridine - 3-carbonitrile, 2,4-diamino-9-hydroxy-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-6,8 -dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamne-8-ethoxy-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-ethoxy-ethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino- 8- (2-aminoethoxy) -5H-chromene [2,3-b] pyridine-3-carbonyiyl, 2J4-d-amino-3-cyano-5H-chromone [2'3-b] pyridine-7-carboxylic acid, , 4-d-amino-8,9-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2) 4-diamino-8- (2-morpholin-4-methoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, [(2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridin-8-yl) oxy]] acetic acid, 2,4-diamino-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-pyrrolidine) n-1-ylethoxy) -5H-chromene [2,3-b] pyridin-3-carbonitrile, 2-amino-7,8-dimethoxy-4- (methylamino) -5H-chromene [2 , 3-b] pyridine-3-carbonitrile, 2,4-diamino-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4- diamino-8- [2- (dimethylamine) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4,7-triamino-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2- (2,4-diamino-3-cyano-8-methoxy-5H-chromene [2,3-b] pyridine -5-yl) malononitrile, 2,4-diamino-7,8-di [2- (amino) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diam No-9-nitro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy-4 - [(4-methoxyphenyl) amino] -5H-chromene [2 , 3-b] pyridine-3-carbonitrile, 2,4-d-amino-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile-2 (2, 4-diamino-3-cyano-7-hydroxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2 (2,4-diamino-3-cyano-7-bromo-5H) -chromeno [2,3-b] pyridin-5-yl) malononitrile, 2-amino-8-ethoxy-4- (ethylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4 , 9-triamino-5H-chromene [ 2,3-b] pyridine-3-carbonitrile, 2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbon tr, 2-amino-7,8-d, methoxy-4 - [(4-methoxy-phenyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2,4-diamino-3-cyano-7-methoxy-5H-chromene [2! 3-b] pyridin-5-yl) malononitrile, 2,4-diammon -9-hydroxy-8- (pyrimidin-1-ylmethyl) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 7,8-bis (allyloxy) -2, 4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-8- (2-ethoxy-ethoxy) -4 - [(2-ethoxyethyl) amino] - 5 H -chromene [2,3-b] pyridine-3-carbonitrile, tert-butyl. { [2,4-d¡amino-7- (2-tert-butoxy-2-oxoethoxy) -3-cyano-5H-chromene [2,3-b] p¡r¡din-8-l ] oxi} acetate, 2-amino-4 - [(2-aminonol) amino] -7,8-dimethoxy-5H-chromene [2,3-b] pyridin-3-carbonitrile, 2 (2,4-d¡amino-3-cyano-8-hydroxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 10,10-dioxide of 2,4,7-triamino-5H-thiochromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-bromo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-d¡methoxy-4- (propylammon) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-hydroxy-5H-thiochromen [2,3-b] pyridine-3-carbonitrile, 2,4-diamne-7- (dimethylammon) -5H-chromene [2, 3-b] pyridine-3-carbonitrile, 2,4-diamino-7-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile! 2 (2,4-diamino-3-cyano-9-methoxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2-amino-4- (benzylamino) -7,8-dimethoxy- 5 H -chromene [2,3-b] pyridine-3-carbonitrile, 8- (allyloxy) -2 ^ -diamino-5 H -chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9 -fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino -9- (2-pyrrolidin-1-ylethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-nitro-5H-chromene [2,3-b] pyridine -3-carbonitrile, 2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -, 8-naphthyridine-3-carbonitrile, [(2,4-diamino-3-cyano-5H-chromene [ 2,3-b] pyridin-9-yl) oxy] acetic, 2-amino-4-. { [2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 10,10-dioxido-2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pir D -na-3-carbonyltryl, ^ -diamino-Z-phenyl-SH-Gromenop ^ -bpyridine-S-carbonitrile, 2,4-d-amino-7-cioro-9-methyl-5H- chromene [2,3-b] pyridine-3-carbonitrile, 10,10-dioxide 2,4-diamino-7-fIuoro-5H-thiochromeno [2,3-b] pyridine-3-carbonomethyl, 8-ethoxy-2,4-bis (ethylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamno-5- (2-fluoro- phenyl) -8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonyl, 2,4-diamino-9- (2-hydroxyethoxy) -5H-chromene [2] 3-b] pyridine-3-carbonitrile, 2,4-diamino-9- (2-aminoethoxy) -5H-chromene [213-b] pyridine-3-carbonitrile, 2 (2, 4-d-amino-3-cyano-7-chloro-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2,4-bis. { [2- (dimethylamine) etl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonomethyl, 2-amino-4-. { [2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-yl) etl] amino} -7,8-dimethoxy-5H-chromene [2I3-b] pyridine-3-carbonitrile, 2,4-diamino-7-fluoro-5H-chromene [2,3-b] pyridine- 3-carbonitrile, 2,4-d-amino-7-bromo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-9- (py Din-4-ylmethoxy) -5H-crorneno [2,3-b] pyridine-3-carbonitrile, 2,4-diammon-7-cioro-5H-chromene [2,3-b] p Ridn-3-carbonyl, 2,4-d-amino-9-tert-butyl-5H-chromene [2,3-b] pyridine-3-carbonyltryl: 2,4-diamino- Ethyl 3-cyano-5H-chromene [2,3-b] pyridine-9-carboxylate, 2,4-diamino-9- [2- (dimethylamine) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-bis (butylamino) -7,8-d-methoxy-5H-chromene [213-b] pyridin-3 carbonitrile, 2-amino-4- (butylamino) -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 7,8-dimethoxy-2,4-bis (propylam) No) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-bis (ethylamine) -7,8-dimethoxy-5H-chromene [2,3-b] pyra Dina-3-carbonitrile, 2-amino-4- (ethylamino) -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-6 8-dimethoxy-5H-chrome no [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-7- (trifluoromethoxy) -5H-chromene [2,3-b] pyridine -3-carbonitrile, 2,4-diamino-7-bromo-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9-methoxy-7-nitro-5H -chromeno [2,3-b] pyridine-3-carbonitrile, 7,9-d¡amino-10H- [1,3] dioxolo [6,7] chromene [2,3-b] pyridine- 8-carbonitrile, 7,9-diamino-10H- [1, 3] dioxolo [6,7] chromene [2,3-b] pyridine-8-carbonitrile, 2,4-diamino-8-methyl-5H-crornene [2,3-b] pyridine-3-carbonitrile, 7,8-dimethoxy-2,4-bis [(2-methoxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 -amino-7,8-dimethoxy-4 - [(2-methoxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy-4 - [( 2-pyrrolidin-1-ylethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 7,8-dimethoxy-2,4-bis [(2-pyrrolidin-1-ylethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-bis (glycinyl) -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, N- (2-amino-3-cyano-7,8-dimethoxy-5H-chromene [2,3-b] pyridin-4-yl) glycine, 2,4-d acid iamino-3-cyano-5H-chromene [2,3-b] pyridine-9-carboxylic acid, 2,4-diamino-6-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2, 4-diamino-9-bromo-7-chloro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-bis (6-tilamno) -7,8-dihydroxy-5H- chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-6-bromo-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4- diamino-8-hydroxy-7,9-bis (piperidin-1-ylmethyl) -5H-chromene [2, 3-b] pyridine-3-carbonyl, 2,4-d-amino-5-phenyl-8-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile , 2,4-diamino-5- (3-fluoro-phenyl) -8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diam No-9-hydroxy-6,8-bs (piperidin-1-ylmethyl) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-bromo- 8-methoxy-5H-chromene [2,3-b] pyridin-3-carbonitrile, 2,4-diamino-5-phenyl-8-methoxy-5H-chromene [2,3-b] ] pyridine-3-carbonitrile, 10,10-dioxide 2,4-diamino-9-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-nitro -5H-thiochromene [2,3-b] pyridine-3-carbonitrile, 10,10-dioxide 2,4-diamino-7-methoxy-5H-thiochromene [2,3-b] pyridine-3-carbonitrile , 2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 0,10-dioxide of 2,4 ^? 3 ????? - 5? -1? ?? G ?? t ???? [2,3-¾ ?? p ^ ?? 3-3- carbonitrile, 2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 2) 4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 2-amino-7,9-dimethyI-5-oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7-isopropyl-5-oxo-5H-chromene [2,3- b] pyridine-3-carbonitrile, 2-amino-7-ethyl-5-oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7-methyl-5-oxo-5H- chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7-chloro-5-oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7-bromo- 5-oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-5-oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, and 3-amino-5H-pyrido [3,4-b] [4] benzothiazine-4-carbonitrile. It should be understood that the salts and prodrugs of the aminocyanopyridine compounds described herein, as well as forms of isomers, tautomers, racemic mixtures of the compounds and the like, which have the same or similar activity as the compounds described , they are considered to be included within the scope of the description of the compound. Aminocyanopyridine MK-2 inhibiting compounds of the type shown in formula II, include the tricyclic aminocypyridine MK-2 inhibiting compounds, such as benzonaptiridines, pyridochromans, and pyridothiochromans. A general method for the synthesis of these tricyclic aminocyanopyridines was shown in Scheme 1, below: Reaction Scheme 1: Z = OH, SH, NRaY G = 0, S, NR¡ In this method, the substituted benzaldehyde is reacted with a tricarbonitrile, preferably 2-amino-1-propene-1,1,3-tricarbonitrile. The reaction was carried out by heating the reagents to reflux in a solution of acetic acid and ethanol. The reaction product was concentrated in vacuo and dissolved in trifluoroacetic acid. Triethylsilane was added and the mixture was stirred. In a preferred method, the mixture was stirred at about 1 hour at 0 ° C. Then dichloromethane was added and the solids were collected. The solids can be collected by filtration, and can be washed with dichloromethane in ether. The solids comprise the desired tricyclic aminocypyridine MK-2 inhibitor compound of the type including benzonaptiridines, pyridochromans, and pyridothiochromans. It refers to the reactants and products shown above in the reaction scheme 1: Z can be OH, SH, or NRaY, where Y is a nitrogen protecting group. The group Y may be benzyl, allyl, an alkyl carbamate, or a benzyl carbamate. Other nitrogen protecting groups are known to people skilled in the art of organic synthesis. A preferred protecting group is tert-butylcarbamate. Ra can be an alkyl group, an aryl group or a heteroaryl group. The benzene ring of benzaldehyde can also be substituted by one, two, three or four additional R groups in 3, 4, 5 or 6 carbons. Each R can independently be hydrogen; I rent; aril; a heteroatom, such as O, N, or S, substituted with hydrogen, Ct-Ce alkyl, branched Ci-Ce alkyl, aryl, heteroaryl (wherein the heteroaryl may include, but are not limited to, pyrazolyl, inidizolyl, pyrryl, pyridyl, thiofile, furyl and pyrimidyl), ester and amido. The advantages of this method include that this is a general method that can be used to produce various types of tricyclic compounds of formula II depending on the types of reactions used. This is also an easy and direct synthesis method that can be carried out in a simple container. In one embodiment of this synthesis method, an MK-2 tricyclic aminocyanopyridine inhibitor compound can be prepared by reacting a substituted benzaldehyde having the structure: With a tricarbonitrile that has the structure: To form an aminocyanopyridine compound having the structure: wherein: Z is selected from the group consisting of -OH, -SH, and -NRaY; Ra is selected from the group consisting of alkyl, aryl, and heteroaryl; And it is a nitrogen protection group. Examples of such nitrogen protecting groups include benzyl, allyl, alkyl carbamates and benzyl carbamates. G is selected from the group consisting of -O-, -S-, and -NRX-; Rx is alkyl; Rb is selected from the group consisting of furyl and -NH-R2; R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl; R3 and R4 are each independently selected from the group consisting of hydrogen, dicyanalkyl, and substituted or unsubstituted heterocyclyl and cielite, wherein the substituents, are any comprising halo portions; and R5, R6, R7 and R8 are each independently selected from the group consisting of hydrogen, hydroxy, alkoxy, halo, alkyl, alkenyl, alkyl, arylalkyl, alkylaryl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, alkylcarboxyalkyl, alkylamino, aminoalkio, nitro, aryl, arylamino, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, heterocyclylalkyl, heterocyclyloalkoxy, carboxyalkoxy, alkylaminoalkoxy, alkylcarboxyalkoxy, pyrrolidylethoxy, hydroxyalkoxy, and alkyicarboxy, wherein R6 and R7 are such that they optionally join to form a 6-membered heterocyclic ring. members. In one embodiment of the general method described above, R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkyicarboxy, and carboxyalkyl; R3 and R4 are each independently selected from the group consisting of hydrogen, dicyanoalkyl, and substituted or unsubstituted heterocyclyl and cielite, wherein the substituents are any comprising the halo portions; R5 is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkyl, arylalkyl, or alkylaryl; R6 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkyaryl, or arylamino; R7 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclyloaikyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy; wherein the groups R6 and R7 can be joined to form a 6-membered heterocyclic ring; and R8 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclyloalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclyloaikyl. In a preferred embodiment of this invention, the substituted benzaldehyde comprises salicaldehyde and tricarbonitrile comprises 2-amino-1-propene-1, 1,3-tricarbonitrile. It is also preferred that the "Y" nitrogen protecting group comprises the tert-butylcarbamate. In one embodiment of the present method, Z is selected from the group consisting of -OH, -SH, and -NRaY; Ra is selected from the group consisting of alkyl, aryl, and heteroaryl; And it is a nitrogen protecting group that is selected from the group consisting of benzyl, allyl, alkyl carbamates and benzyl carbamate; G is selected from the group consisting of -O-, -S-, and -NRx; Rx is C6 alkyl; Rb is selected from the group consisting of furyl and -H-R2; R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl; R3 and R4 are each independently selected from the group consisting of hydrogen, dicyanoaikyl, and substituted or unsubstituted heterocyclyl and cielite, wherein the substituents are any comprising halo portions; and R5, R6, R7 and R8 are each independently selected from the group consisting of: hydrogen, hydroxy, amino, halo, nitro, branched or unbranched C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-6 alkoxy C-6, hydroxy C6 alkyl, hydroxy C6 alkoxy, C6 alkoxy C6 alkoxy C6 alkoxy Ci-C6 alkoxy C6 alkyl, C2-C6 alkenoxy, amino C6 branched or unbranched alkyl, diamino alkyl C2-C6, alkylamino Ci-C6 alkyl CrC6, alkylamino CrC6, di- (cylamino alky, alkylarylamino Ci-C4, alkoxyalkylamino CrC4, amino alkoxy Ci-Ce, di- (alkylamino CiC ^, alkoxy C2-C6, di- (alkyl Ci-C6) amino C1-C6 alkyl, Ci-C6 alkylamino CrC6 alkoxy, Ci-C6 alkoxy halo, Ci-C6 alkoxy dihalo, Ci-C6 trihalo alkoxy, cyano Ci-C6 alkyl, dicyano Ci-C6 alkyl, cyano alkoxy Ci -C6, dicyan C1-C6 alkoxy, carbamyl C1-C4 alkoxy, heterocyclyl C1-C4 alkoxy, heteroaryl C1-C4 alkoxy, sulfo, sulfamyl, alkylaminosulfonyl Ci-C4) hydroxy alkylaminosulfonyl Ci-C4, di- (Ci-C4 alkyl) aminosulfonyl, alkylthio CrC4l C1-C4 alkylsulfonyl, C1-C4 alkylsulfinyl, aryl, aryl C1-C6 alkyl, heterocyclyl C1-C6 alkyl heteroaryl C1-C6 alkyl, heterocyclyl C1-C6 alkoxy, heteroaryl alkoxy C ^ Ce, aryl alkoxy Ci-C6 , wherein the aryl ring may be substituted or unsubstituted and if substituted, the substituted group is selected from one or more of the groups consisting of Ci-C6 alkyl, hal or, amino, and C- -Ce alkoxy, substituted or unsubstituted C3-C6 cyclyl, C3-C6 heterocyclyl, and is substituted, the substituted group is selected from one or more of the groups consisting of Ci-C6 alkyl, Ci-C6 alkoxy, halo, amino, and wherein the C3-C6 heterocyclyl ring contains O, S, or N, Ci-C6 alkoxyC6 branched or unbranched alkoxycarbonyl, and carboxy, carboxyC1-C6 alkoxy, carboxyCi-alkyl C6l hydroxy alkoxycarbonyl C C4, CrC4 alkoxycarbonyl. And where the terms "alkyl, alkenyl, alkynyl, alkoxy, alkoxyalkyl, haloalkoxy, halo, alkylthio, alkylthioalkyl, heterocyclyl, cyclyl, aryl, heteroaryl, cycloaryl, and oxo" have the same meaning as described above. A general method for the synthesis of aminocyanopyridine inhibitors MK-2 which are not tricyclic benzonaphthyridines, pyridochromans, and pyridothiochromans can be found in Kambe, S. et al., Synthesis 5: 366-368 (1980). Further details of the synthesis of aminocyanopyridines are given in the examples. The MK-2 inhibitory activity of an aminocyanopyridine compound can be determined by any of the various methods known to those skilled in the art of enzyme activity testing. One such method is described in detail in the general methods section of the examples. In addition, the efficacy of an aminocyanopyridine-inhibiting compound MK-2 in therapeutic applications can be determined by the inhibition test of TNFa production, in a cell culture and in an animal model assay. In general, it is preferred that the aminocyanopyridine MK-2 inhibiting compounds of the present invention are capable of inhibiting the production and / or release of TNFα in cell cultures and in animal models. In the present method, the compounds of the MK-2 inhibitor aminocyanopyridine described herein can be used as inhibitors of MAPKAP kinase-2. When this inhibition is for a therapeutic purpose, one or more of the present compounds can be administered to a subject that is in need of MK-2 inhibition. As used herein, a "subject in need of MK-2 inhibition" is a subject who has, or is at risk of contracting, a disease or disorder mediated by TNFa. The diseases or disorders mediated by TNFα are described in more detail below. In one embodiment of the present method, a subject in need of prevention or treatment of a disease or disorder mediated by TNFa is treated with one or more of the aminocyanopyridine compounds present. In one embodiment, the subject is treated with an effective amount of the MK-2 inhibitory compound of aminocyanopyridine. The effective amount may be an amount that is sufficient to prevent or treat the disease or disorder mediated by TNFa. The amino-cyanopyridine compound that is used in the method to which it is subjected may be any amino-cyanopyridine compound described above. In the method to which it is subjected, the MK-2 inhibitor compound aminocyanopyridine can be used in any amount which is an effective amount. It is preferred, however, that that amount of the amino-cyanopyridine compound to be administered is within the range of from about 0.1 mg / day per kilogram of the subject to about 150 mg / day / kg. It is more preferred that the amount of the aminocyanopyridine compound be within a range from about 0.1 mg / day / kg to about 20 mg / day / kg. An amount that is within a range from about 0.1 mg / day / kg to about 10 mg / day / kg is even more preferred. When the term "around" is used herein in relation to a dose amount of the aminocyanopyridine compound, this is understood to mean an amount that is within ± 0.05 mg. By way of example, "about 0.1 - 10 mg / day" includes all doses within 0.05 to 10.05 mg / day. In another embodiment of the present invention, a pharmaceutical composition containing one or more of the MK-2 inhibitors of aminocyanopyridine can be administered to a subject for the prevention or treatment of a disease or disorder mediated by TNFa. The pharmaceutical composition includes an aminocypyridine MK-2 inhibitor of the present invention and a pharmaceutically acceptable carrier. In another embodiment, a kit may be produced that is suitable for use in the prevention or treatment of a disease or disorder mediated by TNFa. The kit comprises a dosage form comprising an MK-2 inhibitor of aminocyanopyridine in an amount comprising a therapeutically effective amount. How it is used here, an "effective amount" means the dose or effective amount to be administered to a patient and the frequency of administration to the subject which is easily determined by one of ordinary skill in the art, by the use of known techniques and by observation of the results obtained under analogous circumstances. The dose or effective amount to be administered to a patient and the frequency of administration to the subject can be readily determined by one of ordinary skill in the art by the use of known techniques and by observation of the results obtained under analogous circumstances. In the determination of the effective amount or dose, a number of factors are considered by the attending physician, including, but not limited to, the potency and duration of the action of the compounds used, the nature and severity of the disease to be treated, as well as sex, age, weight, general health and individual sensitivity of the patient to be treated, and other relevant circumstances. The phrase "therapeutically effective" indicates the ability of an agent to prevent, or improve the severity of the disorder, while avoiding adverse side effects commonly associated with alternative therapies. The phrase "therapeutically effective" is to be understood to be equivalent to the phrase "effective for treatment, prevention, or inhibition," and both are projected to qualify the amount of an agent for use in therapy which will achieve the purpose of improve the severity of pain and inflammation and the frequency of incidence, while avoiding adverse side effects commonly associated with alternative therapies. Those skilled in the art will appreciate that dosages can also be determined with Goodman &orientation; Goldman's The Pharmacoloqical Basis of Therapeutics, Ninth Edition (1996), Appendix II, pp. 1707-1711. The frequency of dosing will depend on the half-life of the active components of the composition. If the active molecules have a short half-life (for example, from about 2 to 10 hours) it may be necessary to give one or more doses per day. Alternatively, if the active molecules have a long half-life (for example, from about 2 to about 15 days) it may be necessary to give only one dose once per day, per week or even once every 1 or 2 months. A preferred dosage level is for administering the dose amounts described above to a subject once per day. For the purposes of calculation and expression a dosage degree, all doses expressed herein are calculated on an average quantity per day basis without taking into consideration the dosage degree. For example, a dose of 100 mg of an MK-2 inhibitor of aminocyanopyridine taken once every two days could be expressed as a dosage level of 50 mg / day. Similarly, the dosage degree of an ingredient where 50 mg is taken twice per day could be expressed as a dosage level of 100 mg / day. For purposes of calculating the dose amounts, the weight of a normal human adult will be assumed to be 70 kg. When the aminocypyridine MK-2 inhibitor is supplied together with a pharmaceutically acceptable carrier, the pharmaceutical compositions described above can be formed. Pharmaceutically acceptable carriers include, but are not limited to, physiological saline, Ringer's solution, phosphate solution or buffer solution, buffered saline, and other carriers known in the art. The pharmaceutical compositions may also include stabilizers, anti-oxidants, colorants, and diluents. The pharmaceutically acceptable carriers and additives are selected so that the side effects of the pharmaceutical compounds are minimized and the performance of the compound is not canceled or inhibited to such an extent that the treatment is not effective. The term "pharmacologically effective amount" will mean the amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being treated by a researcher or physician. This amount can be a therapeutically effective amount. The term "pharmaceutically acceptable" is used herein to mean that the modified name is appropriate for use in a pharmaceutical product. The pharmaceutically acceptable cations include metal ions and organic ions. More preferred are metal ions including, but not limited to, appropriate alkali metal salts, ferrous alkali metal salts and other acceptable physiological metal ions. Exemplary ions include aluminum, calcium, lithium, magnesium, potassium, sodium and zinc in their usual valencies. Preferred organic ions include protonated tertiary amines and quaternary ammonium cations, which include in part, trimethylamine, diethylamine, α, γ-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), and procaine. Exemplary pharmaceutically acceptable acids include, without limitation, hydrochloric acid, hydroiodic acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, melic acid, citric acid, isocitric acid, acid succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxalacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid, and the like. Also included in the invention are the isomeric and tautomeric forms and the pharmaceutically acceptable salts of the MK-2 aminocyanopyridine inhibitors. Illustrative pharmaceutically acceptable salts are prepared from formic acids, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranyl, mesylic, stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic , embonic (pamico), matansulfonic, ethanesulfonic, benzenesulfonic, pantothenic, toluenesulfonic, 2-hydroxyethanesulfonic, sulphanilic, cyclohexylaminosulfonic, algenic, ß-hydroxybutyric, galactárico and galacturónico. Suitable pharmaceutically acceptable base addition salts of compounds of the present invention include metal ion salts and inorganic ion salts. More preferred metal ion salts include, but are not limited to, appropriate alkali metal salts (Group a), alkaline earth metal salts (Group lia) and other acceptable physiological metal ions. Such salts may be made from the ions of aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Preferred organic salts can be made from tertiary amines and quaternary ammonium salts, which include in part, trifluoroacetate, trlmethylamine, diethylamine, N, N-dibenzyl-eylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (n-methylglucamine) and Procaine All of the above salts can be prepared by those skilled in the art by conventional means of the corresponding compound of the present invention. The method of the present invention is useful, and is not limited, to the prevention and treatment of diseases and disorders that are mediated by TNFa. For example, the MK-2 aminocianopyridine inhibitors of the invention could be useful for treating arthritis, including, but not limited to, rheumatoid arthritis, spondyloartopathies, gout arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Such inhibitory compounds of MK-2 aminocyanopyridine of the invention may be useful in the treatment of asthma, bronchitis, menstrual cramps, tendinitis, bursitis, connective tissue disorders or disorders, and skin-related conditions such as psoriasis, eczema, burns and dermatitis. The MK-2 aminocyanopyridine inhibitory compounds that are useful in the method of the invention may also be useful for treating gastrointestinal conditions such as inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome and colitis ulcerative and for the prevention or treatment of cancer, such as colorectal cancer. Such compounds that inhibit MK-2 aminocyanopyridine would be useful in the treatment of inflammation in diseases and conditions such as herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylarthrosis, Lumbar spondylorthrosis, vascular disease, migraine headaches, sinus headaches, tension headaches, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type 1 diabetes, myasthenia gravis , multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet syndrome, polymyositis, gingivitis, hypersensitivity, swelling that occurs after injury, myocardial ischemia, and the like. MK-2 inhibitors aminocianopyridine may also be useful in the treatment of ophthalmic diseases, such as retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, and acute injury to eye tissue. These compounds may also be useful in the treatment of pulmonary inflammation, such as associated with viral infections and cystic fibrosis. The compounds may also be useful for the treatment of certain disorders of the central nervous system such as cortical dementia which includes Alzheimer's disease. As used herein, the terms "disease or mediated TNFa disorder" were intended to include, without limitation, each of the symptoms or diseases mentioned above. The terms "treated" or "to treat" mean to alleviate symptoms, eliminate the cause either on a temporary or permanent basis, or to prevent or diminish the appearance of the symptoms. The term "treatment" includes relief, elimination of the cause or prevention of pain and / or inflammation associated with, but not limited to, any of the diseases or disorders described herein. In addition to being useful for human treatment, the compounds that are subjected are also useful for the treatment of mammals, including horses, dogs, cats, rats, mice, sheep, pigs, etc. The term "subject" for treatment purposes includes any human or animal subject that is in need of the prevention or treatment of any of the diseases or disorders mediated by TNF. The subject is commonly a mammal. "Mammal", as that term is used here, refers to any animal classified as a mammal, which includes humans, domestic and farm animals, and zoo animals, sports animals or pets, such as dogs, horses, cats, livestock, etc. Preferably, the mammal is a human. For methods of prevention, the subject is any human or animal subject, and preferably is a subject that is in need of prevention and / or treatment of a disease or disorder mediated by TNFa. The subject may be a human subject who is at risk of obtaining a disease or disorder mediated by TNFα, such as those described above. The subject may be at risk due to genetic predisposition, sedentary lifestyle, diet, exposure to agents that cause disorder, exposure to pathogenic agents and the like. The pharmaceutical compositions that are subjected can be administered enterally and parenterally. Parenteral administration includes subcutaneous, intramuscular, intradermal, intramammary, intravenous, and other administrative methods known in the art. Enteral administration includes solution, tablets, sustained release capsules, enteric coated capsules and syrups. When administered, the pharmaceutical composition may be at or near body temperature. In particular, the pharmaceutical compositions of the present invention can be administered orally, for example, as tablets, coated tablets, dragees, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preservation agents with the purpose of providing tasty and pharmaceutically elegant preparations. The tablets contain the active ingredient in combination with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulation and disintegration agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or may be coated by known techniques to retard disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a prolonged period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may also be presented as gelatin capsules wherein the active ingredients are mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients they are present as such, or mixed with water or an oily medium, for example, peanut oil, liquid paraffin, or olive oil. Aqueous suspensions containing the MK-2 inhibitors of aminocyanopyridine can be produced in addition with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example, sodium carboxymethyl cellulose, methyl cellulose, hydroxypropylmethyl cellulose, sodium alginate, tragacanth gum, polyvinyl pyrrolidone and acacia gum; the dispersing or humidifying agents may be naturally occurring phosphates, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example, polyoxyethylene stearate, or condensation products of ethylene oxide with chain aliphatic alcohols. long, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and anhydrides of hexitol, for example polyoxyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example, ethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, or one or more sweetening agents, such as sucrose or saccharin. . Oily suspensions may be formulated by suspending the active ingredients in an omega-3 fatty acid, a vegetable oil, for example peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as paraffin liquid Oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation. These compositions can be preserved with the addition of an antioxidant such as ascorbic acid. Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in addition with a dispersing agent or humectants, a suspending agent and one or more preservatives. Suitable dispersing or humidifying agents and suspending agents are exemplified by those already mentioned above. Additional excipients may also be present, for example sweetening, flavoring and coloring agents. Syrups and elixirs containing novel compounds can be formulated with sweetening agents, for example glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, preservative and flavoring and coloring agents. The compositions that are subjected may also be administered parenterally, either subcutaneously, or intravenously, intramuscularly, or intramuscularly, or by infusion techniques, in the form of sterile injectable aqueous or oleaginous suspensions. The suspensions may also be formulated according to the known art using those dispersing agents or humectants and appropriate suspending agents which were mentioned above., or other acceptable 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 vehicles and acceptable solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft fixed oil can be employed including mono-, or synthetic di-glycerides. In addition, n-3 polyunsaturated fatty acids may find use in the preparation of injectables. The objective compositions can also be administered by inhalation, in the form of aerosols or solutions for nebulizers, or rectally, in the form of suppositories prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperature but liquid at rectal temperature and therefore melts in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. The novel compositions can also be administered externally, in the form of creams, ointments, gels, eye drops, solutions or suspensions. The daily doses can vary within wide limits and will be adjusted to the individual requirements in each particular case. In general, for administration to adults, an appropriate daily dose was described above, although the limits that were identified as being preferred may be exceeded if appropriate. The daily dose can be administered as a single dose or in divided doses. Various delivery systems include capsules, tablets, and gelatin capsules, for example. The following examples describe the preferred embodiments of the invention. Other embodiments within the scope of the claims of this will be apparent to a person skilled in the art of the consideration of the specification or practice of the invention as disclosed herein. It is projected that the specification, together with the temples, be considered to be exemplary only, with the scope and spirit of the invention indicated by the claims which continue after the examples. In the examples all percentages are given on a weight basis unless indicated otherwise.

General Information for Preparation Methods Unless noted otherwise, reagents and solvents are used as received from commercial suppliers.

NMR analysis: The proton nuclear magnetic resonance spectra were obtained on a Varían Unit innova 400 spectrometer, a Varit Unít Innova 300, a Varity Unity 300, an AMX 500 Broker or an AV-300 Broker. The chemical changes are given in ppm (d) and the coupling constants, J, are reported in Hertz. Tetramethylsilane is used as an internal standard for the proton spectra and the peak of the solvent is used as the reference peak for the carbon spectra. The mass spectra were obtained in an ionization mass spectrum at atmospheric pressure (APCI) Perkin Elmer Sciex 100, an ion trap mass ionization mass spectrometer (ESI) Finnigan LCQ Duo LCMS, an EM-CLAP (ESI) ) PerSeptive Biosystems Mariner TOF, or a mass spectrometer (ESI) Waters ZQ.

Determination of ICsn of MK-2: The recombinant MAPKAPK2 is phosphorylated at a concentration of 42-78 μ? by incubation with 0.23 μ? of p38a active in 50 mM HEPES, 0.1 mM EDTA, 10 mM magnesium acetate, and 0.25 mM ATP, pH 7.5 for one hour at 30 ° C. Phosphorylation of HSP peptide (KKKALSRQLSVAA) by MAPKAPK2 is measured using an ion exchange resin capture assay method. The reaction is carried out in 50 mM of β-glycerol phosphate, 0.04% BSA, 10 mM magnesium acetate, 2% DMSO and 0.8 mM dithiothitol, pH 7.5 in the presence of the HSP peptide with 0.2 μ [? 33] ??? and 0.03mM ATP. The reaction is initiated by the addition of 15 nM MAPKAPK2 and left to incubate at 30 ° C for 30 min. The reaction is over and the [? 33?] ??? is removed from the solution by the addition of 150 μ? of AG 1X8 ion exchange resin in 900 mM sodium format pH 3.0. Remove an aliquot of μ? 50 of the main volume of the quenched reaction mixture and added to a 96-well plate, 150 μ? of Microscint-40 (Packard) and the amount of phosphorylated peptide is determined. The Microscint is left to settle on the plates for 60 minutes before counting. The compounds were evaluated as potential inhibitors of the MK2 kinase by measuring their effects on MK2 phosphorylation of the substrate peptide. The compounds can be separated by exclusion initially in two concentrations before the determination of the IC50 values. The results of the separation by exclusion are expressed as percent inhibition in the concentrations of the compound evaluated. For determinations of IC5o value, the compounds are tested in six concentrations in serial dilutions of multiples of ten with each concentration evaluated in triplicate. The results are expressed as IC50 values in micromolar. The assay is carried out at a final concentration of 2% DMSO. The preferred aminocyanopyridine MK-2 inhibition compounds of the present invention provide IC50 values of MK-2 inhibition of less than 200 μ ?. A method that can be used for the determination of the IC50 value of inhibition of MK-2 is that described just above. The most preferred inhibitory compounds of MK-2 aminocyanopyridine have the ability to provide values of less than 100 μ ?,, still more preferred less than 50 μ ?,, even more preferred less than 20 μ ?,, still more preferred less than 10 μ ?, and even more preferred less than -? ? U937 Cell TNFa Release Assay The human monocyte-like cell line, U937 (ATCC # CRL-1593.2), is grown in RPMI 1640 medium with 10% heat inactivated fetal calf serum (GIBCO), glutamine and pen / strip at 37 ° C and 5% CO2. Differentiation of U937 for monocyte / macrophage-like cells is induced by the addition of phorbol-12-myristate 13-acetate (Sigma) at final concentration of 20 ng / ml for a culture of U937 cells at about 0.5 million cells / ml and they were incubated for 24 hours. The cells were centrifuged, washed with PBS and resuspended in fresh medium without PMA and incubated for 24 hours. The cells adhered to the culture flask were harvested by scrapping, centrifugation, and resuspending in fresh medium at 2 million cells / ml, and 0.2 ml are aliquoted for each of the 96 wells in the flat-bottom plate . The cells were then incubated for an additional 24 hours to allow recovery. The medium is removed from the cells, and 0.1 ml of fresh medium is added per well. 0.05 ml of serially diluted compound or control vehicle (Medium with DMSO) is added to the cells. The final DMSO concentration does not exceed 1%. After 1 hr of incubation, 0.05 ml of 400 ng / ml of LPS (serotype 0111: B4 of E Coli, Sigma) in medium are added for final concentration of 100 ng / ml. The cells were incubated at 37 ° C for 4 hours. After 4 hours of incubation, the supernatants are harvested and assayed by ELISA for the presence of TNFa.

TNFa ELISA in U937 cells ELISA plates (NUNC-lmmuno ™ Píate Maxisorb ™ Surface) were coated with TNFa antibody (R & D Systems # MAB610; 1.25 ug / ml in sodium bicarbonate pH 8.0, 0.1 ml / well) and incubated at 4 ° C. The coating solution was aspirated the next day and the wells were blocked with 1 mg / ml of gelatin in PBS (plus 1x timerasol) for 2 days at 4 ° C. Before use, wells were washed 3x with wash buffer (PBS with 0.05% Tween). Samples of cultured medium were diluted in EIA buffer solution (5 mg / ml bovine? -globulin, 1 mg / ml gelatin, 1 ml / l Tween-20, 1 mg / ml sunflower in PBS), aggregates to the wells (0.1 ml / well) in triplicate and left to incubate for 1.5 hours in a humidified chamber. The plates were washed again and 0.1 ml / well of a mixture of rabbit anti-human TNFα antibodies in EIA buffer solution (1: 400 dilution of Sigma # T8300, and Calbiochem dilution of 1: 400 # 654250 was added. ) for 1 hour at 37 ° C. Plates were washed as before and peroxidase-conjugated goat anti-rabbit IgG (H + L) antibody (Jackson Immuno Research # 1 1-035-144, 1 ug / ml in EIA buffer, 0.1 ml / well) was added during 45 min. After the last wash, the plates were developed with peroxidase-ABTS solution (Kirkegaard / Perry # 50-66-01, 0.1 ml / well). The enzymatic conversion of ABTS to colored product is measured after 5-30 minutes using a SpectroMax 340 spectrometer (Molecular Devices) at 405 nm. TNF levels were quantified from a standard curve of recombinant human TNFα (R & D Systems # 210-TA-010) using a quadratic parameter setting generated by SoftMaxPRO software. The sensitivity of ELISA was approximately 30 pg of TNF / ml. IC50 values for compounds were generated using BioAssay Solver. The preferred aminocyanopyridine MK-2 inhibition compounds of the present invention provide IC50 values of TNFa release of less than 200 μ? in an in vitro test. A method that can be used for the determination of the IC50 of TNFa release in an in vitro cell assay is that described just above. The preferred aminocypyridine MK-2 inhibiting compounds have the ability to provide IC50 values of TNFa release of less than 50 μ ?, still more preferred of less than 10, and even more preferred of less than 1.0 μ ?.

Production of TNFa induced by Lipopolysaccharide (PLS). Adult male Lewis rats of 225-250 grams (Harían Sprague-Dawley) were used. The rats were without food 18 hours before the oral dose, and they were allowed free access to water throughout the experiment. Each group under treatment consists of 5 animals. The compounds were prepared as a suspension in a vehicle consisting of 0.5% methylcellulose, 0.025% Tween-20 in PBS. The compounds or carriers were orally administered in a volume of 1 ml using an 18 gauge priming needle. The LPS (serotype 01 1; B4 from E coli, Lot # 39H4103, Cat. # L-2630, Sigma) is administered from 1-4 hours later by injection into the penile vein at a dose of 1 mg / kg in 0.5 ml of sterile solution. The blood is collected in serum separator tubes by cardiac perforation 1.5 hr after the injection of LPS, a point of time corresponding to the maximum production of TNFa. After coagulation, it is removed and stored at -20 ° C until assayed by ELISA (described below).

ELISA for TNF of Rat LPS. ELISA plates (NUNC-lmmuno ™ Píate Maxisorb ™ Surface) were coated with 0.1 ml per well of a purified fraction of Protein G of about 2.5 ug / ml anti-mouse TNFα monoclonal antibody / hamster rat TN 9.12 (2.5 ug / ml in PBS, 0.1 ml / well). The hybridoma cell line was kindly provided by Dr. Robert Schreiber, Washington University. The wells were blocked the next day with 1 mg / ml gelatin in PBS. The serum samples were diluted in a buffer solution consisting of 5 mg / ml bovine? -globulin, 1 mg / ml of gelatin, 1 ml / l of Tween-20, 1 mg / ml of timeflower in PBS, and 0.1 ml of diluted serum is added to the wells in duplicate and allowed to incubate for 2 hours at 37 ° C . The plates were washed with PBS-Tween, and 0.1 ml per well of a dilution of 1: 300 of anti-mouse TNFa antibody / rabbit rat (BioSource International, Cat. # AMC3012) was added per 1.5 hr at 37 ° C. . The plates were washed, and a dilution of 1: 1000 multiples of peroxidase conjugated donkey anti-rabbit IgG antibody (jackson ImmunoResearch, Cat. # 711-035-152) was added for 45 min. After washing, the plates were developed with 0.1 ml of ABTS peroxide solution (Kirkegaard / Perry, Cat. # 50-66-01). The enzymatic conversion of ABTS to the colored product is measured after -30 minutes using a SpectroMax 340 spectrophotometer (Molecular Devices Corp.) at 405 nm. Serum TNF levels were quantified from the standard curve of recombinant rat TNFα (BioSource International, Cat. # PRC3014) using a quadratic parameter setting generated by SoftMaxPRO software. The sensitivity of ELISA was approximately 30 pg of TNF / ml. The results were expressed in percent inhibition of the TNFa product as compared to the blood collected from the control animals dosed only with vehicle. The preferred aminocyanopyridine MK-2 inhibition compounds of the present invention are capable of providing some degree of inhibition of TNFa in animals. That is, the degree of inhibition of TNFa in animals is about 0%. One method for determining the degree of inhibition of TNFa is the rat LPS assay which is described just below. The more preferred aminocyanopyridine MK-2 inhibiting compounds have the ability to provide TNFα inhibition values of rat LPS of at least about 25%, even more preferred above 50%, even more preferred above. 70% and even more preferred above 80%.

Synthesis of aminocyanopyridine compounds: A general method for the synthesis of aminocyanopyridines described in Examples 1- 213 can be found in Lambe, et al., "A simple method for the preparation of 2-amino-4-aryl-3-cyanopyridines by the condensate of malononitrile with aromatic aldehydes and alkyl ketones in the presence of ammonium acétate ", Synthesis 5: 366-368 (1980). Further details of the aminocyanopyridine synthesis of the present invention are provided below.

EXAMPLE 1 This example illustrates the production of trifluoroacetate of 2-amino-6- (3,4-dihydroxyphenyl) -4- (2-fluorophenyl) nichotonitrile. 2-Fluorobenzaldehyde (5 mmol, 1.0 equiv., 530μ?), 3,4-dihydroxyacetophenone (5 mmol, 1.0 equiv., 760mg), malononitrile (5 mmol, 1.0 equiv., 290 pL) and ammonium acetate (7.5 mmol. , 1.5 equiv., 578mg) were combined in dichloroethane (10 mL) and heated to reflux for 4 hours. The dichloroethane is evaporated and the residue is purified by reverse phase chromatography. The product is isolated as an orange solid (145mg, 8% yield). 1 H NMR (400 MHz, DMSO) 57.70 (d, 1H), 7.59-7.53 (m, 3H), 7.37 (d, 1 H), 7.32 (t, 1H), 7.18 (s, 1 H), 6.90 (d) , 1H), 6.34 (bs, 1H), 3.21 (bs, 4H): m / z 322 (M + H).

EXAMPLE 2 This example illustrates the production of 2-amino-4- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile trifluoroacetate. 2-Fluorobenzaldehyde (2 mmol, 1.0 equiv., 210 pL), and malononitrile (2 mmol, 1.0 equiv., 126 pL) were combined in toluene (3 mL) and heated at 50 ° C for 0.5 hours. 2-acetyl furan (2 mmol, 1.0 equiv., 146 mg) and ammonium acetate (3 mmol, 1.5 equiv., 230 mg) were added and the reaction was stirred at 55 ° C overnight. Amberiist resin (1 g) is added and the reaction is diluted with dichloromethane. After stirring overnight, the resin is isolated by filtration and washed with dichloromethane and methanol. The resin is treated with 2M ammonia in methanol. After stirring at night, the resin is removed by filtration and the filtrate is concentrated under nitrogen vapor. The residue is purified by reverse phase chromatography and the product is isolated as a brown solid (50mg, 9%). 1 H NMR (300 MHz, DMSO) 87.78 (s, 1 H), 7.65-7.75 (m, 2 H), 7.43-7.35 (m, 2 H), 7.22 (d, 1 H), 7.14 (s, 1 H), 6.67 (s) , 1H), 6.48 (bs, 2H): m / z 280 (M + H).

EXAMPLE 3 This example illustrates the production of 2-amino-6 (4-hydroxyphenyl) -4- (1 H-imidazol-5-yl) nicotinonitrile trifluoroacetate. Step 1: The production of 2- (1H-imidazol-5-ylmethylene) malononitrile. 1 H-imidazole-5-carbaldehyde (20 mmol, 1.0 equiv., 1.92 g), and malononitrile (20 mmol, 1.0 equiv., 1.26 mL) were combined in trimethylortoformate (30 mL) and triethylamine (7 mL). After stirring at room temperature overnight, the solvents were evaporated and the residue partitioned between 1M hydrochloric acid (HCl) and dichloromethane. The aqueous layer was neutralized with sodium bicarbonate and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were dried over magnesium sulfate (gS04), filtered and evaporated to give the product as a yellow solid (2.58g, 90%). 1 H NMR (400 MHz, Acetone) d 12.11 (bs, 1H), 8.07 (s, 1H), 8.04 (s, 1 H), 7.95 (s, 1H): m / z 143 (M-H).

Step 2: Production of 2 - [(1- { [2-trimethylsilyl) ethoxy] methyl} -1 H-inidazol-5-yl) methylene) malononitrile; 2- (1 H-imidazol-5-ylmethylene) malononitrile, (2 mmol, 1.0 equiv., 288 mg), prepared as described in Step 1, is added to a cold (0 ° C) suspension of sodium hydride ( 60% in mineral oil, 1.1 equiv., 50 mg) in tetrahydrofuran (THF) (15 ml_). After 20 minutes, [2- (chloromethoxy) ethyl] (trimethyl) silane (2.2 mmol, 1.1 equiv., 390μ? _) Is added and the solution is kept warm at room temperature overnight. The reaction is treated with water (5 mL) and the concentrated residue is extracted with ethyl acetate (25 mL) and the layers are separated. The dried organic extract with MgSO4 is filtered and evaporated to give a brown solid. The product is purified by silica gel chromatography. The product is isolated as a yellow solid (277mg, 50%). 1 H NMR (400 MHz, CDCl 3) 7.98 (s, 1 H), 7.76 (s, 1 H), 5.34 (s, 2 H), 3.52 (dd, 2 H), 0.92 (dd, 2 H), -0.01 (s, 9 H) : m / z 275 (M + H).

Step 3: Production of 2-amino-6- (4-hydroxyphenyl) -4- (1H-imidazoI-5-yl) nicotinonitrile trifluoroacetate. 2 - [(1 - { [2-trimethylsilyl) ethoxy] methyl} -1 H-inidazol-5-yl) methylene) malononitrile (0.8 mmol, 1.0 equiv., 220 mg), prepared as described in Step 2, above, 4-hydroxyacetophenone (0.8mmol, 1.0 equiv., 109mg) and acetate of ammonium (1.2 mmol, 1.5 equiv., 95 mg) are combined in toluene (3 mL) and benzene (1 mL), heating at 80 ° C overnight. After cooling, the Amberlist resin (1 g) is added and the mixture is heated at 50 ° C overnight. The resin is isolated by filtration and washed with dichloromethane and methanol. The resin is treated with 2M ammonia in methanol. The resin is removed by filtration and the filtrate is concentrated under a stream of nitrogen. The residue is purified by reverse phase chromatography and the product is isolated as a solid (25mg, 11%). 1 H NMR (300 MHz, Acetone) d 8.59 (s, 1 H), 8.32 (s, 1 H), 8.12 (d, 2 H), 7.87 (s, 1 H), 6.97 (d, 2 H), 6.73 (bs, 1 H) : m / z 278 (M + H).

EXAMPLE 4 This illustrates the production of trifluoroacetate of 2-amino-6- (3-hydroxyphenyl) -4- (1 H-imidazol-5-yl) nicotinonitrile. The 2-amino-6- (3-hydroxyphenyl) -4- (1H-imidazol-5-yl) n-trinononitrile trifluoroacetate is prepared in the same manner as the 2-amino-6- (4-trifluoroacetate. -hydroxyphenyl) -4- (1 H -amidazol-5-yl) nicotinonitrile, as described in Example 3. The amount produced was 25mg, in a yield of 11%. 1 H NMR (300 MHz, Acetone) d 8.51 (s, 1 H), 8.32 (s, 1 H), 7.93 (d, 1 H), 7.76 (11 H), 7.66 (d, 2 H), 7.34 (t, 1 H), 6.98 (dd, 1H9, 6.59 (bs, 1H): m / z 278 (M + H) IC50 of the TNF release assay: 7.0 μ?; Rat LPS assay: 41% inhibition of TNFa production in 20 mpk (IG).

EXAMPLE 5 This illustrates the production of 2-amino-6- (2-furyl) -4- (1 H -amidazol-5-yl) nicotinonitrile trifluoroacetate. The 2-amino-6- (2-furyl) -4- (1H-imidazol-5-yl) nicotinonitrile trifluoroacetate is prepared in the same manner as the 2-amino-6- (4-hydroxyphenyl) -4 trifluoroacetate - (1 H-imidazol-5-yl) nicotinonitrile, as described in Example 3. The amount produced was 20 mg, with a yield of 1%. 1 H NMR (300 MHz, Acetone) d 8.40 (s, 1 H), 8.29 (s, 1 H), 7.81 (m, 2 H), 7.27 (d, 1 H), 6.70-6.68 (m, 2 H): m / z 252 (M + H).

EXAMPLE 6 This illustrates the production of 2- [1- (1-methyl-H-imidazol-4-yl) ethylidene] malononitrile. The 2- (1 H-imidazol-5-ylmethylene) malononitrile (3.92 mmol, 1.0 equiv., 565 mg), prepared as described in Step 1 of Example 3, was dissolved in THF and cooled to 0 ° C. Sodium hydride (60% in mineral oil, 1.1 equiv., 103 mg) is added followed by dimethylsulfonate (4.31 mmol, 1.1 equiv., 410 pL). The solution is warmed to room temperature overnight. The reaction is treated with water and extracted with ethyl acetate. The organic extract is dried with MgSO 4) filtered and evaporated to give a solid. The product is isolated as a white solid, (500mg, 80%). H NMR (300 MHz, Acetone) 8.01 (s, 2H), 7.85 (s, 1H), 3.92: m / z 159 (M + H). The material can be used as an intermediate as shown below, for the preparation of an aminocyanopyridine compound.

EXAMPLE 7 This illustrates the production of bis (trifluoroacetate) of 2-amino-6- (2-furyl) -4- (1-methyl-H-imidazol-4-yl) nicotinonitrile. 2- [1- (1-methyl-1H-imidazol-4-yl) ethylene] malononitrile (1.0 mmol, 1.0 equiv., 158 mg), 3-acetylfuran (1.0 mmol, 1.0 equiv., 100 pL) and ammonium acetate (1.5 mmol, 1.5 equiv., 115 mg) were combined in toluene (2 mL) and benzene (mL) heated at 70 ° C overnight. After cooling, the Amerlyst resin (1 g) is added and the mixture is stirred overnight. The resin is isolated by filtration and washed with dichloromethane and methanol. The resin is treated with 2M ammonia in methanol. The resin is removed by filtration and the filtrate is concentrated under a stream of nitrogen. The residue is purified by reverse phase chromatography and the product is isolated as a solid (35mg, 13%). 1H R N (400 MHz, Acetone) d 8.08 (s, 1 H), 7.91 (s, 1 H), 7.81 (s, 1H). 7.76 (s, H), 7.19 (d, 1H), 6.64 (d, 1H), 6.46 (bs, 2H), 3.94 (s, 3H): m / z 266 (M + H).

EXAMPLE 8 This illustrates the production of bls (trifluoroacetate) of 2-amino-4- (1-methyl-1 H-imidazoI-4-yl) -6-phenylnicotonitrile. The bis (trifluoroacetate) of 2-amino-4- (1-methyl-1 H-imidazol-4-yl) -6-phenylnicotinonitrile is prepared in the same way as the bis (trifluoroacetate) of 2-amino-6- ( 2-furyl) -4- (1-methyl-1 H-lmidazol-4-yl) nicotinonitrile, as described in Example 7, with the production of 40 mg of solid material and with a yield of 13%. 1 H NMR (400 MHz, Acetone) d 8.15 (bs, 4 H), 7.91 (s, 1 H), 7.48 (s, 3 H), 4.00 (s, 3 H): m / z 276 (M + H).

EXAMPLES 9-58 This illustrates the production of aminocyanopyridine compounds of the present invention. The compounds listed in the following table were prepared by the methods described in Lambe, S. et al., "A simple method for the preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of malononitrile with aromatic aidehydes and alkyl ketones in the presence of ammonium acétate ", Synthesis 5: 366-368 (1980). The NMR analysis was carried out for each compound and the selected data are presented for each compound as shown in the table. 2-amino-6- (4-methoxyphenyl) -4-t-ene-3-308 trifluoroacetate 2-amino-4- (3-furyl) -6- (4,292-methoxyphenyl) nicotinonitrile initidinonitrile trifluoroacetate 2-Amino-6- (4-methoxy-phenyl) -4- (1H-pyrrol-2-yl-2-yl) nicotinonitrile trifluoroacetate 2-amino-6- (4-methoxyphenyl) -4-thien-2 trifluoroacetate - 308 ilnicotinonitrile 2-amino-4- (3-chlorofenyl) -6- (4,336-methoxyphenyl) nicotinonitrile trifluoroacetate 2-amino-4- (2-chlorophenyl) -6- (4- 336 methoxyphenyl) trifluoroacetate nicotinonitrile 2'-amino-6 '- (4-methoxyphenyl) -3,4'-bipyridine-303 3'-carbonitrile trifluoroacetate 2-amino-4-isoquinolin-4-iI-6- (4-353-methoxyphenyl) trifluoroacetate ) Nicotinonitrile 2-amino-4- (1-benzoten-3-yl) -6- (4- 358-methoxyphenyl) nicotinonitrile trifluoroacetate 2-amino-4- (2-furyl) -6 trifluoroacetate - (4- 292 methoxyphenyl) nicotinonitrile 2-amino-4- (2-methylphenyl) -5,6,7,8- 263 tetrahydroquinoline-3-carbonitrile trifluoroacetate 2-amino-4- (4-trifluoroacetate -methoxyphenyl) -5,6,7,8- 280 tetrah idroquinoline-3-carbonitrile 2-amino-4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile 250 2-Amino-6- (4-methoxyphenyl) -4- (2- 316 methylphenyl) n-trinucleotide trifluoroacetate 2-amino-4,6-bis (4- 332 methoxyphenyl) nicotinonitrile trifluoroacetate -amino-6- (4-methoxyphenyl) -4- 302 phenylnicotinonitrile 2-amino-4-butyl-6-methylnicotinonitrile trifluoroacetate 190 2-Amino-6-methyl-4-propylnicotinonitrile trifluoroacetate 176 2-Amino-4-ethyl-6-methylinothionitrile trifluoroacetate 162 2-amino-4,6-dimethylnicotonitrile trifluoroacetate 148 6-amino-4- (3-fluorophenyl) -2,4'-bipyridine-5- 291 carbonitrile trifluoroacetate 2-amino-4- (3-fluorophenyl) -6- (3- 306 hydroxyphenyl) trifluoroacetate ) 2-amino-4- (3-fluorophenyl) -6- (3- 306 hydroxyphenyl) nicotinonitrile trifluoroacetate 6-amino-4- (2-fluorophenyl) -2,4 trifluoroacetate '-bipyridine-5- 291 carbonitrile EXAMPLE 59 This illustrates the production of 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] -1 H-pyrrole-2-carboxamide. A mixture of malononitrile (20mmol, 1.32g), ethyl 4-formylpyrrole-2-carboxylate (20mmol, 3.34g), 2-acetylfuran (20 mmol, 2.2g) and ammonium acetate (30 mmol, 2.32g) in toluene (25ml_) was heated under reflux for 24 hours with azeotropic removal of the water. After cooling to room temperature, the reaction mixture was evaporated under reduced pressure to dryness and the residue was stirred with ethanol (15ml) for 4 hours. The resulting precipitate was collected by filtration, washed with aqueous ethanol and dried in air. Recrystallization of the solid from tetrahydrofuran gave a brown-yellow powder (2.25 g, 35% yield): 1 H NMR (400 MHZ, DMSO) d 12.42 (s, 1 H), 7.836 (s, H), 7.776 ( d, 1 H), 7,404 (d, 1 H), 7,220 (s, 1 H), 7,195 (d, 1H), 6,797 (s, 2H), 6,642 (dd, 1 H), 4,257 (q, 2H) , 1,277 (t, 3H). To a suspension of the previous solid (5mmol, 1.6g) in ethanol (50mL) was added aqueous sodium hydroxide (10% w / v, 15mmol, 6ml) and the mixture was warmed at 60 ° C for 5 hours. The resulting solution is kept at room temperature overnight and then evaporated under reduced pressure. The residue was dissolved in lukewarm water (50 ml), then acid was made with 5% HCl solution until pH = 3. The resulting precipitate was collected by filtration, washed with water and dried under vacuum to give a dry powder. gray tone. To a solution of the above solid (1mmol, 0.294g) in dry dimethylformamide (12ml) was added 1, 1'-carbonyldiimidazole (1.2mmol, 0.195g) in one portion and the mixture was stirred at 50 ° C for 2 hours. After cooling to room temperature, the ammonia was bubbled into the reaction mixture for 30 minutes and then maintained at room temperature for 48 hours. The mixture was evaporated to dryness and the residue was stirred with water (10 ml). The resulting precipitate was collected by filtration, washed successively with water and ether and recrystallized from methanol to give the product as a gray powder (0.182 g, 62% yield): H NMR (400 MHz, DMSO) d 7.812 (s, 1 H), 7,459 (d, 1 H), 7,147 (s, 1H), 7,128 (d, 1H), 6,915 (d, 1H), 6,620 (m, 3H); m / z 294 (M + H).

EXAMPLES 60-75 These illustrate the production of aminocyanopyridine compounds of the present invention. The compounds listed in the table below were prepared by the methods described in Kambe, S. et al., "A simple method for the preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of malononitrile with aromatic aldehydes and alkyl ketones in the presence of ammonium acétate ", Synthesis 5: 366-368 (1980). The NMR analysis is carried out for each compound and the selected data are presented for each compound as shown in the table.

EXAMPLE 76 This illustrates the production of 2-amino-6- (2-furyl) -4- (1H-imidazol-5-yl) nicotinonitrile trifluoroacetate. Step 1: Production of 2-amino-6- (2-furyl) -4- (1- {[[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-4-yl) nicotinonitrile. To a solution of 2-Acetylfuran (0.96 g, 8.71 mmol) and 2 - [(1- {[[2- (trimethylsilyl) ethoxy] methyl} -1 H-imidazol-5-yl) methylen] malononitr (2.0 g, 7.3 mmol) in benzene (15 ml_) at room temperature, ammonium acetate (1.08 g, 14.1 mmol) was added. After heating to reflux for 10 hours, the reaction was cooled to room temperature and diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with brine and dry sodium sulfate (a2S04). The solvent was removed to give a solid, which after chromatography (silica, 30% ethyl acetate / hexane) gave the desired product (0.78 g, 38%). H NMR (300 MHz, d6-DMSO) d 8.14 (s, 1 H), 8.02 (s, 1 H), 7.88 (s, 1 H), 7.57 (s, 1 H), 7.10 (d, J = 3.3 Hz, 1 H), 6.81 (bm, 2H), 6.67 (m, 1 H), 5.44 (s, 2H), 3.53 (t, J = 7.5 Hz, 2H), 0.86 (t, J = 7.5 Hz, 2H ), 0.05 (s, 9H): m / z 382 (+ H).

Step 2: Production of 2-amino-6- (2-furyl) -4- (1H-imidazol-5-yl) nicotinonitrile trifluoroacetate. To a round bottom flask containing 2-amino-6- (2-furyl) -4- (1- {[[2- (trimethylsilyl) ethoxy] methyl} -1H-imidazol-4-yl) nicotinonitrile (0.42 g, 1.10 mmol), prepared as described in Step 1, above, was added HCl / ethyl alcohol (EtOH) 0.5 M (15 ml_) at room temperature. The reaction was heated to reflux for 5 hours and then allowed to cool. A precipitate formed during cooling and was filtered. The solid was collected and purified by reversed-phase high-resolution liquid chromatography (FI-CLAR) (H20: CH3CN + j0.05% TFA) to give the desired product after lyophilization (0.22 g, 61% yield). H NMR (300 MHz, d6-DMSO) d 8.46 (bs, 1H), 8.11 (s, 1H), 7.91 (d, J = 1.2 Hz, 1 H), 7.48 (s, 1H), 7.13 (d, J = 3.6 Hz, 1H), 6.69 (dd, J = 1.8, 3.3 Hz, 1 H), 3.7 (bm, 3H): m / z 252 (M + H).

EXAMPLE 77 This illustrates the production of ethyl 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] benzoate. To a solution of ethyl 4-acetylbenzoate (1.12 g, 5.83 mmol) and 2- (2-fluorobenzilidene) malononitrile (1.0 g, 5.81 mmol) in benzene at room temperature, ammonium acetate (0.67 g, 8.69 mmol) was added. The reaction mixture was heated to reflux for 4 hours and then allowed to cool to room temperature. The reaction mixture was emptied into ethanol and the precipitate was filtered to give a light yellow solid (0.30 g, 14% yield). 1 H NMR (300 MHz, d 6 -DMSO) d 8.24 (d, J = 8.1 Hz, 2H), 8.04 (d, J = 8.1 Hz, 2H), 7.60-7.58 (bm, 2H), 7.40-7.34 (bm, 4H), 7.17 (bs, 1 H), 4.34 (q, 2H), 1.32 (t, 3H): m / z 362 (M + H).

EXAMPLE 78 This illustrates the production of 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] benzoic acid trifluoroacetate. To a solution of ethyl-4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] benzoate (0.20 g, 0.55 mmol) in THF / H 2 O (9: 1) was added aqueous lithium hydroxide (LiOH H2O) at room temperature. The reaction was heated to reflux for 4 hours and the solvent was removed in vacuo to give a solid, which was purified by FI-CLAR to give the desired product (0.091 g, 50% yield). 1 H NMR (300 MHz, d 6 -D SO) d 8.27 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.66-7.62 (bm, 2H), 7.52-7.40 (bm , 3H), 7.21 (bs, 1 H), 4.81 (bs, 2H): m / z 334 (M + H).

EXAMPLE 79 This illustrates the production of 2-amino-4- (2-furyl) -6- (1 H -pyrazol-3-yl) nicotinonitriyl trifluoroacetate. Step 1: Production of 1- (1H-pyrazol-5-yl) -1-ethanone. To a solution of KOH (8 g in 50 mL of water) was added diethyl ether. The solution was cooled to 0 ° C and 1-methyl-3-1-nitrosoguanidine (MNNG), (4.0 g) was slowly added to generate diazomethane (CH2N2). After this addition was complete the CH2N2 in diethyl ether was transferred to a solution of 3-Butin-2-one (4.0 g, 0.058 mol) in ether by means of a pipette. The reaction was stirred at room temperature for 4 hours and the solvent was removed in vacuo to give an oil, which in high vacuum becomes a solid (1.71 g, 26% yield). 1 H NMR (300 MHz, CDCIa) d 7.68 (d, J = 2.1 Hz, 1 H), 6.84 (d, J = 2.1 Hz, 1 H), 2.60 (s, 3 H). Step 2: Production of 2-amino-4- (2-furyl) -6- (1H-pyrazol-3-yl) nicotinonitrile trifluoroacetate. To a solution of 1- (1 H-pyrazol-5-yl) -1-ethanone (0.64 g, 5.80 mmol), prepared as described above in Step 1, furaldehyde (0.48 mL, 5.80 mmol), and malononitrile ( 0.38 g, 5.80 mmol) in benzene (15 mL) at room temperature, ammonium acetate (1.11 g, 14.5 mmol) was added. The reaction was heated to reflux for 10 hours and then allowed to cool to room temperature. The mixture was diluted with water and ethyl acetate. The layers were separated and the organic layer was washed with brine and dried, using Na2SO4. The solvent was removed to give a brown solid, which after FI-CLAR (H2O: CH3CN + 0.05% TFA) gave the desired product (185 mg, 12% yield). 1 H NMR (300 MHz, CD 3 OD) d 8.0 (d, J = 1.2 Hz, 1 H), 7.81 (d, J = 2.1 Hz, 1 H), 7.61 (s, 1 H), 7.46 (d, J = 3.6 Hz, 1 H), 6.84 (d, J = 2.1 Hz, 1 H), 6.78-6.76 (m, 1 H); m / z 252 (M + H).

EXAMPLES 80-91 This illustrates the production of aminocyanopyridine compounds of the present invention. The compounds listed in the table below were prepared by the methods described in Kambe, S. et al., "A simple method for the preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of malononitrile with aromatic aldehydes and alkyl ketones in the presence of ammonium acétate ", Synthesis 5: 366-368 (1980). The NMR analysis is carried out for each compound and the selected data are presented for each compound as shown in the table.

Ex. No. Name of the compound m / z (M + H) 80 trifluoroacetate hydrate of 2-amino-4- (1 H-262 imidazo! -4-yl) -6-phenylnicotonitrile 81 hydrate of trifluoroacetate 2 -amino-4- (2- 279 fIuorophenol) -6- (1 H -pyrrol-2-yl) nicotonitrile 82 hydrate of 2-amino-6- (3- 296 chlorophenyl) -4 trifluoroacetate - (1 H-imidazol-4-yl) nicotinonitrile 83 2-amino-4- (2-fluorophenyl) -6-phenyn-phenyl-nitrile 290 84 4- [6-amino-5-cyano-4- (2-fluorophenyl) ethyl pyridin-2-yl-3-benzoate 85-2-arnino-6- (2-fluorophenyl) -4- (3-2-furyl) nicotinonitrile trifluoroacetate 86 2-amino-4- (2-fluorophenyl) -6 hydrate -tien-2- 296 ilnicotinonitrile 87 6-amino-4- (2-fluorophenyl) -2,2'- 291 trifluoroacetate bipyridine-5-carbonitrile 88-bis (trifluoroacetate) 2-amino-4- (2-furyl) -6- (1H-252 pyrazol-4-yl) nicotinonitrile 89 2-amino-4- (2-furyl) -6- (1-trityl-1 H-pyrazol-4,494 yl) nicotinonitrile 90 2- amino-4- (2-fluorophenyl) -6-tetrahydrofuran-2- 284-ilnicotinonitrile 91 6-amino-5-cyano-4- (2-fluorophene) l) Ethyl pyridine-2-carboxylate 286 EXAMPLE 92 This illustrates the production of 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile trifluoroacetate. One glass vial was loaded with 6-hydroxy-2-tetralone (0.49 g, 3 mmol), malononitrile, (0. g, 3 mmol), ammonium acetate (0. g, 6 mmol), furaldehyde (0. g , 3 mmol) and a magnetic stir bar. Benzene (6 ml_) was added to the vial, which was capped and heated to 80 degrees centigrade for 18 hours. The vial was then cooled to room temperature, and a 1: 2 mixture of methanol and dichloromethane (15 ml_) was added followed by 8 g of Amberlyst resin. The mixture was stirred for 24 hours, then the resin was filtered and washed with dichloromethane (3X15 mL). A 2 M solution of the ammonia in methanol (15 mL) was added to the resin, and the mixture was stirred overnight at room temperature. The resin was filtered and the filtrate was collected in a tared flask. The resin was washed sequentially with a 1: 1 mixture of methanol and dichloromethane (2X15 mL), 2 M ammonia in methanol (2X15 mL), and a 1: 1 mixture of methanol and dichloromethane (2X15 mL). The combined filtrates were concentrated in vacuo, and the residue was purified by reverse phase chromatography. The product was isolated as a brown solid (10.4 mg, 1% yield). 1 H NMR (400 MHz, DMSO) d 2.70 (m, 4 H), 6.63 (d, 1 H), 6.70 (d, 1 H), 6.73 (d, 1 H), 6.87 (d, 1 H), 7.91 ( d, 1 H), 7.96 (d, 1 H); m / z 304 (M + H); HRMS (M + H) calculated for C18H1 N302: 304.1086, found 304.1086.

EXAMPLE 93 This illustrates the production of 2-amino-4- (2-furyl) -6,8-dihydro-5H-pyrrolo [3,4-h] quinoline-3-carbonitrile trifluoroacetate. This material was prepared in a manner similar to that used to produce the trifluoroacetate of 2-amino-4- (2-furyl) -8-hydroxy-5,6-d, hydrobenzo [h] quinoline-3-carbonitrile, as described in Example 92. The product was isolated as a brown solid (171.9 mg, 17% yield). 1 H NMR (400 MHz, DMSO) d 2.60 (m, 2 H), 2.74 (m, 2 H), 6.65 (s, 1 H), 6.73 (dd, 1 H), 6.90 (d, 1 H), 7.30 (s) , 1 H), 7.95 (s, 1 H), 11.9 (br s, 1 H); m / z 277 (M + H); HRMS (M + H) calculated for C 16 H 13 N 40: 277.1089, found 277.1078.

EXAMPLE 94 This illustrates the production of the bis (trifluoroacetate) of 2-amino-4- (2-furyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile. This material was prepared in a manner similar to that used to produce the 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile trifluoroacetate, as is described in Example 92. The product was isolated as a brown solid (248 mg, 17% yield). H NMR (400 MHz, DMSO) d 2.75-2.90 (m, 4H), 6.73 (dd, 1 H), 6.88 (d, 1 H), 7.92 (s, 1 H), 7.95 (d, 1 H); m / z 278 (M + H); HRMS (M + H) calculated for C15H12N50: 278.1042, found 278.1058.

EXAMPLE 95 This illustrates the production of 2-amino-4- (2-fluorophenyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile trifluoroacetate. This material was prepared in a manner similar to that used to produce the 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [] quinoline-3-carbonitrile trifluoroacetate, as described in Example 92. The product was isolated as a brown solid (49.1 mg, 4% yield NMR (400 MHz, DMSO) d 2.38-2.48 (m, 2H), 2.75-2.82 (m, 2H), 7.25- 7.30 (m, 2H), 7.35-7.47 (m, 5H), 7.55-7.64 (m, 1 H), 8.16-8.22 (m, 1 H); m / z 3 6 (M + H);); HRMS (M + H) calculated for C20H15FN3: 316.1250, found 316.1248.

EXAMPLE 96 This illustrates the production of 2-amino-3-cyano-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-8-carboxylic acid trifluoroacetate. This material was prepared in a manner similar to that used to produce the 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [] quinoline-3-carbonitrile trifluoroacetate, as is described in Example 92. The product was isolated as a brown solid (30.1 mg, 5% yield). 1 H NMR (400 MHz, DMSO) d 2.80-2.93 (m, 4H), 6.77 (dd, 1 H), 6.98 (dd, 7.87 (dd, 1 H), 7.92 (d, 1 H), 7.95 (d, 1 H), 7.99 (dd, 1 H), 8.23 (d, 1 H)); m / z 332 (M + H); HRMS (M + H) calculated for C ^ HuNaOa: 332.1035, found 332.1032.

EXAMPLE 97 This illustrates the production of the bis (trifluoroacetate) of 2-amino-3-cyano-4- (4H-1, 2,4-triazol-3-yl) -5,6-dihydrobenzo [h] quinoline-8- carboxylic This material was prepared in a manner similar to that used to produce 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbon trifluoroacetate. The solution was isolated as a brown solid (29.4 mg, 4% yield). 1 H NMR (400 MHz, DMSO) d 2.72-2.92 (m, 4H), 7.86 (s, 1 H), 7.94 (d, 1 H), 8.27 (d, 1 H), 8.78 (br s, 1 H); m / z 333 (M + H); HRMS (M + H) calculated for C17H13N602: 333. 100, found 333.1083.

EXAMPLE 98 This illustrates the production of bis (trifluoroacetate) of 2-amino-4- (2-furyl) -5,6-dihydro-1, 8-phenanthroline-3-carbonyl ether.

The bis (trifluoroacetate) of 2-amino-4- (2-furyl) -5,6-dihydro-1, 8-phenanthroline-3-carbonitrile was prepared in a manner similar to that used to produce 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile trifluoroacetate, as described in Example 92. The product was isolated as a solid brown color (205 mg, 12% yield). H NMR (400 MHz, DMSO) d 2.85-2.98 (m, 4H), 6.79 (dd, 1 H), 7.04 (dd, 1 H), 8.02 (dd, 1 H), 8.19 (1 H), 8.76 ( d, 1 H), 8.77 (s, 1 H); m / z 289 (M + H); HRMS (M + H) calculated for C17H 3N40: 289.1089, found 289.1069.

EXAMPLE 99 This illustrates the production of bis (trifluoroacetate) of 2-amino-4- (2-fluorophenyl) -6, 8-D-Hydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile. The bis (trifluoroacetate) of 2-amino-4- (2-fluorophenyl) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile was prepared in a manner similar to that is used to produce the trifluoroacetate of 2-amino-4- (2-furl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, as described in Example 92. The product is isolated as a yellow solid (173.7 mg, 17% yield). 1 H NMR (400 MHz, DMSO) d 2.50-2.60 (m, 2H), 2.72-2.78 (m, 2H), 7.36-7.48 (m, 3H), 7.55-7.63 (m, 1 H), 7.97 (s, 1 HOUR); m / z 306 (M + H); HRMS (M + H) calculated for Ci 7 H 3 FN 5: 306. 150, found 306.1 78.

EXAMPLE 100 This illustrates the production of bis (trifluoroacetate) of 2-amino-4-phenyl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile. This material was prepared in a manner similar to that used to produce 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile trifluoroacetate, as described in Example 92. The product was isolated as a yellow solid (242 mg, 24% yield). H NMR (400 MHz, DMSO) d 2.50-2.62 (m, 2H), 2.69-2.76 (m, 2H), 7.36-7.46 (m, 2H), 7.50- 7.59 m, 3H), 7.96 (s, 1 H ); m / z 288 (M + H); HRMS (M + H) calculated for Ci 7 H -i 4 N 5: 288.1244, found 288.1253. TNFa release assay lC50 = 17.7 μ ?.

EXAMPLE 101 This illustrates the production of 2-amino-3-cyano-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-8-carboxylic acid trifluoroacetate. Step 1: (Preparation of 5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-trifluoromethanesulfonate) - A round bottom flask was charged with 6-hydroxy-1-tetralone (7.87 g, 48.5 mmol), pyridine (97 ml_) and a magnetic stir bar. The flask was sealed under nitrogen, and the triflic anhydride (8.24 mL, 49 mmol) was added dropwise over 30 minutes. The mixture was stirred at room temperature for 7 days, then the mixture was diluted with diethyl ether. The organic layer was washed with water (1 × 100 ml), 5% aqueous hydrogen chloride (2 × 100 ml), and brine (1 × 100 ml). The organic layer was then dried over magnesium sulfate and concentrated in vacuo. The product was purified by flash column chromatography (0-20% ethyl acetate / hexane) to give 11.72 g of the product as a white solid (81% yield). 1 H NMR (400 MHz, DMSO) d 2.22 (quintet, 2 H), 2.72 (t, 2 H), 3.06 (t, 2 H), 7.22 (s, 1 H), 7.24 (d, 1 H), 8.17 (d, 1 HOUR); HRMS (M + H) calculated for 295.0246, found 295.0285.

Step 2: (Preparation of methyl 5-oxo-5,6,7,8-tetrahydronaphthalene-2-carboxylate) - A three-necked round bottom flask was charged with 5-oxo-5,6,7,8- tetrahydronaphthalen-2-yl-trifluoromethanesulfonate, prepared as described in Step 1, (9.98 g, 33.9 mmol), bis (diphenylphosphonyl) propane (0.42 4, 1 mmol), palladium acetate (0.23 g, 1 mmol), methanol (34 mL), dimethylformamide (68 mL), triethylamine (9.5 mL, 68.3 mmol) and a magnetic stir bar. The flask was filled with a condenser and septum, then the carbon monoxide was bubbled through the solution for 15 minutes. The flask was placed under a nitrogen atmosphere and heated to 70 degrees centigrade for 8 hours. The mixture was diluted with ethyl acetate (200 mL) and washed with water (1X100 mL), 5% aqueous hydrogen chloride (2X200 mL) and brine (1X100 mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo.

The residue was purified by flash column chromatography (0-30% ethyl acetate / hexane) to give 4.08 g of the product as a yellow solid (59% yield). H NMR (400 MHz, DMSO) d 2.21 (quintet, 2H), 2.74 (t, 2H), 3.06 (t, 2H), 3.98 (S, 3h), 7.30 (s, 1 H), 7.97 (d, 1 H), 7.99 (s, 1 H), 8.12 (d, 1 H); m / z 205 (M + H); HRMS (M + H) calculated for C12H1303: 205.0859, found 205.0882.

Step 3: (Preparation of 2-amino-3-cyano-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-8-carboxylic acid trifluoroacetate) - A glass vial was loaded with 5-oxo Methyl -5,6,7,8-tetrahydronaphthalene-2-carboxylate, as prepared in Step 2, above, (1.03 g, 5.06 mmol), malononitrile (0.363, 5.5 mmol), 2-furaldehyde (0.42 ml_, 5.07 mmol), ammonium acetate (0.794 g, 10.3 mmol), toluene (10 mL) and a magnetic stir bar. The vial was capped and heated to 80 degrees centigrade for 24 hours. The vial was cooled to room temperature, then the reaction mixture was diluted with a 1: 1 dichloromethane / methanol (20 mL) mixture, and the amberlyst resin (20 g) was added to the flask. The thick mixture was stirred for 72 hours at room temperature, then the resin was collected by vacuum filtration and washed with dichloromethane (3x30 mL). The resin was then combined with 2M ammonia in methanol and stirred for 4 hours at room temperature. The resin was filtered and washed with a 1: 1 mixture of dichloromethane / 2M ammonia in methanol (6X30 mL). The combined filtrates were concentrated in vacuo. The residue was treated with ethanol (6 mL) and 2 M aqueous lithium hydroxide (6 mL), at 50 degrees Celsius for 1 hour. The mixture was concentrated in vacuo, and the residue was purified by preparative FI-CLAR giving 0.3 g of the product as a white solid (18% yield). 1 H NMR (300 MHz, DMSO) d 2.80-2.96 (m, 4H), 6.79 (m, 1 H), 7.00 (d, 1 H), 7.89 (s, 1 H), 7.95 (d, 1 H), 8.01 (s, 1 H), 8. 26 (s, 1 H); m / z 332 (M + H); HRMS (M + H) calculated for 332.1030, found 332.1039.

EXAMPLE 102 This illustrates the preparation of bis (trifluoroacetate) of 2-amino-4- (2,3-difluorophenyl) -6,7-dihydro-5H-pyrazoo [3,4-h] quinolin-3-carbonitrile. The bis (trifluoroacetate) of 2-amino-4- (2,3-difluoro-phenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile was prepared in a manner similar to that used to produce the trifluoroacetate of 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, as described in Example 06. product was isolated as a yellow solid (205.7 mg, 17% yield). 1 H NMR (400 MHz, DMSO) d 2.55-2.60 (m, 2H), 2.72-2.80 (m, 2H), 6.81 (br s, 1 H), 7.25-7.32 (m, 1 H), 7.38-7.46 ( m, 1 H), 7.58-7.68 (m, 1 H), 7.97 (s, 1 H); m / z 324 (M + H); HRMS (M + H) calculated for C 17 H 2 F 2 N 5: 324.1055, found 324.1030. TNFa release test IC50 = 4.0 μ ?; Rat LPS Assay 83% inhibition at 20 mpk (IG).

EXAMPLE 103 This illustrates the preparation of the bis (trifluoroacetate) of 2-amino-4- (2,4-difluorophenyl) -6,7-dihydro-5H-pyrazoo [3,4-h] quinoline-3-carbonitrile. The bls (trifluoroacetate) of 2-amino-4- (2,4-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinol-3-carbonitrile was prepared in a manner similar to that used to produce the trifluoroacetate of 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, as described in the Example 92. The product was isolated as a yellow solid (149.1 mg, 13% yield). 1 H NMR (400 MHz, DMSO) d 2.55-2.60 (m, 2H), 2.72-2.80 (m, 2H), 6.78 (br s, 1 H), 7.31 (td, 1 H), 7.47-7.58 (m, 2H), 7.96 (s, 1 H); m / z 324 (M + H); HRMS (M + H) calculated for C 17 H 12 F 2 N 5: 324.1055, found 324.1074.

EXAMPLE 04 This illustrates the preparation of the bis (trifluoroacetate) of 2-amino-4- (2,6-difluorophenyl) -6,7-dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbon trilo. The bis (trifluoroacetate) of 2-amino-4- (2,6-d-fluoro-phenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile was prepared in a manner similar to which is used to produce the trifluoroacetate of 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, as described in Example 92. The product is isolated as a white solid (137.7 mg, 12% yield). H NMR (400 MHz, DMSO) d 2.55-2.60 (m, 2H), 2.72-2.80 (m, 2H), 6.85 (br s, 1 H), 7.33-7.40 (m, 2H), 7.62-7.73 (m , 1 H), 7.98 (s, 1 H); m / z 324 (M + H); HRMS (M + H) calculated for C ^ H ^ Ns: 324.1055, found 324.1098.

EXAMPLE 105 This illustrates the preparation of 8-amino-6- (2-furyl) -4,5-dihydro-1 H-pyrazolo [4,3-h] quinoline-7-carbonitrile. 8-Amino-6- (2-furyl) -4,5-dihydro-1 H-pyrazolo [4,3-h] quinoline-7-carbonitrile was prepared in a manner similar to that used to produce trifluoroacetate of 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, as described in Example 92. The product was isolated as a yellow solid (51 mg, 8% yield). 1 H NMR (400 MHz, DMSO) d 2.67 (t, 2 H), 2.83 (t, 2 H), 6.76 (dd, 1 H), 6.93 (d, 1 H), 7.57 (s, 1 H), 7.98 (d , 1 HOUR); m / z 278 (M + H); HRMS (M + H) calculated for C157H12N50: 278.101036, found 278.1051. TNF 1C50 release assay = 0.9 μ ?.

EXAMPLE 106 This illustrates the preparation of 2-amino-4- (2-furyl) -6- (1H-pyrazol-3-yl) nicotinonitrile trifluoroacetate. 2-Amino-4- (2-furyl) -6- (1 H -pyrazol-3-yl) nicotinonitrile trifluoroacetate was prepared in a manner similar to that used to produce 2-amino trifluoroacetate. -4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, as described in Example 92. The product was isolated as a brown solid (110 mg, 6%). % of performance). 1 H NMR (300 MHz, DMSO) d 6.76 (dd, 1 H), 6.84 (br s, 1 H), 6.95 (s, 1 H), 7.46 (d, 1 H), 7.64 (s, 1 H), 7.86 (s, 1 H), 8.03 (s, 1 H); m / z 253 (M + H); HRMS (M + H) calculated for C 13 H 2 N 50: 252.0880, found 252.0855. TNFa release assay IC5o = 4.0 μ?).

EXAMPLE 107 This illustrates the preparation of 8-amino-6- (2-furyl) -4,5-dihydro-1 H-pyrazolo [4, 3-h] quinoline-7-carbonitrile trifluoroacetate. The 8-amino-6- (2-furyl) -4,5-dihydro-1 H-pyrazolo [4,3-h] quinolin-7-carbonitrile trifluoroacetate was prepared in a manner similar to that used to produce the 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonyltrifluorifluoroacetate, as described in Example 92. The product was isolated as a brown solid (379 mg, 38% yield). 1 H NMR (300 MHz, DMSO) d 2.69 (t, 2 H), 2.84 (t, 2 H), 6.76 (dd, 1 H), 6.94 dd, 1 H), 7.58 (s, 1 H), 7.99 (dd, 1 HOUR); m / z 278 (M + H); HRMS (M + H) calculated for C15H12N50: 278.1036, found 278.1054.

EXAMPLES 108-174 This illustrates the production of aminocyanopyridine compounds of the present invention. The compounds listed in the table below were prepared by the methods described in Kambe, S. et al., "A simple method for the preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of malononitrile with aromatic aldehydes and alkyl ketones in the presence of ammonium acétate ", Synthesis 5: 366-368 (1980). The analysis of R N is carried out for each compound and the selected data are presented for each compound as shown in the table.

Ex. No. Name of m / z EMAR EMAR Composite formula (M + H) Theor. Found calculated 108 bis (trifluoroacetate) 306 306,115 306.1168 C17H13FN5 of 2-amino-4- (3-fluorophenyl) -6,8-dihydro-5H-pyrazole [3,4-h] quinoline-3-carbonitrile 109 Trifluoroacetate of 355 355.0859 355.0853 C -i7Hi5 403 N-. { 4- [6-amino-5- Scyano-4- (2-furyl) pyridin-2-yl] phenyl} methanesulfone mida 110 Trifluoroacetate 2- 377 277.1089 277.1063 C16Hi3N40 amino-4- (2-furyl) -6,7-dihydro-5H-pyrrolo [2,3-h] quinoline-3-carbonitrile Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 111 bis (trifluoroacetate 318 318.1349 318.1349 C18H16N50) of 2-amino-4- (4-methoxyphenyl) ~ 6,7-dihydro-5H-pyrazolo [3,4- h] quinoline-3-carbonitrile 112 bis (trifluoroacetate 324 324.1055 324.1098 C17H12F2 5 ) of 2-amino-4- (2,5-difluoro-phenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile 113 bios (trifluoroacetate 306 306,115 306.1 55 C17H13FN5 ) of 2-amino-4- (4-fluorophenyl) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile 114 bis (trifluoroacetate 289 289.1202 289.1173 C16H13 6 ) of 2-amino-4- (4H-1, 2,4-triazoI-3-yl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile 115 bis (trifluoroacetate 293 293.1151 293.1137 Ci5H13N60) of 2 -amino-6- (4-methoxyphenyl) -4- (4H-1, 2,4-triazol-3-yl) nicotinonitrile 116 Trifluoroacetate 280 280.0881 280.0916 of 2-amino-4HuFNaO ( 2- fiuorophenyl) -6- (3- furyl) nichinonitrile 117 8-amino-6- (2- 278 278.1036 278.1018 C15H12N5O furyl) -4,5-dihydro-2H-pyrrazolo [4, 3- h] quinoline-7-carbonitrile Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 118 Bis (trifluoroacetat 318 318.1349 318.1361 C13H16N50 o) 2-amino-4- (3-methoxyphenyl) -6,7-dihydro-5H-prazolo [3,4-h] quinoline-3-carbonitrile 119 bs ( trifluoroacetate 292 292. 198 292.1201 C16H14N50) of 2-amino-4- (2-furyl) -7-methyl-6,7-dihydro-5H-pyrazole [3,4- h] quinoline-3-carbonitrile 120 bis (trifluoroacetate 303 303. 353 303.1399 C19H17N60) of N- [4- (2-amino-3-cyano-6,7-dlhydro-5H-pyrazolo [3,4- h] quinolin-4-yl) phenyl] acetamide 121 6-amino-4 - [(4- 351 351.1063 351.1078 C 16 H 14 F 3 N 4 O 2 methoxyphenyl) amino] -2- (trifluoromethyl) -2,3-dihydrofuro [2,3-b] p Ridin-5-carbonitrile 122 Trifluoroacetate 205 205. 089 205.1056 CioH-) 3N40 4,6-diamino-2-ethyl-2,3-dihydrofuro [2,3-b] pyridin-5-carbonitrile 123 bis (trifluoroacetate 332 332. 42 332.1148 C13H14N5O2 ) of 3- (2-amino-3-cyano-6,7-dihydro-5H-pyrrazolo [3,4- h] quinolln-4-l) benzoic acid Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 124 bis (trifluoroacetate) 332 332.1142 332.1124 C18H14N5O2 of 2-amino-4- (1, 3-benzodioxol-4-yl) -6,7-dihydro-5H-pyrazole [3,4- h] quinoline-3-carbonitrile 125 Trifluoroacetate from 191 191.0933 191.0896 C9HnN40 4,6-d-amino-2-methyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile 126 Trifluoroacetate from 303 303.1246 303.1237 C18H15N40 2,8-d-amino-4- (2-furyl) -5,6-dihydrobenzo [h] quinol-3-carbonyltrium 127 Trifluoroacetate of 233 233.1402 233.1378 C12H17N40 4,6-diamino-2-butyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile 128 bis (trifluoroacetate) 313 313.1196 313.1244 C18H13N6 of 2-amino-4- (4-cyanophenyl) -6 7- dihydro-5H-pyrazole [3,4- h] quinoline-3-carbonitrile 129 bis (trifluoroacetate) 322 322.0854 322.089 C17H13CIN5 of 2-amino-4- (2-chlorophenyl) -6,7-dihydro- 5H-pyrazole [3,4-h] quinolin-3-carbonitrile 130 bis (trifluoroacetate) 289 289.1196 289.1209 C16H13N6 of 2-amino-4-pyridin-3-yl-6,8-dihydro-5H-pyrazolo [3 , 4- h] quinoline-3-carbonitrile Ex. No. Name of m / z E AR EMAR Compound formula (+ H) Theor. Found calculated 131 Trifluoroacetate 304 304.1086 304.1076 C18H14 3O2 2-amino-4- (2-furyl) -7-hydroxy-5,6-dihydrobenzo [h] quinol-3-carbonitrile 132 Trifluoroacetate of 301 301.1084 301.1078 C18H13N40 2-amino-4- (2-furyl) -6- (1H-indol-3-yl) nicotonitrile 133 bis (trifluoroacetate) 289 289.1196 289.1218 of 2-amino-4-pyridin-4-yl-6,8 - dihydro-5H-pyrrazolo [3,4-h] quinolin-3-carbonitrile 134 bis (trifluoroacetate) 354 354.1161 354.1162 C18H14F2N50 of 2-amino-4- [2- (difluoromethoxy) phenyl] -6,7-dihydro -5H- pyrazolo [3,4- h] quinoline-3-carbonitrile 135 Trifluoroacetate of 245 245.1039 245.1019 C12H13 4O2 4,6-d-amino-2- [(prop-2-ynyloxy) methyl] -2,3- di idrofuro [2,3- b] pyridine-5-carbonitrile 136 Trifluoroacetate of 247 247.1195 247.1179 Ci2H15 402 2 - [(allyloxy) methyl] -4,6-diamino-2,3-dihydrofuro [2,3- b] pyridin-5-carbonitrile 137 Trifluoroacetate of 221 221.1039 221.1015 C10H13 4O2 4,6-diamino-2- (methoxymethyl) ) -2,3- dihydrofuro [2,3- b] pyridin-5-carbonitrile Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 138 Trifluoroacetate 302 302.1293 302.1269 C19H16N30 of 2-amino-4- (2-furyl) -6-methyl-5,6-dihydrobenzo [h] quinolin-3-carbonitrile 139 Trifluoroacetate 249 249.1352 249.1336 C12H17N4O2 of 4,6-diamino -2- (sopropoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile 140 Trifluoroacetate 235 235.1 195 235.1 18 CnHi5N402 of 4,6-d-amino-2- (ethoxymethyl) -2, 3- dihydrofuro [2,3- b] pyridin-5-carbonitrile 141 4,6-diamino-2- 307 307.0813 307.0819 C iHi- | F4N402 [(1, 1, 2,2-tetrafluoroethoxy) m ethyl] -2,3-dihydrofuro [2,3-b] pyridin-5-carbonitrile 142 bis (trifluoroacetate 318 318.1349 318.1357 Cl8H16N50) of 2-amino-4 - (2-methoxyphenyl) -6,8-dihydro-5H-pyrazole [3,4-h] quinoline-3-carbonitrile 143 bs (trifluoroacetate 332 332.1 142 332.1 153 ?? 8 ?? 4? D? 2 ) 4- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4- h] quinolin-4-yl) benzoic acid Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 144 4,6-diamino-2- 263 263.1503 263.1506 C13H19N4O2 (tert-butoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile 145 bis (trifluoroacetate 346 346.1299 346.1318 CigHi6 s02 ) of methyl 3- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) benzoate 146 Trifluoroacetate 253 253.1038 253.1082 C14H13N40 of 4,6-diamino- 3-phenyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile 147 Trifluoroacetate 203 203.0933 203.0904 10H-11N4.O 4,6-diamino-3-vinyl-2,3-dihydrofide [ 2,3- b] pyridine-5-carbonitrile 148 Trifluoroacetate 283 283.1167 283.1195 C- | 5Hi5N402 of 4,6-diamino-2- (phenoxymethyl) -2,3-dihydrofuro [2,3- b] pyridine-5 - carbonitrile 149 Trifluoroacetate 316 316,145 316.1441 C20H18N3O 2-amino-4- (2-furyl) -7,9-dimethyl-5,6-dihydrobenzo [h] quinoline-3-carbonitrile 150 Trifluoroacetate 318 318.1243 318.124 C-igHi6 302 of 2-amino-4- (2-furyl) -7-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonitride Ex. No. Name of m / z EMAR EMAR Compound formula (M + H ) Theor. Found calculated 151 Trifluoroacetate 348 348.1348 348.1351 C20H18 3O2 2-amino-4- (2-furyl) -8,9-dimethoxy-5,6-dihydrobenzo [] quinoline-3-carbonitrile 152 Trifluoroacetate 318 318.1243 318.1232 CigH- | 6 302 2-amino-4- (2-furyl) -8-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile 153 Trifluoroacetate 318 318.1243 318.1243 C19H16 302 of 2-amino-4- (2 - furyl) -9-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile 154 Trifluoroacetate 274 274,098 274.1051 C17H12N30 of 2-amino-4- (2-furyl) -5H-indene [, 2- b ] pyridine-3-carbonitrile 155 Trifluoroacetate 302 302.1293 302.1285 C19Hi6N30 of 2-amino-4- (2-furyl) -6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-b] pyridine- 3-carbonitrile 156 Trifluoroacetate 316 316.125 316.149 C-20H15FN3 of 2-amino-4- (3-fluorophenyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile Ex. No. Name of m / z EMAR EMAR Composite formula (M + H) Theor. Found calculated 157 Trifluoroacetate 332 332.1506 332.1507 C19H18N50 of 2-amino-4- (2-ethoxy-phenyl) -67- dihydro-5H-pyrazolo [3,4- h] quinoline-3-carbonitrile 158 Bis (trifluoroacetate 376 376.1404 376.1403 C20H18N5O3 o) methyl [2- (2-amino-3-cyano-6, 7-Dihydro-5H-pyrazole [3,4- h] quinoline-4-yl) phenoxy] acetate 159 Bis (trifluoroacetat 344 344.1506 344.1507 C20H18N5O o) of 4- [2- (allyloxy) phenyl] -2- amino-6 , 7-dihydro-5H-pyrazolo [3,4- h] quinoline-3-carbonitrile 160 Bis (trifluoroacetat 466 466.1721 466.1742 C23H24 5O6 o) of 2-amino-4- [2- (beta-D-glucopyranosyloxy) Phenyl] -6,7-dihydro-5H-pyrazolo [3,4- h] quinoline-3-carbonitrile 161 Bis (trifluoroacetat 388 388.2132 388.2136 C23H26N5O o) of 2-amino-4- [2- (hexyloxy) phenyl] - 6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile 62 Bis (trifluoroacetat 346 346.1299 346.1345 C15H-16N5O2 o) of methyl 2- (2-amino-3-cyano- 6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) benzoate Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 163 B1s (trifluoroacetate) 327 327.1353 327.164 C19H15N6 of 2-amino-4- (1 H- ndol-7-yl) -6,7-dhydro-5H-pyrrazolo [3,4- h] quinoline-3-carbonitrile 164 Bis (trifluoroacetate) 346 346.1299 346.1329 C19H16N5O2 methyl 4- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4- h] quinoline-4-yl) ) benzoate 165 Bis (trifluoroacetate) 331 331.1666 331.1684 C19H19N6 of 2-amino-4- [4- (dimethylamine) phenyl] -6,7-dihydro-5H-pyrrazolo [3,4- h] quinolone -3- carbonitrile 166 bis (trifluoroacetate) 302 302.14 302.1408 C18H16N5 of 2-amino-4- (2-methylphenyl) -6,7-dihydro-5H-pyrazole [3,4- h] quinoline-3 carbonitrile 167 Bis (trifluoroacetate) 348 348.1455 348,149 C19H18 5O2 of 2-amino-4- [2- (2-hydroxyethoxy) phenyl] -6,7-dihydro-5H-pyrazolo [3,4- h] quinoline-3 ? ß ???? p ?? 168 B1s (trifluoroacetate) 370 370.1775 370.1754 C21 H20N7 of 2-amino-4-. { 4- cyanoethyl) (methyl) amin or] phenyl} -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3? 3 ???? p ?? Ex. No. Name of m / z EMAR EMAR Composite formula (M + H) Theor. Found calculated 169 Trifluoroacetate 306 306.0696 306.07 Ci7H-) 2 30S of 2-amino-4- (2-furyl) -5H-thiochromeno [4,3-b] pyridine-3-carbonitriio 170 Bis (trifluoroacetat 372 372.1067 372.1095 C18H13F3N5O or) 2-amino-4- [2- (trifluoromethoxy) faith nyl] -6,7-dihydro-5H-pyrazole [3,4- h] quinoline-3-carbonitrile 171 Bios (trifluoroacetate 362 362.1248 362.1233 C19H-16 5O3 o) of [2- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4- h] quinolin-4-yl) phenoxy] acetic acid 172 Bis (trifluoroacetat 332 332.1142 332.1131 C18H14N5O2 o) 2- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4- h] quinolin-4-yl benzoic acid 173 2-amino-4- [2- 354 354.1161 354.1163 C-18H14F2N5O (difluoromethoxy) faith nyl] -6,7-dihydro-5H-pyrazolo [3,4- h] quinoline-3-carbonitrile 174 4,6-diamino-2 276 276.1455 276.1455 C13H-18 5O2 (morpholin-4-ylmethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile EXAMPLE 175 This illustrates the preparation of 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzoic acid trifluoroacetate. A glass vial was charged with 4-acetylbenzoic acid (0.33 g, 2 mmol), malononitrile, (0.12 g, 3 mmol), ammonium acetate (0.23 g, 6 mmol), furaldehyde (0.19 g, 3 mmol) and a magnetic stirring bar. Toluene (3 ml_) was added to the vial, which was capped and heated to 80 degrees centigrade for 18 hours. The vial was then cooled to room temperature, and a 1: 2 mixture of methanol and dichloromethane (15 ml_) was added followed by 8 g of Amberlyst resin. The mixture was stirred for 24 h, then the resin was filtered and washed with dichloromethane (3X15 mL). A 2 M solution of ammonia in methanol (15 mL) was added to the resin, and the mixture was stirred overnight at room temperature. The resin was filtered and the filtrate was collected in a tared flask. The resin was washed sequentially with a 1: 1 mixture of methanol and dichloromethane (2X15 mL), 2 M ammonia in methanol (2X15 mL), and a 1: 1 mixture of methanol and dichloromethane (2X15 mL). The combined filtrates were concentrated in vacuo, and the residue was purified by reverse phase chromatography. The product was isolated as a brown solid (9.1 mg, 1% yield). 1 H NMR (300 MHz, CDCl 3 -CD 3 OD) d 6.60 (dd, 1 H), 7.49 (d, 1 H), 7.54 (s, 1 H), 7,663 (d, 1 H), 8.02 (d, 2 H), 8.12 (d, 2H); m / z 306 (M + H); HRMS (M + H) calculated for C17Hi3N303: 306.0879, found 306.0874.

EXAMPLES 176-213 This illustrates the production of aminocyanopyridine compounds of the present invention. The compounds listed in the table below were prepared by the methods described in Kambe, S. et al., "A simple method for the preparation of 2-amino-4-aryl-3-cyanopyridines by the condensation of malononitrile with aromatic aldehydes and alkyl ketones in the presence of ammonium acétate ", Synthesis 5: 366-368 (1980). The NMR analysis is carried out for each compound and the selected data are presented for each compound as shown in the table.

Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 176 Bis (trifluoroacetate) 283 283.1559 283.1577 C16H19N40 of 2-amino-4- (2-furyl) -6-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile 177 Trifluoroacetate of 346 346.0803 346.0831 C17H11F3N3O2 2-amino-4- (2-furyl) -6- [4- (trifluoromethoxy) phenyl] nicotinonitrile 178 Trifluoroacetate of 276 276.1137 276,116 C17H14N30 2-amino-4- (2-furyl) -6-methyl-5-phenyl-nicotinonitrile 179 Trifluoroacetate 276 276.1137 276.117 C17H14N30 2-amino-6-benzyl-4- (2-furyl) n-trinonitrile 180 2-amino-4- (2-furyl) -242 242.1293 242.1319 Ci4H16N30 6-isobutyl-nicotinonitrile Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 181 2-amino-4- (2-furyl) - 240 240.1137 240.11574 CHH14N3O 5,6,7,8-tetrahydroquinoline-3-carbonitrile 182 Trifluoroacetate 294 294.1043 294.1053 C17Hi3FN30 2-amino-5- (4- fluorophenyl) -4- (2-furyl) -6-methylnicotinonitrile 183 Trifluoroacetate 294 294.1043 294.1063 C17H13FN30 2-amino-6- (4-fluorobenzyl) -4- (2-furyl) nicotonitrile 184 Trifluoroacetate 280 2808886 280.0904 C16HnFN30 2-amino-6- (4-fluoropheni) -4- (2-furyl) nicotinonitrile 185 Trifluoroacetate of 252 252.1137 252.1136 C15H14N30 2-amino-4- (2-furyl) -5,6,7,8-tetrahydro - 5,8-methanoquinol-na-3-carbonitrile 186 Trifluoroacetate 290 290.1293 290.1292 C-i8Hi6N30 2-amino-6- (3,4-dimethylphenyl) -4- (2-furyl) nicotinonitrile 187 Trifluoroacetate 2- 288 288.1137 288.1139 C-i8Hi4 30 amino-4- (2-furyl) -5,6-dihydrobenzoth] quinoline-3-carbonitrile 188 Trifluoroacetate 276 276.1137 276.1 43 C17Hi4N30 2-amino-4- (2-furyl) -5-methyl -6- phenyl-nicotinonitrile 189 Trifluoroacetate 338 338.1293 338.1294 C-22Hi6N30 2-amino-4- (2-furyl) -5,6-diphenyl-nicotinonitrile Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 190 Trifluoroacetate 294 294.1043 294.1044 C17H13FN30 of 2-amino-6- (4-fluorophenyl) -4- (2-furyl) -5-methylnicotinonitrile 191 Trifluoroacetate 306 306.1243 306.1235 C18H16N3O2 of 2-amino-4- (2- furyl) -6- (4-methoxyphenyl) -5- methylnicotinonitriio 192 Trifluoroacetate 278 278,093 278,093 C16H12N3O2 of 2-amino-4- (2-furyl) -6- (3-hydroxyphenyl) nicotin onitrile 193 Trifluoroacetate 292 292.1086 292.1086 C17H14N302 of 2-amino-4- (2-furyl) -6- (4-hydroxyphenyl) -5-methylnicotinonitrile 194 Trifluoroacetate 278 278,093 278.0934 C16H-12 3O2 of 2-amino-4- (2-furyl) -6- (4 hydroxyphenol) nicotinonitrile 195 Bis (trifluoroacetat 241 241.1089 241.1076 Ci3Hi3 402 o) of 2-amino-4- (2-furyl) -5,6,7,8-tetrahydro-1,6-naphthyridine-3 - carbonitrile 196 Trifluoroacetate 328 328. 086 328.1095 C2oHi N302 of 2-amino-4- (2-furyl) -6- (8-hydroxy-1-naphthyl) nicotinonitrile 197 Trifluoroacetate 312 312.1348 312.1342 C17H18 3O2 of ethyl 2-amine - 3-cyano-4- (2-furyl) - 5,6,7,8-tetrahydroquinoline-6-carboxylate Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 198 Trifluoroacetate 287 287.0933 287.0941 C17H11N4O 2-amino-6- (4-cyanophenyl) -4- (2-furyl) nicotonitrile 199 2-amino-4- (2-furyl) -265 265.1089 265.1123 Ci5Hi3N40 6- (1-methyl-1H-pyrrol-2-yl) nicotonitrile 200 2-amino-4,6-di (2-252 252.0773 252.0751 C-] 4H-io 303fol) nicotinonetrile 201 2-amino-4- (2-furl) - 251 251.0933 251.0928 C14HiiN40 6- (1H-pyrro! -2-yl) nicotinonitrile 202 2-amino-4- (2-furyl) - 328 328.1 98 328.1194 CigHi4NsO 6- [4- (1 H -amidazol-1-yl) phenyl] nicotonitrile or 203 Bs (trifluoroacetate 269 269.0497 269.0479 C13H9N40) of 2-amino-4- (2- furyl) - 6- (1, 3-thiazol-2-yl) n-trinonitrile 204 2-amino-4- (2-furyl) - 268 268.0545 268.0545 C14H10N3O 6-thien-3-ylnicotinonitrile 205 2-amino-6- (1, 3- 306 306.0879 306.0888 C17H12 3O3 benzodioxol-5-yl) -4- (2-furyl) nicotinonitrile 206 Bs (trifluoroacetate 326 263.0933 263.0945 C15HiiN40) of 6-amino-4- (2-furyl) -2,2'-b-pyridine-5-carbonitrile 207 6-amino-4- (2-furyl) - 263 263.0933 263.0935 Ci5HnN40 2,3'-bipyridine-5-carbonitrile 208 Bis (trifluoroacetate 263 263.0933 263.0928 C15HnN40) of 6-amino-4- (2-furyl) -2,4'-bipyridine-5-carbonitrile Ex. No. Name of the m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 209 2-amino-4- (2- 262 262,098 262.0971 C16H12N30 furyl) -6- phenylnicotinonitrile 210 2-amino-4- (2- 276 276.1137 276.1121 C17H14N30 furyl) -6- (4-methylphenyl) nicotinone nitrile 211 2 -amino-4- (2- 265 265.1089 265.1088 C15H13N40 furiI) -6- (1-methyl-1 H -pyrrol-3-yl) nicotinonetria 212 2- amino-4- (2- 301 301.1089 301.1107 C18H13 4O furyl) -6- (1H-indol-3-yl) nicotonnonitrile 213 2-amino-4- (2- 286 C18H12N3O furyl) benzo [h] quinoline-3-carbonitrile EXAMPLE 214 This illustrates the production of 2-amino-4- (2-furyl) -5H-chromene b] pyridine-3-carbonitrile. 3- (2-furyl) -3-oxopropanonitrile (10 mmol, 1.0 equiv., 1.35 g) and Malononitrile (10 mmol, 1.0 equiv., 600 μ? _) is combined in pridine (10 mL). The mixture was heated to 100 ° C for 1 hour. The reaction mixture was diluted with 150 mL dichloromethane and washed with 1 M HCl (3 x 50 mL). The organic layer was dried and evaporated to give a dark oil (GDS-13695-130). The oil was dissolved in EtOH (30 mL) and treated with salicaldehyde (10 mmol, 1.0 equiv, 1.0 mL) and acetic acid (AcOH) (10 mL). The resulting mixture was heated to reflux for 2 hours. The solvent was evaporated and the in vacuo and the residue were dissolved in trifluoroacetic acid (15mL). The triethylsilane (10 mL) was added and the solution was stirred overnight. The solvents were evaporated and the residue was purified by reverse phase chromatography. The product was isolated as a solid (370mg, 13%). H NMR (400 MHz, DMSO) d 7.99 (s, H), 7.24-7. 20 (m, 2H), 7.08-7. 04 (m, 3H), 6.94 (bs, 2H), 6.76 (s, 1 H), 3.96 (s, 2H): m / z 290 (M + H).

EXAMPLE 215 This illustrates the production of trifluoroacetate 2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile.

Stage 1: (synthesis of t-Butyl 2-bromophenyl (methyl) carbamate) 2-bromoaniline (25 mmol, 1.0 equiv 4.3g) was dissolved in THF (150 mL). Sodium hydride (60% in mineral oil, 1.1 g) was added and the mixture was heated to reflux for 1 hour. After cooling to room temperature, a solution of di-t-butyl-dicarbonate in THF (1.0M, 30 mmol, 1.2 equiv., 30 mL) was added followed by sodium hydride (1.1 g). The resulting mixture was heated to reflux for 14 hours. After cooling to room temperature, iodomethane (28 mmol, 1.12 equiv., 1.75 mL) was added and the mixture was heated to reflux for 3 hours. After cooling to room temperature, the reaction was quenched with water and diluted with ether. The organic layer was washed with saturated aqueous ammonium chloride (NH4CI), saturated aqueous sodium bicarbonate (NaHCO3), and saturated aqueous sodium chloride (NaCl). The organic layer was dried over MgSO4, filtered and evaporated to give a yellow oil. Chromatography of purified silica gel gave the product as a yellow oil (5.9g, 82%). 1 H NMR (400 MHz, CDCl 3) d 7. 58 (d, 1 H), 7.29 (t, 1 H), 7.21 (d, 1 H), 7.12 (t, 1 H), 3.13 (s, 3 H), 1.33 (s, 9H): m / z 271 (M + H).

Step 2: (synthesis of trifluoroacetate 2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile) T-Butyl 2-bromophenyl (methyl) carbamate ( 2.65 mmol, 1.0 equiv., 759 mg) was dissolved in THF (20 mL). The solution was cooled in a dry acetone bath with ice and a solution of n-BuLi in hexane (1.6M, 1.1 equiv 1.8 mL) was added dropwise. After 15 minutes, dimethylformamide (DMF) (1 mL) was added and the reaction was allowed to warm to room temperature. The reaction mixture was quenched with saturated aqueous NH 4 Cl, and partitioned between ether and water. The organic layer was washed with water and dried over MgSO4, filtered and evaporated to obtain 820 mg of a yellow oil. This oil was taken immediately without purification or characterization. The resulting oil was treated with 2-amino-1-propene-1, 1,3-tricarbonitrile (2 mmol, 265mg), acetic acid (2.0mL), and ethanol (10mL) and the resulting solution was heated to reflux during the night. The thick mixture reaction was concentrated in vacuo and then dissolved in trifluoroacetic acid (7mL) at 0 ° C. Triethylsilane (5. OmL) was added via syringe. The reaction was stirred for 2 hours forward, the solvents were evaporated, a brown solid was acquired. The solid was washed with dichloromethane and dried to give the product as a light brown solid. (90mg, 9%). 1 H NMR (400 MHz, DMSO) d 7. 16 (t, 1 H), 7.03 (d, 1 H), 6.97-6. 91 (m, 2H), 3.70 (s, 2H), 3.34 (s, 3H): m / z 252 (M + H).

EXAMPLE 216 This illustrates the production of 2,4-diamino-8-ethoxy-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile.

The 2,4-diamino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile (400 mg, 1.0 mmol) and NaOH (166 mg, 42 mmol) was suspended in dimethylsulfoxide (DMSO) ) (5 mL) and warmed until dissolved. Ethyl bromide was added to the reaction mixture, which was heated to 85 ° C until it disappeared from the starting material (monitored in CLAR). After neutralizing with NH 4 Cl, the crude reaction mixture was purified by reverse phase column chromatography. Evaporation of the solvent in a lyophilizer gave an orange solid as a salt TFA 2,4-diamino-8-ethoxy-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, the which was confirmed by 2D NMR analysis. 1 H-NMR (300 MHz, CD 3 OD): d 1.47 (t, 3 H), 3.63 (s, 2 H), 4.12 (quartet, 2 H), 6.59-6. 81 (m, 2H). HRMS calculated for C15H14N403 (M + H): 299.1 1. Found: 299.1 32.

EXAMPLE 217 This illustrates the production of 2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonomethyl. 2,4-Diamino-8- (2-ethoxy-ethoxy) -7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy -5H-chromene [2,3-b] pyridine-3-carbonitrile in the same method as described above in Example 216, using 2-bromoethyl ethyl ether instead of 2-bromoethyl ethyl ether. 1 H-NMR (300 MHz, CD 3 OD): d 1.28 (t, 3H), 3.60 (s, 2H), 3.67 (quartet, 2H), 3.86 (s, 2H), 4.19 (s, 2H), 6.58-6.82 ( m, 2H). HRMS calculated for C 17 H 18 N 404 (M + H): 343.13. Found: 343.1418.

EXAMPLES 218-219 This illustrates the production of aminocyanopyridine compounds of the present invention. The aminocyanopyridine compounds shown in the table below were prepared according to the general method described in Example 216. The NMR analysis was carried out according to the method described above, and the resulting data of each of the compounds were provided in picture.

EXAMPLE 220 This illustrates the production of 2,4-diamino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonomethyl. To a cold solution (0 ° C) of 2,4-diamino-7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile (1.34mmol, 400mg) and dichloromethane (4.0mL) Boron tribromide (1M, dichloromethane, 8.04mmol, 8.04mL) was slowly added. The suspension was stirred at 0 ° C for 15 minutes, then the ice bath was removed and the reaction was heated at 23 ° C overnight. After 16h at 23 ° C the reaction was cooled to 0 ° C and carefully neutralized with 2.5N sodium hydroxide to a pH = 7. The product was collected by filtration, dissolved in dimethyl sulfoxide (1.0 mL) and purified by reverse phase chromatography. The product was isolated as a pale orange solid (62mg, 17% yield). 1 H NMR (400 MHz, DMSO) d 9,071 (s, H), 8,795 (s, 1 H), 6,520 (s, 1 H), 6,410 (bs, 2 H), 6,405 (s, 1 H), 6,244 (bs) , 2H), 3.48 (s, 2H): m / z 271 (M +); HRMS (M + H) calculated for C13H11N403 271.0753, found 271.0721.

EXAMPLE 221 This illustrates the production of 2,4-diamino-8-hydroxy-5H-chromene [2,3-b] pyridin-3-carbonyltryl. 2,4-Dihydroxy-benzaldehyde (43.4mmol, 6.0g), 2-amino-1-propene-1, 1,3-tricarbonitrile (43.4mmol, 5.74g), acetic acid (13.0mL), and ethanol were combined. (125.0ml_) and heated to reflux for 2 hours. The thick mixture of the reaction was concentrated in vacuo and then dissolved in a trifluoroacetic acid (160.0 mL) at 0 ° C. Triethylsilane (0-28mol, 32.76g, 45. OmL) was added via syringe. The reaction was stirred for 1 hour at 0 ° C. 300mL of dichloromethane was added to the reaction and the solid was collected by filtration and washed (2x75mL) with dichloromethane and ether. The product was isolated as a pale orange solid (13.10 g, 63% yield NMR (400 MHz, DMSO) d 6.958 (d, 1 H), 6.537 (dd, 1H), 6.390 (d, 1 H), 3.510 (s, 2H): m / z 255 (M +); HRMS (M + H) calculated for C13H11N402 255.0804, found 255.0894.

EXAMPLE 222 This illustrates the production of 8, 10-diamino-2,3-dihydro-11 H- [1,4] dioxino [2 ', 3': 6,7] chromene [2,3-b] pyridin-9-carbonitrile. The 2,4-diamino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile (0.56mmol, 150mg) was dissolved in DMSO (3.0ml_) and sodium hydroxide (2.24mmol, 90mg) was added followed by dibromoethane (0.56mmol, 105.20mg, 48.26 μ). The dark homogenous solution was heated to 70 ° C for 16 hours. The crude reaction mixture was cooled to 23 ° C, neutralized with trifluoroacetic acid and purified directly by reverse phase chromatography. The product was isolated as a pale orange solid (30mg, 18% yield). 1 H NMR (400 MHz, CD 3 OD) d 6.715 (s, 1 H), 6.553 (s, 1 H), 4.215 (bs, 4H), 3.575 (s, 2H): m / z 298 (M + H).

EXAMPLE 223 This illustrates the production of 2,4-diamino-8- (2-ethoxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile. The 2,4-diamino-8-hydroxy-5H-chromene [2,3-b] pyridine-3-carbontrile (0.62mmol, 300mg) was dissolved in DMSO (4.OmL) and solid sodium hydroxide ( 2.79 mmol, 111.6 mg) was added followed by 2-bromoethyl ethyl ether (0.62 mmol, 69.9 μ). The reaction was heated to 80 ° C with stirring for 9 hours. The crude reaction was filtered and diluted with DMSO (4.OmL) and purified by reverse phase chromatography. The product was isolated as a brown solid (80mg, 40% yield). H NMR (400 MHz, CD3OD) d 7.180 (d, 1 H), 6.795 (d, 1H), 6.46 (d, 1 H), 4090 (t, 2H), 3766 (t, 2H), 3.607 (s, 2H), 3.572 (t, 2H), 1200 (t, 2H); m / z 327 (M + H).

EXAMPLE 224 This illustrates the production of 2,4-d-amino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromene [2,3-b] pyridin-3-carbonitrile. 2,4-Diamino-8- (2-pyrrolidin-1-ylethoxy) -5H-chromene [2,3-b] pyridin-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy -5H-chromene [2,3-b] pyridine-3-carbonitrilein in the same manner as described in Example 223, using 1- (2-chloroethyl) pyridine in place of 2-bromoethyl ethyl ether. The product was isolated as a brown solid (100mg, 46% yield). 1 H NMR (400 MHz, CD 3 OD) d 7.199 (d, 1 H), 6,680 (d, 1 H), 6,668 (d, 1 H), 4,290 (t, 2 H), 3,618 (s, 2 H), 3,562 (t , 2H), 3.375 (bs, 4H), 2.077 (bs, 4H); m / z 352 (M + H). TNFa IC50 release assay: 2.9 μ ?; Rat LPS assay 60% inhibition at 20 mpk (IP).

EXAMPLE 225 This illustrates the production of 2,4-diamino-8- (2-aminoethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile. 2,4-Diamino-8- (2-aminoethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromene [2 , 3-b] pyridine-3-carbonomethyl in the same manner as described in Example 223 using 2-bromoethylamine in place of 2-bromoethyl ethyl ether. The product was isolated as a brown solid (167mg, 51% yield). H NMR (400 MHz, DMSO) d 8.180 (bs, 2H), 7.100 (d, 1H), 6.762 (d, 1 H). 6.646 (bs, 1H), 4.154 (t, 2H), 3.573 (s, 2H), 3.155 (t, 2H); m / z 398 (M + H). TNFa IC50 release assay: 6.9 μ ?; Rat LPS assay 88% inhibition at 20 mpk (IP).

EXAMPLE 226 This illustrates the production of [(2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridin-8-yl) oxy] acetic acid. [(2,4-Diamino-3-cyano-5H-chromene [2,3-b] pyridin-8-yl) oxy] acetic acid was prepared from 2,4-diamino-8-hydroxy-5H- chromene [2,3-b] pyridyl-3-carbonitrile in the same manner as described in Example 223 using bromoacetic acid in place of 2-bromoethyl ethyl ether. The product was isolated as a brown solid (110.6mg, 31% yield). 1 H NMR (400 MHz, DMSO) d 7.030 (d, 1 H), 6,640 (d, 1 H), 6,516 (d, 1 H), 6,474 (bs, 2 H), 6,278 (bs, 2 H), 4,633 (s, 2H), 3.543 (s, 2H); m / z 427 (M + H).

EXAMPLE 227 This illustrates the production of 2,4-diamino-8- (2-hydroxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile. 2,4-D-amino-8- (2-hydroxyethoxy) -5H-chromene [2,3-b] pyridin-3-carbonitrile was prepared from 2,4-diam No-8-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonyl ester in the same manner as described in Example 223 using 2-bromoethanol in place of 2-bromoethyl- etiEther. The product was isolated as a brown solid (120mg, 35% yield). 1 H NMR (400 MHz, DMSO) d 7,025 (d, 1 H), 6,670 (d, 1 H), 6,550 (d, 1 H), 3,931 (t, 2 H), 3,662 (t, 2 H), 3,546 (s, 2 H) ); m / z 413 (M + H).

EXAMPLE 228 This illustrates the production of 2,4-diamino-8- (2-morpholin-4-ylethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile. 2,4-Diamino-8- (2-morpholin-4-ylethoxy) -5H-chromene [2,3-bjpyridin-3-carbonitrile was prepared from 2,4-diamino-8-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile in the same manner as described in Example 223 using 1- (2-chloroethyl) morpholine in place of 2-bromoethyl ethyl ether. The product was isolated as a brown solid (80mg, 17% yield). 1 H NMR (400 MHz, DMSO) d 7.071 (d, 1 H), 6,714 (d, 1 H), 6,654 (d, 1 H), 6,527 (bs, 2 H), 6,323 (bs, 2 H), 4,311 (t, 2H), 3,938 (m, 2H), 3,664 (t, 2H), 3,558 (s, 2H), 3,534 (m, 2H), 3,451 (m, 2H), 3,158 (m, 2H); m / z 482 (+ H).

EXAMPLES 229-235 This illustrates the production of aminocyanopyridine compounds of the present invention. The aminocyanopyridine compounds shown in the table below were prepared according to the general method described in example 223. The NMR analysis was carried out according to the method described above, and the resulting data of each of the compounds were provided in picture.

Ex. No. Name of compound m / z (M + H) 229 2,4-diamino-8-methoxy-5H-chromene [2,3-b] pyridine-3- 269 carbonitrile 230 7,9-diamino-10 H- [1,3] dioxolo [6,7] chromene [ 2,3-b] pyridine-8-283 carbonitrile 231 8- (allyloxy) -2,4-diamino-5H-chromene trifluoroacetate [2,3-295 b] pyridine-3-carbonitrile 232 2-amino-8- ethoxy-4- (ethylamino) -5H-chromethane [2,3-b] pyridine-3-3 1 carbonitrile 233 8-ethoxy-2,4-bis (ethylamino) -5H-chromene [2,3-b] pyridine-3- 339 carbonitrile 234 2-amino-8- (2-ethoxyethoxy) -4 - [(2-ethoxyethyl) amino] -5H- 399 chromene [2,3-b] pyridine-3-carbonitrile 235 Trifluoroacetate 2 , 4-diamino-8- [2- (dimethylamino) ethoxy} - 326 5 H -chromene [2,3-b] pyridine-3-carbonitrile EXAMPLE 236 This illustrates the production of b1s (trifluoroacetate) of 2,4-diamino-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile. 3-Methoxy-sodium-aldehyde (10mol, 1.52 g), 2-amino-1-propene-1, 1,3-tricarbonitrile (10 mmol, 1.32 g), acetic acid (2.5 mL), and ethanol (40 mL) were combined and They heated until reflux during the night. The thick mixture of the reaction was concentrated in vacuo and then dissolved in trifluoroacetic acid (15 mL) at 0 ° C. Triethylsilane (62 mmol, 7.2 g, 10 mL) was added via syringe. The reaction was stirred for 1 hour at room temperature. Dichloromethane (100 mL) was added to the reaction and the solid formed was collected by filtration and washed with dichloromethane (2x). The product was isolated as a white solid (2.5 g, 50% yield). 1 H NMR (300 MHz, DMSO-d 6): d 7.08 (t, J = 8 Hz, 1 H), 7.00-6.80 (m, 2 H), 6.73 (d, J = 7.4 Hz, 2 H), 3.83 (s, 3 H) 3.68 (s, 2H); m / z 269 (M + H); Analysis calculated for C 14 H 12 N 4 O 2-2CF 3 CO 2 H: C, 43.56; H, 2.84; N, 11.29, found: C, 43.40; H, 2.98; N, 11.32.

EXAMPLE 237 This illustrates the production of trifluoroacetate of 2,4-diamino-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile.

The 2,4-diamamido-7-hydroxy-5H-chromene [2,3-b] pyridyl-3-carbonomethyl was prepared in the same manner as described in Example 236, except that 5-hydroxysameIdehyde was used in place of methoxysialdehyde. The product was isolated as a pink solid (951 mg, 30% yield). 1 H NMR (300 MHz, DMSO-d 6): d 6.88 (d, J = 8.8 Hz, 1 H), 6.63 (d, J = 8.7 Hz, 1 H), 6.55 (s, 1 H), 3.6 (s, 2H): m / z 255 (M + H); analysis calculated for C13H 0N4O2-1.5CF3CO2H-0.5 H20: C, 44.25; H, 2.90; N, 12.90, found: C, 44.04; H, 3.05; N, 12.84.

EXAMPLE 238 This illustrates the production of Bis (trifluoroacetate) from 2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile. The 2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile was prepared in the same manner as described in Example 236 except that the salicialdehyde was used in place of methoxysialidedehyde. The product was isolated as a light brown solid (1.26 g, 33% yield). H NMR (300 MHz, DMSO-d6), d 7.30-6.90 (m, 6H), 3.7 (s, 2H); m / z 239 (M + H); Analysis Calculated for C 13 H 10 N 4 O-2 CF 3 CO 2 H-O 25 H 20: C, 43.37; H, 2.68; N, 11.90, found: C, 43.07; H, 2.81; N, 11.79.

EXAMPLE 239 This illustrates the production of 2,4-diamino-8,9-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile trifluoroacetate. 2,4-Diamino-8,9-dihydroxy-5H-chromene [2,3-b] pyridin-3-carbonitrile was prepared in the same manner as described in Example 236, except that 2.3 , 4-trihydroxybenzaldehyde was used in place of methoxysalicylaldehyde. The product was isolated as a white solid (3.6 g, 82% yield). H NMR (500 MHz, DMSO-d6): d 7.1 (bs, 3H), 6.58 (d, J = 8 Hz, 1 H), 6.47 (d, J = 8 Hz, 1 H), 3.75 (s, 2H) ); m / z 271 (M + H).

EXAMPLE 240 This illustrates the production of trifluoroacetate 2, 4-diamino-9-hydroxy-8-methoxy-5H-chromene [2,3-b] pyridin-3-carbonomethyl. 2,3-Dihydroxy-4-methoxybenzaldehyde (3 mmol, 506 mg), 2-amino-1-propene-1, 1,3-tricarbonitrile (3 mmol, 398 mg), acetic acid (1 mL) were combined. ), and ethanol (15 mL) and heated to reflux overnight. The thick mixture of the reaction was concentrated in vacuo and then dissolved in trifluoroacetic acid (10 mL) at 0 ° C. Triethlysilane (25 mmol, 2.88 g, 4 mL) was added via syringe. The reaction was stirred overnight at room temperature to give a thick yellow mixture. Dichloromethane (50 mL) was added to the reaction and the solid formed was collected by filtration and washed with dichloromethane (2x). The product was isolated as a yellow solid (482 mg, 35% yield). H NMR (300 MHz, DMSO-d6): d 6.73 (d, J = 8.5 Hz, 1 H), 6.57 (d, J = 8.5 Hz, 1 H), 3.77 (s, 3 H), 3.57 (s, 2 H) ); m / z 285 (M + H); Analysis calculated for C14Hi2N403-1.25CF3C02H-1.5H20: C, 43.58; H, 3.62; N, 12.32, found: C, 43.80; H, 3.22; N, 12.65.

EXAMPLE 241 This illustrates the production of trifluoroacetate of 2,4-diamino-9-hydroxy-5H-chromene [2,3-bpyridine-3-carbonitrile. 2,3-Dihydroxybenzaldehyde (5 mmol, 691 mg), 2-amino-1-propene-1, 1,3-tricarbonitrile (5 mmol, 661 mg), acetic acid (1.2 mL), and ethanol (20 mL) were combined. mL) and warmed to reflux overnight. The thick mixture of the reaction was concentrated in vacuo and then dissolved in trifluoroacetic acid (20 mL) at 0 ° C. Triethylsilane (62 mmol, 7. 2 g, 10 mL) was added via syringe. The reaction was stirred for two and a half days at room temperature to give a solution, which was concentrated in vacuo. The residue was stirred in methanol and the thickened mixture was filtered. The product was obtained as a brown solid by concentration of the filtrate (167 mg, 9% yield). H NMR (300 MHz, DMSO-d6): d 6.91 (t, J = 7.7 Hz, H), 6.86-6.70 (m, 2H), 6.59 (d, J = 7.3 Hz 1 H), 3.61 (s, 2H ); m / z 255 (M + H).

EXAMPLE 242 This illustrates the production of 2,4,7-triamino-5H-chromene [2,3-b] pyridine-3-carbonitrile. Step 1: Preparation of 2,4-diamino-7-nitro-5H-chromene [2,3-b] pyridin-3-carbonitrile: 5-Nitrosalicylaldehyde (132 mmol, 22.00 g) was combined, amino-1-propene-1,1,3-tribecarbonitrile (132 mmol, 17.39 g), acetic acid (31 mL), and ethanol (500 mL) and were heated to reflux overnight. The resulting thick mixture was concentrated in vacuo and then dissolved in trifluoroacetic acid (350 mL) at 0 ° C. Triethylsilane (1.40 mol, 162 g, 225 mL) was added. The mixture was heated overnight at 66CC. The mixture was cooled and concentrated in vacuo. Triturated with methanol to give 2,4-diamino-7-nitro-5H-chromene [2,3-b] pyridine-3-carbonitrile as a yellow solid (22.48 g, 60% yield). 1 H NMR (300 MHz, DMSO-d 6): d 8.13 (d, J = 9.0 Hz, 1 H), 8.00 (s, 1 H), 7.25 (d, J = 9.0 Hz, 1 H), 6.70 (br s) , 2H), 6.50 (bs, 2H), 3.82 (s, 2H); m / z 284 (M + H); Analysis Calculated for C 13 H 9 N 5 O 3-0.5H 2 O: C, 53.43; H, 3.45; N, 23.96, found: C, 53.41; H, 3.17; N, 23.71.

Step 2: A mixture of 2,4-diamino-7-nitro-5H-chromene [2,3-b] pyridine-3-carbonitrile, are produced as described above (0.55 mmol, 155 mg) and palladium on carbon ( Pd / C) (35 mg, 10% on activated carbon) in DMF (15 mL) was stirred under a hydrogen atmosphere (balloon) for 3.5 hours. The catalyst was removed by filtration using a plug of celite. The filtrate was concentrated in vacuo and the residue was triturated with methanol to give 2,4,7-triamino-5H-chromene [2,3-b] pyridine-3-carbonitrile as a gray solid (109 mg, 79% strength). performance). 1 H R N (300 MHz, DMSO-d 6): d 6.72 (d, J = 8.0 Hz, 1 H), 6.39-6.5 (m, 4H), 6.25 (s, 2H), 3.52 (s, 2H); m / z 254 (M + H).

EXAMPLE 243 This illustrates the production of 2,4-diamino-9-fluoro-5H-chromene [2,3-b] pyridine-3-carbonitrile trifluoroacetate. 3-Fluoro-2-hydroxybenzaldehyde (3.45 mmol, 484 mg), 2-amino-1-propene-1, 1,3-tribecarbonitrile (3.50 mmol, 463 mg), acetic acid (0.9 mL) and ethanol (27 mL) and were heated to reflux for 14 hours. The thick mixture of the reaction was concentrated in vacuo and then dissolved in trifluoroacetic acid (10.5 mL). Triethylsilane (43mmol, 4.97 g, 6.9 mL) was added via syringe. The reaction was heated to reflux for 5 hours. The dichloromethane (50 mL) was added to the reaction and the solid formed was collected by filtration and washed with methanol. The product was isolated as a white solid (377 mg, 30% yield). H NMR (500 MHz, DMSO-d6): d 7.25-7.19 (m, 1 H), 7.15-7.08 (m, 1 H), 7.00-6.96 (m, 1 H), 6.70 (bs, 2H), 6.51. (bs, 2H), 3.75 (S, 2H); m / z 257 (M + H).

EXAMPLE 244 This illustrates the production of Bis (trifluoroacetate) from 2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridine-7-carboxylic acid. 5-carboxy-aldehydedehyde (3 mmol, 500 mg), 2-amino-1-propene-1, 1,3-tricarbonitrile (3 mmol, 396 mg), acetic acid (1.2 mL), and ethanol (15 mL) were combined. ) and heated to reflux for 2.5 days. The thick mixture of the reaction was concentrated in vacuo and then dissolved in trifluoroacetic acid (10 mL). Triethylsilane (62 mmol, 7.2g, 10 mL) was added by means of a syringe. The reaction was stirred for 4 hours at 50 ° C and then stirred overnight at room temperature. The dichloromethane (20 mL) was added to the reaction and the solid formed was collected by filtration and washed with dichloromethane (2x). The product was isolated as a yellow solid (560 mg, 36% yield). 1 H NMR (500 MHz, D SO-d 6): d 7.86 (d, J = 7.4 Hz, 1 H), 7.85 (s, 1 H), 7.31 (d, J = 7.4 Hz, 1 H), 6.80 (br s, 2H), 3.85 (s, 2H); m / z 283 (M + H); Analysis Calculated for C 14 H 1 o N 403-2CF 3 C0 2 H -0.25 H 20: C, 42.00; H, 2.45; N, 10.88, found: C, 42.30; H, 2.31; N, 10. 51.

EXAMPLE 245 This illustrates the production of trifluoroacetate of 2,4-diamino-6,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile.

The 2,4-diamino-6,8-dihydroxy-5H-chromene [2,3-b] pyridn-3-carbonitrile was prepared in the same manner as described in Example 244, except that 2,4,6-trihydroxybenzaldehyde was used in place of 5-carboxysialicialdehyde. The product was isolated as an orange colored solid (106 mg, 9% yield). H NMR (free base, 300 MHz, DMSO-d6): d 9.65 (s, 1H), 9.40 (s, 1 H), 6.41 (s, 2H), 6.35 (s, 2H), 6.10 (s, 1H) , 5.85 (s, 1H), 3.31 (s, 2H); m / z 271 (M + H).

EXAMPLES 246-264 This illustrates the production of aminocyanopyridine compounds of the present invention. The aminocyanopyridine compounds shown in the table below were prepared according to the general method described in example 242. The NMR analysis was carried out according to the method described above and the resulting data of each of the compounds were provided in picture.

Ex. No. Name of compound M + H 246 2,4-diamino-7- (dimethylamino) -5H-chromene [2,3-282 b] pyridin-3-carbonitrile 247 2,4-diamino-7-nitride 5H-chromene [2,3-b] pyridin-3-284 carbonitrile 248 2,4-diam-7-chloro-9-methyl-5H-chromene [2,3- 287 b] pyridine n-3-carbonitrile 249 2,4-diamino-6,8-d¡methoxy-5H-chromene [2,3- 299 b] pyridin-3-carbonitrile 250 2,4-diamino- trifluoroacetate 7- 323 (trifluoromethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile 251 2,4-diamino-7-bromo-9-347 trifluoroacetate methoxy-5H-chromene [2,3-b] pyra D-n-3-carbonitrile 252 2,4-diamno-9-methoxy-7-nitro-314 5H-chromene [2,3-b] pyridine-3-carbonitrile trifluoroacetate Trifluoroacetate of 2, 4-diamino-8-methyl-5H-253 chromene [2,3-b] pyridine-3-carbonyl ether Ex. No. Name of compound M + H 254 bis (trifluoroacetate) of 2,4-diamino-3- 283 cyano-5H-chromene [2,3-b] pyridine-9-carboxylic acid 255 bis (trifluoroacetate) of 2,4-diamino-6-methoxy -5H- 269 chromene [2,3-b] pyridine-3-carbonitrile 256 2,4-diamino-9-bromo-7-chloro-351 5H-chromene [2,3-b] pyridine trifluoroacetate -3-carbonitrile 257 2,4-diamino-6-bromo-9-347 trifluoroacetate methoxy-5H-chromene [2,3-b] pyridin-3-carbonitrile 258 Trifluoroacetate of 2,4,7- triamino-9-methoxy-5H-284 chromene [2,3-b] pyridine-3-carbonitrile 259 2,4-diamino-9-nitro-5H-chromene [2,3-b] pyridn-3 - 284 carbonitrile 260 2,4,9-Triamline-5H-254 trifenoxy-chromene [2,3-b] pyridine-3-carbonitrile 261 2,4-diamino-7-fluoro-5H-257 chromenne trifluoroacetate [ 2,3-b] pyridine-3-carbonitrile 262 2,4-diamino-7-chloro-5H-chromene [2,3-b] pyridine-3- 273 carbonitrile 263 2,4-dimanium-9-tert -butyl-5H-chromene [2,3-b] pyridin-295 3-carbonitrile 264 2,4-diammon-3-cyano-5H-chromene [2,3-b] pyrid n-9- 311 ethyl carboxylate EXAMPLE 265 This illustrates the production of 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile. Stage 1: Production of 5-Nitrothiosalicylaldehyde: A mixture of 2-Chloro-5-nitrobenzaldehyde (2 g, 11 mmol) and lithium sulfide (0.54 g, 11.7 mmol) in 30 mL of anhydrous DMSO was stirred under nitrogen at room temperature overnight. The solution was then added to a mixture of ice water, acidified with 2N HCl and extracted with ether 3 times. The combined ether layers were washed with water, brine, dried, filtered and concentrated to give the crude 5-nitro-2-thiosalicylaldehyde as an orange-colored solid (1.3g, 65% yield).

Step 2: A solution of crude 5-nitro-2-thiosylamino-dihydride (1.3 g, 7.1 mmol), 2-amino-1-propene-1,11,3-tricarbonitrile (7.6 mmol, 1 g), acetic acid (2.5 mL) in 70 mL of ethanol was heated at 76 ° C under nitrogen overnight. The reaction mixture was cooled to room temperature and filtered. The solid was washed with ethanol to give the desired tricyclic intermediate as a light brown solid (1.5g, 71.4% yield).

Step 3: A reaction mixture of the aforementioned tricyclic intermediate (1.2 g, 4 mmol) and triethylsilane (15 mL) in 100 mL of trifluoroacetic acid was heated between 60-65 ° C under nitrogen for 2 hours.

After the solution was cooled to room temperature and concentrated in vacuo. The ether was added to the residue. The solid was filtered, washed with additional ether to give 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile as an orange powder (0.9 g, 75% performance). H NMR (400 MHz, CD3CN + D20) d 8.089 (d, 1H), 8.046 (dd, 1 H), 7.609 (d, 1H), 3898 (s, 2H); m / z 300 (M + H).

EXAMPLE 266 This illustrates the production of trifluoroacetate of 2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile. To 2,4-d-amino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile (provided as described above in Example 265; 0.8 g, 2.7 mmol) in 9 mL of 50 % (by weight) of ethanol-water was added iron powder (0.55 g, 10 mmol). The mixture was heated to 60 ° C and then 0.5 mL of HCl / ethanol (prepared from 5.2 mL of concentrated HCl and 25 mL of 50% ethanol-water) was added. The resulting mixture was heated at 76 ° C for 2.5 hours and filtered hot. The solid was washed with 50% ethanol-water. The filtrates were combined and concentrated in vacuo to give a brown-yellow solid. The solid was then dissolved in acetonitrile, filtered to remove a small amount of an insoluble solid and concentrated in vacuo. The resulting solid was then washed with methanol and trifluoroacetic acid. The trifluoroacetic acid filtrate was concentrated in vacuo to give an amber oil. Ether was added and the solid was filtered, washed with ether, air dried overnight and then dried in a vacuum oven at 44 ° C for 2 hours to give the product as a gray solid (0.53 g). , 71% yield NMR (400 MHz, CD3CN + D20) d 7.153 (d, 1 H), 6,792 (s, 1H), 6,698 (d, 1H), 3,628 (s, 2H); m / z 270 (M + H) EXAMPLE 267 This illustrates the production of 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbontromyl 10,10-dioxide. To a solution of 2,4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridin-3-carbonitrile, provided as described in Example 265, (3 g, 10 mmol) in 125 ml_ of trifluoroacetic acid cooled with a water bath was added dropwise 30% hydrogen peroxide (8 g). After the addition was complete, the water bath was removed. After 4 hours, 30% additional hydrogen peroxide (2 g) was added and stirred at room temperature continuously for 2 hours. After water (20 ml_) was added and the resulting solution was concentrated around 70 ml. Then more water was added and the yellow suspension was stirred at room temperature overnight. The suspension was filtered and washed with water to give the desired product as a yellow solid (2 g, 60.4% yield). 1 H NMR (400MHz, DMSO + D 20) d 8.350 (dd, 1H), 8.265 (d, 1H), 8.220 (d, 1H), 4.160 (s, 2H); m / z 332 (M + H).

EXAMPLE 268 This illustrates the production of 10,10-d-oxide 2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile. A mixture of 2,4-diamino-7-nitro-5H-thiochromene [2,3-b] pyridine-3-carbonitrile 10,10-dioxide, provided as described in Example 267, (0.8 g, 2.4 mmol) and iron powder (0.58 g, 10 mmol) in 50% ethanol-water (10 mL) was heated to 70 ° C, then 1 mL of HCl / ethanol (prepared from 5.2 mL of HCl was added. concentrate and 25 mL of 50% ethanol-water). The resulting mixture was heated at 76 ° C for 3 hours and filtered hot. The solid was washed with methanol and trifluoroacetic acid. The trifluoroacetic acid filtrate was concentrated in vacuo and the ether was added to the viscous oil. The solid was filtered and washed with ether to give the desired product as a beige solid (0.42 g, 57.5% yield). H NMR (400 MHz, DMSO + D20) d 7.521 (d, 1 H), 6.60 (dd, 1H), 6,529 (s, 1H), 3,753 (s, 2H); m / z 302 (M + H).

EXAMPLE 269 This illustrates the production of 2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbontril. The 2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbontrile was prepared as a bis-trifluoroacetate in the same manner as described in Example 265, except that the 2,5-difluorobenzaldehyde was used as the starting material in place of 2-chloro-5-nitrobenzaldehyde. The product was isolated as a beige solid (0.35 g, 35% yield). H NMR (400 MHz, CD3CN + D20) d 7.425 (dd, 1 H), 7.153 (dd, 1 H), 7.088 (dt, 1 H) 3.743 (s, 2H); m / z 273 (M + H).

EXAMPLE 270 This illustrates the production of Bis (trifluoroacetate) from 2,4-diamino-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile. 2,4-Diamino-5H-thiochromeno [2,3-b] pyridin-3-carbonitrile was prepared in the same manner as described in Example 265, except that 2-fluorobenzaldehyde was used as the material of starting in place of 2-chloro-5-nitrobenzaldehyde. The product was isolated as a beige solid (1.8 g, 47.4% yield). 1 H NMR (400 MHz, CD 3 CN + D 20) d 7.271-7.435 (m, 4H), 3.785 (s, 2 H); m / z 255 (M + H).

EXAMPLE 271 This illustrates the production of 2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile. 2,4-Diamino-7-methoxy-5H-thiochromene [2,3-b] pyridin-3-carbonitrile was prepared in the same manner as described in Example 265, except that 2-fluoro-5 -methoxybenzaldehyde was used as the starting material. The product was isolated as a beige solid (0.5 g, 49% yield). 1 H NMR (400 MHz, CD 3 CN + D 20) d 7329 (d, 1 H), 6,938 (d, 1 H), 6,885 (dd, 1 H), 3,795 (s, 3 H), 3,710 (s, 2 H); m / z 285 (M + H).

EXAMPLE 272 This illustrates the production of 2,4-diamino-7-hydroxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile. A mixture of 2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile (0.3 g, 0.59 mmol), provided as described in Example 271, and 0.6 mL of tribromide of boron (6.4 mmol) in 30 mL of methylene chloride was stirred at room temperature for 18 h. After the solid was filtered, it was washed with methylene chloride, water and methanol. The filtered methanol was concentrated to a solid, which was washed with water, acetonitrile and ether to give the desired product as a red solid (54 mg, 33.6% yield). 1 H NMR (400 MHz, DMSO + D 20) d 9.520 (s, 1H), 8.111 (d, 1H), 7.561 (d, 1H), 7.522 (s, 2H); m / z 271 (M + H).

EXAMPLE 273 This illustrates the production of 2,4-diamino-7-nitro-5H-thiochromene [2,3-b] pyridine-3-carbonitrile 10,10-dioxide (an alternative procedure). A mixture of 2,4,7-triamino-5H-thiochromeno [2,3-b] pyridin-3-carbonitrile (0.1 g, 0.26 mmol), provided as described in Example 268, and 30% of hydrogen peroxide (1.5 mL) in 3 mL of trifluoroacetic acid was stirred at room temperature overnight. Then water (30 mL) was added and the resulting suspension was stirred at room temperature for 2 hours. The solid was filtered to give the desired product as a yellow solid (8 mg, 8.6% yield): HRN (400 MHz, DMSO + D20) d 8.353 (dd, 1 H), 8.263 (d, 1 H), 8.228 (d, 1 H), 4.163 (s, 2H); m / z 332 (M + H).

EXAMPLE 274 This illustrates the production of 2,4,10-dioxy-7-fluoro-5H-thiochromene [2,3-b] pyridine-3-carbonitrile. The 10,10-dioxide of 2,4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile was prepared in the same manner as 10,10-dioxide of 2, 4-diamino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbontrile, as described in Example 273. The product was isolated as a yellow solid (51 mg, 32.7% yield) ). 1 H NMR (400 MHz, DMSO) d 8.028 (q, H), 7.433 (dt, 1H), 7.253 (d, 1 H), 7.162 (bs, 1H), 6.917 (bs, 1 H), 4.024 (s, 2H); m / z 305 (M + H).

EXAMPLE 275 This illustrates the production of 2,4-diamino-5H-thiochromene [2,3-b] pyridine-3-carbonitrile 10,10-dioxide. The 10,10-dioxide of 2,4-diamino-5H-thiochromeno [2,3-b] pyridin-3-carbonitrile was prepared in the same manner as the 2,4-diamino-10,10-dioxide. 7-Nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile as described in example 273. The product was isolated as a yellow solid (73 mg, 42.9% yield) 1 H NMR (400 MHz, DMSO) d 7.945 (dd, 1 H), 7.762 (dt, 1 H), 7.568 (t, 1H), 7.467 (d, 2H), 7.179 (bs, 2H), 6.886 (bs, 1H), 4.009 (s) 2H); m / z 287 (M + H).

EXAMPLE 276 This illustrates the production of 2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile 10,10-dioxide. The 10,10-dioxide of 2,4-diamino-7-methoxy-5H-thiochromeno [2,3-b] pyridin-3-carbonitrile was prepared in the same manner as 10,10-dioxide of 2, 4-d-amino-7-nitro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, as described in Example 273. The product was isolated as a light brown solid (110 mg, 34.2% of performance). H NMR (400 MHz, DMSO + D20) d 7,858 (d, 1 H), 7,107 (dd, 1H), 6,972 (d, 1H), 3,942 (2, 2H), 3,833 (s, 3H); m / z 316 (M + H).

EXAMPLES 277-278 This illustrates the production of aminocyanopyridine compounds of the present invention. The aminocyanopyridine compounds shown in the table below were prepared according to the general method described in Example 273. The NMR analysis was carried out in accordance with the method described above and the resulting data of each of the compounds are given in picture.

EXAMPLES 279-294 This illustrates the production of certain aminocyanopyridine compounds of the present invention.

General procedure for N-alkylation: To a solution of 2,4-diamino-7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile (1.34 mmol) and the corresponding halide ( 2.01 mmol) in dimethylformamide (5 mL) was added sodium hydride (80 mg, 2.01 mmol). The reaction mixture was stirred at room temperature or heated to 40 ° C until complete. The mixture was quenched with saturated aqueous ammonium chloride and purified directly by reverse phase chromatography. Both mono alkylated or dialkylated products were isolated. The following compounds were prepared using the procedure described above: Example 279: 2-amino-4-. { [2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, Example 280: 2,4-bis. { [2- (dimethylamine) ethyl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, Example 281: 2-amino-4 - [(2-aminoethyl) amino] -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, Example 282: 2-amino-4-. { [2- (1, 3-d -oxo-1,3-dihydro-2H-isoindol-2-yl) ethyl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, Example 283: 2-amino-7,8-dimethoxy-4 - [(2-pyrrolidin-1-ethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, Example 284: 7,8-dimethoxy-2,4-bis [(2-pyrrolidin-1-ylethyl) amino] -5H- chromene [2,3-b] pyridine-3-carbonitrile, Example 285: 2,4-bis (glycinyl) -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-trifluoroacetate carbonitrile, Example 286: N- (2-amino-3-cyano-7,8-d-methoxy-5H-chromene [2,3-b] pyridin-4-yl) glycine, Example 287: 7,8-dimethoxy -2,4-bis [(2-methoxyethyl) amino] -5H-chromene [2,3-b] pyridin-3-carbonitrile, Example 288: 2-amino-7,8-dimethoxy -4 - [(2-methoxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonomethyl, Example 289: 2,4-bis (butylamino) -7,8-dimethoxy-5H -chromeno [2,3-b] pyridine-3-carbonitrile, Example 290: 2-amino-4- (butylamino) -7,8-dimethoxy-5H-chromene [2,3-b] pyridin-3- carbonitrile, Example 291: 7,8-dimethoxy-2,4-bis (propylamino) -5H-chromene [2,3-b] pyridyl-3-carbonomethyl, Example 292: 2-amino -7,8-dimethoxy-4- (propylamino) -5H-c romeno [2,3-b] pyridine-3-carbonitrile, Example 293: 2,4-bis (ethylamino) -7,8-dimethoxy-5H-chromene [2,3-b] pyridin -3-carbonyl ether, and Example 294: 2-amino-4- (ethylamine) -7,8-d-methoxy-5H-chromene [2,3-b] pyridn-3 -carbontril.

General Procedure for Demethylation: To a solution of the corresponding analogous aryl dimethoxy (0.68 mmol) in dichloromethane (2 ml_) boron tribromide (1 M, dichloromethane, 3.38 mmol, 3.38 mL) was slowly added. The reaction mixture was stirred at room temperature for 4 hours, quenched with 5% aqueous sodium hydroxide, then neutralized with 5% aqueous HCl. The resulting solid was collected and the aqueous layer was extracted with dichloromethane. The organic layer was concentrated under vacuum and combined with the solid. The residue was purified by reverse phase chromatography.

EXAMPLE 2T5 This illustrates the production of 2-amino-4- (eti-amino) -7,8-d-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile. 2-Amino-4- (ethylamino) -7,8-dihydroxy-5H-chromene [2,3-bjpyridin-3-carbonitrile was prepared using the demethylation procedure described above starting with 2-amino-4- ( ethylamino) -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile. 1 H NMR (400 MHz, DMSO) d 6.5 (s, 1H), 6.4 (s, 1H), 3.65 (q, 2H), 2.5 (s, 2H), 1.25 (t, 3H); m / z 299.15 (M + H); HRMS (M + H) calculated for Ci5H15N403299.1 39, found 299.1113.

EXAMPLE 296 This illustrates the production of 2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromene [2,3-b] pyridin-3-carbonitrile. 2-Amino-7,8-dihydroxy-4- (propylamino) -5H-chromene [2,3-b] pyridn-3-carbonitrile was prepared using the demethylation procedure described above by the examples 279-294 starting with 2-amino-7,8-dimethoxy-4- (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile. 1 H NMR (400 MHz, DMSO) d 6.5 (s, 1 H), 6.4 (s, 1 H), 3.55 (m, 2 H), 2.5 (s, 2 H), 1.6 (m, 2 H), 1.35 (t, 3H); m / z 313. 16 (M + H); HRMS (M + H) calculated for C 16 H 17 N 403 313.1295, found 313.1325.

EXAMPLE 297 This illustrates the production of 2-amino-7,8-dihydroxy-4 - [(2-hydroxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile. The 2-amino-7,8-dihydroxy-4 - [(2-hydroxyethyl) amino] -5H-chromene [2,3-bjpyridine-3-carbonitrile was prepared using the demethiation method described above by the Examples 279-294, starting with 2-amino-7,8-dimethoxy-4 - [(2-methoxyethyl) amino] -5H-chromene [2,3-b] pyridin-3-carbonitrile. H NMR (400 MHz, DMSO) d 6.5 (s, 1H), 6.4 (s, 1 H), 3.65 (m, 2H), 3.55 (m, 2H), 2.5 (s, 2H); m / z 315.13 (M + H).

EXAMPLE 298 This illustrates the production of 2,4-bis (ethylamino) -7,8-dihydroxy-5H-chromene [2,3-b] pyridin-3-carbonomethyl. 2,4-Bis (ethylamino) -7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile was prepared by using the procedure described in Examples 279-294.

EXAMPLES 299-304 This illustrates the production of certain aminocyanopyridine compounds of the present invention. General procedures of the O-alkylation of phenol 2,4-diamino-9-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile: A solution of 2,4-dinamino-9-hydroxy- 5 H -chromene [2,3-b] pyridin-3-carbonitrile (0.73 mmol), and sodium hydroxide powder (117 mg, 2.93 mmol)) in dimethyl sulfoxide (4 mL) was heated to 50 ° C. for 5 minutes. The corresponding halide was added and the reaction mixture was stirred at 50 ° C or 75 ° C until complete. The mixture was quenched with saturated aqueous ammonium chloride and purified directly by reverse phase chromatography. The following compounds were prepared using the procedure above: Example 299: 2,4-diamino-9- (2-aminoethoxy) -5H-chromene [2,3-b] pyridin-3-carbonomethyl, Example 300: acid (2,4-diamino- 3-cyano-5H-chromene [2,3-b] pyridin-9-yl) oxy] acetic acid, Example 301: 2,4-diamino-9- (2-hydroxyethoxy) -5H-chromene [2,3 -b] pyridyl-3-carbonitrile, Example 302: 2,4-diamino-9- [2- (dimethylamino) ethoxy] -5H-chromene [2,3-b] pyridin-3 -carbonitrile, Example 303: 2,4-diamino-9- (pyridin-4-ylmethoxy) -5H-chromene [2,3-b] pyridin-3-carbonitrile, and Example 304: 2, 4-diamino-9- (2-pyrrolidin-1-ylethoxy) -5H-chromene [2,3-b] pyridine-3-carbonyl ether.

EXAMPLES 305-333 This illustrates the production of certain aminoclanopyridine compounds of the present invention. General procedure for Mannich condensation: To a solution of the corresponding phenol (0.92 mmol) in ethanol (5 mL) was added formic acid (37% solution, 76 μ ?,, 1.01 mmol) and piperidine (100 μ ?,, 1.01 mmol) . The reaction mixture was stirred at 75 ° C until complete. The mixture was quenched with saturated aqueous ammonium chloride and purified directly by reverse phase chromatography and each regioisomer was isolated. The following compounds were prepared using the above procedure: Example 305: 2,4-diamino-9-hydroxy-6,8-bis (piperidin-1-ylmethyl) -5H-chromene [2,3-b] pyridin-3 -carbonitrile, and Example 306: 2,4-dlamino-9-hydroxy-8- (piperidin-1-ylmethyl) -5H-chromene [2,3-b] pyridine-3-carbonitrile, was provided starting with 2.4 -diamino-9-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, provided as described in Examples 299-304, and Example 307: 2,4-diamino-8-hydroxy-7 , 9-b1s (piperidin-1-ylmethyl) -5H-chromene [2,3-b] pyridine-3-carbonitrile, was provided starting with 2,4-diamino-8-hydroxy-5H-chromene [ 2,3-b] pyridin-3-carbonitrile, provided as described in example 221. Other aminocyanopyridine compounds of the present invention can be provided by the same general method, and are shown in the table below along with parameters RMn, which are determined as described above.

Ex. No. Name of m / z EMAR EMAR Compound formula (M + H) Theor. Found calculated 332 2,4-bis (ethylamino) - 355.27 355.1765 355.1784 C-19H22N4O3 7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile 333 2-amino-4- 327.21 327.1452 327.142 C17H18N4O3 (ethylamino) -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile EXAMPLE 334 This illustrates the production of 2,4-diamino-7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile. To a stirred solution of 3,4-dimethoxyphenol (35.7mmol, 5.5g) and piperidine (40 mmol, 3.4 g) in ethanol (50 mL) was slowly added formaldehyde (37%, water, 39.5 mmol, 3.2 g). The mixture was stirred at temperature environment for 4 hours and then evaporated in vacuo and the resulting residue it was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic layer was washed with water, dried (MgSO 4) and evaporated to give a residue of colorless oil. To a solution of the oily product from above in acetone was added methyl iodide (100mol, 14.2g) and the mixture was stirred at room temperature overnight. The resulting white precipitate was collected by filtration, washed with ether and dried in air to give 8.14 g of a white solid. To a thick mixture of the above solid (1 mmol, 390mg) and 2-amino-1-propene-1, 1,3-tricarbonitrile (1 mmol, 132mg) in ethanol (10mL) was added triethylamine (0.5mL) and The resulting solution was heated to reflux for 30 minutes. After cooling to room temperature, the precipitate was collected by filtration, washed with ethanol and air dried to give the product as a white solid (178 mg, 60% yield). 1 H NMR (400 MHz, DMSO) d 6,582 (s, 1 H), 6,574 (s, 1 H), 6,406 (s, 2 H), 6,241 (s, 2 H), 3,686 (s, 3 H), 3,671 (s, 3 H) 3,524 (s, 2H); m / z 299 (M + H).

EXAMPLE 335 This illustrates the production of 2 (2,4-diamino-3-cyano-8-methoxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile. To a solution of 2-hydroxy-4-methoxybenzaldehyde (10 mmol, 1.52 g) and malononitrile (40 mol, 2.64 g) in ethanol (250 mL) were added 6 drops of piperidine. The mixture was heated at 50 ° C for 0 minutes and then stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration and recrystallized from methanol to give the product as a pale yellow solid (1.19 g, 36% yield). H NMR (400 MHz, DMSO) d 7,274 (d, 1 H), 6,999 (s, 2H), 6,817 (dd, 1H), 6,733 (d, 1H), 6,619 (s, 2H), 4,804 (d, 1H) ), 4734 (d, 1H), 3.757 (s, 3H); m / z 333 (M + H).

EXAMPLE 336 This illustrates the production of 2 (2,4-diamino-3-cyano-7-bromo-5H-chromene [2,3-b] pyridin-5-yl) malononitrile. To a solution of 5-bromo-2-hydroxybenzaldehyde (10mmol, 2g) and malononitrile (35mmol, 2.31 g) in ethanol (200mL) was added 6 drops of piperidine and the mixture was stirred at room temperature for 30 hours. The resulting precipitate was collected by filtration and recrystallized from methanol to give the product as a white solid (1.68 g, 44% yield). 1 H NMR (400 MHz, DMSO) d 7489 (dd, 1 H), 7344 (d, 1H), 7,230 (d, 1 H), 7,063 (s, 2H), 6,686 (s, 2H), 4,876 (d, 1 H), 4,850 (d, 1 H); m / z 381, 383 (M + H).

EXAMPLE 337 This illustrates the production of 2 (2,4-diamino-3-cyano-7-methoxy-5H-chromene [2,3-b] pyridin-5-yl) malononitry. To a solution of 2-hydroxy-5-methoxybenzaldehyde (10mmol, 1.52g) and malononitrile (40mmol, 2.64g) in ethanol (350mL) was added 6 drops of piperidine and the mixture was stirred at room temperature for 18 hours. The resulting precipitate was collected by filtration, successively washed with ethanol and ether and dried in air to give the product as a gray solid (1.42 g, 43% yield). 1 H NMR (400 MHz, DMSO) d 7.107 (d, 1H), 6.990 (m, 3H), 6.865 (d, 1H), 6.603 (s, 2H), 4.850 (d, 1H), 4.794 (d, 1 H) ), 3724 (s, 3H); m / z 333 (M + H).

EXAMPLE 338 This illustrates the production of 2 (2,4-d-amino-3-cyano-8-hydroxy-5H-chromene [2,3-b] pyridin-5-ll) malononltryl. To a solution of 2,4-dihydroxybenzaldehyde (10 mmol, 1.38g) and malononitrile (40mmol, 2.64g) in ethanol (350mL) was added 6 drops of piperidine and the mixture was stirred at room temperature for 5 hours. The resulting precipitate was collected by filtration, washed successively with ethanol and ether and dried in air to give the product as a yellow solid (1.62g, 51% yield). 1 H NMR (400 Hz, DMSO) d 9,887 (s, H), 7,162 (d, 1 H), 6,971 (s, 2 H), 6,613 (dd, 1 H), 6,597 (s, 2 H), 6,497 (d, 1 H), 4.743 (d, 1H), 4.687 (d, 1 H); m / z 319 (M + H).

EXAMPLES 339-348 This illustrates the production of certain aminocyanopyridine compounds of the present invention. The aminocyanopyridine compounds listed in the table below were provided according to the general method described in Example 336. NMR analysis was carried out for each material according to the method described above. The names and NMR data for each compound are given in the table.

EXAMPLE 349 This example illustrates that MK2 agonomic mice (MK2 (- / -)) are resistant to arthritis formation induced by K / BN serum. A strain of mice has been reported to develop symptoms similar to human rheumatoid arthritis. Mice were designated K / BxN mice. See, Wipke, B. T. and P. M. Alien, J. of Immunology, 167: 1601-1608 (2001). The serum of the mice can be injected into the host animals to elicit a common RA response. The progress of RA symptoms in mice is measured by measuring the thickness of the paw as a function of time. In the present example, host mice that have normal MK-2 production (MK2 (+ / +)) were genetically altered by inability of the gene encoding MK-2 to produce mice that do not have endogenous MK-2 synthesis capability active (MK2 (- / -)). The normal host mice (MK2 (+ / +)) and the MK-2 agonist mice (MK2 (- / -)) were separated into four groups with each group containing male and female mice. All groups of mice were treated similarly, except that one group (Normal), composed of (+/-) MK2 mice that serve as the control group, was not injected with serum from K / BxN mice, while the other three Groups were injected with K / BxN serum on day 0. The other three groups of mice were MK2 (+ / +), MK2 (- / -), and anti-TNF. The Anti-TNF group was composed of MK2 (+ / +) mice which were also injected on day 0 with anti-TNF antibody. The thickness of the paw of all mice was measured immediately after the injections on day 0, and then on each succeeding day thereafter for 7 days. Figure 1 is a graph showing the thickness of the leg as a function of time from day 0 to day 7 for MK2 (+ / +) and MK2 (- / -) mice, which have received serum injection. It can be seen that the thickness of the leg increased significantly for the MK2 (+ / +) mice, considering that there was no substantial increase in the thickness of the paw for MK2 agonic mice. This indicated the requirement for an MK2 regulatory system of function for the inflammatory response elicited by the immunogenic serum test. When the anti-TNF antibody was administered to the MK2 (+ / +) mice together with the serum injection, the swelling response was significantly reduced. This can be seen in Figure 2, which is a bar chart showing the thickness of the paw in seven days after injection for normal mice, MK2 (+ / +) mice that received serum, MK2 mice (- / -) who received serum, and MK2 (+ / +) mice that received serum and anti-TNF antibody. These data show that the MK2 agénic mice do not show an arthritic response to an immunogenic serum test, considering that the MK2 (+ / +) mice show a normal response. Treatment of MK2 (+ / +) mice that received an immunogenic serum test with anti-TNF antibody reduced the response back to near-normal levels. This illustrates the utility of the MK2 regulatory system as a control point for the modulation of TNF production, and indicates that such regulation can serve as a treatment for inflammation - such as that caused by arthritis, for example. If it is further shown that the inhibition of MK2 may have a beneficial effect on inflammation, and indicates that the administration of an MK2 inhibitor may be an effective method of prevention or treatment of diseases or modulated disorders of TNF. All references cited in this specification, including without limitation all documents, publications, patents, patent applications, presentations, texts, reports, manufactures, brochures, books, Internet mailings, magazine articles, newspapers, and the like, by this medium is incorporated by reference in this specification in its entirety. The discussion of the references herein is merely intended to summarize the successes made by their authors and no admission is made that any reference constitutes prior art. Applicants reserve the right to challenge the accuracy and pernce of the references cited. In view of the above, it will be seen that the different advantages of the invention are achieved and that other profitable results are obtained. Since various changes can be made to the above methods and compositions without departing from the scope of the invention, it is intended that all the material contained in the above description should be interpreted as illustrative and not in a sense of limitation.

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - The use of an aminocyanopyridine MK-2 inhibitor compound, or a pharmaceutically acceptable salt thereof, to prepare a medicament for the inhibition of mitogen-activated protein kinase-activated protein kinase-2 in a subject in need of such inhibition, where: the compound has the structure: R 1 is selected from the group consisting of -H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, carboxy, C 1 -C 4 alkyl, aryl C 1 -C 4 alkyl, amino, C 1 -C 4 alkyl, C 1 -C 6 alkoxy C4, C 1 -C 4 alkylamino, C 1 -C 4 alkyl, di- (CrC ^ amino alkyl, C 1 -C 4 alkyl, Ci-C 4 alkylC 4 alkyl, hydroxy C 4 alkyl, and aryl alkyl CrC 4; R 2 is selected from the group consists of -H, CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, amino, C-] - C4 alkyl amino, C1-C4 alkylamino, aryl, heteroaryl, heterocyclyl, carboxy, carboxyCi-C4 alkyl, C-alkoxy 1-C4, hydroxy, hydroxy C1-C4 alkyl, hydroxy C4 alkylamino, hydroxy C1-C4 alkoxy, C1-C4 alkoxy C1-C4 alkyl, C1-C4 alkoxy C1-C4 alkylamino, amino C4 alkylamino, aryl C1-6 alkyl C4, C 1-4 alkylamino C 4 alkyl, C 1-4 dialkylamino C 1 -C 4 alkyl, C 4 alkyl C 1 C 4 alkyl) C 1 -C 4 alkyl, aryl C 1 -C 4 alkylcarbonyl, C 1 -C 4 alkyl phthaloamino, halo, carbamyl, alkylthio C- | -C4, C 1 -C 4 alkoxyarylamino, C 1 C 0 monocycloalkyl and bicyclic cycloalkyl, wherein: the aryl, heteroaryl, heterocyclyl, mono- and bicyclic cycloalkyl may be optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy, aryloxy, C2-C4 alkenyloxy, alkynyloxy C2-C4, C1-C4 alkyl, carboxy, carbamyl, C1-C4 alkoxycarbonyl, C1-C4 alkoxycarbonyl C1-C4 alkoxy, carboxy alkoxy amino Ci-C4, alkylamino C1-C4, di-alkylamino C1-C4, N-alkyl C C4-N-cyano C1-C4 alkylamino, nitro, C1-C4 alkylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri-halo C1-C4 alkyl, hydroxy C1 alkoxy -C4, haloalkoxy Ci-C4, tri-haloalkoxy CrC4, R3 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, amino C1-C4 alkyl, amino and aryl, wherein: the aryl optionally can be substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C1-C4 alkoxy, C1-C4 alkyl, carboxy, C1-C4 alkoxycarbonyl, carboxy C1-C4 alkoxy, amino, C1-C4 dialkylamino, N-Ct-C4 alkyl -N-cyano C1-C4 alkylamino, nitro, C1-C4 alkylcarbonylamino, cyano, halo C1-C4 alkyl, di-halo C1-C4 alkyl, tri- halo C1-C4 alkyl, halo C1-C4 alkoxy, di-halo alkoxy C-1-C4 and tri-halo alkoxy Ci-C4, and R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R4 is selected from the group consisting of -H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, hydroxy, C1-C4 alkylthio, C1-C4 alkoxy, C1-C4 alkoxycarbonyl, mercapto, N-imidazoylphenyl , C 1 -C 4 isoalkyl, aminofluorobenzhydryl, aryl and heteroaryl, wherein: the aryl and heteroaryl may optionally be substituted with one or more substituents selected from the group consisting of halogen, hydroxy, C 1 -C 4 alkoxy, C 1 alkyl -C 4, C 1 -C 4 alkylthio, C 1 -C 4 alkylsulfonyl, Ci-C 4 alkylsulfinyl, cartoxy, carbamyl, C 1 -C 4 alkoxycarbonyl, carboxy C 1 -C 4 alkyl, carboxy C 1 -C 4 alkoxy, amino, C 1 -C 4 alkylamino, N- C 1 -C 4 alkyl-N, C 1 -C 4 alkylamino, nitro, C 1 -C 4 alkylcarbonylamino, cyano, halo C 4 alkyl, di-halo C 1 -C 4 alkyl, tri-halo C 1 -C 4 alkyl, halo C 1 -C 4 alkoxy, di -halo C1-C4 alkoxy, tri-halo C1-C4 alkoxy R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of -H and C1-C5 alkyl; R and R5 optionally join to form a piperidyl ring or oxazinyl ring; R6, R7, R8, R9, R10, R1, R12, 9, R30 R3 R32 R33 R34 R35 R36 R37 R38 R39 R40 R41 R42 R43 R44 R45 R46 R47 R47 R64, R65, R66, R67, R68, R69, R70, R71, R72, R73, R74, R75, and R76, each is optionally presented and are each independently selected from the group consisting of -H, Ci-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C- | - isoalkyl C, amino, nitro, hydroxy, CrC4 alkoxy, C-1-C4 alkenoxy, oxo, carboxy, halo, halo Ci-C4 alkyl, dihalo C-1-C4 alkyl, trihalo Ci-C4 alkyl, cyano, cyano C- alkyl 1-C4, dicyano C4 alkyl, halophenyl, hydroxy alkoxy C4, alkoxy Ci-C4 alkoxy Ci-C4, - (CH2) -0- (C6H4) -0- (CH3), carboxy alkoxy Ci-C, alkylcarboxy C1 -C4 alkoxy CrC4, alkoxyamino CrC4, alkylamino CC, dialkylamino C1-C4, trialkylamino C1-C4, amino alkoxy CrC4, diamino alkoxy C1-C4, alkylamino C C4 alkoxy C1-C4l dialkylamino C1-C4 alkoxy C4, cyano alkoxy C1- C4 alkyl Ci-C4) - (CH2) -0- (CF2) -CHF2, tetra alkoxy CrC4 alkyl Cr C4, phenyl, benzyl, benzoyl, aryl, N- morphonyl, morphonyl C 1 -C 4 alkoxy, pyrrolidyl C 1 -C 4 alkoxy, N-pyrrolidyl alkoxy CrC 4, C 1 -C 4 alkylcarboxy, carboxy C 1 -C 4 alkyl-ethyl ester, pyridyl C 4 alkyl, pyridyl C 1 -C 4 alkoxy, and -COO-CH 2 -CH3; and R38 and R39 are such that they optionally join to form a ring system of the type selected from the group consisting of:

2. - The use claimed in claim 1, wherein: the aminocyanopyridine inhibiting compound MK-2 has the structure: R1 is selected from the group consisting of -H, methyl, ethyl, propyl, butyl, - (CH2) COOH, phenyl, pridyl, dimethylaminoethyl, methoxyethyl, tetramethylaminoethyl, carboxymethyl, and phenylacetyl; R 2 is selected from the group consisting of -H, methyl, ethyl, propyl, butyl, amino, phenyl, methoxy, carboxy, carboxymethyl, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, ammonioylamino, benzylamino, dimethylaminoethylamino, phthaloaminoethyl, fluorophenylated , difluorophenyl, chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl, 1,3-isodiazoyl, 1,4-triazoyl, methoxyphenyl, -S (CH 3), tetramethylaminoethyl, acetylaminophenyl, methoxyphenylamino, carobiphenyl, carboxy - 3-isopyrryl, cyanophenyl, cyclopropyl, phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl, trifluoromethylphenyl, trifluoromethyl-fluorophenyl, hydroxyphenyl, methylaminomethyl, methylaminoethyl, thiofyl, pyrryl, aminomethyl, R3 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyano, aminomethyl, phenyl, fluorophenylated, and amino; R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R is selected from the group consisting of -H, methyl, ethyl, propyl, hydroxy, furyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl , carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxypheyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrryl, N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl, mercapto, N-isoimidazoylphenyl, isopropyl , amino, hydroxynaphthyl, thiazoyl, carboxymethylphenyl, trifluoromethylphenyl, methylphenyl, cyanophenyl, dimethylphenyl, fluorobenzhydryl, methoxyfuryl, aminosulfonylphenyl, R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: 327 D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of -H and C-i-C5 alkyl; R1 and R5 optionally join to form a piperidyl ring; R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, p17 p18 D19 p20 p21 22 p23 p24 p25 p26 p27 p28 p29 p30 p31 p32 p33 p37 p38 D39 p40 p41 p42 p43 p44 p45 p46 p47 p48 p48 p49 D50 R51? 52? 53? 54? 55 D56 D57 D58 59? 60 D61 D62? 63 D64 D65? 66 D67, G \,? , G \,? ,? ,? , G? , G? , G, G? ,? , G, G, G,? , G? , R68, R59, R70, R71, R72, R73, R74, R75, and R76, each is optionally presented and are each independently selected from the group consisting of -H, methyl, ethyl, propyl, butyl, isobutyl, amino, nitro, hydroxy, methoxy, ethoxy, propoxy, 2-propenoxy, oxo, carboxy, bromo, chloro, fluoro, trifluoromethyl, chloromethyl, hydroxymethyl, dicyanomethyl, 2-fluorophenyl, 3-fluorophenyl, hydroxyethoxy, ethoxyethoxy, - (CH2) -0 - (C6H4) -0- (CH3), carboxymethoxy, isopropylcarboxymethoxy, isobutylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, dimethylaminoethoxy, cyanomethoxymethyl, 2-propenoxymethyl, methoxymethyl, isopropoxymethyl, ethoxymethyl, - (CH2) -0- (CF2) - CHF2, isobutoxymethyl, benzoyl, phenyl, N-morpholinyl, morpholinyl ethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, oxo, ethylcarboxy, ethyl carboxymethyl ester, pyridylmethyl, 4-pyridylmethoxy, 2-pyridylmethyl, and -COO-CH2-CH3; and R38 and R39 are such that they optionally join to form a ring system selected from the group consisting of:

3. - The use claimed in claim 2, wherein: R is selected from the group consisting of -H, methyl, ethyl, - (CH2) COOH, and phenyl; R 2 is selected from the group consisting of -H, methyl, ethyl, amino, phenyl, methoxy, carboxy, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, furyl , carbamylpyrryl, methyl-1,3-isodiazoyl, 1,3-isodiazoyl, 1,4-triazoyl, methoxyphenyl, -S (CH3), acetylaminophenyl, methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl, phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl , trifluoromethylphenyl, trifluoromethylfluorophenyl, hydroxyphenyl, R3 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyano, and aminomethyl; R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R is selected from the group consisting of -H, methyl, ethyl, propyl, hydroxy, furyl, indolyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrryl , N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl, N-isoimidazoylphenyl, amino, hydroxynaphthyl, thiazoyl, carboxymethylphenyl, aminosulfonylphenyl, and R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of -H and C1-C5 alkyl; R6, R7, R8, R9, R10, R11, R12, R3, R14, R15, R43, R44, R45, R46, R71, R72, R73, R74, R75, and R76 are each optionally present and are each independently selected from the group consisting of -H, methyl, ethyl, butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, chloro, fluoro, trifluoromethyl, chloromethyl, hydroxymethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy, - (CH2) -0- (C6H4) -0- (CH3), carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, cyanomethoxymethyl, methoxymethyl, isopropoxymethyl, ethoxymethyl, - (CH2) -0- (CF2) -CHF2, isobutoxymethyl, phenyl, morphonyl ethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, and pyridylmethyl, and R38 and R39 are such that they optionally join to form a ring system selected from the group consisting of:

4. - The use claimed in claim 2, wherein: R is selected from the group consisting of -H, methyl, and ethyl; R 2 is selected from the group consisting of -H, methyl, amino, phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl -1,3-isodiazoyl, 1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S (CH 3), acetylaminophenyl, methoxyphenylamino, carboxyphenyl, cyanophenyl, cyclopropyl, phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl, and selects from the group consisting of -H, methyl, ethyl, propyl, isopropyl, and cyano; R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, hydroxy, furyl, indolyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrryl , N-methylpyrryl, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl, amino, and aminosulfonylphenyl; R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is -H; R6, R7, R8, R9, R10, D11 p12 p13 D14 r-, 15 16 D17 p18 p19 p20 p35 p36 p37 p38 R39 p40 p41 R42, R71, R72, R73, R74, R75, and R76 are each optionally present and are each independently selected from the group consisting of -H, methyl, ethyl, butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo , 2-propenoxy, carboxy, bromo, fluoro, trifluoromethyl, chloromethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy, - (CH2) -0- (C6H4) -0- (CH3), carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, phenyl, morphonyl ethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, and pyridylmethyl, and R38 and R39 are such that they optionally join to form the following ring system:

5. - The use claimed in claim 2, wherein: R is selected from the group consisting of -H, methyl, and ethyl; R 2 is selected from the group consisting of -H, methyl, amino, phenyl, methoxy, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, fluorophenyl, difluorophenyl, chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl -, 3-isodiazoyl, 1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S (CH3), acetylaminophenyl, methoxyphenylamino, carboxyphenyl, and R3 is selected from the group consisting of -H, methyl, ethyl, propyl, and isopropyl; R2 and R3 are such that they optionally join to form the following ring system: R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, furyl, indolyl, methylfuryl, methylimidazolyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl, pyrrhoyl, N methylpyrryl, pyridyl, methylthio, methylisulfonylphenyl, carboethoxyphenyl, and aminosulfonylphenyl; R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is -H; R6, R7, R8, R9, R10 are each optionally present and are each independently selected from the group consisting of -H, methyl, ethyl, butyl, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy , carboxy, bromo, fluoro, trifluoromethyl, chloromethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy, carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, morphonyl ethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, and pyridylmethyl, and R38 and R39 are such that optionally join to form the following ring system:

6. - The use claimed in claim 2, wherein: R is -H; R 2 is selected from the group consisting of amino, phenyl, fluorophenyl, difluorophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl, 1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, acetyllaminophenyl, methoxyphenylamino, and carboxyphenyl; R3 is selected from the group consisting of -H, methyl, ethyl, and propyl; R 4 is selected from the group consisting of methyl, ethyl, propyl, furyl, phenyl, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, dihydroxyborophenyl, and aminosulfonylphenyl; R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: Y D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is -H; R6, R7, R8, R9, R10, R11, R2, R35, R36, R37, R38, R39, R40, R41, R42, R71, R72, R73, R74, R75, and R: are each optionally present and are each independently selected from the group consisting of -H, amino, nitro, hydroxy, methoxy, ethoxy, oxo, 2-propenoxy, carboxy, bromo, fluoro, trifluoromethyl, chloromethyl, dicyanomethyl, hydroxyethoxy, ethoxyethoxy, carboxymethoxy, isopropylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, morphonyl ethoxy, pyrrolidylethoxy , and pyridylmethyl, and R38 and R39 are such that they optionally join to form the following ring system:

The use claimed in claim 2, wherein the compound inhibits the aminocyanopyridine MK-2 comprises at least one compound selected from the group consisting of: 2-amino-4- (2-fluorophenyl) -6,8-dihydro-5H -pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline -3-carbonitrile, 2-amino-4- (2,3-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 8-amino-6- (2- furl) -4,5-dhydro-1 H -pyrazolo [4,3-h] quinoline-7-carbonitrile, 2-amino-3-cyano-4- (2-furyl) -5 acid , 6-D-Hydrobenzo [H] quinoline-8-carboxylic acid, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] -1H-pyrrole-2-carboxamide, 2-amino-4-phenyl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (2-furyl) -4- (1 - methyl-1 H- midazol-4-yl) nicotinonitrile, 8-amino-6- (2-furyl) -4,5-dihydro-1 H-pyrazolo [4,3-h] qu Noline-7-carbonitrile, 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2 , 6-difluorophenyl) -6,7-dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (4-hydroxy) L) -4- (1 H-imidazol-5-yl) nicotinonitrile, 2-amino-4- (2-fluorofenii) -6- (2-furyl) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (2-furyl) nicotinnonyl, 2-amino-4- (2-fluorophenyl) -5,6-d.hydrobenzo [h] quinoline-3-carbonyl ester lo, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzoic acid, 2-amino-6- (2-furyl) -4- (1H-imidazole) 5-yl) nicotinonitrile, 2-amino-4- (2-furyl) -6- (1 H -pyrazol-3-yl) n-trinonitrile, 2-amino-3-cyano-4- (4H-) acid 1, 2,4-triazol-3-yl) -5,6-dihydrobenzo [h] quinoline-8-carboxylic acid, 2-amino-6- (3-hydroxyphenyl) -4- (1 H -amidazole-5- il) nicotinonitrile, 2-amino-6- (2 -furyl) -4- (1 H -amidazol-4-yl) nicotinonitrile, 2-amino-4- (2,4-difiuorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h ] quinoline-3-carbonyltria, 4,6-diamino-2- (trifluoromethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2- furyl) -6,8-dihydro-5H-pyrrolo [3,4-h] quinoline-3-carbonitrile, 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridyl- 2-yl] benzoic acid, 2-amino-4- (2-furyl) -5,6-dihydro-1, 8-phenanthroline-3-carbonitrile, 2-amino-6- (3,4-dihydroxyphenyl) -4- (2-fluorophenyl) nicotinonitrile, 2-amino-4- (1-methyl-1 H-imidazol-4-yl) -6-phenylnicotinonitrile, 2-amino-4- (2-furyl) -6- (1 H- pyrazol-3-yl) nicotinonitrile, 4- [6-amino-5-cyano-4- (1 H -imidazol-5-yl) pyridin-2-yl] benzoic acid, 2-amino-4- (3-fluorophenyl) ) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (3,4-dihydroxyphenyl) -4- (2-fluorophenyl) nicotinonitrile , N-. { 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] phenyl} methanesulfonamide, 2-amino-4- (2-furyl) -6,7-dithy-5H-pyrrolo [2,3-h] quinoline-3-carbonitrile, 2-amino-4- (1H-imidazole) -5-ii) -6-phenylnicotinonitrile, 2-amino-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (1 H-imidazole-5- il) -6- (4-methoxyphenyl) nicotinonitrile, 2-amino-6- (3-chlorophenyl) -4- (1H-imidazol-5-yl) nicotinonitrile, 2-amino-4- (2-furyl) -6 - (1 H-pyrazol-4-yl) nicotinonitrile, 2-amino-4- (4-methoxyphenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino -4- (2,5-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (4-fluorophenyl) -6,8-dihydro -5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (4H-1, 2,4-triazol-3-yl) -5,6-dihydrobenzo [h] quinine! Ina -3-carbonitrile, 4,6-diamino-2- (cioromethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (1 H-imidazol-4-yl) ) -6-phenylnicotinonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzenesulfonamide, 4- [6-amino-5-cyano-4- (2 -furyl) pyridin-2-phenyl], 2-amino-6- ( 4-methoxyphenyl) -4- (4H-1, 2,4-triazol-3-yl) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (3-furyl) nicotinonitrile, 2-amino -6- (2-furyl) -4- (methylthio) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (3-hydroxyphenyl) nicotinonitrile, 8-amino-6- (2-furyl) -4 , 5-dihydro-2H-pyrazolo [4,3-h] quinoline-7-carbonitrile, 2-amino-4- (2-bromophenyl) -6- (2-furyl) nicotinonitrile, 2-amino-4- (2 -fluorofenii) -6- (4-hydroxyphenyl) nicotinonitrile, 2-amino-4-phenyl-6-thien-2-ylnicotinonitrile, 2-amino-4- (3-methoxyphenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonyltria, 2-amino-4- (2-furyl) -7-methyl-6,7-dihydro-5H-pyrazolo [3,4-h] quinoline -3-carbonitrile, 2-amino-4- (2-fluorophenyl) -6- (1 H -pyrrol-2-yl) nicotinonitrile, 2-amino-4- (2-furyl) -5-methyl -6,8-dihydro-5H-pyrazoo [3,4-h] quinoline-3-carbonitriyl, 2-amino-4- (2-furyl) -6- (1-methyl-1 H-pyrrole -3-yl) nicotinonitrile, 3-amino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile, N- [4- (2-amino-3-cyano-67-dihydro-5H-pyrazolo [3,4 -h] quinolin-4-yl) phenyl] acetamide, 6-amino-4 - [(4-methoxypheni l) amino] -2- (trifluoromethyl) -2,3-dihydro [2,3-b] pyridine-5-carbonitrile, 4- [6-amino-5- cyano-4- (2-furyl) pyridin-2-yl] -N- (tert-butyl) benzenesulfonamide, 4,6-diamino-2-ethyl-2,3-dihydrofuro [2, 3-b] pyridine-5-carbonitrile, 6-amino-4- (2-furyl) -2,4'-bipindine-5-carbonityl, 2,4-diamino-6- (methylthio) nicotinonitrile, 3- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) benzoic acid, 2-amino-6- (4-chlorophenyl) -4- (1 H -imidazol-5-yl) nicotinonitrile, 2-amino-4- (1,3-benzodioxol-4-yl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, , 6-diamino-2-methyl-2,3-dihydrofuran [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (1 H-imidazoI-5-yl) -6- [4- (methylsulfonyl) phenyI] nicotinonitrile, 2,4-diaminoquinoline-3-carbonitrile, 2,8-diamino-4- (2-furyl) -5,6-dihydrobenzo [h3quinoline-3-carbonitrile, 2-amino-4.6 -di (2-furyl) nicotinonitrile, 4,6-diamino-2-butyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4- [6-amino-5-cyano-4- (1 H-imidazol-5-yl) pyridin-2-yl] ethyl benzoate, 2,4-diamino-6-methoxynicotinonitrile, 2-amino-4-methylnicotinonitrile, 2-amino-4- (4-cyanophenyl) - 6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4-cyclopropyl-6-methylnicotinonitrile, 2-amino-4- (2-furyl) -6- (1 -methyl-1 H-pyrrol-2-yl) nicotinonitrile, 2-amino-4- (2-chlorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2- amino-6- (2-furyl) -4- (4-phenoxyphenyl) nicotinonitrile, 2-amino-4-pyridin-3-yl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3 -carbonitrile, 2-amino-6-. { [2- (4-chlorophenyl) -2-oxoetiyl] thio} -4- (2-furyl) pyridine-3,5-dicarbonitrile, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] phenylbenzoic acid, 2 -amino-6- (3-chlorophenyl) -4- (1 H -imidazol-4-yl) nicotinonitrile, 4- (6-amino-5-cyano-4-phenylpyridin-2-yl) -N- (tert- butyl) benzenesulfonamy, 2-amino-4-methoxynicotinonitrile, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] benzoic acid, 4,6-diamino -2 - [(4-methoxyphenoxy) methyl] -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-fluorophenyl) -6- (4-methoxyphenyl) nicotinonitrile 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] -N- (tert-butyl) benzenesulfonamide, (2,4-diamino-3-cyano-5H) -chromeno [2,3-b] pyridin-9-yl) oxy] acetic acid, 3-pyridinecarbonitrile, 2-amino-4-methylim-2-amino-6- (2-furyl) nicotinonitrile , 2-amino-4- (2-furyl) -6- (3-hydroxyphenyl) nicotinonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzamide, 2- amino-4- (2-furyl) -7-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6- (1 H -indol-3- il) nicotinonitrile, 2-amino-4-pyridin-4-yl-6,8-dihydro -5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (3-fluorophenyl) -6- (4-hydroxyphenyl) nicotinonitrile, 2-amino-4- [2- (difluoromethoxyl) phenyl] -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6-thien-3-ylnicotinonitrile, 2-amino-4 - (3-fluorophenyl) -6- (4-methoxyphenyl) n-trinonitrile, 2- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] phenolboronic acid, 2,4 -diamino-6-propylpyridine-3,5-dicarbonitrile, 4,6-diamino-2 - [(prop-2-ynyloxy) methyl] -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4,6-diamino-2- (hydroxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-6- (2-furyl) -4- [4- (trifluoromethyl) phenyl] nicotinonitrile, 5-amino-7-methylthieno [3,2-b-pyridine-6-carbonitrile, 2-amino-4- (2-furyl) -5,5-dimethyl-6,8-dihydro-5H-pyrazoic [ 3,4-h] quinoline-3-carbonitrile, N- [3-cyano-4- (2-fluorophenyl) -6- (2-furyl) pyridin-2-ylglycine, 2 - [(allyloxy) methyl] -4 , 6-diamino-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6-methyl-5,6-dihydrobenzo [h] quinoline-3 - carbonitrile or, 4,6 - ?? 3 ??? - 2- (G? T ????? t ?????) - 2,3-? 1 ?????? G ??? G? [2,3-β-p p-3-5-carbonitrile, 2-amino-4- (2-furyl) -6- (1 H-indol-3-yl) n-trinonitrile, 2-amino-4- (2-furyl) -6- [4- (1 H-imidazol-1-yl) pheny] nicotonitrile, 2-amino-4- (2-furyl) -6- ( 4-hydroxy-phenyl) nicotinone, 2-amino-4- (2-furyl) -5,6,7,8-tetrahydro-5,8-methanoquinoline-3-carbonitrile, 4,6- diamino-2- (isopropoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 3- [6-amino-5-cyano-4- (2-furyl) ) pyridin-2-yl] phenylboronic acid, 4,6-diamino-2- (ethoxymethyl) -2,3-dihydrohydro [2,3-b] pyridine-5-carbonitrile, 2-amino-4 - (4-bromophenyl) -6- (2-furyl) n-trinonitrile, 4,6-d-amino-2 - [(1, 1,2,2-tetrafluoroethoxy) methyl] -2,3-dih Drofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- [2-fluoro-4- (trifluoromethyl) phenyl] -6- (2-furyl) nicotinonitrile, 2-amino-4- (2-methoxyphenyl) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-fluorophenyl) -5 -meti-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 3,6-diamino-4-ethyl-1 Hp -razolo [3,4-b] pyridine- 5-carbonyl, 6-amino-4- (2-furyl) -2,2, -bipyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6- (8- hydroxy-1-naphthyl) nitrotonitrile, 4- (2-amino-3-cyano-6,7-dihydro-5H-pyrazoyl [3,4-h] quinolin-4-yl) benzoic acid, 2-amino-6- (3,4-dichlorophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-4- (2-furyl) -6- (10H-) phenothiazin-2-yl) nicotinonitrile, sodium 2-amino-3-cyano-4-quinolinecarboxylate, 2-anilino-4- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile, -amino-4- (3-fluorophenyl) -6- (2-furyl) nicotinonitrile, 2-amino-4- (4-phlorophenyl) -6- (2-furyl) n-trichnonitrile, 4,6-d Amino-2- (tert-butoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6- (1,3-thiazole) 2-l) nicotonitrile, 4- (2-fluorophenyl) -6- (2-furyl) -2-piperidin-1-ylnicotinonitrile, 2-amino-6- (4- clo rofenil) -4- (2-furyl) nicotonitrile, 2-amino-6- (4-hydroxyphenyl) -4- (2-methoxyphenyl) nicotinonitrile, 2-amino-6- (2-furyl) -4 - (2-hydroxyphenyl) nicotinonitrile, 3- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) methyl benzoate, 2-amino-4 - (2-chlorophenyl) -6- (5-metii-2-furyl) nicotinonitrile, 3,6-diamino-2-benzoyl thieno [2,3-b] pyridine-5-carbonitrile, methyl 4- [6-amino- 5-cyano-4- (2-furyl) pyridin-2-yl] benzoate, 2-aminonicotinonitrile, 2-amino-4- (2-furyl) -8-. { [2- (trimethylsilyl) ethoxy] methyl} -6,8-dihydro-5H-pyrazole [3,4-h] quinoline-3-carbonitrile, 3-amino-5H-pyrido [4,3-b] indole-4-carbonitrile, 2- (2-amino) acid -3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) benzoic acid, 2-amino-6- (4-methoxyphenyl) -4-phenyl-nicotinonitrile, 2-amino-4 - (2-furi -S ^ J ^ -tetrahydroquinoline-S-carbonitrile, 2-amino-4- (2-furyl) -6-isobutyl-nicotinonitrile, 2-amino-6-benzyl-4- (2-furyl) nicotinonitrile, 2-amino-4- (2-furyl) -6-methyl-5-phenyl-nicotinonitrile, 2-amino-4- (2-furyl) -6- [4- (trifluoromethoxy) phenyl] nicotinonitrile, 2-amino-4- (2-furyl) -6-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile, 2-amino-4- (2-furyl) benzo [h] quinoline-3-carbonitrile , 2-amino-6- (4-methoxyphenyl) -4-thien-2-iInicotinonitrile, 2-amino-4- (2-fluorophenyl) -6-tetrahydroforan-2-ylnicotinitrile, 6-amino-5-cyano-4 - (2-furyl) pyridine-2-carboxylic acid ethyl ester, 2-amino-4- (2-furyl) -9-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -8-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonyltrio, 2-amino-4- (2-furyl) -8,9-dimethoxy-5,6- d ihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -7-methoxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2 -furyl) -7,9-dimethyl-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzoate of ethyl, 2-amino-6- (3-bromophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-4- (2-furyl) -6- [4- (trifluoromethyl) phenyl] nicotinonitrile, 2-amino -4- (2-furyl) -6- [3- (trifluoromethyl) phenyl] nicotinonitrile, 2-amino-4- (2-furyl) -6- [4- (methylsulfonyl) phenol] nichonin Trilo, 4,6-diamno-2- (phenoxymethyl) -2,3-dihydro [2,3-b] pyridine-5-carbonitrile, 4,6-dia No-3-phenyl-2,3-dihydrofuro [2,3-b] pyridin-5-carbonitrile, 4,6-diamino-3-vinyl-2,3-dihydrofuro [2,3 -b] pyridine-5-carbonitrile, 2-amino-4- (2-fluorophenyl) -5-methyl-6,8-dihydro-5H-pyrazoo [3,4-h] quinoline-3-carbon Triyl, 3-amino-1-methyl-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile, 2-amino-4- (2-fluorophenyl) -5,5-dimethyl-6,8 -dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-fluorophen) il) -6- (3-hydroxyphenyl) nicotonitrile, 2-amino-4- [2- (di-fluoroutoxy) phenyl] -6,7-dihydro-5H-pyrazolo [3,4-h] ] quinoline-3-carbonitrile, 2- (benzylamine) -4- (2-fluoropheni!) - 6- (2-furyl) nicotinonitrile, 2-amino-4- (2-furyl) -6,7 -dihydro-5H-benzo [6,7] cyclohepy [1,2-b] pyridine-3-carbonitrile, 2-amino-4- (2-furyl) -5H-indene [1,2-b] pyridine -3-carbonitrile, 3-amino-1-methyl-5,6,7,8-tetrahydroquinoline-4-carbonitrile, 2-amino-4- (2-fluorophenyl) -6- (3- hydroxyphenyl) n-phenyl-nitrile, 2-amino-4- (2-t-ene) -5,6,7,8-tetrahydro-3-quinolinecarbonitrile, 2-amino-4- (3-fluorophen L) -5,6,7, 8-tetrahydro-3-quinolylcarbonitrile, 2- (1-piperidinyl) -6- (2-thyl) -4- (trifluoromethyl) nicotinonitrile, 2- (dimethylamino) -6- (2 -thienl) -4- (trifluoromethyl) nicotinonitrile, 3-quinolinecarbonitrile, 2-amino-4-methyl-3-quinolinecarbonitrile, 2-amino-4- (4-methoxyphenyl) -6- (2-thienyl) n cotinonitrile, 2-amino-6-cyclopropyl-4- (2-methoxyphenyl) nichotonitrile, 2-amino-4- (2-fluorophenyl) -6-phenylnicotinonitrile, (4bS, 8aR) -2,4-diamino-4b, 5,6,7,8,8a-hexahydro [1] benzofuro [2,3-b] pyridin-3-carbonitrile, 2-amino-4- ( 2-fluorophenyl) -S ^ -dimethyl-e ^ -dihydro-SH-pyrazolopy-3-quinoline-S-carbonitrile, 2-amino-4- (2-furyl) -5-phenyl-6,8-dihydro- 5H-pyrazolo [3,4-h] quinoline-3-carbonyltria, 3-amino-1,6-dimethyl-5,6,7,8-tetrahydro-2,6-naphthyridine-4- carbonitrile, 3-amino-1, 7-dithmetol-5,6,7,8-tetrahydro-2,7-naphthridine-4-carbonyl ether, 2-amino-4- (2 -fluorophenol) -5-phenyl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonyl, 2-amino-4- (2-fluorophenyl) ) -5-phenyI-6,8-dihydro-5H-pyrrazolo [3,4-h] quinoline- 3-carbonitrile, 4,6-d-amino-2- (morpholin-4-ylmethyl) -2,3-dihydro [2,3-b] pyridine-5-carbonyl ester lo, (4,6-diamamno-5-cyano-2-oxo-2,3-dihydro-1 H-pyrrolo [2,3-b] pyridin-1-l ) ethyl acetate, 2-amino-4- (2-methoxyphenyl) -6- (5-methyl-2-furyl) nicotonitrile, 2-amino-6-methyl-4- (4-nitrophenol) ) n-trinonitrile, 2-amino-4- (3,4-dimethoxyphenyl) -6- (5-methyl-2-furyl) n-trichloromethyl, 2,4-diamino-6 - [( 4-methoxyphenyl) thio] nicotonitrile, 4,6-diamino-2- (phenoxymethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4,6-diamino-3-phenyl l-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 4,6-diamino-2 - [(2-methylphenoxy) methyl] -2,3-dihydrofuro [2 , 3-b] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6- (4-methoxyphenyl) nicotinonitrile, 2-amino-4- (3-phorophenyl) -5, 6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (4-methoxyphenyl) -6,7-hydroxy-5H-cyclopenta [b] pyridine-3- carbonitrile, 2-amino-9-etl-9H-pyridyl [2,3-b] indol-3-carbonitrile, 2-amino-6-butyl-4- (4-methylphenyl) nicotinonitrile, 1 - (2-furyl) - 3 - [(3-hydroxypropyl) amino] -5,6,7,8-tetrahydroisoquinoline-4-carbonitrile, 2-azepan-1-yl-6- (4-fluorophenyl) -4-phen Lnicotinonitrile, 2-amino-6-tert-butyl-4- (4-methylphenyl) nicotinone, 2-amino-4- (4-bromophenyl) -6-methylnicotinonitrile, 2-amino ^ -thien ^ -il-S.ej.SglO-hexahydrocyclooctafbJpyridine-S-carbonitrile, 2-amino-4- (4-chlorophenyl) -6,7) 8,9-tetrahydro-5H-cyclohepta [b] pyridine-3-carbonitrile, 2- (allylamino) -5-amino-7- (4-bromophenyl) t-ene [3,2-b] pyridine-3, 6-dicarbonitrile, 2-amino-4-pyridin-3-yl-5,6J, 8,9,10-hexahydrocycloocta [b] pyridine-3-carbonitrile, 2-amino-4- (4 -bromophenyl) -6-tert-butylnotronic acid, 1- (2-furyl) -3-morpholin-4-yl-5,6,7,8-tetrahydroisoquinoline-4 -carbonitrile, 2-amino-4- (4-methylphenyl) -6,7-dihydro-5H-cyclopenta [b] pyridine-3-carbonomethyl, 2-amino-7,7-dimethyl-7 , 8-dihydro-5H-pyran [4,3-b] pyridine-3-carbonitrile, 2-amino-6-isobutyl-4- (4-methoxyphenyl) nicotinonitrile, 4,6-diamino-2- oxo-1-phenyl-2,3-dihydro-1 H-pyrrolo [2,3-b] pyridine-5-carbonitrile or, 2-amino-4- (2-methoxyphenyl) -5,6-dimethylnucleotide, 2- (dimethylamino) -4- (2-fluorofonyl) -6- (2-furyl) n Cotinonitrile, 2- (dimethylamino) -4- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile, 4- (2-fluorophenyl) -6- (2-fur) I) -2- (methylamino) nicotinonitrile, 4- (2-fluorophenyl) -6- (2-furyl) -2-morpholin-4-yN-nicotinonitrile, tert-butyl N- [3-cyano-4- (2 -fluorophenyl) -6- (2-furyl) pyridin-2-1-glycinate, 2- (ethylamine) -4- (2-fluorophenyl) -6- (2-furyl) n Cotinonitrile, ethyl 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] benzoate, 2-amino-6- (2-fluorophenyl) -4- (3-furyl Nicotinonitrile, 6-amino-4- (2-fluorophenyl) -2,2'-bipyridine-5-carbonitrile, 2-amino-4- (2-fluorophenyl) -6-thien-2-ylnicotinonitrile, 6- amino-5-cyano-4- (2-fluorophenyl) pyridine-2-carboxylic acid ethyl ester, 2-amino-6- (2-furyl) -4-phenylnicotinonitrile, 2-amino-3-cyano-4- ( 2-furyl) -5,6,7,8-tetrahydroquinoline-6-carboxylic acid ethyl ester, 2-amino-4- (2-furyl) -6- (4-hydroxyphenyl) -5-methyl-phenyl-trinomethyl ester, -amino-4- (2-furyl) -6- (4-methoxyphenyl) -5-methylnyl otinonitrile, 2-amino-6- (4-fluorophenyl) -4- (2-furyl) -5-methylnicotinonitrile, 2-amino-4- (2-furyl) -5,6-diphenyl-nicotinonitrile, 2-amino-4- (2-furyl) -5-methyl-6-phenyl-nicotinonitrile, 2-amino-6- (3,4-dimethylphenyl) -4- (2-furyl) nicotinonitrile, 2-amino-6- (4-fluorophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-4 - (3-fluorophenyl) -6- (3-hydroxyphenyl) n-phenyl-nitrile, 6-alan-4- (3-fluorophenyl) -2,4'-b-pyridine-5-carbonitrile It is 6-amino-4- (2-fluorophenyl) -2,4'-bipyridine-5-carbonitrile, 2-amino-4-butyl-6-methylenetriotonitrile, 2-amino- 6-methyl-4-propylnicotinonitrile, 2-amino-4-ethyl-6-methylisotinonitrile, 2-amino-4,6-dimethylnicotinonitrile, 2-amino-4- [2- (hexyloxy) phenyl] -6 , 7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- [2- (beta-D-glucopyranosyloxy) phenyl] -6,7-dihydro -5H-pyrazole [3,4-h] quinoline-3-carbonitrile, 4- [2- (allyloxy) phenyl] -2-amino-6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, [2- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) phenoxy] acetate methyl, 2-amino-4- (2-ethoxyphenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 4- [2-amino-3-cyano] -6- (2-furyl) pyridin-4-yl] -1 H-pyrrole-2-carboxylic acid ethyl ester, 2-amino-6 -methylnicotinonitrile, 2-amino-6- (4-cyanophenyl) -4- (2-furyl) nicotinonitrile, 2-amino-6- (4-fluorobenzyl) -4- (2-furyl) nicotinonitrile, 2-amino-5 - (4-fluorophenyl) -4- (2-furyl) -6-methylnicotinonitrile, 2-amino-4- (2-furyl) -6- (4-methoxyphenyl) nicotinonitrile, 2-amino-4- (2 -methylphenyl) -5,6,7,8-tetrahydroquinoline-3-carbonitrile, 2-amino-4- (4-methoxyphenyl) -5,6,7,8-tetrahydroquinoline-3-carbonitrile, 2-amino- 4-phenyl-5,6,7,8-tetrahydroquinoline-3-carbonitrile, 2-amino-6- (4-methoxyphenyl) -4- (2-methylphenyl) nicotinonitrile, 2-amino-4,6-bis (4 -methoxyphenyl) n-phenyl-nitrile, 2-amino-4- (3-chlorophenyl) -6- (4-methoxyphenyl) n-phenyl-nitrile, 2-amino-4- (2-chlorophenyl) -6- (4 -methoxyphenyl) nicotinonitrile, 2-amino-4- (2-furyl) -5,6,7,8-tetrahydro-1,6-naphthyridine-3-carbonitrile, 2-amino-4- (2-furyl) -6- (4-methylphenyl) nicotinonitrile, 2-amino-4- (2-furyl) -6-phenyl-phenyl-trinitrile, 6-amino-4- (2-furyl) -2,3'-bipyridine-5 -carbonitrile, 2-amino-6- (1,3-benzodioxol-5-yl) -4- (2-furyl) nicotinonitrile, 2-amino-4-isoquinolin-4-yl-6- (4-methoxy) phenol) n-phenylnucleotide, 2-amino-4- (1-benzoten-3-yl) -6- (4-methoxyphenyl) nicotinonitrile, 2-amino-6- (4- methoxyphenyl) -4-thien-3-ylnicotinonitrile, 2-amino-4- (3-furyl) -6- (4-methoxyphenyl) nicotinone, 2-amino-6- (4-methoxyphenyl) - 4- (1 H-pyrrol-2-yl) nicotinonitrile, 2-amino-4- (2-furyl) -6- (1 H -pyrrol-2-yl) nicotinonitrile, '-amino-e' ^ -methoxypheni- S ^ '- bipyridine-S'-carbonitrile, 2-amino-4- [2- (trifluoromethoxy) phenyl] -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2- amino-4- (2-furyl) -5H-thiochromeno [4,3-b] pyridine-3-carbonitin, 2-amino-4-. { 4 - [(2-Cyanoethyl) (methyl) amino] phenyl} -6,7-dihydro-5H-pyrazole [3,4-h] quinoline-3-carbonitrile, 2-amino-4- [2- (2-hydroxyethoxy) phenyl] -6,7-dihydro-5H-pyrazolo [ 3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-methylphenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino- 4- [4- (dimethylamino) phenyl] -6,7-dihydro-5H-pyrazoo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (1 H -indo-7-yl) - 6,7-dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonitrile, 4- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4 -h] quinolin-4-yl) methyl benzoate, 2- (2-amino-3-cyano-6,7-dihydro-5 H -pyrazolo [3,4-h] quinolin-4-yl) benzoate of methyl, [2- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3,4-h] quinolin-4-yl) phenoxy] acetic acid, 2-amino-6-phenyl-nicotinonitrile, 2-amino-6-cyclohexylnicotinonitrile, 2-amino-4- (2-furyl) -6- (1-trityl-1 H -pyrazol-4-yl) nicotinonitrile, 2-amino-4- (2-fluorophenyl) - 6- (4-hydroxyphenyl) nicotinonitrile, 2,4-diamino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-hydroxy-5H-chromene [213-b] pyridine-3-carbonitrile, 2-amino-7,8 -dihydroxy-4 - [(2-hydroxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7,8-dimethoxy-5H-chromene [2,3- b] pyridine-3-carbonitrile, 2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-4- (ethylamino) - 7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diammon-9-hydroxy-5H-chromene [2,3-b] pyridine- 3-carbonyltryl, 2,4-diamino-9-fluoro-5H-chromene [2,3-b] pyridin-3-carbonitrile, 2,4-d-amino-7-hydroxy -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-hydroxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 8,10-d-amino-2,3-dihydro-11 H- [1,4] dioxin [2 ', 3': 6,7] chromene [2,3-b] pyridine-9-carbonitrile, 2,4,7-triamino-5H-chromene [2] , 3-b] pyridine-3-carbonitrile, 2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxyl-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9-hydroxy-8-methoxy-5H-chromene [2,3-b] ] pyridine-3-carbonitrile, 2,4-diamino-6,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-ethoxy- 7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-8- (2-ethoxy-ethoxy) -5H-chromene [2,3- b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-aminoethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, acid 2,4-d Amino-3-cyano-5H-chromene [2,3-b] pyridine-7-carboxylic acid, 2,4-diamino-8,9-dihydroxy-5H-chromene [2,3-b] ] pyridine-3-carbonitrile, 2,4-d-amino-8- (2-morpholin-4-ylethoxy) -5H-chromene [2,3-b] pyridine-3-carbon trílo, acid [(2,4-d-amino-3-cyano-5H-cro Meno [2,3-b] pyridin-8-yl) oxy] acetic acid, 2,4-diamino-9-methoxy-5H-chromene [2,3-b] pyridn-3- carbonitrile, 2,4-diamino-8- (2-pyrrolidin-1-methoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8 -dimethoxy-4- (methylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-methoxy-5H-chromene [2,3-b] p Ridin-3-carbonitrile, 2,4-diamino-8- [2- (dim6-ylamino) -ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4,7-triamine -9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2- (2,4-diamino-3-cyano-8-methoxy-5H-chromene [2,3- b] pyridin-5-yl) malononitrile, 2,4-diamino-7,8-di [2- (amino) ethoxy] -5H-chromene [2,3-b] pyridine -3-carbonitrile, 2,4-diamino-9-nitro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy-4- [ (4-methoxyphenyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2,4-diamino-3-cyano-7-hydroxy-5H-chromene [2,3-b] pindin-5-ii) malononitrile, 2 (2,4-diamino-3-cyano-7-bromo- 5 H -chromene [2,3-b] pyridin-5-yl) ma lononitrile, 2-amino-8-ethoxy-4- (ethylamino) -5H-chromene [2,3-b] pyridine-3-carbonitide, 2,4,9-triamino-5H-chromene [2,3- b] pyridine-3-carbonitrile, S ^^ -? G ^ ????? - d? - ???? G ??????? ^ - b] pyridine-3-carbonitrile, 2-amino- 7,8-dinfethoxy-4 - [(4-rrietoxyphenyl) arnino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2,4-diamino-3-cyano-7-methoxy-5H -chromeno [2,3-b] pyridin-5-yl) malononitrile, 2,4-diamino-9-hydroxy-8- (piperidin-1-methylmethyl) -5H-chromene [2,3-b] pyra dna-3-carbonitrile, 7,8-bis (allyloxy) -2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-8- (2-ethoxyethoxy) -4 - [(2-ethoxyethyl) amino] -5H-chromene [2,3-b] p! Ridine-3-carbonitriyl, tert-butyl. { [2,4-diamino-7- (2-tert-butoxy-2-oxoethoxy) -3-cyano-5H-chromene [2,3-b] pyridn-8-yl] oxy} acetate, 2-amino-4 - [(2-aminoethyl) amino] -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2,4-diamino-3-cyano) -8-hydroxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 10,10-2,4,7-triamino-5H-thiochromene [2,3-b] pyr Dina-3-carbonitrile, 2,4-diamino-7-bromo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy-4- (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-hydroxy-5H-thiochromeno [2J3-b] pyridine-3-carbonitrile, 2,4-diamino-7- ( dimethylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2.4 -diamino-3-cyano-9-methoxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2-amino-4- (benzylamino) -7,8-di methoxy -5H-chromene [2,3-b] pyridine-3-carbonyl,

8- (aliIoxi) -2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9-fluoro-5H-thiochromeno [2,3-b] pyridine- 3-carbonitrile, 2,4-diamino-7-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9- (2-pyrrolidin-1-ylethoxy) -5H- chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-nitro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-10-methyl- 5, 0-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile, [(2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridin-9-yl) oxy]] acetic, 2-amino-4-. { [2- (dimethylamino) ethyl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-nitro-5H-thiochromen-2-dioxide dioxide [2] , 3-b] pyridine-3-carbonitrile, 2,4-diamino-7-phenyl-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-chloro-9-methyl -5H-chromene [2,3-b] pyridine-3-carbonitrile, 10,10-dioxido-2,4-diamino-7-fiuoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 8 -ethoxy-2,4-bis (ethylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-5- (2-fluoro-phenyl) -8-methoxy-5H- chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9- (2-hydroxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino- 9- (2-aminoethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2,4-diamino-3-cyano-7-chloro-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2,4-bis. { [2- (dimethylamine) ethyl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-4-. { [2- (1, 3-dioxo-1, 3-dihydro-2H-isoindol-2-y1) ethyl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-fluoro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 , 4-diamino-7-bromo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9- (pyridin-4-lmetoxy) -5H-chromene [2,3- b) pyridine-3-carbonitrile, 2,4-diammine-7-chloro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diammon-9- tert-butyl-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridine-9-carboxylate ethyl, 2,4-diamino-9- [2- (dimethylamino) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-bis (butylamino) -7, 8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonyl, 2-amino-4- (butylamino) -7,8-dimethoxy-5H-chromene [2, 3-b] pyridine-3-carbonitrile, 7,8-dimethoxy-2,4-bs (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2, 4-bis (ethylamino) -7,8-dimethoxy-5H-chromene [2,3-b] pyridin-3-carbontrotyl, 2-amino-4- (ethylamino) -7,8-dimethoxy -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-6,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile ilo, 2,4-d-amino-7- (trifluoromethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diam-7-bromo-9-methoxy-5H -chromeno [2,3-b] pyridine-3-carbonitrile, 2) 4-diammon-9-methoxy-7-nitro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 7, 9-diamino-10 H- [1,3] dioxolo [6,7] chromene [2,3-b] pyridine-8-carbonitrile, 7,9-diamino-10 H- [1,3] dioxolo [6, 7] chromene [2,3-b] pyridine-8-carbonitrile, 2,4-diamino-8-methyl-5H-chromene [2,3-b] pyridine-3-carbonitrile, 7.8- dimethoxy-2,4-bis [(2-methoxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonyl, 2-amino-7,8- dimethoxy-4 - [(2-methoxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-d-methoxy-4 - [(2 -pyrrolidin-1-ylethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 7,8-dimethoxy-2,4-bis [(2-pyrrolidin-1-ylethyl) amino] - 5 H -chromene [2,3-b] pyridine-3-carbonitrile, 2,4-bι (glycine) -7,8-dι-methoxy-5H-chromene [2,3-b] pyridine-3-carbon Tr, N- (2-amino-3-cyano-7,8-dimethoxy-5H-chromene [2,3-b] pyridin-4-yl) glycine, 2,4-diamino-3-cyano acid -5H-chromene [2,3-b] pyridine-9-carboxylic acid, 2,4-diamino-6-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-9-bromo-7- chloro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-bis (ethylamino) -7,8-dihydroxy-5H-chromene [2,3-b] pyr Dna-3-carbonitrile, 2,4-diamino-6-bromo-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8 -hydroxy-7,9-bs (piperidin-1-ylmethyl) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-5-phenyl-8-hydroxy- 5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-5- (3-fluoro-phenyl) -8-methoxy-5H-chromene [2, 3-b] pyridine-3-carbonitrile, 2,4-diamam-9-hydroxy-6,8-bis (piperidin-1-methylmethyl) -5H-chromene [2,3 -b] pyridine-3-carbonitrile, 2,4-diamino-7-bromo-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-5-phenyl-8-methoxy- 5 H -chromene [2,3-b] pyridine-3-carbonitrile, 10,10-2,4-diamino-9-fluoro-5H-thiochromene [2,3-b] pyridine-3-dioxide carbonitrile, 2,4-diamino-7-nitro-5H-thiochromene [2,3-b] pyridine-3-carbonitrile, 10,10-dioxide 2,4-diamino-7-methoxy-5H- thiochromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-7-methoxy-5H-thiochromene [2,3-b] pyridine-3-carbonomethyl, 10,10- 2,4-diamino-5H-thiochromene dioxide [2,3-b] pyridine-3-carbonyl ether, 2,4-diamino-5H-thiochromene [2,3-b-pyridine-3-carbonitrile, 2, 4-diamino-7-fluoro-5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 2-amino-7,9-dimethyl-5-oxo-5H-chromene [2,3-b] pyridine- 3-carbonitrile, 2-amino-7-isopropyl-5-oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7-ethyl-5-oxo-5H-chromene [ 2,3-b] pyridine-3-carbonitrile, 2-amino-7-methyl-5-oxo-5H-cramene [2,3-b] pyridine-3-carbonitrile, 2-amino-7-chloro-5- oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7-bromo-5- oxo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-5-oxo-5H-chromene [2,3-b] pyridine-3-carbonomethyl, and 3-amino-5H-pyridyl [3,4-b] [1,4] benzothiazine-4-carbonitrile. 8. The use of a compound, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the inhibition of mitogen-activated protein kinase-activated protein kinase-2 in a subject in need of such inhibition, wherein the compound has the structure: G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R41 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is-H or C4 alkyl; each of R1, R2, R35, R36, R37, R38, R39, and R40 is independently: hydrogen, hydroxy, amino, halo or nitro, branched or unbranched Ci-C6 alkyl, C2-C6 alkenyl, C2 alkynyl -C6, CrC6 alkoxy, Ci-C6 hydroxy alkyl, Ci-C6 alkoxy hydroxy, Ci-C6 alkoxy Ci-C6 alkoxy, C6 alkoxy C1-C6 alkyl, or Ci-C6 alkenoxy, Ci-C6 amino branched or unbranched alkyl , diamino C2-C6 alkyl, Ci-C6 alkylamino Ci-C6 alkyl, alkylamino C Ce, di- (C6 alkyl) amino, alkoxyarylamino C- | -C4, alkoxyalkylamino Ci-C4, amino alkoxy C - \ - Ce, di - (CrC6 alkylamino, C2-C6alkoxy, di- (CiC-6alkyl) aminoCirC6 alkyl, Ci-C6 alkylaminoCiC6 alkoxy, Ci-C6 halo alkoxy, Ci-C6 dihalo alkoxy, Ci-C6 trihalo alkoxy, Ci cyano alkyl -C6, dicyan alkyl 0? -06, cyano alkoxy Ci-C6) dicyan alkoxy Ci-C6, carbamyl alkoxy C-1-C4, heterocyclyl alkoxy Ci-C4, heteroaryl alkoxy C1-C4, sulfo, sulfamyl, alkylaminosulfonyl C C4l hydroxy C1-C4 alkylaminosulfonyl, di- (Ci-C4 alkyl) aminosulfonyl, alkylthio C C4, CC alkylsulfonyl, or C1-C4 alkylsulfinyl, aryl, aryl Ci-C6 alkyl, heterocyclyl C6 alkyl, heteroaryl CtC-6 alkyl, heterocyclyl alkoxy Ci-Ce, heteroaryl alkoxy Ci-C6, or aryl alkoxy Ci-C6, in wherein the aryl is optionally substituted with one or more substituents selected from the group consisting of Ci-C6 alkyl, halo, amino, and Ci-C6 alkoxy, C3-C6 cielite, or C3-C6 heterocyclyl, wherein any said substituent is optionally substituted with one or more substituents, selected from the group consisting of C1-C6 alkyl, Ci-C6 alkoxy, halo and amino, and wherein the C3-C6 heterocyclyl ring contains O, S, or N, C-1-C6 alkoxycarbonyl C1-C-6 branched or unbranched, or carboxy, carboxy Ci-C6 alkoxy, carboxy Ci-Ce alkyl, hydroxyC1-C4 alkoxycarbonyl, or Ci-C4 alkoxycarbonyl; and R38 and R39 are such that they optionally join to form a ring system selected from the group consisting of:

9. - The use claimed in claim 8, wherein: the compound has the structure: G is selected from the group consisting of -O-, -S- and -N-; when G is -O-, R41 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R4 is absent, and R42 is-H or C1-C4 alkyl; R is selected from the group consisting of hydrogen, branched alkyl, unbranched alkyl, ayanyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy, carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl, alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl , monocyclyl, bicyclyl, polycyclyl, and heterocyclyl; R 2 is selected from the group consisting of hydrogen, alkyl, anynyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl; R35 is selected from the group consisting of hydrogen, dicyanoalkyl, heterocyclyl and cyclyl, wherein: the heterocyclic and the cyclyl are optionally substituted with one or more halo; R36 is selected from the group consisting of hydrogen, dicyanoalkyl, heterocyclyl, and cyclyl, wherein: the heterocyclic and the cyclic are optionally substituted with one or more halo; R37 is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, aikenyl, alkylo, arylalkyl and alkylaryl; R38 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, ayanyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkylaryl and arylamino; R39 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclyloalkyl, heterocyclyloalkyloxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy; R38 and R39 can be joined to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclylaoxy, carboxyalkoxy, pyrrolidylethoxy, carboxy methoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclyloalkyl. 10. The use of a compound, or a pharmaceutically acceptable salt thereof, for preparing a medicament for the inhibition of mitogen-activated protein kinase-activated protein kinase-2 in a subject in need of such inhibition, wherein: compound have the structure:

G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R41 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is-H or -CH3; R1 is selected from the group consisting of hydrogen, ethyl, dimethylaminoethyl, butyl, propyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl; R 2 is selected from the group consisting of hydrogen, hydroxyethyl, propyl, ethyl, methyl, 4-methoxyphenyl, ethoxyethyl, aminoethyl, phenylmethyl, dimethylaminoethyl, phthalaminomethyl, butyl, methoxyethyl, tetramethylaminoethyl, and carboxymethyl; R35 is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl; R3S is selected from the group consisting of hydrogen, dicyanomethyl, 2-fluorophenyl, phenyl, and 3-fluorophenyl; R37 is selected from the group consisting of hydrogen, hydroxy, methoxy, bromo, and 2-pyridomethyl; R38 is selected from the group consisting of hydrogen, hydroxy, methoxy, amino, carboxy, diaminoethoxy, bromine, propoxy, isobutylcarboxymethoxy, dimethylamino, nitro, phenyl, chloro, pyridylmethyl, and fluoro; R39 is selected from the group consisting of hydrogen, hydroxy, methoxy, hydroxyethoxy, ethoxyethoxy, ethoxy, aminoethoxy, morpholinoethoxy, carboxymethoxy, N-pyrrolidylethoxy, dimethylaminoethoxy, pyridylmethyl, 2-propenoxy, and isobutylcarboxymethoxy, R38 and R39 optionally join to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, fluoro, methoxy, nitro, amino, pyrrolidylethoxy, carboxymethoxy, methyl, hydroxyethoxy, aminoethoxy, 4-pyridylmethoxy, isobutyl, ethylcarboxy, dimethylaminoethoxy, carboxy, bromine, and pyrridylmethyl.

11. The use claimed in claim 9, wherein: G is selected from the group consisting of -O- and -S-; when G is -O-, R41 and R42 are absent; when G is -S-, R4 and R42 are optionally absent, or are oxo; R 1 is selected from the group consisting of hydrogen and C 1 -C 2 alkyl; R 2 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, hydroxy C 1 -C 2 alkyl, C 1 -C 2 alkoxyphenyl, C 1 -C 2 alkoxy C 2 alkyl C 1 C 2 alkyl, C 1 -C 2 phenyl alkyl, and Ci-C 2 dialkylamino Ci-C 2 alkyl; R and R are each independently selected from the group consisting of hydrogen, dicyano Ci-C2 alkyl, and halophenyl; R37 is selected from the group consisting of hydrogen and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, C-1-C3 alkoxy, amino, nitro, carboxy, diamino alkoxy Ci-C2) halo, propenoxy, iso alkylcarboxi Ci-C2 C3-C4 alkoxy, dialkylamino C1-C2, and phenyl; R39 is selected from the group consisting of hydrogen, hydroxy, C1-C3 alkoxy, hydroxy C1-C2 alkoxy, C1-C2 alkoxy CrC2 alkoxy, amino alkoxy CrC2, morpholino Ci-C2 alkoxy, carboxyl alkoxy CrC2, pyrrolidyl Ci-C2 alkoxy, dialkylamino C C2 Ci-C2 alkoxy, pyrrolidyl Ci-C2 alkyl, C3-C4 isoalkylcarboxyCi-C2 alkoxy, and 2-propenoxy, R38 and R39 optionally join to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, CrC2 alkyl, Ci-C2 alkoxy, nitro, amino, pyrrolidyl C -] - C2 alkoxy, Ci-C2 alkoxy carboxy, C2 C2 hydroxy alkoxy, and C1 alkoxy amino -C2.

12. The use claimed in claim 10, wherein: G is selected from the group consisting of -O- and -S-; when G is -O-, R41 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; R1 is hydrogen; R2 is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy Ci-C2 alkyl, Ci-C2 alkoxyphenyl, C2 alkoxy C1-C2 alkyl, amino C1-C2 alkyl, phenyl C1-C2 alkyl, and dialkylamino C1- C2 Ci-C2 alkyl; R35 and R36 are each independently selected from the group consisting of hydrogen and dicyanoCi-C2 alkyl; R37 is selected from the group consisting of hydrogen and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, Ci-C2 alkoxy, amino, carboxy, nitro, diamino C1-C2 alkoxy, halo, 2-propenoxy, C3-C4 isoalkylcarboxy C2 alkoxy, C-1-C2 dialkylamino , and phenyl; R39 is selected from the group consisting of hydrogen, hydroxy, alkoxy CrC2, hydroxy alkoxy CrC2, alkoxy C C2 alkoxy Ci-C2, amino alkoxy C1-C2, morpholino alkoxy C C2, carboxyl alkoxy C1-C2, pyrrolidyl alkoxy C1-C2, C1-C2 dialkylamino alkoxy CrC2, pyrrolidyl C1-C2 alkyl, C3-C4 isoalkylcarboxyCi-C2 alkoxy, and 2-propenoxy; R38 and R39 optionally join to form a 6-membered heterocyclic ring and R40 is selected from the group consisting of hydrogen, hydroxy, halo, C1-C2 alkoxy, nitro, amino, pyrrolidyl C1-C2 alkoxy, and carboxy C4 alkoxy- C2.

13. The use claimed in claim 10, wherein: G is selected from the group consisting of -O- and -S-; when G is -O-, R41 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; R1 is hydrogen; R 2 is selected from the group consisting of hydrogen, C 1 -C 3 alkyl, hydroxy C 1 -C 2 alkyl, C 1 -C 2 alkoxyphenyl, C 2 C 2 alkyl C 1 -C 2 alkyl, C 1 -C 2 amino alkyl, and phenyl C 1 -C 2 alkyl; R35 and R36 are each independently selected from the group consisting of hydrogen and dicyanoCi-C2 alkyl; R37 is selected from the group consisting of hydrogen and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, alkoxy CrC2, amino, carboxy, diamino C1-C2 alkoxy, halo, 2-propenoxy, C3-C4 isoalkylcarboxyCi-C2 alkoxy, and C-i-C2 dialkylamino; R39 is selected from the group consisting of hydrogen, hydroxy, alkoxy CrC2, hydroxy alkoxy C-¡-C2, alkoxy Ci-C2 alkoxy C- | -C2, amino alkoxy Ci-C2, morpholino alkoxy Ci-C2, carboxyl alkoxy C1- C2, pyrrolidyl C1-C2 alkoxy, C1-C2 dialkylamino Ci-C2 alkoxy, pyrrolidyl C2 alkyl, C3-C4 isoalkylcarboxyC12 alkoxy CrC2, and 2-propenoxy; R38 and R39 optionally join to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, CrC2 alkoxy, nitro, amino, and pyrrolidyl C-i-C2 alkoxy.

14. The use claimed in claim 10, wherein: G is selected from the group consisting of -O- and -S-; when G is -O-, R41 and R42 are absent; when G is -S-, R4 and R42 are optionally absent, or are oxo; R1 is hydrogen; R2 is selected from the group consisting of hydrogen, Ci-C3 alkyl, hydroxy C2 alkyl, Ci-C2 alkoxyphenyl, C1-C2 alkoxy CrC2 alkyl, and CrC2 amino alkyl; R35 and R38 are each independently selected from the group consisting of hydrogen and dicyanoethyl; R37 is selected from the group consisting of hydrogen and hydroxy; R38 is selected from the group consisting of hydrogen, hydroxy, CrC2 alkoxy, amino, carboxy, C 1 -C 2 diamino alkoxy, halo, 2-propenoxy, C 3 -C 4 isoalkylcarboxy C 1 -C 2 alkoxy, and C 1 -C 2 dialkylamino; R39 is selected from the group consisting of hydrogen, hydroxy, Ci-C2 alkoxy, C 1 -C 2 hydroxy alkoxy, Ci-C 2 alkoxy Cr C 2 alkoxy, C 1 -C 2 amino alkoxy, Ci-C 2 alkoxy morfoiino, C 1 alkoxy carboxy -C2, pyrrolidyl C1-C2 alkoxy) dialkylamino Ci-C2 C1-C2 alkoxy, pyrrolidyl C2 alkyl, C3-C4 isoalkylcarboxy C1-C2 alkoxy, and 2-propenoxy; R38 and R39 optionally join to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, methoxy, nitro, and amino.

15. The use claimed in claim 1, wherein the compound inhibits the aminocyanopyridine MK-2 comprising at least one compound that is selected from the group consisting of: 2-amino-4- (2-fluorophenyl) - 6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furi-ej-dihydro-SH-pyrazolop ^ -hlquinoline-S-carbonitrile, 2- amino-4- (2,3-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-ina-3-carbonitrile, 8-amino-6- (2-fu) rü) -4, 5-dih id ra- 1 H-pyrazolo [4,3-h] quinoline-7-carbonitrile, 2-amino-3-cyano-4- (2-furyl) -5,6 acid -dihydrobenzo [h] quinoline-8-carboxylic acid, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] -1 H -pyrrole-2-carboxamide, 2-amino-4 phenyl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (2-furyl) -4- (1-methyl-1 H-imidazole) -4-yl) nicotinonitrile, 8-amino-6- (2-furyl) -4, 5-dihydro-1 H -pyrazolo [4,3-h] quinoline-7-carbonitrile, 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3 carbonitrile, 2-amino-4- (2,6-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (4-hydroxyphenyl) - 4- (1 H-imidazol-5-yl) nicotinone, 2-amino-4- (2-fluorophenyl) -6- (2-fu ri I) n icotin on tril, 2-amino -4- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 4- [6-] amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzoic acid, 2-amino-6- (2-furyl) -4- (1 H -imidazol-5-yl) nicotinonitrile, 2-amino -4- (2-furyl) -6- (1 H -pyrazol-3-yl) nicotinonitrile, 2-amino-3-cyano-4- (4H-1,2,4-triazol-3-yl) - 5,6-dihydrobenzo [h] quinoline-8-carboxylic acid, 2-amino-6- (3-hydroxyphenyl) -4- (1H-imydazoI-5-yl) n-trichonitrile, 2 -amino-6- (2-furyl) -4- (1 H -imidazol-4-yl) nicotinonitrile, 2-amino-4- (2,4-difluorophenyl) -6,7-d! hydro-5H-pyrazolo [3,4-h] quinoline-3-carbonyl, 4,6-diamino-2- (trifluoromethyl) -2,3-dihydrate ofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) -6,8-dihydro-5H-pyrrolo [3,4-h] quinoline-3-carbonitri lo, 4- [6-amino-5-cyano-4- (2-fluorophenyl) pyridin-2-yl] benzoic acid, 2-amino-4- (2-furyl) -5,6-dihydro -1, 8-phenanthroline-3-carbonitrile, 2-amino-6- (3,4-dihydroxypheni) -4- (2-fluorophenyl) nicotinonitrile, 2-amino-4- (1-methyl-1H-imidazole-4) -l) -6-phenylnicotinonitrile, 2-amino-4- (2-furyl) -6- (1H-pyrazol-3-yl) nicotinonitrile, 4- [6-amino-5-cyano-4-] (1H-imidazol-5-yl) pyridin-2-yl] benzoic acid, 2-amino-4- (3-fluorophenyl) -6,8-dhydro-5H-pyrazolo [3,4-h] ] quinoline-3-carbonitrile, 2-amino-6- (3,4-dihydroxyphenyl) -4- (2-fluorophenyl) nicotinonitrile, N-. { 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] phenyl} methanesulfonamide, 2-amino-4- (2-furyl) -6,7-dithy-5H-pyrrolo [2,3-h] quinoline-3-carbonitrile, 2-amino-4- (1 H-Midazol-5-yl) -6-phenylnicotinonitrile, 2-amino-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (1 H-imidazol-5-yl) -6- (4-methoxy-phenyl) nicotonitrile, 2-amino-e-IS-chlorophenyl-IIH-imidazole-Si nicotinonitrile, 2-amino-4- (2-furyl) -6- (1 H-pyrazol-4-yl) nicotinonitrile, 2-amino-4- (4-methoxyphenii) -6,7-dihydro-5H-pyrrazolo [3,4-h] quinoline-3 -carbonyltrile, 2-amino-4- (2,5-di-fluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4 - (4-fluorophenyl) -6,8-dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (4H-1, 2,4-triazole-3- il) -5,6-d.hydrobenzo [h] quinoline-3-carbonitrile, 4,6-diamino-2- (chloromethyl) -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2 -amino-4- (1H-imidazol-4-yl) -6-phenyl-nicotinonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] -benzenesulfonamide, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] phenylboronic, 2-ami no-6- (4-methoxyphenyl) -4- (4H-1,2,4-triazol-3-yl) n-phenyl-n-triyl, 2-amino-4- (2-fluorophenyl) -6- ( 3-furyl) nicotinonitrile, 2-amino-6- (2-furyl) -4- (methylthio) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (3-hydroxyphenyl) nicotinonitrile, 8-amino- 6- (2-furyl) -4,5-dihydro-2H-pyrazolo [4,3-h] quinol-7-carbonyltria, 2-amino-4- (2-bromophenyl) - 6- (2-furyl) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (4-hydroxyphenyl) nicotinonitrile, 2-amino-4-phenyl-6-thien-2-ylnicotinonitrile, 2-amino- 4- (3-methoxyphenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -7-methyl-6,7- dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-fluorophenyl) -6- (1 H -pyrrol-2-yl) nicotinonitrile, 2-amino-4- (2-furyl) -5-methyl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6- (1-methyl) -1 H-pyrrol-3-yl) nicotinonitrile, 3-amino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile, N- [4- (2-amino-3-cyano-6,7-dihydro- 5H-pyrazolo [3,4-h] quinolin-4-yl) phenyl] acetamide, 6-amino-4 - [(4-m) ethoxyphenyl) amino] -2- (trifluoromethyl) -2,3-dihydrofuro [2,3-b] pyridine 5-carbonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-) il] -N- (tert-butyl) benzenesulfonamide, 4,6-diamino-2-ethyl-2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 6-amino-4- (2-furyl ) -2,4'-bipyridine-5-carbonitrile, 2,4-diamino-6- (methylthio) nicotinonitrile, 3- (2-amino-3-cyano-6,7-dihydro-5H-pyrazolo [3], 4-h] quinolin-4-yl) benzoic acid, 2-amino-6- (4-chlorophenyl) -4- (1H-imidazol-5-yl) nicotinonitrile, 2-amino-4- (1,3-benzodioxole) -4-yl) -6,7-dihydro-5H-pyrazolo [3,4-hJquinoline-3-carbonitrile, 4,6-diamino-2-methyl-2,3-dihydrofuro [2,3-b] pyridine- 5-carbonitriio, 2-amino-4- (1 H-imidazol-5-yl) -6- [4- (methylisulfonyl) phenyl] nicotinonitrile, 2,4-diaminoquinoline-3-carbonitrile, 2,8-diamino-4 - (2-furyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitriyl, 2-amino-4,6-di (2-furyl) nicotinonitrile, 4,6-diamino-2-butyl-2,3 -dihydrofuro [2,3-b] pyridine-5-carbonitrile, ethyl 4- [6-amino-5-cyano-4- (1 H-imidazol-5-yl) pyridin-2-yl] benzoate, 2,4-diamino-6-methoxynicotinonitrile, 2-amino-4-methylnicotinonitrile, 2-amino-4- (4-cyanophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoh'na- 3-carbonitrile, 2-amino-4-cyclopropyl-6-methylnicotinonitrile, 2-amino-4- (2-furyl) -6- (1-methyl-1 H-pyrrol-2-yl) nicotinonitrile, 2-amino- 4- (2-chlorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (2-furyl) -4- (4-phenoxyphenyl) nicotinonitr ilo, 2-amino-4-pyridin-3-yl-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6-. { [2- (4-chlorophenyl) -2-oxoethyl] thio} -4- (2-furyl) pyridine-3,5-dicarbonitrile, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] phenylboronic acid, 2-amino-6 - (3-chlorophenyl) -4- (1H-imidazol-4-yl) nicotinonitrile, 4- (6-amino-5-cyano-4-phenylpyridin-2-yl) -N- (tert-butyl) benzenesulfonamide, -amino-4-methoxynicotinonitrile, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] benzoic acid, 4,6-diamino-2 - [(4-methoxyphenoxy) methyl] -2,3-dihydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-fluorophenyl) -6- (4-methoxyphenyl) nicotinonitrile, 4- [6-amino-5-cyano -4- (2-fluorophenyl) pyridin-2-yl] -N- (tert-butyl) benzenesulfonamide, (2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridine-9-) acid L) oxy) acetic acid, 3-pyridinecarbonitrile, 2-amino-4-methylim 2-amino-6- (2-furyl) nicotinonitrile, 2-amino-4- (2-furyl) -6- (3-hydroxyphenyl) nicotinonitrile, 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] benzamide, 2-amino-4- (2-furyl) -7-hydroxy-5,6-dihydrobenzo [ h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6- (1 H -indol-3-yl) nicotinonitriio, 2-amino-4-pyridin-4-yl-6,8- dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (3-fluorophenyl) -6- (4-hydroxyphenyl) nicotinonitrile, 2-amino-4- [2- (difluoromethoxyl) phenyl] -6 , 7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6-thien-3-ylnicotinonitrile, 2-amino-4- (3- fluorophenyl) -6- (4-methoxyphenyl) nicotinonitrile, 2- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] phenolboronic acid, 2, 4-diamino-6-propylpyridine-3,5-dicarbonitrile, 2,4-diamino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4- diamino-8-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dihydroxy-4 - [(2-hydroxyethyl) amino] -5H- chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2- amino-7,8-dihydroxy-4- (propyllamine) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-4- (ethylamino) -7,8-dhydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2) 4-d-amino-9-hydroxy-5H-chromene [2,3-b] pyr Dina-3-carbonitrile, 2,4-diamno-9-fluoro-5H-chromene [2,3-b] pyridine-3- carbonyl, 2,4-diamino-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-hydroxyethoxy) -5H- chromene [2,3-b] pyridine-3-carbonitrile, 8,10-diamino-2,3-dihydro-11 H- [1,4] dinoxin [2 ', 3': 6,7] chromene [2,3-b] pyridine-9-carbonitrile, 2,4,7-triamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4- diamino-5H-chromene [2,3-b] pyridn-3-carbonitrile, 2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromene [2,3- b) pyridine-3-carbonitrile, 2,4-diamino-9-hydroxy-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4 -diamino-6,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-ethoxy-7-hydroxy-5H-chromene [2] , 3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-ethoxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4- diamino-8- (2-aminoethoxy) -5H-chromene [2,3-b] pyridin-3-carbonitrile, 2,4-diamino-3-cyano-5H-chromene [2,3-b] ] pyridine-7-carboxylic acid, 2,4-d-amino-8,9-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-morpholin-4-methoxy) -5H-chromene [2,3-b] pyridine-3-carbonitride [(2,4-diamne-3-cyano)] -5H-chromene [2,3-b] pyridin-8-yl) oxy] acetic acid, 2,4-diamino-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2.4 -diam -no-8- (2-pyrrolidn-1-ylethoxy) -5H-chromene [2,3-b] pyridine-3-carbonyl, 2-amino-7 , 8-dimethoxy-4- (methylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonyltryl, 2,4-diamino-8- [2- (dimethylarnino) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile], 2,4 , 7-triamino-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2,4-d-amino-3-cyano-8-methoxy-5H-chromene [2 , 3-b] pyridin-5-yl) malononitrile, 2,4-diamino-7,8-di [2- (amino) ethoxy] -5H-chromene [2,3- b) pyridine-3-carbonitrile, 2,4-diammino-9-nyrro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy-4 - [(4-methoxyphenyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diammon-8- methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2 (2,4-diam No-3-cyano-7-hydroxyl-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2 (2,4-diamino-3-cyano-7) -bromo-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2-amino-8-ethoxy-4- (ethylamino) -5H-chromene [2,3-b] pyridine -3-carbonitrile, 2,4,9-triamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4,7-triamino-5H-thiochromeno [2,3-b] pyridine-3 -carbonyl ether, 2-amino-7,8-d¡-methoxy-4 - [(4-methoxy-phenyl) amino] -5H-chromene [2,3-b] pyridine-3- carbonitrile, 2 (2,4-diamno-3-cyano-7-methoxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2,4-diamino-9 -hydroxy-8- (piperidin-1-ylmethyl) -5H-chromene [2,3-b] pyridin-3-carbonitrile, 7,8-bis (allyloxy) -2,4- diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-8- (2-ethoxyethoxy) -4 - [(2-ethoxyethyl) amino] -5H-chromene [2,3 -b] pyridine-3-carbonyl ether, tert-butyl. { [2,4-diamino-7- (2-tert-butoxy-2-oxoethoxy) -3-cyano-5H-chromene [2,3-b] pyridin-8-yl] oxy} acetate, 2-amino-4 - [(2-aminoethyl) amino] -7,8-dimethoxy-5 H -chromene [2,3- b] pyridine-3-carbonitrile, 2 (2,4-diamino-3-cyano) -8-hydroxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 10,10-2,4,7-triamino-5H-thiochromen [2,3] -b] pyridine-3-carbonyl, 2,4-d-amino-7-bromo-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7 , 8-D-methoxy-4- (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-7-hydroxy-5H-thiochromen [2,3 -b] pyridine-3-carbonitrile, 2,4-diamino-7- (dimethylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-methoxy-5H-chromene [2,3-b] pyridine-3-carbonyl, 2 (2,4-diamino-3-cyano-9-methoxy-5H-chromene [2,3-b] pyr) D-n-5-yl) malononitrile, 2-amino-4- (benzamino) -7,8-d¡methoxy-5H-chromene [2,3-b] pyridine-3-carbonitride lo, 8- (allyloxy) -2,4-diamno-5H-chromene [2,3-b] pyridine-3-carbonomethyl, 2,4-diamino-9-fluoro-5H-thiochromen [2, 3-b] pyridine-3-carbonitrile, 2,4-diamino-7-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diammine-9- (2-pirrol¡d¡n -1-ylethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-nitro-5H-chromene [2,3-b] pyridine-3- carbonitrile, 2,4-diamino-10-methyl-5,10-dihydrobenzo [b] -1,8-naphthyridine-3-carbonitrile, [(2,4-diamino-3-cyano-5H-chromene [ 2,3-b] pyridin-9-yl) oxy] acetic, 2-amino-4-. { [2- (dimethylamino) etl] amino} -7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-pyrrolein-1-ylethoxy) -5H-chromene [2 , 3-b] pyridine-3-carbonitrile, 2-amino-7,8-d-methoxy-4- (methylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4 -diamino-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- [2- (dimethylamino) ethoxy] -5H-chromene [2,3- b] pyridine-3-carbonitrile, 2,4,7-triamino-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitriio, 2 (2,4-diamino-3-cyano-8- methoxy-5H-chromene [2,3-b] pyridin-5-yl) maononitrile, 2,4-diamino-7,8-di [2- (amine) ethoxy] -5H-chromene [2,3- b] pyridine-3-carbonitrile, 2,4-diamino-9-nitro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-d-methoxy-4- [(4-methoxyphenyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-methoxy-5H-chromene [2,3-b] p Rutin-3-carbonitrile-2- (2,4-diamino-3-cyano-7-hydroxy-5H-chromene [2,3-b] pyridin-5-yl) malononitri ^ 2 ( 2,4-diamino-3-cyano-7-bromo-5H-chromene [2,3-b] pyridin-5-yl) malonon M 2-amino-8-ethoxy-4- (ethylamino) -5H-chromene [2, 3-b] pyridine-3-carbonitrile, 2,4,9-triamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4,7-triamino-5H-thiochromen [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy-4 - [(4-methoxyphenyl) amino] -5H-chromene [2,3-b] p Ridin-3-carbonitrile, 2 (2,4-diamino-3-cyano-7-methoxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2,4-diamino-9 -hydroxy-8- (piperidn-1-methylmet) -5H-chromene [2,3-b] pyridine-3-carbonyltria, 7,8-bis (allyloxy) -2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 10,10-2,4,7-diamino-7-nitride- 5H-thiochromeno [2,3-b] pyridine-3-carbonitrile, 2,4-diam-7-phenyl-5H-chromene [2,3-b] pyridine-3-carbonitrile, and prodrugs, salts , tautomers and combinations thereof.

16. The use claimed in claim 1, wherein the compound that inhibits the aminocyanopyridine MK-2 comprises at least one compound that is selected from the group consisting of: 2-amino-4- (2-fluorophenyl) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6,7-dihydro-5H-pyrazolo [3 , 4-h] quinoline-3-carbonitrile, 2-amino-4- (2,3-d-fluoro-phenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbon Trilo, 8-amino-6- (2-furyl) -4,5-dihydro-1 H-pyrazolo ^. S-hJquinoline ^ -carbonitrile, 2-amino-3-cyano-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-8-carboxylic acid, 4- [2-amino-3-cyano-6- (2-furyl) pyridin-4-yl] - H -pyrrole- 2-carboxamicla, 2-amino-4-phenyI-6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonyl, 2-amino-6- (2-furyl) ) -4- (1-methyl-1 H-imidazol-4-yl) nicotonitrile, 8-amino-6- (2-furyl) -4J5-dihydro-1 H-pyrazolo [4,3-h] quinoline -7-carbonyltryl, 2-amino-4- (2-furyl) -8-hydroxy-5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino-4- (2,6-difluorophenol) -6,7-dihydro-5H-pyrrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (4-hydroxy-phenyl) -4- (1H-imidazole-5-) il) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (2-furyl) nicotinonitrile, 2-amino-4- (2-fluorophenyl) -6- (2-furyl) nicot Nitric acid, 2-amino-4- (2-fluorophenyl) -5,6-dihydrobenzo [h] quinoline-3-Garbonitrile, 4- [6-amino-5-cyano-4- (2-furyl) p. Ridin-2-yl] benzoic acid, 2-amino-6- (2-furyl) -4- (1H-imidazol-5-yl) n-trinonitrile, 2-amino-4- (2-furyl) ) -6- (1 Hp -razol-3-yl) nicotinonitrile, 2-amino-3-cyano-4- (4H-1, 2,4-triazol-3-yl) -5,6-d acid Hydrobenzo [h] quinoline-8-carboxylic acid, 2-amino-6- (3-hydroxyphenyl) -4- (1 H-imidazol-5-yl) n-trichloride, 2-amino-6- (2 -furyl) -4- (1 H-imidazol-4-yl) nicotonitrile, 2-amino-4- (2,4-difluorophenyl-J-ej-dihydro-SH-pyrazolopy-3-quinoline-S-carbonitrile, 4, 6-d.amino-2- (trifluoromethyl) -2,3-d.hydrofuro [2,3-b] pyridine-5-carbonitrile, 2-amino-4- (2-furyl) - 6,8-dihydro-5H-pyrroIo [3,4-h] quinoline-3-carbonitrile, 4- [6-amino-5-cyano-4- (2-fluorophenyl) pi] Ridin-2-yl] benzoic acid, 2-amino-4- (2-funl) -5,6-dihydro-1, 8-phenanthroline-3-carbonitrile, 2-amino-6- (3,4 -dihydroxyphenyl) -4- (2-fluorophenyl) nicotinonitrile, 2-amino-4- (1-methyl-1H-imidazol-4-yl) -6-phenylnicotinonitrile, 2-amino-4- (2-fur L) -6- (1 H -pyrazol-3-yl) nicotinonitrile, 4- [6-amino-5-cyano-4- (1 H -imidazol-5-yl) pyridin-2-yl] benzoic acid, 2-amino-4- (3-fluorophenyl) -6,8-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-6- (3,4-dihydroxyphenyl) - 4- (2-fluorophenyl) n-phenyl-nitrile, N-. { 4- [6-amino-5-cyano-4- (2-furyl) pyridin-2-yl] phenyl} methanesulfonamide, 2-amino-4- (2-furyl) -6,7-dihydro-5H-pyrrolo [2,3-h] quinoline-3-carbonitrile, 2-amino- 4- (1 H-imidazol-5-yl) -6-phenylnicotinonitrile, 2-amino-4- (2-furyl) -5,6-dihydrobenzo [h] quinoline-3-carbonitrile, 2-amino- 4- (1 H-imidazol-5-yl) -6- (4-methoxy-phenyl) nicotinonitrile, 2,4-diamino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-hydroxyl-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dihydroxy-4 - [(2-hydroxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonomethyl, 2-amino-4- ( ethylamino) -7,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonyl, 2,4-diammon-9-hydroxy-5H-chromene [2, 3-b] pyridine-3-carbonitrile, 2,4-diamino-9-fIuoro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonyl, 2,4-d-amino-8- (2-hydroxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 8,10-diamino-2,3-dihydro-11H- [1,4] dioxin [2 ', 3 ': 6,7] chromene [2,3-b] pyridine-9-carbonitrile, 2,4,7-triammine-5H-chromene [2,3-b] pyr dna-3-carbonitrile, 2,4-d-amino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-8- (2-ethoxy-ethoxy) -7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diammon-9-hydroxy-8-methoxy -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-6,8-dihydroxy-5H-chromene [2,3-b] pyridine-3- carbonitrile, 2,4-diamno-8-ethoxy-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-8- (2 -ethoxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-aminoethoxy) -5H-chromene [2,3-b] pyridine-3- carbonitrile, 2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridin-7-carboxylic acid, 2,4-diamino-8,9-d Hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamno-8- (2-morpholin-4-ylethoxy) ) -5H-chromene [2,3-b] pyridine-3-carbonitrile, [(2,4-diammon-3-cyano-5H-chromene [2,3-b] pyridine]] -8-l) oxy] acetic acid, 2,4-diamino-9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-pyrrol) d-n-1-methoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy-4- (methylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2.4 -d-amino-8- [2- (dimethylamino) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4,7-triamino-9-methoxy-5H- chromene [2,3-b] pyridine-3-carbonyl, 2 (2,4-diamino-3-cyano-8-methoxy-5H-chromene [2,3-b] pyridine- 5-yl) malononitrile, 2,4-d-amino-7,8-d¡ [2- (amino) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4 -diamino-9-nitro-5H-chromene [2,3-b] pyridin-3-carbonomethyl, 2-amino-7,8-dimethoxy-4 - [(4-methoxyphenyl) am No] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8-methoxy-5H-chromene [2,3-b] pyridine-3-carbonyltryl , 2 (2,4-diamino-3-cyano-7-hydroxy-5H-chromene [2,3-b] p irdin-5-yl) malonion, 2 (2,4-diamino-3-cyano-7-bromo-5H-chromene [2,3-b] pyridium-5- L) malononitrile, 2-amino-8-ehusoxy-4- (ethylamino) -5H-chromene [2,3-b] pyridine-3-carbonityl, 2,4,9-triamino-5H-chromene [2] , 3-b] pyridine-3-carbonitrile, 2,4,7-triamino-5H-thiochromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dimethoxy -4 - [(4-methoxy-phenyl) amino] -5H-chromene ^ .S- ^ pyridine-S-carbonitrile, 2 (2,4-diamino-3-cyano-7-methoxy-5H-chromene [2,3-b] pyridin-5-yl) malononitrile, 2,4-diamino-9-hydroxy-8- (piperidin-1-ylmethyl) -5H-chromene [2,3- b] pyridine-3-carbonitrile, 7,8-bis (allyloxy) -2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonyl ether, 2- amino-8- (2-ethoxyethoxy) -4 - [(2-ethoxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonyl ether, and prodrugs, salts, tautomers and combinations thereof.

17. The use claimed in claim 1, wherein the compound that inhibits the aminocyanopyridine MK-2 is selected from the group consisting of: 2-amino-4- (2-fluorophenyl) -6,8-dihydro- 5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 2-amino-4- (2-furyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbon trilo, 2-amino-4- (2,3-difluorophenyl) -6,7-dihydro-5H-pyrazolo [3,4-h] quinoline-3-carbonitrile, 8-amino-6- (2-furyl) - 4,5-dihydro-1 H -pyrazolo [4,3-h] quinoline-7-carbonitrile, 2,4-d¡amino-7,8-dihydroxy-5H-chromene [2,3-b] pyridine -3-carbonitrile, 2,4-diamino-8-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-7,8-dihydroxy-4 - [(2- hydroxyethyl) amino] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7,8-dimethoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile , 2-amino-7,8-dihydroxy-4- (propylamino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2-amino-4- (ethylamino) -7,8-dihydroxy-5H -chromeno [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-di amine-9-fluoro-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-7-hydroxy-5H-chromene [2,3-b] pyridine-3- carbonitrile, 2,4-diamino-8- (2-hydroxyethoxy) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 8,10-diamino-2,3-dihydro-11 H- [1 ^ IdioxinoP'.S'rSJlcromenop.Sb] pyridine-9-carbonitrile, 2,4,7-triamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-ethoxyethoxy) -7-hydroxy-5H-chromene [ 2,3-b] pyridine-3-carbonitrile, 2,4-diamino-9-hydroxy-8-methoxy-5H-chromene [2,3-b] pyridine-3 -carbonyl, 2,4-diamino-6,8-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonyl, 2,4-diam no-8-ethoxy-7-hydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diamino-8- (2-ethoxyethoxy) -5H -chromeno [2,3-b] pyridine-3-carbonyl, 2,4-diamino-8- (2-aminoethoxy) -5H-chromenoyl-2,3-b] pyridine-3-carbon Trilo, 2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridine-7-carboxylic acid, 2,4-diamino-8,9-dihydroxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-d-amino-8- (2-morfoiin-4-yl-ethoxy) -5H-chromene [2,3-b] pyridine -3-carbonitrile, [(2,4-diamino-3-cyano-5H-chromene [2,3-b] pyridin-8-yl) oxy] acetic acid, 2,4-diamino- 9-methoxy-5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4-diammon-8- (2-pyrrolidin-1-ylethoxy) -5H-chromene [ 2,3-b] pyridine-3-carbonyl, 2-amino-7,8-dimethoxy-4- (meth) mino) -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2) 4-d-amino-8-methoxy-5H-chromene [2I3-b] pyridine-3-carbonitrile, 2,4- diamino-8- [2- (dimethylamino) ethoxy] -5H-chromene [2,3-b] pyridine-3-carbonitrile, 2,4,7-triamino-9-methoxy-5H-chromene [2! 3-b] pyridine-3-carbonyl, 2 (2,4-diamino-3-cyano-8-methoxy-5H-chromene [2,3-b] pyridin-5-yl) maiononitrile, and prodrugs, salts, tautomers and combinations thereof.

18. The use of a compound that inhibits the aminocyanopyridine MK-2 to prepare a medicament for preventing or treating a disease or disorder mediated by TNFa in a subject in need of such prevention or treatment, wherein the method comprises administering to the subject a effective amount of a compound that inhibits the aminocyanopyridine MK-2.

19. The use claimed in claim 18, wherein: the compound that inhibits the aminocyanopyridine MK-2 has the formula: R1 is selected from the group consisting of -H, methyl, ethyl, propyl, butyl, - ( ChyCOOH, phenyl, pyridyl, dimethylaminoethyl, methoxyethyl, tetramethylaminoethyl, carboxymethyl, and phenylacetyl; R 2 is selected from the group consisting of -H, methyl, ethyl, propyl, butyl, amino, phenyl, methoxy, carboxy, carboxymethyl, hydroxyethylamino, propylamino, ethylamino, methylamino, methoxyethyl, ethoxyethylamino, aminoethylamino, benzylamino, dimethylaminoethylamino, phthalamethyl, fluorophenyl , difluorophenyl, chlorophenyl, bromophenyl, furyl, carbamylpyrryl, methyl-1,3-isodiazoyl, 1,3-isodiazoyl, 1,3,4-triazoyl, methoxyphenyl, -S (CH 3), tetramethylaminoethyl, acetylaminophenyl, methoxyphenylamino, carboxyphenyl, carboxy-3-isopyrryl, cyanophenyl, cyclopropyl, phenoxyphenyl, pyridyl, dihydroxybromophenyl, difluoromethoxyphenyl, trifluoromethylphenyl, trifluoromethyl-fluorophenyl, hydroxyphenyl, methylaminomethyl, methylaminoethyl, thiophyl, pimium, aminomethyl, R3 is selected from the group consisting of -H, methyl, ethyl, propyl, isopropyl, cyano, aminomethyl, phenyl, fluorophenyl, and amino; R2 and R3 are such that they optionally join to form a ring system selected from the group consisting of: R 4 is selected from the group consisting of -H, methyl, ethyl, propyl, hydroxy, furyl, methylfuryl, methylimidazolyl, fenium, hydroxyphenyl, carboxyphenyl, pyrazolyl, hydroxy, dihydroxyphenyl, methoxyphenyl, chlorophenyl, bromophenyl, fluorophenyl, dichlorophenyl, dihydroxyborophenyl, thienyl , pyrryl, N-methylpyrrol, pyridyl, methylthio, methylsulfonylphenyl, carboethoxyphenyl, methoxy, carbamylphenyl, mercapto, N-isoimidazoylphenyl, isopropyl, amino, hydroxynaphthyl, thiazoyl, carboxymethylphenyl, trifluoromethylphenyl, methylphenyl, cyanophenyl, dimethylphenyl, fluorobenzhydryl, methoxyfuryl, aminosulfonyl phenyl , R3 and R4 are such that they optionally join to form a ring system selected from the group consisting of: twenty D, E and G are each independently selected from the group consisting of carbon, oxygen, sulfur and nitrogen; R5 is selected from the group consisting of -H, and C1-C5 alkyl; R1 and R5 can be joined to form a piperidyl ring; R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, c P19 D20 p21 p22 D23 p24 p25 p26 p27 p28 p29 D30 D31 p31 p32 p33 p34 p35 O G? G? , G \, G \,? , G \, G \, G? , G \,? ? 36? 37? 38? 39? 40? 41? 42? 53? 54? 55? 56? 57? 58? 59? 60? 61? 62? 63? 64 D65? 66? 67? 68? 69 G, G, G \, G, G \, G? , G, R70, R71, R72, R73, R74, R75, and R76 are each optionally present (for example, these may be present when required to balance the valence of the atom to which they are shown as a link) and are each independently selected of the group consisting of -H, methyl, ethyl, propyl, butyl, isobutyl, amino, nitro, hydroxy, methoxy, ethoxy, propoxy, 2-propenoxy, oxo, carboxy, bromo, chloro, fluoro, trifluoromethyl, chloromethyl, hydroxymethyl, dicyanomethyl, 2-fluorophenyl, 3-fluorophenyl, hydroxyethoxy, 5-ethoxyethoxy, - (CH 2) -0- (C 6 H 4) -0- (CH 3), carboxymethoxy, isopropylcarboxymethoxy, isobutylcarboxymethoxy, methylamino, dimethylamino, aminoethoxy, diaminoethoxy, dimethylaminoethoxy, cyanomethoxymethyl, 2-propenoxymethyl, methoxymethyl, sopropoxymethyl, ethoxymethyl, - (CH2) -0- (CF2) -CHF2, isobutoxymethyl, benzoyl, phenyl, N-morphonyl, morphonyl ethoxy, pyrrolidylethoxy, N-pyrrolidylethoxy, oxo, or ethylcarboxy, carboxymethyl-ethyl ester, pyridylmethyl, 4-pyridylmethoxy, 2-pyridine lmethyl, and -COO-CH2-CH3; and R38 and R39 are such that they optionally join to form a ring system selected from the group consisting of:

20. - The use claimed in claim 18, wherein: the compound that inhibits the aminocyanopyridine MK-2 has the structure: G is selected from the group consisting of -O-, -S-, and -N-; when G is -O-, R4 and R42 are absent; when G is -S-, R41 and R42 are optionally absent, or are oxo; when G is -N-, R41 is absent, and R42 is-H or C1-C4 alkyl; R1 is selected from the group consisting of hydrogen, branched alkyl or unbranched alkyl, alkenyl, alkynyl, alkoxy, alkylaryl, arylalkyl, carboxy, carboxyalkyl, hydroxyalkyl, alkylcarboxy, aryl, amino, aminoalkyl, alkylamino, halo, alkylaminoalkyl, alkoxy, alkoxyalkyl , monocyclyl, bicyclyl, polycyclyl, and hetecicyl; R 2 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkoxy, hydroxyalkyl, alkylaryl, arylalkyl, alkoxyaryl, aminoalkyl, alkylaminoalkyl, arylaminoalkyl, alkoxyalkyl, alkylcarboxy, and carboxyalkyl; R35 is selected from the group consisting of hydrogen, dicyanoalkyl, heterocyclyl, and cyclyl, wherein: heterocyclyl and cyclyl are optionally substituted with one or more halo; R36 is selected from the group consisting of hydrogen, dicyanoalkyl, heterocyclyl and cyclyl, wherein: heterocyclyl and cyclyl are optionally substituted with one or more halo; R37 is selected from the group consisting of hydrogen, alkoxy, halo, alkyl, alkenyl, alkyl, arylalkyl, and alkylaryl; R38 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkyl, alkenyl, alkynyl, amino, alkylamino, arylamino, alkylaminoalkyl, carboxy, aminoalkoxy, halo, alkylcarboxyalkyl, alkylamino, aminoalkyl, nitro, aryl, arylalkyl, alkylaryl and arylamino; R39 is selected from the group consisting of hydrogen, hydroxy, alkoxy, alkenoxy, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, heterocyclylalkyl, heterocyclylalkoxy, carboxyalkoxy, alkylaminoalkoxy, and alkylcarboxyalkoxy; R38 and R39 can be joined to form a 6-membered heterocyclic ring; and R40 is selected from the group consisting of hydrogen, hydroxy, halo, nitro, amino, alkyl, alkoxy, heterocyclyloalkoxy, carboxyalkoxy, pyrrolidylethoxy, carboxymethoxy, hydroxyalkoxy, aminoalkoxy, alkylcarboxy, alkylaminoalkyl, carboxy, and heterocyclylalkyl.

21. - The use claimed in claim 18, wherein the subject is a mammal.

22. - The use claimed in claim 21, wherein the subject is a human.

23. - The use claimed in claim 22, wherein the TNFa mediated disease or disorder is selected from the group consisting of: arthritis, rheumatoid arthritis, spondyloartopathies, gout arthritis, osteoarthritis, systemic lupus erythematosus, juvenile arthritis, asthma, bronchitis, menstrual cramps, tendonitis, bursitis, connective tissue lesions, connective tissue disorders, skin-related conditions such as psoriasis, eczema, burns, dermatitis, gastrointestinal conditions, inflammatory bowel disease, gastric ulcer, gastric varices, Crohn's disease, gastritis, irritable bowel syndrome, ulcerative colitis, cancer, colorectal cancer, herpes simplex infections, HIV, pulmonary edema, kidney stones, minor injuries, wound healing, vaginitis, candidiasis, lumbar spondylarthrosis, lumbar spondylarthrosis , vascular disease, migraine headaches, sinus headaches, pain head tension, dental pain, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease, sclerodoma, rheumatic fever, type I diabetes, myasthenia gravis, multiple sclerosis, sarcoidosis, nephrotic syndrome, Behcet's syndrome, polymyositis, gingivitis, hypersensitivity, swelling which occurs after injury, myocardial ischemia, ophthalmic diseases, retinitis, retinopathies, conjunctivitis, uveitis, ocular photophobia, acute injury to eye tissue, lung inflammation, viral infections, cystic fibrosis, central nervous system disorder, cortical dementias, and disease of Alzheimer's 24 - The use claimed in claim 18, wherein the medicament comprises an effective amount of the compound that inhibits the aminocyanopyridine MK-2. 25. The use claimed in claim 24, wherein the medicament comprises within a range from about 0.1 mg / kg / day to about 150 mg / kg / day. 26. - The use claimed in claim 25, wherein the medicament comprises within a range from about 0.1 mg / kg / day to about 10 mg / kg / day. 27. The use claimed in claim 18, wherein the aminocyanopyridine inhibiting compound MK-2 provides an IC50 value of TNF release below 200 μ? in an in vitro cell assay. 28. The use claimed in claim 18, wherein the aminocyanopyridine inhibiting compound MK-2 provides an IC50 value of TNFa release below 1 μ? in an in vitro cell assay. 29. The use claimed in claim 18, wherein the aminocyanopyridine inhibiting compound MK-2 provides a degree of inhibition of TNFa in a rat LPS assay of at least about 25%. 30. The use claimed in claim 18, wherein the aminocyanopyridine inhibiting compound MK-2 provides a degree of inhibition of TNFa in an LPS rat assay of about 80%. 31. The use claimed in claim 18, wherein the aminocyanopyridine inhibiting compound MK-2 provides an IC50 value of MK-2 inhibition below 200 μ ?. 32. The use claimed in claim 18, wherein the aminocyanopyridine inhibiting compound MK-2 provides an IC50 value of inhibition of MK-2 below 1 μ ?.