MXPA06008025A

MXPA06008025A - Substituted diazabicycloheptanes and their use as protein kinase inhibitors

Info

Publication number: MXPA06008025A
Application number: MXPA/A/2006/008025A
Authority: MX
Inventors: Dominguez Celia; Cao Guoqiang; K C Sham Kelvin; J Chen Jian; Reed Anthony; C Thaman Maya; Zhang Dawei; J Herberich Bradley
Original assignee: Amgen Inc; Cao Guoqiang; J Chen Jian; Dominguez Celia; J Herberich Bradley; Reed Anthony; K C Sham Kelvin; C Thaman Maya; Zhang Dawei
Priority date: 2004-01-14
Filing date: 2006-07-13
Publication date: 2006-12-13

Abstract

The present invention relates to therapeutic diazobicyclo pyridines and their use in the treatment of arthritis, rheumatoid arthritis, psoriatic arthritis or osteoarthritis, organ transplant, acute transplant or heterograft and homograft rejection, ischemic and reperfusion injury, transplantation tolerance induction, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lupus, graft vs. host diseases, T -cell mediated hypersensitivity diseases, contact hypersensitivity, delayed-type hypersensitivity, gluten-sensitive enteropathy, Type 1 diabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism,Graves'Disease, Addison's disease, autoimmune polyglandular disease, autoimmune alopecia, pernicious anemia, vitiligo, autoimmune hypopituatarism, Guillain-Barre syndrome, autoimmune diseases, glomerulonephritis, serum sickness, uticaria, respiratory allergies, asthma, hayfever, allergic rhinitis, skin allergies, scleracielma, mycosis fungoides, acute inflammatory responses, acute respiratory distress syndrome, dermatomyositis, alopecia areata, chronic actinic dermatitis, eczema, Behcet's disease, Pustulosis palmoplanteris, Pyoderma gangrenum, Sezary's syndrome, atopic dermatitis, systemic schlerosis, morphea, Type II diabetes and cancers where PKC theta or other PKC-family kinases are activated, overexpressed or facilitate tumor growth or survival of tumor cells, T cell leukemia, thymoma, T and B cell lymphoma, colon carcinoma, breast carcinoma and lung carcinoma or provides resistance to chemotherapeutic drugs.

Description

SUBSTITUTE HETEROCICLES COMPOUNDS AND METHODS OF USE BACKGROUND OF THE INVENTION T cells play a dominant role in the regulation of immune responses and are important in establishing immunity to pathogens. In addition, T cells are frequently activated during autoimmune inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, multiple sclerosis, Sjogren's disease, myasthenia gravis, psoriasis, and lupus. Activation of T cells is also an important component of transplant rejection, allergic reactions, and asthma. T cells are activated by specific antigens through the T cell receptor (TCR) that is expressed on the surface of the cell. This activation triggers a series of intracellular signaling cascades mediated by the enzymes expressed inside the cell (Kane, LP et al.

Opinion in Immunol. 200, 12, 242). These waterfalls lead to 'the events of gene regulation that give rise to the production of cytokines, such as interleukin-2 (IL-2).

IL-2 is a critical cytokine in the activation of T cells, leading to the proliferation and amplification of REP. DO NOT. 174305 specific immune responses. One class of enzymes that has been shown to be important in signal transduction are protein kinases. PKC enzymes are members of a family other than the serine / threonine protein kinases, which contain nine members (isotype a, ß,?, D, e,?,?,?,) (Reviewed in Nishizuka Y., Science 1992; 258: 607-614): some of which are expressed at particular high levels in T cells (including,, d, e,?,?), (Reviewed in Baier, G., Immunological Reviews 2003 192: 64-79 ). Studies of gene alteration suggest that the inhibition of some members of the PKC family of kinases potentially leads to therapeutic benefits. PKCa mice (- / -) and mice deficient in PKC? both have defects in T cells (Baier, G., Immunological Reviews 2003 192: 64-79; Pfeifhofer C. et al, Journal of Experimental Medicine, 197: 1525-1535; Sun, Nature 2000, 40: 402-407) , suggesting that the inhibition of any of these kinases would be useful in diseases of inflammation and autoimmunity mediated by T. PKC cells? in particular it may be a first target for new anti-inflammatory or immunosuppressive therapies, due to its restricted tissue expression and its critical role not redundant in the secretion of TCR-mediated IL-2 (N. Isakov and A. 7Ammon 7Annu. Rev. Im unol. 2002 20: 761-94). The drugs of small molecule that selectively inhibit PKC? and / or other certain PKC isoenzymes such as PKC alpha, beta, epsilon and zeta, may manifest improved efficacy and / or improved side effect profile over drugs directed against other immuno-mediators such as calcineurin and Aktl / PKBalfa, by example, a dual inhibitor of PKC theta and PKC alpha can prevent - indeed activation of mature T cells. Alpha PKC, as well as PKC theta, is involved in TCR signaling in T cells (Iwamoto 1992 JBC 267: 1644-18648, Ohkusu 1997 J. Immunol 159: 2082-2084). PKC family kinases are also important for signaling downstream of other immune cell • receptors. PKC beta participates in the signaling of the B-cell receptor (Leitges M. et al., 1996 Science 273: 788-791), neutrophils (Dekker LV and 'collaborators, 2000 Biochem J. 347: 285-289), and mast cells ( Nechushian H et al., 2000 Blood 95: 1752-1757). PKC zeta also plays a role in the signaling and function of B cell (Martin P. et al., 2002 EMBO J. 15: 4049-4057) and PKC epsilon is required for macrophage activation (Castrillo A. et al., 2001 J. Exp. Med. 194: 1231-1242). These results suggest that inhibitors of PKC family kinases may be useful in treating inflammatory, autoimmune and allergic diseases and asthma.

In addition to its essential function in the activation of mature T cells and the secretion of IL-2, the PKC theta provides a survival signal that protects leukemic T cells against apoptosis induced by the Fas-ligand (M.Villalba and A Altman 2002 Current Cancer Drug Targets: 2: 125-134). This characteristic and the location of the constitutive membrane of PKC theta in some leukemic T cells suggest that it plays a role in the growth and survival of leukemic T cells. In addition, the high-affinity IL2 receptor (IL-2R alpha) is constitutively expressed by some malignant T-cell leukemias suggesting that the expansion of these cells can be supported by an autocrine bucel (M. Villalba and A. Altman 2002 Current Cancer Drug Targets: 2: 125-134). The PKC theta can also promote the survival of malignant cells functioning in the development of a phenotype of resistance to multiple drugs. The expression of PKC theta correlates positively with the expression of some genes involved in MDR including MDR1 and MRP1 in patients with acute myelogenous leukemia (Beck J. et al., 1996 Leukemia 10: 426-433) and PKC theta regulates promoter activity MDR1 in human breast carcinoma cells (Gilí PK et al., 2001 Eur. J. Biochem 268: 4151-4157). Therefore, a small molecule PKC theta inhibitor can facilitate the elimination of leukemic T cells and other malignant cells that over-express PKC tit. Over-expression / concomitant activation of PKC alpha and PKC theta has also been implicated in the development of multidrug resistance. Therefore a small molecule inhibitor of PKC theta and dual alpha PKC, may also facilitate the removal of malignant cells that over-express PKC alpha and PKC theta.

Other groups have published on the kinase inhibitors of the PKC family and the activities of these inhibitors in various biological systems in vitro and in vivo For example, PCT publication No. WO 2004067516 describes useful 2,4-diaminopyrimidine derivatives as PKC-theta inhibitors WO 2003082859 discloses indolylmaleimide derivatives as useful compounds in the prevention and / or treatment of diseases or disorders mediated by T-lymphocytes and / or PKC The protein inhibitor C beta beta-ruboxistaurin (LY-333531), The compound conducting a series of 14-member macrocycles has been developed for the potential treatment of diabetic retinopathy, diabetic macular edema and diabetic neuropathy (Investigational Drug Data, December 19th 2003, Ruboxistaurin update). It was also investigated as a potential treatment for cardiovascular disease in diabetic patients. III for diabetic retinopathy and macular edema at the beginning of 2001.

BRIEF DESCRIPTION OF THE INVENTION The compounds described in the present invention possess pharmacological activity not only by virtue of an effect on a single biological process, but it is believed that the compounds modulate the activation of T cells by the inhibition of one or more of the proteins. Multiple kinases involved in the early stages of signal transduction leading to T cell activation, for example by the inhibition of the PKC theta kinase. The compounds of the present invention inhibit serine-threonine kinases, especially • PKC theta and to a varying degree other isoenzymes of PKC, and are thus useful in the treatment, including prevention and therapy, of disorders associated with serine / threonine protein kinases such as immunological disorders. "Disorders associated with serine / threonine protein kinases" are those disorders that result from aberrant activity of the serine-threonine kinase, which are alleviated by the inhibition of one or more of these enzymes. For example, inhibitors of PKC theta are of value in the treatment of a number of such disorders (for example, the treatment of autoimmune diseases), since the inhibition of PKC theta blocks the activation of T cells. The treatment of T cell-mediated diseases, including the inhibition of T cell activation and proliferation, is a modality preferred of the present -invention. Preferred are compounds of the present invention that selectively block the activation and proliferation of T cells. Also, the compounds of the present invention that can block the activation of serine-threonine protein kinases of endothelial cells by oxidative stress, so which limit the surface expression of adhesion molecules that induce neutrophilic binding, and which can inhibit the serine-threonine protein kinases necessary for neutrophil activation, would be useful, for example, in the treatment of ischemic and reperfusion injury. The present invention also provides methods for the treatment of disorders associated with serine-threonine protein kinases, comprising the step of administering to a subject, such as those in need thereof, consequently at least one compound of the present invention in an effective amount. The compounds can be administered in a pharmaceutical formulation, which has been formulated with a convenient pharmaceutically acceptable carrier. Other therapeutic agents such as those described below may be employed with the compounds inventive in the present methods. In the methods of the present invention, such other therapeutic agent can be administered before, simultaneously with or after administration of the compounds or pharmaceutical composition of the present invention. The use of the compounds of the present invention in the treatment of disorders associated with serine-threonine protein kinases is exemplified by, but is not limited to, treating a range of disorders such as: arthritis (such as rheumatoid arthritis, psoriatic arthritis or osteoarthritis) ); transplant rejection (such as organ transplantation, transplantation or heterograft or acute homograft (as used in the treatment of burns)); protection against ischemic or reperfusion injury such as ischemic or reperfusion injury incurred during organ transplantation, myocardial infarction, sudden attack or other causes; induction of tolerance of the transplant; multiple sclerosis; inflammatory bowel disease, including ulcerative colitis and Crohn's disease; lupus (systemic lupus erythematosus); grafting against host diseases; T-cell-mediated hypersensitivity diseases, including contact hypersensitivity, late-type hypersensitivity, and Gluten-sensitive enteropathy (Celiac disease); Diabetes type 1; psoriasis; contact dermatitis (including that due to poison ivy); Thyroiditis Hashimoto; Sjogren's syndrome; Autoimmune hyperthyroidism, such as Graves' disease; Addison's disease (autoimmune disease of the adrenal glands); autoimmune polyglandular disease (also known as autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; autoimmune hypopituitarism; Guillain Barre syndrome; other autoimmune diseases; cancers where the PKC theta or other kinases of the PKC family such as PKC alpha are activated or overexpressed, such as T-cell leukemia, thymoma, T-cell and B-cell lymphoma, colon carcinoma, breast cancer and lung carcinoma, or cancers where the kinase activity of the PKC family facilitates tumor growth or survival or provides resistance to drugs or chemotherapeutic radiation; glomerulonephritis, serum sickness; urticaria; allergic diseases such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracema; mycosis fungoides; Acute inflammatory responses (such as acute respiratory anxiety syndrome and ischemic / reperfusion injury); dermatomyositis, alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease; Pustulosis Palmoplantaris; Pyoderma gangrenosum; Syndrome of . Sezary; atopic dermatitis; systemic sclerosis; morphea; type II diabetes; insulin resistance; Diabetic retinopathy; diabetic macular edema; diabetic neuropathy; and cardiovascular disease in diabetic patients. The present invention also provides a method for treating the above-mentioned disorders such as dermatitis Atopic by administering a therapeutically effective amount of a compound of the present invention, which is an inhibitor of the serine-threonine protein kinases, to a patient in need of such treatment. * Other kinases of the PKC family, such as PKC beta and zeta are also important in the function of the B cell (Leitges M. et al., 1996 Science 273: 788-791; Martin P. et al., 2002 EMBO J. 15: 4049-4057). This activity would result in additional anti-autoimmune activity for the present compounds in addition to their effects on T cells. ~ This activity will be of special value, for example, in the treatment of autoimmune / inflammatory diseases, such as lupus, arthritis or Inflammatory bowel disease. PKC theta can also function in B cells (Krappmann D. 2001 Molecular &Cellular Biology, 21: 6640-6650). The PKC theta is also expressed in mast cells and PKC beta and epsilon play a role in macrophage function and neutrophils / mast cells, respectively. The ability to inhibit monocyte and macrophage neutrophil responses would result in additional anti-inflammatory activity for the present compounds in addition to their effects on T cells. The present compounds may also be of value for the treatment of autoimmune glomerulonephritis and other cases of glomerulonephritis induced by the deposition of immune complexes in the kidney.

In addition, certain PKC isoenzymes including PKC theta and beta-may function in the degranulation of mast cells and basophils that play an important role in asthma, allergic rhinitis, and other allergic disease. The ability to inhibit mast cell and basophil responses may result in additional anti-inflammatory activity for the present compounds beyond their effect on T cells. The combined activity of the present compounds towards B cells,. monocytes, macrophages, T cells, mast cells, endothelial cells, etc. , can prove to be a valuable tool in the treatment of any of the aforementioned disorders. In a particular embodiment, the compounds of the present invention are useful for the treatment of the aforementioned exemplified disorders independent of their etiology, for example, for the treatment of rheumatoid arthritis, rejection to transplantation, multiple sclerosis, inflammatory bowel disease, lupus. Injury includes host disease, T cell-mediated hypersensitivity disease, psoriasis, Hashimoto's thyroiditis, Guillain-Barre syndrome, cancer, contact dermatitis, allergic disease such as allergic rhinitis, asthma, ischemic or reperfusion injury, or dermatitis Atopic whether or not they are associated with serine-threonine kinases. PKC theta and certain other PKC isoenzymes are abnormally activated in the skeletal muscle of human patients with type II diabetes as well as in muscle skeletal model of a high-fat-induced insulin resistance rodent model (Gray S et al., 2003 European Journal of Clinical Investigation 33: 983-987 and references therein). In addition, a small molecule inhibitor of PKC beta is in clinical trials in the last stage for the treatment of diabetic retinopathy, neuropathy and macular degeneration (IDDB: ruboxistaurin LY- 333531). The ability of the present compounds to inhibit abnormal PKC theta and other activity of the PKC isoenzyme associated with the development of insulin resistance, type II diabetes and side effects thereof, may result in a beneficial therapeutic reversal of the resistance to insulin and retinopathy associated with type II diabetes. Abnormal activation of PKC theta and other PKC isoenzymes such as PKC alpha has been associated with the development of resistance to multiple drugs (Beck J. et al., 1996 Leukemia 10: 426-433; Gilí PK et al., 2001 Eur. J. Biochem 268: 4151-4157). The present compounds can be used to increase the potency of other medicines such as for example chemotherapeutic drugs in cancer patients. In addition to the T cells, mast cells and skeletal muscle, the PKC theta is also specifically expressed in platelets (Chang JD et al., 1993 Journal of Biological Chemistry, 268: 14208-14214). The present compounds, by virtue of inhibiting PKC theta, can be used therapeutically to prevent or treat thromboembolic events Adverse events regulating the activation of platelets. PKC isoenzyme inhibitors such as PKC beta also inhibit angiogenesis in rodent solid tumor models in vivo (IDDB: LY-317615 Update November 24 * 2003; Teicher BA et al., International Journal of .Antimicrobial Agents 2001, 17: Suppl 1 Abs S6.03). The present compounds can have a therapeutic effect on solid tumors such as brain, breast, ovarian, gastric cancer, non-small cell lung cancer, small cell lung cancer, gastric cancer, hepatocellular cancer, renal cell cancer and colon by decreasing the number of intratumoral vessels. PKC isoenzyme inhibitors such as PKC alpha, theta and beta inhibit the growth of B and T cells and may be useful in treating leukocyte cancers including B and T cell lymphomas and leukemias (IDDB abstract: LY-317615). The compounds of the invention are represented by the following general formula: Formula I Formula II wherein R1, R2, R3, R4, R5, R7, J, K, m and n are defined in the present. The foregoing simply summarizes certain aspects of the invention and is not intended, nor should it be construed, to limit the invention in any way. All patents and other publications cited herein are hereby incorporated by reference in their entirety. DETAILED DESCRIPTION OF THE INVENTION In accordance with one embodiment of the present invention, compounds of formula I are provided: or a pharmaceutically acceptable salt thereof, wherein J is NH, N (Rβ), O or S; m is independently in each case 0, 1, 2 or 3; n is 1 or 2; R1 is selected from R is a 5-, 6- or 7-membered monocyclic ring 0 bicyclic of 6-, 7-, 8-, 9-, 10- or 11-member saturated, partially saturated or unsaturated containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of the atoms of O and S is not greater than 2, where the ring carbon atoms are replaced by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _g alkyl, C halo _ haloalkyl, halo, cyano, nitro, -C (= 0) Rb, - C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2R, -OCalkyl2_6NRaRa, -Calkyl2_6? Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC26alkyNRaRa and -NRaC2-6alkyloRa; R3 is independently in each case H, C? _8alkyl, L-haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OC2-6alkylNRaRa, -OC2-6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) R, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (R) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkyNRaRa or R4 is independently in each case Ci-galkyl, C? _ 4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) R, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OC2-6alkylNRaRa, -OC2-6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (R) C (= 0) 0Rb, -S (= 0) 2N (Ra) C ( = 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_ 6alkylNRaRa or -NRaC2_6alkyl0Ra; R5 is H or Cx-ealkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H, Rf, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf. R7 is independently, in each case, H or C? _6alkyl; Ra is independently, in each case, H or Rb; Rb is independently, in each case, phenyl, benzyl or C? _6 alkyl, phenyl, benzyl and C? -6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C;? _ Alkyl, C? _3haloalkyl, - OC? _alkyl, -NH2, -NHC-alkyl, and N (C? -4alkyl) C? -4alkyl; Rc is independently in each case a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of the O and S atoms is not greater than 2, where the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, Rd is independently in each case Ci-salkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaR \ -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkylNRaRa, -OC2_6alkyloor, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, - S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, ~ -N (Ra) C (= 0) 0R, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkyl? NRaRa or Re is independently in each case Rd or H; and Rf is independently in each case, a 5, 6 or 7 monocyclic or 6, 7, 8, 9, 10 or 11 member saturated, partially saturated or unsaturated bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from O-salkyl, C? -4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) R, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (-O) 2Rb, -0C2-6alkylNRaRa, -OC2-6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C AO) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (R) C (= 0) NRaR, -NRaRa, -N (Ra) C (= 0) R, -N (Ra) C (= 0) 0R, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2-6alkyl0Ra. In another embodiment, together with the previous and following embodiments, J is NH. In another embodiment, together with the previous and following embodiments, J is N (Rb). In another modality, together with the previous and following modalities, J is 0.

In another embodiment, together with the previous and following embodiments, n is 1. In another embodiment, together with the previous and following embodiments, n is 2. In another embodiment, together with the previous and following embodiments, R1 is selected from In another embodiment, together with the previous and following embodiments, R1 is selected from In another embodiment, together with the previous and following embodiments, R1 is selected from In another modality, together with the previous and following modalities, R1 is In another modality, together with the previous and following modalities, R1 is In another modality, together with the previous and following modalities, Rl is In another embodiment, together with the previous and following embodiments, Rl is selected from In another modality, together with the previous and following modalities, Rl is In another modality, together with the previous and following modalities, Rl is In another embodiment, together with the foregoing and following embodiments, R2 is a 5-, 6- or 7-membered, saturated, partially saturated or unsaturated monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S , as long as the combination of the O and S atoms is not greater than 2, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and where the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C? -4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (- = 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -0Calkyl2_ 6NRaRa, -0Calkyl2_60Ra, -SRa , -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N ( Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) R, -N (Ra) C (= 0) ) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa and -NRaC2_6alkyl0Ra. In another embodiment, together with the previous and following embodiments, R2 is a 5-, 6- or 7-membered, saturated, partially saturated or unsaturated monocyclic ring containing 1, 2, 3 or 4 selected atoms of N, 0 and S , as long as the combination of the 0 and S atoms is not greater than 2, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C? -4haloalkyl, halo, cyano, nitro, -C (= 0) R, -C (= 0) 0Rb, -C (= 0) NRaR, -C (= NRa) NRaRa, -ORa, -0C (= 0) Rb, -0C ( = 0) NRaR, -OC (- = 0) N (Ra) S (= 0) 2Rb, -0Calkyl2_ 6NRaRa, -OCalkyl2-6ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb , -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb,. -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRRa, -N (Ra) C (= NRa) NRaRa, -N (R) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa and -NRaC2-6alkyloRa . In another embodiment, in conjunction with the foregoing and following embodiments, R2 is a 6-, 7-, 8-, 9-, 10-, or 11-membered saturated, partially saturated, or bicyclic ring. -unsaturated containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of the atoms of 0 and S is not greater than 2, whe the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and whe the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? -8alkyl, C? _4haloalkyl, halo, X cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NR) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, -0C (- = 0) N (Ra) S (= 0) 2Rb, -0Calkyl2-6NRaRa, -0Calkyl2_60Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NR3 ^ 6alkylNRaRa and -NRaC2_alkyloRa. In another embodiment, together with the foregoing and following embodiments, R2 is a 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated bicyclic ring containing 1, 2, 3 or 4 selected atoms of N, O and S, provided that the combination of the atoms of 0 and S is not greater than 2, where the carbon atoms of the ring. they are substituted by 0, 1 or 2 oxo groups, and whe the ring is substituted by 0, 1, 2 or 3 substituents independently selected from Ci-salkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0R, -0C (= 0 ) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2R, -0Calkyl2-6NRaRa, -0Calkyl2_60Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) R15, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0R, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, - R ^ 6alkylNRaRa and -NRaC2_6alkylorA. - 'In another embodiment, together with the foregoing and following embodiments, R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, -dihydrobenzofuranyl, cyclopropyl, cyclobutyl , cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, whe the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and whe the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C ? _8alkyl, C? -haloalkyl, halo, ci anus, nitro, -C. { = 0) B¡ °, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, '-OC (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkylNRaRa, -0C2_6alkyl0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0 ) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2R, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaR and -NRaC2_6alkyl0Ra. In another modality, together with the previous ones and following embodiments, R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from QL-8alkyl, C? -4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkylNRaRa, -0C2_6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (R) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaR, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and In another embodiment, together with the previous and following embodiments, R3 is H. In another embodiment, together with the foregoing and following embodiments, in at least each occurrence, R3 is C? _ 8alkyl, C? -4haloalkyl, halo, cyano , nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkyNRaRa, -0C2_6alkyl0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N "(Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (R) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRRa and -NRaC2-6alkyl0Ra. In another embodiment, together with the foregoing and following embodiments, R3 is independently in each case H, C? _ 8alkyl, C? _4haloalkyl or halo. In another embodiment, together with the foregoing and following embodiments, R3 is H, C? ~ 8alkyl, C? 4haloalkyl, halo, cyano, nitro, -0Ra, -OC2-6alkylNRaRa, -OC2-6alkyloRa, -SRa, -NRaRa , -NRaC2-6alkylNRaRa or -NR C2-6alkyloor. In another embodiment, together with the above and following embodiments, R3 is H, C? _8alkyl, C? _4haloalkyl, halo, -0Ra, -SRa or -NR Ra. In another embodiment, together with the foregoing and following embodiments, R3 is H, C-8alkyl, C4haloalkyl, halo or -0Ra. In another embodiment, together with the previous and following embodiments, R3 H, -CH3, -CH2CH3 or -0Ra. In another embodiment, together with the foregoing and following embodiments, R 4 is C? -8alkyl, C? _4haloalkyl or halo.

In another embodiment, together with the foregoing and following embodiments, R4 is cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkylNRaRa, -0C2_6alkyl0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, '-S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaR, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa or -NRaC2_6alkyloor. In another embodiment, together with the foregoing and following embodiments, R4 is C? _8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -0Ra, -0C2_6alkylNRaRa, -0C2-6alkyloRa, -SRa, -NRaRa, - R ^ -alkyl R ^ or -NRaC2_6alkyl0Ra. In another embodiment, together with the foregoing and following embodiments, R4 is C? _8alkyl, G] _4haloalkyl, halo, cyano, nitro, -0Ra, -SRa, -NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkyloor. In another embodiment, together with the foregoing and following embodiments, R4 is H or C? -8alkyl. In another embodiment, together with the previous and following embodiments, R4 is H or is absent. In another embodiment, together with the previous and following modalities, R5 is H. In another embodiment, together with the previous ones and following embodiments, R5 is C6_6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf. In another embodiment, together with the foregoing and following embodiments, R5 is C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf. In another embodiment, together with the foregoing and following embodiments, R5 is C6_6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 1 substituent selected from Rf. In another embodiment, together with the foregoing and following embodiments, R5 is H, -CH3, -CH2CH3, -C (= 0) CH (OH) CH3, -S02CH3, -C (= 0) CH (CH3) OC (= 0) CH3, propyl, -isopropyl, -CH2CHCF2, -n-butyl, -t-butyl, -isobutyl, - (CH2) 2C00H, - ( CH2) 2COOCH3, (CH2) 2OPh, -CH (CH3) ethyl, -CH (CH3) CF3, -cyclopentyl or 0Ra. In another embodiment, together with the previous and following embodiments, R5 is H. In another embodiment, together with the previous and following embodiments, R6 is H. In another embodiment, together with the preceding and following embodiments, R5 is Rf, Rd, or a C? _5alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf. In another embodiment, together with the previous and following embodiments, R6 is H, ~ CH3, -CH2CH3. In another embodiment, together with the foregoing and following embodiments, R6 is H or C? _6 alkyl. In another embodiment, together with the foregoing and following embodiments, R6 is Rc, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf. In another embodiment, together with the previous and following embodiments, R6 is H. In another embodiment, together with the foregoing and following embodiments, R6 is independently, in each case, C? _6alkyl. According to another embodiment of the present invention, compounds of the formula II are provided: or a pharmaceutically acceptable salt thereof, wherein J is NH, N (R), O or S; - K is -C (R3R3) m, -C (= 0), -C (= 0) 0-, -C (= 0) N (Ra) -, -C (= NRa) N (Ra) -, -0- -0C (= 0) -, -OC (= 0) N (Ra) -, -0C2. 6alkylN (Ra), -0C2-6alkyl0-, -S-, -S (= 0) -, -S (= 0) -S (= 0) 2N (Ra) -, -N (Ra) -, -N (Ra) C (= 0) -, -N (Ra) C (= 0) 0-, -N (Ra) C (= 0) N (Ra) -, -N (Ra) C (= NR) N (Ra) -, -N (Ra) S (= 0) 2-, -N (Ra) S (= 0) 2N (Ra) - or -N (Ra) C2-6alkylN (Ra); R1 is selected from R2 is a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, 0 and S, as long as the combination of the atoms of 0 and S is not greater than 2, in wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _ salkyl, C1_ haloalkyl, halo, cyano, nitro , -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NR) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0Calkyl? 2-6NRaRa, -0Calkyl2_60Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaR, -S (= 0) 2N (Ra) C (= 0) Rb, -S ( = 0) 2N (Ra) C (= 0) 0Rb, -S "(= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (R) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaR and -NRaC2_6alkyloor; R3 is independently in each case H, Cj-salkyl, C? _ 8alkylORa, C? _4haloalkyl, C? _4haloalkyloor, halo, cyano, nitro, oxo, -C (= 0) Rb, -C (= 0) 0Rb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb , -0C2-6alkylNRaRa, -0C2-6alkyl0Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 5alkylNRaRa or -NRaC2 6alkyl0Ra; R4 is independently in each case Ci-salkyl, Ca_4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2-6alkylNRaRa, -0C2_6alkyloRa, -SRa, -S ( = 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (R) C (= 0) ORb,, -S (= 0) 2N (Ra) C (- = 0) NRaRa, -NRaRa, -N (Ra) C (= 0) R , -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaR, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2 6alkyl0Ra; R5 is H, C (= 0) Rb, -S (0) pRb, C (- = 0) Rc, -S (0) PRC, or C? _6 alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H, Rc, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R is independently, in each case, H or Rb; R b is independently, in each case, phenyl, benzyl or Cx-galkyl, the phenyl, benzyl and C-L_6 alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C 4 alkyl, C 3 haloalkyl, 0 C 4 alkyl, 4 NH 3, -NHC x alkyl, and N (C 4 alkyl) C 4 alkyl; Rc is independently in each case, a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 1, 2 , 3 or 4 selected atoms of N, O and S, as long as the combination of the O and S atoms is not greater than 2, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups; Rd is independently in each case C? _8alkyl C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC '(= 0) Rb, -OC (= 0) NRaR? -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2-6alkylNRaRa, -OC2_6alkyloor, -SRa -S (= 0) Rb, -S (= 0) 2R, -S (= 0) 2NRaRa , -S (= 0) 2N (Ra) C (= 0) Rb -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa , -NRaRa -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2R, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaR or -NRaC2-6alkyl0Ra; Re is independently in each case Rd or H; Rf is independently, in each case, a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, 0 and S, where the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and the ring is substituted by 0, 1, 2 or 3 selected substituents of Cx-salkyl, C1_4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (Y)) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OCalkyl2_6NRaRa, -OCalkyl2_6ORa, ~ SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaR, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa, and -NRaC2_6alkylore; m is independently in each case 0, 1, 2 or 3; n is 1; and p is 0, 1 or 2. In another embodiment, together with the preceding and following embodiments, J is NH. In another embodiment, together with the previous and following embodiments, J is NCH3. In another embodiment, together with the foregoing and following embodiments, K is -C (R3R3) m, -C (= 0), -C (= 0) 0-, -C (= 0) N (Ra) -, - C (= NRa) N (Ra) -, -S (= 0) -, -S (= 0) 2-, -S (= 0) 2N (Ra) -or -N (R) -. In another embodiment, together with the foregoing and following embodiments, K is -C (R3R3) m, -C (= 0), -C (= 0) N (Ra) -, -S (= 0) -, -S (= 0) 2- or -S (= 0) 2N (Ra) -. In another embodiment, together with the previous and following embodiments, R1 is selected from In another embodiment, together with the previous and following embodiments, R1 is selected from In another embodiment, together with the foregoing and following embodiments, R2 is a ring selected from phenyl, dihydroin.denyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? -8alkyl, C? _haloalkyl, halo, cyano, n Ithro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -ORa, -0C (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -OC2-6alkylNRaRa, -OC2_6alkylore, -SRa, -S (= 0) Rb, -S '(= 0 ) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRC2_6alkyloor. In another embodiment, together with the above and following embodiments, R 2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl., quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C -? _ galkyl, C-L_4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, - 0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, -OC (- = 0) N (Ra) _S (= 0) 2Rb, '-OC2_6alkyl? NRaRa, -OC2_6alkylore, -SRa, -S (- = 0) Rb, -S ( = 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb,.-N (Ra) S (- = 0) 2NRaRa, -NRaC2-6alkyl? NRaR and -NRaC2-6alkyloRa. In another embodiment, together with the foregoing and following embodiments, R3 is H, Ci-ßalkyl, C? -haloalkyl, halo or 0Ra. In another embodiment, together with the foregoing and following embodiments, R3 is independently in each case H, Cx-salkyl, C? _4 haloalkyl, halo, -0Ra, -SRa or -NRaRa. In another embodiment, together with the foregoing and following embodiments, R4 is H or C? _6 alkyl. In another embodiment, together with the previous and following embodiments, R4 is H. In another embodiment, together with the above and following modalities, R4 is C? _8alkyl, C? _haloalkyl, halo, cyano, nitro, -0Ra, -SRa , -NRaRa, -NRaC2_6alquiloNRaRa or -NRaC2_6alquilo0Ra. In another embodiment, together with the previous and following embodiments, R5 is H, C (= 0) Rb, S (0) pRb, C (= 0) Rc, S (0) PRC, or Ca-βalkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and - additionally substituted by 0 or 1 substituents selected from Rf; In another embodiment, together with the previous and following embodiments, R5 is H. In another embodiment, together with the previous and following embodiments, R6 is C? _6 alkyl. In another embodiment, in conjunction with the above "" and following embodiments, R6 is H. According to another embodiment, the invention provides compounds of formula II wherein J is NH or NCH3; K is C (R3R3) m, -C (= 0), -C (= 0) 0-, -C (= 0) N (Ra) -, -C (= NRa) N (Ra) -, -S (= 0) -, -S (= 0) 2 -S (= 0) 2N (Ra) - or -N (Ra) -; R1 is selected from R is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C -? _ 8 alkyl, C? _4 haloalkyl , halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2-6alkylNRRa, -0C2_6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NR) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2-6alkyl0Ra. R3 is independently in each case H, C? _8alkyl, Cx-? Haloalkyl, halo, -0Ra, -SRa or -NRaRa; R4 is independently in each case C? _8alkyl, C! _4haloalkyl, halo, cyano, nitro, -0Ra, -SRa, -NRaR, -NRaC2_6alkylNRaRa or -NRaC2_6alkyl0Ra; R5 is H, C (= 0) Rb, S (0) pRb, C (= 0) Rc, S (0) pRc, or C? _6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H, Rc, Rd, or a C? -6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; Ra is independently in each case, H or Rb; Rb is independently in each case, phenyl, benzyl or C ?_6alkyl, phenyl, benzyl or C? -6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C? _alkyl, C; L_3haloalkyl, -OC? _4alkyl, -NH2, -NHC! -4alkyl and N (C? _4alkyl) C? _alkyl; Rc is independently, in each case, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl-. piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0 , 1 or 2 oxo groups; Rd is independently- in each case, C? -8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (- = 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -0C2-6alkylNRaRa, -OC2_6alkyloor, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, ~ N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2- 6alkyloor; Re is independently in each case Rd or H; Rf is independently, in each case, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the ring carbon atoms they are substituted by 0, 1 or 2 oxo groups; and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C] _ haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) NRaRa, -0Ra, -OC2_6alkylNRaR, -OC2_6alkyloorA, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -NRaRa, -N ( Ra) C (= 0) Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2_6alkyloor; m is independently in each case 0, 1, 2 or 3; n is 1; and p is 0, 1 or 2. According to another embodiment, the invention provides compounds of formula II wherein J is NH or NCH3; K is C (R3R3) m, -C (= 0), -C (= 0) N (Ra) -, -S (= 0) -, -S (= 0) 2- or S (= 0) 2N (Ra) -; R1 is selected from R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 independently-selected substituents of Cx- salkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb -C (= 0) 0R, -C (= 0) NRaRa, -C (= NR) NRaRa, -0Ra, -0C (= 0) Rb -0C (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -0C2-6alkylNRaRa -OC2_6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb -N (Ra) C ( = 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2_6alkyl0Ra; R3 is independently in each case H, C? -6alkyl, C? _4haloalkyl, halo or 0Ra; R4 is H or C? -6alkyl; R5 is H, C (= 0) Rb, S (0) pRb, C (= 0) Rc, S (0) pRc, or C? _6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and additionally replaced by 0 or 1 substituents selected from Rf; R6 is H or C? _6 alkyl; Ra is independently in each case, H or Rb; Rb is independently in each case, phenyl, benzyl or C6-6alkyl, the phenyl, benzyl or C i -alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C? _ Alkyl, C? _ Haloalkyl, '-OC? -alkyl, -NH2, -NHC? _ Alkyl and N (C? _ Alkyl) C? _ Alkyl; Rc is independently, in each case, phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups; Rd is independently in each case, C? -8alkyl, C? -haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) OR, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -OC2_6alkylNRaRa, -OC2_6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2R, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, - N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N ( Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2_6alkyl0Ra; Re is independently in each case, H, Cl, F, Br, I, CH3, N02, NHS02CH3, OH, CF3 or N-Acetyl; Rf is independently, in each case, phenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C] _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) NRaRa, -0Ra, -0C2_6alkylNRaRa, -0C2_6alkyl0Ra, -SRa , -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRRa, -NRC2_6alkylNRaRa and -NRaC2_6alkyl0Ra; m is independently in each case 0, 1, 2 or 3; n is 1; and p is 0, 1 or 2. According to another embodiment, the invention provides the specific compounds of formula I and / or II, which are described in the examples described herein. Another aspect of the invention relates to a pharmaceutical composition comprising at least one compound according to the above embodiments and a pharmaceutically acceptable carrier Another aspect of the invention relates to a method of treatment of arthritis, rheumatoid arthritis, psoriatic arthritis or osteoarthritis, organ transplantation, acute rejection to transplantation or heterograft and homograft, ischemic and reperfusion injury, induction of tolerance to transplantation, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lupus, graft against host diseases, T-cell-mediated hypersensitivity diseases, contact hypersensitivity, late-type hypersensitivity, Gluten-sensitive enteropathy, type 1 diabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, Graves' disease , Addison's disease, enf polyglandular disease autoimmune, autoimmune alopecia, pernicious anemia, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, autoimmune diseases, glomerulonephritis, serum sickness, urticaria, respiratory allergies, asthma, hay fever, allergic rhinitis, skin allergies, sclera, mycosis fungoides, acute inflammatory responses, acute respiratory anxiety syndrome, dermatomyositis, alopecia areata, chronic actinic dermatitis, eczema, Behcet's disease, Palmoplantaris pustulosis, Pyoderma gangrenosum, Sezary's syndrome, atopic dermatitis, systemic sclerosis, morphea, type II diabetes, resistance insulin, diabetic retinopathy, diabetic macular edema, diabetic neuropathy; and cardiovascular disease in a mammal comprising administering an effective amount of a compound according to any of the foregoing embodiments, to a mammal in need thereof. Another aspect of the invention relates to a method of treating cancers where the PKC theta or other kinases of the PKC family are activated, overexpress or facilitate tumor growth or survival or resistance to chemotherapeutic tumor cell drugs, T-cell leukemia, thymoma, T-cell and B-cell lymphoma, colon carcinoma, breast carcinoma and lung carcinoma, which comprises administering an effective amount of a compound according to any of the modalities above, to a mammal in need thereof. Another aspect of the invention relates to a method of treating a disease or disorder mediated by PKC-theta, the method comprising administering an effective amount of a compound according to any of the above embodiments within formulas I or II, to a mammal. Another aspect of the invention relates to a method of treating a disease or disorder associated with the activation of T cells, the method comprising administering to the mammal an effective amount of a compound according to any of the above embodiments within formulas I or II, to a mammal. Another aspect of the invention relates to the manufacture of a medicament comprising a compound according to any of the foregoing modalities. Another aspect of the invention relates to the manufacture of a medicament for the treatment of arthritis, rheumatoid arthritis, psoriatic arthritis or osteoarthritis, organ transplantation, acute rejection to transplantation or heterograft and homograft, ischemic and reperfusion injury, induction of the transplant tolerance, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lupus, graft against host diseases, T cell-mediated hypersensitivity diseases, hypersensitivity by contact, late type hypersensitivity, Gluten-sensitive enteropathy, type 1 diabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sj ogren's syndrome, autoimmune hyperthyroidism, Graves' disease, Addison's disease, autoimmune polyglandular disease, autoimmune alopecia, anemia pernicious, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, autoimmune diseases, glomerulonephritis, serum sickness, urticaria, respiratory allergies, asthma, hay fever, allergic rhinitis, skin allergies, sclera-chlamy, .micosis fungoides, acute inflammatory responses , acute respiratory anxiety syndrome, dermatomyositis, alopecia areata, chronic actinic dermatitis, eczema, Behcet's disease, Palmoplantaris pustulosis, Pyoderma gangrenosum, Sezary's syndrome, atopic dermatitis, systemic sclerosis, morphea, type II diabetes, insulin resistance, retinopathy Diabetic, diabetic macular edema, neuropathy diabetic and cardiovascular disease in a mammal comprising administering an effective amount of a compound according to any of the foregoing modalities. Another aspect of the invention relates to. the manufacture of a medicament for the treatment of cancers where PKC theta or other kinases of the PKC family are activated, overexpress or facilitate tumor growth, survival of tumor cells, resistance to chemotherapeutic agents or radiation, leukemia of T cells, thymoma, T and B cell lymphoma, colon carcinoma, breast carcinoma, and lung carcinoma in a mammal comprising administering an effective amount of a compound according to any of the foregoing modalities. The compounds of this invention can generally have several asymmetric centers and are typically represented in the form of racemic mixtures. This invention is intended to comprise racemic mixtures, partially racemic mixtures and enantiomers and diastereomers. The specification and claims contain the list of species that use the language "selected from ... and ..." and "is ... or ..." (sometimes referred to as Markush groups). When this language is used in this application, unless otherwise indicated, it means that it includes the group as a whole, or any member thereof, or any subgroup thereof. The use of this language is simply for purposes of shorthand and is not meant to in any way limit the removal of individual elements or subgroups, as necessary. Unless otherwise specified, the following definitions apply to the terms found in the specification and claims: "Aryl" means a phenyl or naphthyl radical, wherein the phenyl may be fused with a C3_4 cycloalkyl bridge.

"Benzo group", alone or in combination, means the divalent radical CH4 =, a representation of which is -CH = CH-CH = CH-, which when bound close to another ring, forms a benzene-type ring - for example tetrahydronaphthylene, indole and the like. "Ca-palkyl" means an alkyl group comprising from a to ß carbon atoms in a branched, cyclic or linear relationship or any combination of the three. The alkyl groups described in this section may also contain double or triple bonds. Examples of C? _8alkyl include, but are not limited to the following: "Halogen" and "halo" mean atoms of a halogen selected from F, Cl, Br and I. "Ca_ßhalokyl" means an alkyl group, as described above, wherein any number - at least one - of the hydrogen atoms attached to the alkyl chain, is replaced by F, Cl, Br or I. "Heterocycle" means a ring comprising at least one carbon atom and at least one other atom selected from N, O, and S. Examples of heterocycles which may be found in the claims include, but are not limited to, the following: "Oxo" means an oxygen atom covalently bound to a carbon atom by a double bond, also commonly referred to as a carbonyl group. It is readily appreciated that given an aromatic ring (completely unsaturated), the ring can not be substituted with an "oxo" group, that is, there can be no carbonyl group in the ring. However, where the ring is partially or completely saturated, it may contain a carbonyl group. For example, a pyrimidinone ring is a 6-membered, partially saturated heteroaryl ring wherein one of the carbon atoms in the ring is a ketone. "Pharmaceutically acceptable salt" means a salt prepared by conventional means, and are well known to those skilled in the art. "Pharmacologically acceptable salts" include basic salts of inorganic and organic acids, including but not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid , citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like. When the compounds of the invention include an acid function such as a carboxy group, then suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, ammonium cations quaternary and the like. For additional examples of "pharmacologically acceptable salts" "see below and Berge et al., J. Pharm. Sci. 66: 1 (1977)." Treatment "of diseases and disorders herein is also intended to include the prophylactic administration of a compound of the invention, a pharmaceutical salt thereof, or a pharmaceutical composition of either to a subject (ie, an animal, preferably a mammal, preferably a human) that is believed to be in need of preventive treatment, such as, for example, example, pain, inflammation and the like. "Salting Group" generally refers to groups easily displaceable by a nucleophile, such as an amine, a thiol or a nucleophilic alcohol.Such leaving groups are well known in the art Examples of such groups salients include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates, and the like. Appropriate: "Protective group" generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from experiencing undesired reactions, such as a nucleophilic reaction , electrophilic, oxidation, reduction and the like. They indicated The preferred protective groups are attached where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl, and the like. Examples of aralkyl include, but are not limited to, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as salts of phosphonium and ammonium. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-f-enylf-lorenyl) -phenanthrenyl, -durenyl and the like. Examples of cycloalkenylalkyl or substituted cycloalkenylalkyl radicals, preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like. Convenient groups acyl, alkoxycarbonyl and aralkoxycarbonyl include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, tri-fluoroacetyl, tri-chloro acetyl, phthaloyl and the like. A mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by an aralkyl group and an aralkoxycarbonyl group. The amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, eg, 1,2-bis (methylene) benzene, phthalimidyl, succinimidyl, maleimidyl and the like and where these heterocyclic groups may further include the adjacent aryl and cycloalkyl rings. In addition, the heterocyclic groups may be mono-, di- or tri-substituted, such as nitrofimimidyl. The amino groups can also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid, and the like. Many of the amino protecting groups are also convenient for protecting carboxy, hydroxy and mercapto groups. For example, aralkyl groups are commonly used to protect amines, as well as hydroxyl and mercapto groups, as appreciated by those skilled in the art. Alkyl groups are also convenient groups for protecting hydroxy and mercapto groups, such as tere-butyl. Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and dif-enylmethylsilyl. Silylation of amino groups provides mono- or di-silylamino groups. The silylation of the aminoalcohol compounds can lead to a N, N, O-tri-silyl derivative. The removal of the silyl function of a silyl ether function is easily achieved by the treatment with, for example, a metal hydroxide or ammonium fluoride reagent, as a discrete reaction step or in situ during a reaction with the alcohol group. Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride or their combination products with imidazole or DMF. Methods for the silylation of amines and removal of silyl protecting groups are well known to those skilled in the art. Methods of preparing these amine derivatives from amino acids, amino acid amides or corresponding amino acid esters, are also well known to those skilled in the art of organic chemistry including amino acid / amino acid ester or aminoalcohol chemistry. The protecting groups are removed under conditions, which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like. A preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on the carbon in a convenient solvent system such as an alcohol, acetic acid, and the like or mixtures thereof. A t-butoxycarbonyl protecting group can be removed using a inorganic or organic acid, such as HCl or trifluoroacetic acid, in a convenient solvent system, such as methylene chloride or dioxane. The resulting amino salt can be readily neutralized to provide the free amine. The carboxy protecting group, such as methyl, ethyl, benzyl, tere-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art. It should be noted that the compounds of the invention may contain groups which may exist in tautomeric forms, such as cyclic and acyclic amidine and guanidine groups, heteroatom substituted heteroaryl groups (Y '= O, S, NR), and the like, which are illustrated in the following examples: and although a form is named, described, exhibited and / or claimed as an attachment, it is desired that all tautomeric forms are intrinsically included in such a name, description, display and / or claim. The prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an active or inactive compound that is chemically modified through physiological action in vivo, such as hydrolysis, metabolism and the like, in a compound of this invention after administration of the prodrug to a patient. The applicability and techniques involved in the manufacture and use of prodrugs are well known to those skilled in the art. For a general discussion of prodrugs involving esters, see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985). Examples of a masked carboxylate anion include a variety of esters, such as alkyl (eg, methyl, ethyl), cycloalkyl (eg, cyclohexyl), aralkyl (eg, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (eg. example, pivaloyloxymethyl). Amines have been masked as substituted arylcarbonyloxy ethyl derivatives, which are divided by esterases in vivo that release the free drug and formaldehyde (Bundgaard J. Med. Chem. 2503 (1989)). Also, drugs that contain an acidic NH group, such such as imidazole, imide, indole and the like, have been masked with N-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)). The hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloan and Little, 11/4/81) describes prodrugs of. Hydroxamic acid with Mannich base, its preparation and use. "Cytokine" means a secreted protein that affects the functions of other cells, particularly as it is related to the modulation of interactions between the cells of the immune system or cells involved in the inflammatory response. Examples of cytokines include, but are not limited to, interleukin 1 (IL-1) preferably IL-1β, interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-a (factor a of tumor necrosis). The compounds according to the invention can be synthesized according to one or more of the following methods. It should be noted that the general procedures are shown as they relate to the preparation of the compounds having unspecified stereochemistry. However, such procedures generally apply to compounds of a specific stereochemistry, for example, where the stereochemistry on a group is (S) or (R). In addition, compounds that have a stereochemistry (eg, (R)) can be used frequently to produce those that they have an opposite stereochemistry (ie, (S)) using well-known methods, for example, by inversion. ACRONYM The acronyms used throughout the specification will have the following meaning: - BINAP: 2,2 '-bis-diphenylphosphanyl- [1, 1 *] binaphthalenyl DCM: dichloromethane DIEA: N, N-diisopropylethylamine DME: 1,2-dimethoxyethane DMF: dimethylformamide LHMS: lithium bis (trimethylsilyl) amide NMP: N -methyl-2-pyrrolidone rac-BINAP: 2,1 '-bis-diphenylphosphanyl- [1, 1'] racemic binaphthalenyl RBF: round bottom flask TBAF: tetra-butyl ammonium fluoride TBDPSC1: tert-butyldiphenylsilyl chloride THF: tetrahydrofuran TMS: trimethyl silane TMSCH2C: trimethylsilanylacetonitrile TsCl: tosyl chloride Synthesis of 5-chloro-7- (2-chloro-pyridin-4-yl) -imidazo [1,2-c] pyrimidine m% in 2 stages Example 1 Stage A: 2-chloro-isonicotinic acid ethyl ester - (1) • The mixture of 2-chloro-isonicotinic acid (16.8 g, 0.107 mol), 100 ml of absolute ethanol and concentrated H2SO4 (3.28 0.118 mol) were refluxed under nitrogen for 15 h. After all the starting material was converted, the mixture was cooled to below room temperature, and all the ethanol was evacuated. The resulting mixture was diluted with 250 ml of ethyl acetate, washed with saturated Na 2 HCO 3, dried over anhydrous Na 2 SO 4. Purified by a short column, the title compound was obtained as the pale yellow liquid. MS (ES +): 186 (M + H) A Step B: 3- (2-chloro-pyridin-4-yl) -3-oxo-propionic acid ethyl ester (2) The mixture of 15 g of 2-ethyl ester Chloro-isonicotinic (1) (81.4 mmol) and 8.75 g of ethyl acetate (88 mmol) in 200 ml of anhydrous THF was stirred at 0 ° C under nitrogen. The mixture was treated with 100 ml of LHMS (1.0 M in THF) for 30 minutes. The resulting mixture was stirred at 0 ° C - room temperature for 15 h, then quenched with 200 ml of saturated NHC1 at 0 ° C and adjusted pH6-7. The water layer was extracted with ethyl acetate 3 x 50 ml. The combined organics were dried over anhydrous Na2SO4 and purified by column. The title compound was obtained as a pale yellow solid. -EM (ES +): 228 (M + H) +. Step C: 6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-3H-pyrimidin-4-one (3) The mixture of 11.2 g of ethyl ester of 3- (2-chloro-pyridin-4) -yl) -3-oxo-propionic acid (2) (49.4 mmol) and 13.74 g of 2-methyl-isothiourea sulfate in 182 ml of ethanol and 50 ml of water were stirred at 0 ° C under nitrogen. The mixture was treated with 4.39 g of CA (0H) 2, and stirred at 0 ° C - room temperature for 15 h. The mixture was quenched rapidly with 200 ml of water and adjusted pH 6-7, then filtered and washed with 200 ml of water, and 100 ml of hexane. The filtered cake was dissolved in 1.5 1 to 10% methanol / DCM and filtered again. The organic was dried over concentrated Na2SO4. The title compound was obtained as the white solid. MS (ES +): 254 (M + H) A Step D: 4-chloro-6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidine (4) The mixture of 8.6 g of 6 - (2-chloro-pyridin-4-yl) -2-methylsulfanyl-3H-pyrimidin-4-one (3) (34 mmol) in 100 ml of P0C13 was heated to 80 ° C and stirred under nitrogen for 4 h. The TLC showed that all the starting material was converted. The mixture was cooled to below room temperature and all P0C13 was vacuum-stripped. The black cake was dissolved in 200 ml of DCM, washed with saturated NaHCO3 carefully, dried on Na2S0 anhydrous. The crude product was purified by column and the title compound was obtained as the white solid. MS (ES +): 272 (M + H) +. Step E: [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin-4-yl] - (2,2-dimethoxy-ethyl) -amine (5) To 250 ml (RBF) 5.95 g (21.96 mmol) of 4-chloro-6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidine (4), 100 ml of CH 3 CN and 20 ml of DCM were added. The mixture was stirred at room temperature under nitrogen, and was treated with 3.0 g of K2CO3 (21.96 mmol), and 4.73 ml (43.9 mmol) of indoacetaldehyde dimethylacetal at room temperature.

The obtained mixture was refluxed under nitrogen for 6 h. The TLC and EM showed that all the starting materials were converted. The mixture was cooled to below room temperature and quenched with 200 ml of water, extracted with DCM 3 x 100 ml. The combined organic was washed with brine and dried over Na2S04. The crude product was purified by column (driven by hexane / ethyl acetate / methanol: 1: 1: 0.05), and the title compound was obtained as a white solid. MS (ES +): 341 (M + H) +. Step F: 7- (2-Chloro-pyridin-4-yl) -imidazo [1,2-c] pyrimidin-5-ol (6) To 500 ml of RBF was added 7.5 g (21.96 mmol) of [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin-4-yl] - (2,2-dimethoxy-ethyl) -amine (5) and 100 ml of water solution 2N HCl, the mixture was reflowed for 2 h. The EM showed that all the starting materials were converted. Mix was cooled below room temperature, 100 ml of toluene and 5 ml of concentrated H2SO4 were added at room temperature, and the mixture was refluxed with a Dean-Stark trap for 4 h. The reaction was followed using MS. After all the starting materials were consumed, the mixture was cooled to below room temperature. The toluene layer was decanted, the water layer was diluted with 100 ml of water and neutralized with 5N NaOH to pH 7 carefully. A pale yellow solid was precipitated and filtered and washed with 50 ml of 50 water. The crude product (6) was azotropic dried with toluene 2 x 50 ml at the beginning, then dried at 50 ° C in a vacuum oven for 24 hours. h. The crude product was used directly in the next step without further purification. The raw product must be kept very dry for the next stage). MS (ES +): 265 (M + H) +. Step G: 5-chloro-7- (2-chloro-pyridin-4-yl) -imidazo [1,2-c] pyrimidine (7) To 250 ml of RBF were added 5.5 g (20.3 mmol) of 7- ( 2-chloro-pyridin-4-yl) -imidazo [1, 2-c] pyrimidin-5-ol (6) and 100 ml of P0C13, the mixture was treated with 3.55 ml of DIEA (20 mmol) at the beginning. The mixture was sonicated to dissolve all the starting material. The mixture was heated to 95 ° C and treated with another 3.55 ml of DIEA (20 mmol) slowly. The mixture was stirred at 95 ° C for 4 h, and all materials of home were converted. TLC and EM were used to follow the reaction. All P0C13 was subjected to vacuum. The residue was dissolved in 500 ml of DCM, washed with saturated NaHCO and carefully adjusted to pH 8. The organic phase was dried over concentrated Na2SO and purified by column (conducted by 4: 1 to 1: 1: 0.05 hexane / ethyl acetate methanol), and yielding a pale yellow product (7). MS (ES +): 265 (M + H) +. Example 2 - [7- (2-Chloro-pyridin-4-yl) -Lmidazo [1, 2c] pyrimidin-5-yl] - (1S, 4S) -2,5-diaza-bicyclo [2.2. 1] heptane-2-carboxylic acid To 100 ml of RBF were added 5-chloro-7- (2-chloro-pyridin-4-yl) -i_trLdazo [1,2-c] pyridinmidine (2.0 g, 7.6 mmol), ml of NMP, (S) -N-Boc-2,5-Diaza-bicyclo [2.2.1] heptane (1.6 g, 8.3 mmol), K2C03 (1.05 g, 7.6 mmol) and DIEA (1.3 mL, 7.6 mmol) . The mixture was stirred at room temperature under nitrogen for 15 h, and all the starting material was converted. The reaction mixture was added to 100 ml of ice water slowly, and a white solid precipitated. The precipitate was filtered and washed with 50 ml of water, and further purified by instant chromatography. The title compound was obtained. MS (ES +): 427 (M + H) +. Example 3: (S) -. { 4- [5- ((lS, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimid'in-7-yl] -pyridin- 2-il} - (1-phenylethyl) -amine Step A: To 100 ml of RBF, 5- [7- (2-chloro-pyridin-4-yl) -imidazo [1,2-c] pyrimidin-tert-butylester was added. -5-yl] -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid (0.426 g, 1 mmol), 50 ml of toluene and 2.5 ml of DMF, and (S) -a-methylbenzylamine ( 0.14 ml1.08 mmol). The mixture was degassed by bubbling nitrogen for 1 h. Then Pd (0Ac) 2 (23 mg, 0.1 mmol), BINAP (62 mg, 0.1 mmol) and NaOtBu (0.192 g, 2.0 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen . The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3 and dried over anhydrous Na2SO4. After purification by flash chromatography, the - tert-butylester. { 7- { 2- (1-phenyl-ethylamino) -pyridin-4-yl] -imidazo [1,2-c] pyrimidin-5-yl} -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid as a pale yellow solid. MS (ES +): 512 (M + H) A Step B: To 50 ml of RBF 0.5 g (0.98 mmol) of tert-butylester of 5- acid was added. { 7- { 2- (1-phenyl-ethylamino) -pyridin-4-yl] -imidazo [1,2-c] pyrimidin-5-yl} -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid, 10 ml of methanol and stirred at room temperature under nitrogen. The mixture was treated with and 2.5 ml of 4N HCl in dioxane and stirred at room temperature for 1 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3 and dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as a pale yellow solid. MS (ES +): 412 (M + H) A Example 4 (S) -. { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] - pyridin-2-yl} - (1-phenyl-ethyl) -amine The mixture of 100 mg (0.24 mmol). { 4- [5 (2, 5-diaza- bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 5 ml of chloroform was treated with 0.2 ml (2.4 mmol) of acetone, 45 mg (0.72 mmol) of NaBH 3 (CN) and 1 ml of methanol accordingly. The mixture was stirred at room temperature for 15 h. The EM showed that all the starting materials were converted.

The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCC3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES +): 454 (M + H) A Example 5 (S) - (4- [5- (5-ethyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidine- 7-yl] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine The mixture of 50 mg (0.12 mmol) of. {4- [5- (2, 5-diaza-bicyclo [ 2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine in 20 ml of CH3CN was treated with 26 mg (0.24 mmol) of bromoethane and 33 mg (0.24 mmol) of K2C03 The mixture was stirred at room temperature for 15 h.The MS showed that all the starting materials were converted.The mixture was diluted with 50 ml. of DCM, washed with 20 ml of saturated NaHCO3 dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained in 20 mg as a yellow solid. MS (ES +): 440 (M + H) +. Example 6 (R) -. { 4- [5- ((1S, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2- il} - (1-phenyl-ethyl) -amine Step A: To 100 ml of RBF, 5- [7- (2-chloro-pyridin-4-yl) -imidazo [1, 2-c] tert-butylester was added. ] pyrimidin-5-yl] -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid (0.22 g, 0.5 mmol), 50 ml of toluene and 2.5 ml of DMF, and (R) -a -methylbenzylamine (0.07 ml, 0.55 mmol). The mixture was degassed by nitrogen at a for 1 h. then Pd (OAc) 2 (12 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) and NaOtBu (0.69 g, 1.0 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous Na2SO4. After purification by flash chromatography, the tert-butylester of (R) -5- acid was obtained. { 7- [2- (1-phenyl-ethylamino) - pyridin-4-yl] -imidazo [1,2-c] pyrimidin-5-yl} -2, 5-diaza-bicyclo [2.2. 1) heptane-2-carboxylic acid as the pale yellow solid. MS (ES +): 512 (M + H) +. Step B: To 50 ml of RBF was added 0.25 g (0.49 mmol) of tert-butylester of (R) -5- acid. { 7- [2- (1-f-enyl-ethylamino) -pyridin-4-yl] -imidazo [1,2-c] pyrimidin-5-yl} -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid, -5 ml of methanol and stirred at room temperature under nitrogen. The mixture was treated with 2.0 ml of 4N HCl in dioxane and stirred at room temperature for 1 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3 and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, the title compound was obtained as a pale yellow solid. MS (ES +): 412 (M + H) +. Example 7 (R) -. { 4- [5- (5-isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] - pyridin-2-yl} - (1-phenyl-ethyl) -amine The mixture of 100 mg (0.24 mmol) of (R) -. { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - Imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl (1-phenyl-ethyl) -amine in 5 ml of chloroform was treated with 0.2 ml (2.4 mmol) of acetone, 45 mg ( 0.72 mmol) of NaBH 3 (CN) and 1 ml of methanol. The mixture was stirred at room temperature for 15 h. The EM showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3, dried over anhydrous Na 2 SO 4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES +): 454 (M + H) A Example 8 . { 4- [5- ((1S, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] irimidin-7-yl] -pyridin-2- il} - (1,2-dimethyl-propyl) -amine Step A: To 100 ml of RBF, 5- [7- (2-chloro-pyridin-4-yl) -imidazo [1,2] -butyl ester was added. -c] pyrimidin-5-yl] -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid (0.14 g, 0.33 mmol), 20 ml of toluene and 2.5 of DMF, and 1,2-dimethyl -propylamine (0.057 g, 0.66 mmol). The The mixture was degassed by nitrogen for 1 h. Then Pd (0Ac) 2 (7.4 mg, 0.033 mmol), BINAP (21 mg, 0.033 mmol) and NaOtBu (0.063 g, 0.66 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous Na2SO4. After purification by flash chromatography, tert-butylester of 5- acid was obtained. { 7- [2- (1, 2-dimethyl-propylamino) -pyridin-4-yl] -imidazo [1, 2-c] pyrimidin-5-yl} -2, 5-diaza-bicyclo [2.2. 1) heptane-2-carboxylic acid as a pale yellow solid. MS (ES +): 478 (M + H) A Step B: To 50 ml of RBF was added 0.1 g (0.21 mmol) of 5- tert-butylester. { 7- [2- (1, 2-dimethyl-propylamino) -pyridin-4-yl] -imidazo [1, 2-c] pyrimidin-5-yl} -2, 5-diaza-bicyclo [2.2.1] -heptane-2-carboxylic acid, 5 ml of methanol and stirred at room temperature under nitrogen. The mixture was treated with 2.0 ml of 4N HCl in dioxane and stirred at room temperature for 1 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, the title compound was obtained as a pale yellow solid. MS (ES +): 378 (M + H) A Example 9 (1, 2-dimethyl-propyl) -. { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] - pyridin-2-yl} -amine The mixture of 25 mg (0.066 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1,2-dimethyl-propyl) -amine in 5 ml of chloroform was treated with 38 mg (0.66 mmol) of acetone, 41 mg (0.66 mmol) of NaBH 3 (CN) and 1 ml of methanol. The mixture was stirred at room temperature for 15 h. The EM showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3 over anhydrous Na 2 SO 4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES +): 420 (M + H) Example 10 . { 4- [5- ((SS, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyrimidin-2- il} Naf talen-1-ylmethyl-amine Step A: A .100 ml of RBF, 5- [7- (2-chloro-pyridin-4-yl) -imidazo [1, 2-tert -butylester] was added. c] pyrimidin-5-yl] -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid (0.22 g, 0.5 mmol), 50 ml of toluene and 2.5 ml of DMF, and C-naphthalene-1 -yl-methylamine (94 mg, 0.6 mmol). The mixture was degassed by bubbling nitrogen for 1 h. Then Pd (OAc) 2 (12 mg, 0.05 mmol) was added, BINAP (31 mg, 0.05 mmol) and NaOtBu (0.69 g, 1.0 mmol), the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, 5- (7-. {2- 2- [(naphthalen-1-ylmethyl) -amino] -pyridin-4-yl}. -imidazo [1], tert-butylester was obtained. 2-c] pyrimidin-5-yl) -2,5-diaza-bi [2.2.1] heptane-2- cycle carboxylic acid in 0.25 g as a pale yellow solid. MS (ES +): 548 (M + H) +. Step B: To 50 ml of RBF 0.25 g (0.46 mmol) of 5- (7-. {2- [(naphthalen-1-ylmethyl) -amino] -pyrimidin-4-yl tert-butylester was added} -imidazo [1, 2-c] pyrimidin-5-yl) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid, 5 ml of methanol and stirred at room temperature under nitrogen. The mixture was treated with and 2.0 ml of 4N HCl in dioxane and stirred at room temperature for 1 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3 and dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as a pale yellow solid. MS (ES +): 448 (M + H) +. Example 11 . { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] - pyrimidin-2-yl} -naphthalen-1-ylmethyl-amine The mixture of 92 mg (0.2 mmol) of. { - [5- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] - pyrimidin-2-yl Ynaphthalen-1-ylmethyl-arnine in 5 ml of chloroform was treated with 0.12 g (2.0 mmol) of acetone, 41 mg (0.66 mmol) NaBH 3 (CN) and 1 ml of methanol. The mixture was stirred at room temperature for 15 h. The EM showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3 and dried over anhydrous Na 2 SO 4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES +): 490 (M + H) +. Example 12 (S) -. { 4- [6- ((lS, 4S) -2,5-diaza-bicyclo [2.1.1] hept-2-yl) -2-methylsulfate-pyrimidin-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine Step A: To 250 ml of RBF was added 4-chloro-6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidine (2.13 g, 7.86 mmol) , 100 ml of CH3CN, (S) -N-boc-2, 5-diaza-bicyclo [2.2. 1) heptane (1.71 g, 8.65 mmol), K2CO3 (1.1 g, 7.86 mmol). The mixture was refluxed under nitrogen for 4 h, and all the starting material was converted. The reaction mixture was cooled to below room temperature, diluted with 200 ml of ethyl acetate, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, the intermediate of tert-butylester of 5- [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin-4-yl] -2, 5- was obtained. diaza-bicyclo [2.2.1] heptane-2-carboxylic acid. MS (ES +): 434 (M + H) A Step B: To 100 ml of RBF, 5- [6- (2-chloro-pyridin-4-yl) -2-methylsulfanylpyrimidin- tert -butylester was added. 4-yl] -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid (0.433 g, 1 mmol), 50 ml of toluene, and (S) -a-methylbenzylamine (0.15 ml, 1.2 mmol ). The mixture was degassed by bubbling nitrogen for 1 h. Then Pd (OAc) 2 (23 mg, 0.1 mmol), BINAP (62 mg, 0.1 mmol) and NaOtBu (0.192 g, 2.0 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3 and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, tert-butylester of 5- acid was obtained. { 2-methylsulfanyl-6- [2- (1-phenyl-ethylamino) -pyridin-4-yl] -pyrimidin-4-yl} -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid as a solid of color pale yellow. MS (ES +): 519 (M + H) +. Step C: To 50 ml of RBF was added 0.4 g (0.77 mmol) of 5- tert-butylester. { 2-methylsulfanyl-6- [2- (1-phenyl-ethylamino) -pyridin--i1] -pyrimidin-4-yl} -2, 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid, 10 ml of methanol and stirred at room temperature under nitrogen. The mixture was treated with and 2.5 ml of 4N HCl in dioxane and stirred at room temperature for 1 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, the title compound was obtained as a pale yellow solid. MS (ES +): 419 (M + H) Example 13 (S) -. { 4- [6- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -2-methylsulfanyl-pyrimidin-4-yl] -pyridin-2- il} - (1-phenyl-ethyl) -amine The mixture of 0.13 g (0.31 mmol) of. { 4- [6- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -2-methylsulfanyl-pyrimidin-4- il] -pyridin-2-il} - (1-phenyl-ethyl) -amine in 5 ml of chloroform was treated with 0.2 ml (3.1 mmol) of acetone, 0.19 g (3.1 mmol) of NaBH 3 (CN) and 1 ml of methanol. The mixture was stirred at room temperature for 15 h. The EM showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3, dried over anhydrous Na 2 SO 4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES +): 461 (M + H) +. Example 14 (S) - (2,2-dimethoxy-ethyl) -. { 2- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6- [2- (1-phenyl-ethylamino) -pyridin-4-yl ] -pyrimidin-4-il} -amine Step A: The mixture of 0.36 g (1.06 mmol) of [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin-4-yl] - (2,2-dimethoxy-ethyl) -amine in 15 ml of methanol and 10 ml of acetone was treated with 0.37 g (0.6 mmol) of Oxone and 32 mg (0.106). mmol) of tetrabutylammonium nitrate in 4 ml of water at 0 ° C. The mixture was stirred at 0 ° C for 4 h, all the starting material was converted. The reaction mixture was treated with 10 ml of saturated Na2S203, extracted with DCM 3 x 50 ml, dried with anhydrous Na2SO4. After purification by flash chromatography, the intermediate [6- (2-chloro-pyridin-4-yl) -2-methanesulfonyl-pyrimidin-4-yl] - (2,2-dimethoxy-ethyl) -amine was obtained. MS (ES +): 357 (M + H) +. Step A: [6 (2-Chloro-pyridin-4-yl) -2-methanesulfinyl-pyrimidin-4-yl] - (2,2-dimethoxy-ethyl) -amine (0.21 g) was added to 100 ml of RBF. 0.59 mmol), 10 ml of DMF, hydrochloride salt of (S) -2-isopropyl-2,5-diaza-bicyclo [2.2.1] heptane (0.15 g, 0.7 mmol), K2C03 (0.24 g, 1.77 mmol) . The mixture was stirred at 100 ° C under nitrogen for 15 h, and all the starting material was converted. The reaction mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, the intermediate was obtained [6- (2-chloro-pyridin-4-yl) -2- (5-isopropyl-2,5-diaza-bicyclo [2.2.1] hept-2 il) -pyrimidin-4-yl] - (2,2-dimethoxy-ethyl) -amine. MS (ES +): 433 (M + H) +. Step B: To 100 ml of RBF, [6- (2-chloro-pyridin-4-yl) -2- (5-isopropyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl was added. ) -pyrimidin-4-yl] - (2,2-dimethoxy-ethyl) -amine (0.2 g, 0.46 mmol), 25 ml of toluene, and (S) -a-methylbenzylamine (0.071 ml, 0. 55 mmol). -The mixture was degassed by bubbling nitrogen for 1 h. Then Pd (OAc) 2 was added (11 mg, 0.046 mmol), BINAP (29 mg, 0.046 mmol) and NaOtBu (0.088 g, 0.92 mmol), the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHC03, and dried over Na2SO4 anhydrous. After purification by flash chromatography, the compound was obtained as a pale yellow solid. MS (ES +). : 518 (M + H) +. Example 15 (S) -. { 4- [5- ((SS, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) - [1, 2, 4] triazole [1, 5-c] pyramidin-7 il] -pyridin-2-il} - (1-phenyl-ethyl) -amine A tert-butyl ester of the acid. { 7- [2- (1-f-enyl-ethylamino) -pyridin-4-yl] - [1, 2, 4] triazole [4, 3-c] pyrimidin-5-yl] -2,5-diaza-bicyclo [2.2.1] Heptene-2-carboxylic acid (0.022 g, 0. 043 mmol) were added 4N HCl (1 mL) in dioxane and a few drops of methanol. After 1 h, the reaction was concentrated in vacuo and the residue taken up in water and extracted with ethyl acetate. The aqueous layer was neutralized with bicarbonate saturated sodium and extracted with chloroform (3x). The combined organic extract was dried (K2C03), filtered, and concentrated in vacuo to give the title compound as "a golden yellow solid, MS (ES +): 413.1 [M + H] +, 411.2 [MH]". Example 16 (S) -. { 4- [5- (5-isoyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - [1, 2, 4] triazole [1, 5-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine To a solution of. { 4- [5- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) - [1, 2, 4] triazol [4, 3-c] pyrimidin-7-yl] -pyridin-2 -il} - (1-phenyl-ethyl) -amine (0.25 g, 0.61 mmol) in chloroform (5 ml) was added acetone (1 ml) and sodium triacetoxyborohydride (0.45 g, 2.14 mmol) and stirred for 2 h. Upon cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate, brine, and dried (K2C03). Flash chromatography of the crude uct with 1% 2M NH3 in MeOH / CHCl3 afforded the title compound as an off-white solid. MS (ES +): 455.2 [M + H] +, 453.2 [MH] -.

Example 17 (S) -. { 4- [5- ((1S, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) - [1,2, 4] triazolo [1, 5-c] pyrimidin-7- il] -pyridin-2-il} - (1-naphthalen-1-yl-ethyl) -amine The title compound was analogously prepared following the edure described in Example 2 from 5- tert-butylester. { 7- [2- (1-naphthalen-1-yl-ethylamino) -pyridin-4-yl] - [1,2, 4] triazolo- [4, 3-c] pyrimidin-5-yl} -2, 5-diaza-bicyclo [2.2.1] heptene-2-carboxylic acid. MS (ES +): 463.3 [M + H] +, 461.3 [M-H] "Example 18 (S) -. { 4- [5- (5-isoyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - [i; 2,4] triazolo [1, 5-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-naphthalen-1-yl-ethyl) -amine The title compound was analogously prepared following the edure described in Example 3 from from . { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) - [1,2,4] triazolo [4, 3-c] pyrimidin-7-yl] -pyridin-2 -il} - (1-naphthalen-1-yl-ethyl) -amine. MS (ES +): 505.3 [M + H] +, 503.4 [M-H] "Example 19 (S) - [2r -. { (SS, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) - [4, 4 '] bipyridinyl-2-yl] - (1-phenyl-ethyl) -amine Al terc- 5- [2 '- (1-phenyl-ethylamino) - [4,4'] bipyridinyl-2-yl] -2,5-diazabicyclo [2.2.1] -heptane-2-carboxylic acid butyl ester (0.027) g, 0.058 mmol) were added 4N HCl (1 ml) in dioxane and a few drops of methanol. After 1 h, the reaction was concentrated in vacuo and the residue taken up in water and extracted with ethyl acetate. The aqueous layer was neutralized with saturated sodium bicarbonate and extracted with chloroform (3x). The combined organic extract was dried (K2C03), filtered, and concentrated in vacuo to give the title compound as a gold yellow solid. MS (ES +): 372.4 [M + H] +, 370.3 [M-H]. " Example 20 (S) - [2 '- (5-isoyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - [4,'] bipyridinyl-2-yl] - (1-f-enyl-ethyl) -amine The title compound was analogously prepared following the edure described in Example 3 from [2 '- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) ) - [, '] bipyridyl-2-yl] - (1-f-enyl-ethyl) -amine. MS (ES +): 414.2 [M + H] +, 412.3 [M-H]. "Example 21 3-methyl-2- (5-methyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6- [2- (S) - (1-phenyl- ethylamino) -pyridin-4-yl] -3H-pyridin-4-one To a solution of 2- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6- [ 2- (1-phenyl-ethylamino) -pyridin-4-yl] -3H-pyrimidin-4-one (0.05 g, 0.13 mmol, 1.00 equivalents) in 15 ml of methanol was added formaldehyde (37% by weight, 0.07 g , 5.40 mmol, 20 equivalents) and sodium triacetoxyborohydride (0.06 g, 0.27 mmol, 2.00 equivalents) at 0 ° C. The reaction was heated to room temperature during night, after the solvent was evaporated. Filtration and purification of CIAP gives the desired uct as an off-white solid. XH NMR (CDC13, 400 MHz) d 8.13 (d, J = 5.2 Hz, 1H), 7.39 (d, J = 8.4 Hz, 2H), 7.337-7.35 (, 2H), 6.98 (dd, J = 5.2, 1.6 Hz, 1H), 6.76 (s, 1H), 6.35 (s, 1H), 5.09 (s, broad, 1H), 4.78-4.74 (m, 1H), 4.42 (s, 1H), 3.51-3.42 (m, 6H), 3.05 (d, J = 10.4 Hz, 1H), 2.89 (dd, J = 6.0, 2.4 Hz, 1H), 2.43 (s, 3H), 1.95 (d, J = 9.6 Hz, 1H), 1.74 ( d, J = 10.0 Hz, 1H), 1.58 (d, J = 6.8 Hz, 3H); 13 C NMR (CDC 13, 400 MHz) d 165.25, 158.66. 157.76, 156.90, 148.57, 145.93, 144.52, 128.71, 12.07, 125.82, 110.56, 104.18, 101.38, 63.30, 61.55, 59.63, 54.20, 52.21, 41.28, 34.49, 32.71, 24.51 ppm; MS (ES +): 417.2 (M + H) +; (ES-): 415.5 (M-H). "HRMS calculated for C24H29N60 417.2403, found 417.2414, Example 22 2- ((1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6- [2- ((S) -1-phenyl-ethylamino) -pyridin -4-yl] -3H-pyrimidin-4-one Stage A: 3- (2-chloro-pyridin-4-yl) -propionic acid ethyl ester To 60.8 ml of LHMS (1.0 M in THF) was added slowly a solution of 2-chloro-isonicotinic acid ethyl ester (10.28 g, 55 mmol) and 4.8 g of ethyl acetate - (65 mmol) in 5 ml of anhydrous THF at 0 ° C under nitrogen. The resulting mixture was stirred at 0 ° C - room temperature for 15 h, then quenched with 900 ml of hexanes. After stirring for 2 h at room temperature, the solids formed were filtered and washed with hexanes to give lithium enolate of 3- (2-chloro-pyridin-4-yl) -3-oxo-propionic acid ethyl ester. Step B: 6- (2-chloro-pyridin-4-yl) -2-methylsulfañil-3-methyl-pyrimidin-4-one The mixture of 7.44 g of lithium enolate of ethyl ester of 3- (2-chloro- pyridin-4-yl) -3-oxo-propionic acid (32 mmol), thiourea (2.42 g, 32 mmol), and potassium carbonate (4.6 g, 33 mmol) in 10 ml of ethanol and 10 ml of DMF was heated at 95 ° C under nitrogen overnight. The mixture was cooled to room temperature, and treated with methyl iodide (4.8 ml) and then stirred overnight. The mixture was cooled rapidly with 150 ml of ice water. The formed solids were filtered and washed with water to give the title compound. MS (ES +): 268 (M + H) A: Step C: 5- (1-methyl-6-oxo-4- (2-chloro-4-pyridinyl) -1,6-dihydro-2-pyrimidinyl) -2 , 1,1-dimethylethyl 5-diazabicyclo [2.2.1] heptane-2-carboxylate To 6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-3-methyl-pyridin-4-one (2.39 g, 8.9 mmol) in acetonitrile (50 mL) at 0 ° C was added 33 mL of solution of trifluoroperacetic acid, formed in situ from the addition compound of urea hydrogen peroxide (Aldrich, 10.44 g, 110 mmol) and trifluoro acetic anhydride (46.8 g, 222 mmol) in 78 ml of acetonitrile at 0 ° C . The mixture was stirred at 0 ° C for 40 minutes, and sodium carbonate (18.4 g) was added slowly. After 20 minutes, 1,1- of the acid (IS, 4S) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid was added.

(Aldrich, 2.3 g, 11.6 mmol). The mixture was stirred at 0 ° C at room temperature overnight. Ethyl acetate (700 ml) was added and the mixture was washed with brine (4x 100 ml), dried, filtered, and evaporated to give the crude product. Purification of column chromatography ('silica gel, 20-75% EtOAc / hexanes) gave 5- (1-methyl-6-oxo-4- (2-chloro-4-pyridinyl) -1,6-dihydro -2-pyrimidinyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylic acid 1,1-dimethylethyl ester. MS (ES +): 418.3 (M + H) Step D: 2- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6- [2- ((SS) - 1-phenylethyl) -amino) -pyridin-4-yl] -3H-pyrimidin-4-one The title compound was made from 5- (l-methyl-6-oxo-4- (2-chloro-4 -pyridin) -1,6-dihydro-2-pyrimidinyl) -2,2-diazabicyclo [2.2 -.1] heptane-2-carboxylate of 1,1- dimethylethyl according to the procedures described in Example 3. MS (ES +): 403.4 (M + H) A Example 23 (S) -. { 4- (5- (5-tert-butyl- (SS, S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl ] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine Step A: To 250 ml of RBF, trans-4-hydroxy-L-proline, (2S, 4R) -4- acid was added hydroxy-pyrrolidine-2-carboxylic acid (13.1 g, 100 mmol), and 50 ml of absolute ethanol The above mixture was cooled to below 0 ° C and saturated with HCl gas until all the suspension was dissolved. refluxed under nitrogen for 2 h.The mixture was cooled below room temperature, and all the solvent was removed by vacuum.The residue was kept in the refrigerator for 15 h, the white precipitate was filtered and washed with 3 x 50 ml of ether anhydrous, to obtain the (2S, 4R) -4-hydroxy-pyrrolidine-2-carboxylic acid ethyl ester HCl salt as a white solid. MS (ES +): 160 (M + H) +. Step B: The mixture of 19.5 g (100 mmol) of (2S, 4R) -4-hydroxy-pyrrolidine-2-carboxylic acid ethyl ester HCl salt in 250 ml of IN NaOH was cooled below 0 ° C and stirred under nitrogen. The mixture was treated with 26 g (Boc) 20, and the mixture was stirred at 0 ° C at room temperature for 1 h. The mixture was quenched rapidly with 100 ml of saturated NH 4 Cl, extracted with 3 x 100 ml of ethyl acetate. The combined organic was washed with 50 ml of brine, and dried over anhydrous Na2SO4. After purification by flash chromatography, 23 g of 1-tert-butylester 2-ethyl ester of (2S, 4R) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid as the white solid.

MS (ES +): 260 (M + H) A Step C: The mixture of 5.2 g (20 mmol) of 1-tert-butylester 2-ethyl ester of (2S, 4R) -4-hydroxypyrrolidine-1,2-dicarboxylic acid in 100 ml of THF was treated with 0.76 g (20 mmol) of LAH at 0 ° C. The mixture was stirred at 0 ° C at room temperature for 3.5 h. The mixture was cooled to below 0 ° C, the excess LAH was quenched with 10 ml of ethyl acetate. The saturated NHC1 was carefully added until the white precipitate was formed, filtered and washed with 3 x 100 ml of ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. After purification by flash chromatography, (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butylester was obtained as a colorless oil. MS (ES +): 218 (M + H) A Step D: The mixture of 4.0 g (18 mmol) of (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butylester in 20 ml of pyridine was cooled to below 0 ° C and stirred- under nitrogen. The mixture was treated with 14 g (mmol 74) of TsCl. The mixture was stirred at room temperature for 15 h. The mixture was added to 100 ml of ice water and stirred for 10 minutes. The pale yellow solid was collected and further purified by flash chromatography, yielding 6.7 g of (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butylester protected with Ts as a solid. White color. MS (ES +): 548 (M + H) +. Step E: The mixture of 0.52 g (1 mmol) of 6.7 g of (2S, 4R) -4-hydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butylester protected with Ts, and 1.1 ml (10 mmol) ) of tert-butylamino in 10 ml of toluene was heated to 110 ° C in a sealed tube and stirred for 15 h. The mixture was cooled to below room temperature, all the solvent was removed by vacuum, and purified by flash chromatography. The tert-butylester of acid (SS, 4S) -5-tert-butyl-2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid was obtained as a white solid. MS (ES +): 255 (M + H) A Step F: To 50 ml of RBF 0.12 g (0.47 mmol) of (1S, 4S) -5-tert-butyl-2, 5-tert-butylester was added. diaza-bicyclo [2, 2, 1] heptane-2-carboxylic acid, 10 ml of methanol and stirred at room temperature under nitrogen. The mixture was treated with 2.5 ml of 4N HCl in dioxane and stirred at room temperature for 1 h. The solvent was removed in vacuo to give crude (S, 4S) -2-tert-butyl-2,5-diaza-bicyclo [2.2.1] heptane as a pale yellow solid. MS (ES +): 155 (M + H) A Stage G: The mixture of crude (1S, 4S) -2-tert-butyl-2, 5-diaza-bicyclo [2.2.1] heptane in 20 ml of DCM was treated in 0.245 ml of DIEA (1.3 mmol) and 0.124 g (0.6 mmol) of 5-chloro-7- (2-chloro-pyridin-4-yl) -imidazo [1,2-c] pyrimidine. The mixture was stirred at room temperature under nitrogen for 15 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of NaHCO 3, dried over saturated Na 2 SO 4. After purification by flash chromatography, (S, S) -7- (2-chloro-pyridin-4-yl) -5- (5-tert-butyl-2,5-diaza-bicyclo [2.2. 1] hept-2-yl) -imidazo [1,2-c] pyrimidine as the yellow solid. MS (ES +): 383 (M + H) +. Step H: To 100 ml of RBF, (S, S) -7- (2-chloro-pyridin-4-yl) -5- (5-tert-butyl-2,5-diaza-bicyclo [2.2. 1] hept-2-yl) -imidazo [1,2-c] pyrimidine (0.15 g, 0.39 mmol), 20 ml of toluenes, and (S) -a-methylbenzylamine (0.061 0.47 mmol). The mixture was degassed by bubbling nitrogen for 1 h. Then Pd (OAc) 2 (9 mg, 0.039 mmol), BINAP (25 mg, 0.039 mmol) and NaOtBu (0.075 g, 0.78 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous NaS0. After purification by flash chromatography, obtaining the title compound as a pale yellow solid. MS (ES +): 468 (M + H) Example 24 (S) -. { 4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} - [1- (2-Fluoro-phenyl) -ethyl] -amine The title compound was analogously synthesized by the method described in Example 1. The 2-bromo- benzoic acid, was used instead of 2-bromo-4-fluoro-benzoic acid. 1- (2-Fluoro-phenyl) -ethylamine was used instead of 1-phenyl-ethylamine. MS (ES +): 427 (M + H) +; 425 M-H) ".

Example 25 (S) -. { 4- [5- (5-isopropyl-6-methyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidine-7 -yl] -pyridin-2-il} - (1-phenyl-ethyl) -amine Step A: The mixture of 4.2 (16.2 mmol) of 1-tert-butylester 2-ethyl ester of (2S, 4R) -4-hydroxy-pyrrolidine-1,2-dicarboxylic acid in 20 ml of DMF was treated with 1.65 g (24.3 mmol) of imidazole, and 5.1 ml (19.5 mmol) of TBDPSC1 therefore at 0 ° C. The mixture was stirred at 0 ° C at room temperature for 2 h. The mixture was diluted with 200% ethyl acetate, washed with 3 x 50 ml of H20, 50 ml of brine, and dried over anhydrous Na2SO4. After purification by flash chromatography, the tert-butylester of (2S, 4R) -4-TBDPShydroxy-2-acid was obtained hydroxymethyl-pyrrolidine-1-carboxylic acid as a colorless oil. MS (ES +): 498 (M + H) +. Step B: The mixture of 1.0 g (2 mmol) of tert-butyl ester-r of (2S, 4R) -4-TBDPShydroxy-2-hydroxymethyl-pyrrolidine-1-carboxylic acid and 0.23 g (2.4 mmol) of HCl salt N, 0-dimethylhydroxylamine in 50 ml of THF was cooled to below 0 ° C and stirred under nitrogen. The mixture was treated with 7.2 ml (10 mmol) of MeMgBr dropwise. The mixture was stirred at 0 ° C at room temperature for 4 h. The mixture was added to 100 ml of ice water containing 10 ml of IN HCl and stirred for 10 minutes. The mixture was 3 x 50 of ethyl acetate extracted. The combined organics was washed with 50 ml brine, dried over anhydrous Na2SO4. After purification by flash chromatography, (2S, 4R) -2-acetyl-4-TBDPShydroxy-pyrrolidine-1-carboxylic acid tert-butylester is obtained as a pale yellow oil. MS (ES +): 468 (M + H) +. Step C: The mixture of 0.65 g (1.39 mmol) of (2S, 4R) -2-acetyl-4-TBDPShydroxy-pyrrolidine-1-carboxylic acid tert-butylester in 20 ml of THF / H20 (9: 1) was treated with 0.11 g (2.78 mmol) of NaBH at 0 ° C. The mixture was stirred at 0 ° C at room temperature for 2 h, diluted with 100 ml of ethyl acetate, washed with saturated NaHCO3, dried over anhydrous Na2SO4. After purification by flash chromatography, tert-butyl ester is obtained from (2S, 4R) -4-TBDPShydroxy-2- (1-hydroxy-ethyl) -pyrrolidine-1-carboxylic acid as a pale yellow oil. MS (ES +): 47O (M + H) +. Step D: The mixture of 0.36 g (0.77 mmol) of (2S, 4R) -4-TBDPShydroxy-2- (1-hydroxy-ethyl) -pyrrolidine-1-carboxylic acid tert-butylester in 10 ml of THF was treated with 1.2 ml (1.15 mmol) of TBAF at 0 ° C. The mixture was stirred at 0 ° C at room temperature for 1 h, filtered through Celite, and washed with 3 x 50 ml of ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4. The solvent was removed by vacuum to give tert-butylester of crude (2S4R) -4-hydroxy-2- (1-hydroxy-ethyl) -pyrrolidine-1-carboxylic acid as a pale yellow oil. MS (ES +): 242 (M + H) +. Step E: The mixture of 0.18 g of (2S, R) -4-hydroxy-2- (1-hydroxyethyl) -pyrrolidine-1-carboxylic acid tert-butylester in 10 ml of pyridine was cooled below 0 ° C and stirred under nitrogen. The mixture was treated with 0.6 g (3.1 mmol) of TsCl. The mixture was stirred at room temperature for 15 h. After all the solvent was removed by vacuum, the residue was diluted with 100 ml of DCM, washed with 3 x 50 ml of H20, 50 ml of brine, dried over anhydrous Na2SO4. The solvent was removed in vacuo to give the (2S, 4R) -4-hydroxy-2- (1-hydroxy-ethyl) -pyrrolidine-1-tert-butylester. carboxylic protected with crude Ts as a pale yellow solid. MS (ES +): 540 (M + H) Step F: The mixture of tert-butylester of the acid (2S), 4R) -4-hydroxy-2- (1-hydroxy-ethyl) -pyrrolidine-1-carboxylic acid protected with crude Ts, and 0.6 ml (7.4 mmol) of isopropylamine in 10 ml of toluene was heated to 130 ° C in a tube sealed and agitated for 15 h. The mixture was cooled to below room temperature, all the solvent was removed by vacuum, and purified by flash chromatography. The tert-butylester of 5-isopropyl-6-methyl-2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid was obtained as a white solid. MS (ES +): 255 (M + H) Step G: To 50 ml of RBF was added 30 mg (0.12 mmol) of (1S, 4S) -5-isopropyl-6-methyl-2, tert -butylester. -diazabicyclo [2.2.1] heptane-2-carboxylic acid and 2 ml of methanol and the mixture was stirred at room temperature under nitrogen. The mixture was treated with and 0.5 ml of 4N HCl in dioxane and stirred at room temperature for 1 h. The solvent was removed in vacuo to give crude (1S, 4S) -2-isopropyl-3-methyl-2, 5-diaza-bicyclo [2.2.1] heptane as a pale yellow solid. MS (ES +): 155 (M + H) A Step H: A mixture of 20 mg of (lS, 4S) -2-isopropyl-3-methyl-2, 5-diaza-bicyclo [2.2.1] heptane crude in 20 ml of DCM was treated in 0.1 ml of DIEA and 40 mg of 5-chloro-7- (2-chloropyridin-4-yl) -imidazo [1,2-c] pyrimidine. The mixture was stirred at room temperature under nitrogen for 15 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3, dried over anhydrous Na 2 SO 4. Purification by flash chromatography gave (S, S) -7- (2-chloro-pyridin-4-yl) -5- (5-isopropyl-6-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazole [1,2-c] pyrimidine as a yellow solid. MS (ES +): 383 (M + H) A Step I: To 100 ml of RBF, (7- (2-chloro-pyridin-4-yl) -5- (5-isopropyl-6-methyl-2) was added. , 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidine (20 mg), 20 ml of toluene, and (S) -a-methylbenzylamine (0.061 ml, 0.47 The mixture was degassed by bubbling nitrogen for 1 h, then Pd (OAc) 2 (9 mg, 0.039 mmol), BINAP (25 mg, 0.039 mmol) and NaOtBu (0.075 g, 0.78 mmol) were added. The mixture was heated to 90 ° C and stirred for 2 h under nitrogen.The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 saturated NaHCO3, and dried over anhydrous Na2SO4. purification by flash chromatography, the title compound is obtained as a pale yellow solid MS (ES +): 468 (M + H) Example 26 2- . { 2- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2. 2, 1] hept-2-yl) -6- [2- (S) - (1-phenyl-ethylamino) -pyridin-4-yl] -pyrimidin-4-ylamino) -ethanol Step A: To 250 ml 'of RBF were added 4-chloro-6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidine (0.54 g, 2.0 mmol), 50 mL of CH3CN, 2-aminoethanol (0.24 mL, 4.0 mmol), K2CO3 (0.27 g, 2.0 mmol). The mixture was refluxed under nitrogen for 4 h, and all the starting material was converted. The reaction mixture was cooled to below room temperature, diluted with 200 ml of ethyl acetate, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by flash chromatography, the intermediate of 2- [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-4-yl) -2-methylsulfanyl-pyrimidin-4-ylamino] - ethanol. MS (ES +): 297 (M + H) +. Step B: A mixture of 0.47 g (1.58 mmol) of 2- [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin-4-ylamino] - Ethanol in 3 ml of DMF was stirred at 0 ° C under nitrogen. The mixture was treated with 0.45 ml (1.74 mmol) of TBDPSC1 and stirred at 0 ° C at room temperature for 15 h. The mixture was diluted with 100 ml of ethyl acetate, washed with 3 x 50 ml of H20, 20 ml of brine, dried over anhydrous Na2SO4. After purification by flash chromatography, the intermediate of [2- (tert-butyl-diphenylsilanyloxy) -ethyl] - [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin- was obtained. 4-yl] -amine. MS (ES +): 535 (M + H) +. Step C: A mixture of 0.73 g (1.36 mmol) of 2- (tert-butyl-diphenyl-silanyloxy) -ethyl] - [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin-4 -yl] -amine in 20 ml of THF was treated with 0.5 g (0.82 mmol) of Oxone and mg 41 mg (0.136 mmol) of tetrabutylammonium nitrate in 4 ml of H20 at 0 ° C. The mixture was stirred at 0 ° C for 4 h, all the starting material was converted. The reaction mixture was treated with 10 ml of saturated Na2S203, extracted with 3 x 50 ml of DCM and dried with anhydrous Na2SO4. After purification by flash chromatography, the intermediate of [2- (tert-butyl-diphenyl-silanyloxy) -ethyl] - [6- (2-chloro-pyridin-4-yl) -2-methylsulfanyl-pyrimidin- was obtained. 4-yl] -amine. MS (ES +): 551 (M + H) Step D: To 100 ml of RBF were added [2- (tert-butyl-diphenyl-silanyloxy) -ethyl] - [6- (2-chloro-pyridin-4-yl) ) -2-methylsulfanyl-pyrimidin-4-yl] -amine (0.5 g, 0.91 mmol), 10 ml DMF, hydrochloride salt (S) -2-isopropyl-2,5-diaza-bicyclo [2.2.1] heptane (0.23 g, 1.1 mmol), K2C03 (0.313 g, 2.28 mmol). The mixture was stirred at 100 ° C under nitrogen for 15 h, and all the starting material was converted. The reaction mixture was cooled below room temperature, diluted with 100 ml of DCM, washed with 50 ml of saturated NaHCO3, 3 x 50 ml of H2O, 20 ml of brine, and dried over anhydrous Na2SO4. After purification by flash chromatography, the intermediate of [2- (tert-butyl-diphenyl-silanyloxy) -ethyl] - [6- (2-chloro-pyridin-4-yl) -2- (5-isopropyl) was obtained. -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -pyrimidin-4-yl] -amine. MS (ES +): 627 (M + H) +. Step E: To a 100 ml round bottom flask, [2- (tert-butyl-diphenyl-silanyloxy) -ethyl] - [6- (2-chloro-pyridin-4-yl) -2- (5 -isopropyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -pyrimidin-4-yl] -amine (0.35 g, 0.6 mmol), 50 ml of toluene, and (S) -a- methylbenzylamine (0.11 ml, 0.84 mmol). The mixture was degassed by bubbling nitrogen for 1 h. Then Pd (0Ac) 2 (14 mg, 0.06 mmol), BINAP (37 mg, 0.06 mmol) and NaOtBu (0.12 g, 1.2 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous Na2SO4. After purification by flash chromatography, the intermediate of [2- (tert-butyl-diphenyl-silanyloxy) -ethyl] - was obtained. { 2- (5-isopropyl-2, 5-diaza-bicyclo [2.2.1] ept-2-yl) -6- [2- (1-phenyl-ethylamino) -pyridin-4-yl] - pyrimidin-4-yl} -amine as a solid of pale yellow color. MS (ES +): 712 (M + H) +. Step F: [2- (tert-Butyl-diphenyl-silanyloxy) -ethyl] -. { 2- (5-isopropyl-2,5-diaza-bicyclo [2.2.] Hept-2-yl) -6- [2- (1-phenyl-ethylamino) -pyridin-4-yl] -pyrimidin-4-yl } -amine (0.15 g, 0.2 mmol) in 10 ml of THF was stirred at 0 ° C under nitrogen and treated with 0.32 ml (0.32 mmol) of TBAF (1.0 M in THF), and stirred for 1 h. The mixture was rapidly quenched with 20 ml of saturated NHC1, extracted with 3 x 50 ml of DCM. The combined organics were dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound is obtained as a pale yellow solid. MS (ES +): 474 (M + H) +. Example 27 (S) -. { 4- [5- (5-n-butyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl ] -pyridin-2-il} - (1-phenyl-ethyl) -amine A solution of 25 mg (0.06 1 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 1 ml of chloroform was treated with 0.011 ml (0.12 mmol) of butyraldehyde and 26 mg (0.12 mmol) of NaBH 3 (CN) before 1 ml of methanol was then added. The mixture was stirred at room temperature for 15 h when the MS showed that all the starting materials had been converted to the product. The reaction mixture was diluted with 20 ml of DCM, washed with 20 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by chromatography, the title compound was obtained. MS (ES +): 468 (M + H) +. Example 28 (S) -. { 4- [5- (5- (2.2.2-trifluoro-l-methyl-ethyl) - (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1 , 2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine A solution of 40 mg (0.098 mmol) of. { 4- [5- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 1 ml of chloroform was treated with 1 ml (large excess) of trifluoroacetone and 62 mg (0.29 mmol) of NaBH 3 (CN) followed by the addition of 1 ml of methanol. The mixture was stirred at room temperature for 15 h when it was cooled rapidly before complete conversion of the product. The reaction mixture was diluted with 20 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a mixture of diastereomers (9: 1 by CLAP). EM (ES +): 508 (M + H) +. Example 29 (S) -. { 4- [5- (5-sec-butyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] -pyrimidin-7- il] -pyridin-2-il} - (1-phenyl-ethyl) -amine A solution of 130 mg (0.32 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 3 ml of chloroform was treated with 0.29 ml (3.2 mmol) of 2-butanone and 210 mg (1.0 mmol) of NaBH3 (CN), followed by the addition of 5 ml of methanol The mixture was stirred at room temperature for 3 h when the MS showed that all the starting materials had been converted to the product. The reaction mixture was diluted with 50 ml of DCM, washed with 50 ml of NaHCO3 saturated, and dried over anhydrous Na2SO4. After purification by CLAP, the title compound was obtained. MS (ES +): 468 (M + H) +. Example 30 (S) -. { 4- [5- (5-cyclopentyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin- 2-il} - (1-phenyl-ethyl) -amine A solution of 120 mg (0.28 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 3 ml of chloroform was treated with 0.25 ml (2.8 mmol) of cyclopentanone and 180 mg (0.84 mmol) of NaBH 3 (CN), followed by the addition of 5 ml of methanol. It was stirred at room temperature for 3 h when the MS showed that all the starting materials had been converted to the product. The reaction mixture was diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by CLAP, the title compound was obtained. MS (ES +): 480 (M + H) +. Example 31 (S) -. { 4-. { 5- (5-methyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2 -il} - (1-phenyl-ethyl) -amine A solution of 96 mg (0.23 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 3 ml of methanol was treated with 0.17 ml (2.3 mmol) of formaldehyde (37% in water) and 150 mg (0.70 mmol) of NaBH3 (CN). The mixture was stirred at room temperature for 1 h when the MS showed that all the starting materials had been converted to the product. The reaction mixture was diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by CLAP, the title compound was obtained. MS (ES +): 426 (M + H) +. Example 32 (S) -. { 4- [5- (5-propyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] - pyridin-2-yl} - (1-phenyl-ethyl) -amine A solution of 113 mg (0.27 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 2.5 ml of chloroform was treated with 0.20 ml (2.7 mmol) of propionaldehyde and 180 mg (0.82 mmol) of NaBH3 (CN), followed by the addition of 2.5 ml of methanol. The mixture was stirred at room temperature for 1 h when the MS showed that all the materials of start had been converted to the product. The reaction mixture was diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by CLAP, the title compound was obtained. MS (ES +): 454 (M + H) +. Example 33 (S) -. { 4- [5- (5-isobutyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin- 2-il} - (1-phenyl-ethyl) -amine A solution of 110 mg (0.26 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 2.5 ml of chloroform was treated with 0.24 ml (2.6 mmol) of isobutyraldehyde and 170 mg (0.78 mmol) of NaBH 3 (CN), followed by the addition of 2.5 ml of methanol. The mixture was stirred at room temperature for 1 h when the MS showed that all the materials of start had been converted to the product. . The reaction mixture was diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification of CLAP, the title compound was obtained. MS (ES +): 468 (M + H) +. Example 34 (S) -. { 4-. { 5- (5-benzyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2 -il} - (1-phenyl-ethyl) -amine A solution of 100 mg (0.24 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 2.5 ml of chloroform was treated with 0.25 ml (2.4 mmol) of benzaldehyde and 160 mg (0.73 mmol) of NaBH3 (CN), followed by the addition of 2.5 ml of methanol. The mixture was stirred at room temperature for 5 minutes when the MS showed that all the starting materials had been converted to the product. The reaction mixture was diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4.

After purification of CLAP, the title compound was obtained. MS (ES +): 5.02 (M + H) +. Example 35 (S) -. { 4- [5- (5- (2-phenoxy-ethyl) - (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidine -7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine To a solution of 100 mg (0.24 mmol) of. { 4- [5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine and 70 mg (0.48 mmol) potassium carbonate in 5 ml of acetonitrile was treated with 0.074 ml (0.48 mmol) of β-bromophenetol at 0 ° C. The mixture was stirred at 50 ° C for 8 h before cooling to room temperature for 16 h at which time EM showed that all the starting materials had been converted to the product. The reaction mixture was diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by chromatography, the title compound was obtained. MS (ES +): 532 (M + H) +.

Example 36 (S) -. { 4- [5- (5- (2-phenoxy-propyl) - (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidine -7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine A solution of 50 mg (0.12 mmol) of. { 4-. { 5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine and 30 mg (0.24 mmol) of potassium carbonate in 2 ml of acetonitrile, was treated with 0.040 ml (0.24 mmol) of 3-phenoxy-propyl bromide at 0 ° C. The mixture was stirred at 50 ° C for 16 h at which time the MS showed that all the starting materials had been converted to the product. The reaction mixture was cooled to room temperature, diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4. After purification by CLAP, the title compound was obtained. MS (ES +): 546 (M + H) +.

Example 37 (S) -. { 4-. { 5- (5- (2-phenoxy-propyl) - (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidine-7- il] -pyridin-2-il} - (1-phenyl-ethyl) -amine A solution of 100 mg (0.25 mmol) of. { 4-. { 5- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 20 ml of methanol was treated with 5 ml (excess) of propylene oxide at 0 ° C. The mixture was stirred at room temperature for 16 h at which time the MS showed that all the starting materials had been converted to the product. The reaction mixture was cooled to room temperature and concentrated in vacuo. After purification by chromatography, the title compound was obtained. MS (ES +): 470 (M + H) +.

Example 38 (S) - (4- { 5- [5- (2, 2-difluoro-ethyl) - (SS, 4S) -2, 5-diaza-bicyclo [2. "2. L] hept-2 -yl] -imidazo [1, 2-c.] pyrimidin-7-yl.} - pyridin-4-yl) - (1-f-enyl-ethyl) -amine Step A: 7- (2-chloro- pyridin-4-yl) -5- [5- (2, 2-difluoro-ethyl) -2,5-diaz-a-bicyclo [2.2.1] -hept-2-yl] -imidazo [1, 2 -c] pyrimidine To a RBF was added 5-chloro-7- (2-chloro-pyridin-4-yl) -lmidazo [1,2-c] pyrimidine (54 mg, 0.17 mmol), 2,2-difluoroethyl ester of the trifluoromethanesulfonic acid (32 mg, 0.18 mmol), K2CO3 (27 mg, 0.20 mmol), and 5 mL of acetonitrile The mixture was stirred at reflux under nitrogen for 4 h, at which time no starting material was observed. The reaction mixture was cooled to room temperature, diluted with 50 ml of DCM, washed with 50 ml of saturated NaHCO 3, and dried over anhydrous Na 2 SO 4 After purification by silica gel chromatography, the title compound was obtained. ES +): 391 (M + H) A Stage B: (4-. {5- [5- (2, 2-difluoro-ethyl) -2,5-diaza-bicyclo [2.2.1] hept-2-yl] Imidazo [1,2-c] pyrimidin-7-yl.} - pyridin-4-yl) - (1-f-enyl-ethyl) -amine To a RBF was added 7- (2-chloro-pyridin-4) -il) -5- [5- (2,2-difluoro-ethyl) -2,5-diaza-bicyclo [2.2.1] hept-2-yl] -imidazo [1,2-c] pyrimidine (40 mg, 0.10 mmol), 1 ml of toluene , and (S) - -methylbenzylamine (0.015 ml, 0.11 mmol). The mixture was degassed by bubbling nitrogen through the solution for 1 h. Then Pd (OAc) 2 (2 mg, 0.01 mmol), rac-BINAP (6 mg, 0.01 mmol), and NaOtBu (0.20 mg, 0.21 mmol) were added, the mixture was heated to 90 ° C and stirred for 3 h under nitrogen. The mixture was cooled to below room temperature, diluted with 50 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous Na2SO4. After purification by preparative TLC, the title compound was obtained. MS (ES +): 476 (M + H) +.

Example 39 (S) -. { 4-. { 2- ((1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -thiazol-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amino Step A: To 250 ml of RBF, 2-chloro-isonicotinic acid (7.9 g, 50 mmol), 100 ml of DCM was added. Mix The previous one was cooled to below 0 ° C and treated with 8.7 ml (100 mmol) (C0C1) 2 and 1 ml of DMF. The mixture was heated and refluxed under nitrogen for 2 h. The mixture was cooled to below room temperature, all the solvent was removed by vacuum. The residue was dissolved in CH3CN / THF (1: 1) 100 ml, cooled to below 0 ° C, and treated with 2.0 M TMSCH2CN in hexane (38 mL, 75 mmol). The mixture was stirred at 0 ° C at room temperature for 2 h, all the solvent was removed by vacuum. The residue was dissolved in 100 ml of DCM, cooled to below 0 ° C, and treated with IN HCl in ether (100 ml, 100 mmol). The mixture was stirred at 0 ° C at room temperature for 15 h. The mixture was poured into 100 g of ice, stirred for 30 min, extracted with 3 x 50 ml of DCM. The combined organics were washed with 50 ml of brine, and dried over anhydrous Na2SO4. After purification by flash chromatography, 2-chloro-l- (2-chloro-pyridin-4-yl) -ethanone was obtained as a yellow solid. MS (ES +): 190 (M + H) A Step B: The mixture of 3.75 ml (26.6 mmol) of TMSisothiocyanate in 50 ml of stirred THF under nitrogen was treated with 3.52 g (17.8 mmol) of 2-tert-butylester. , 5-diaza-bicyclo [2.2.1] - heptane-2-carboxylic acid. The mixture was stirred at room temperature for 15 h, then heated to 50 ° C and stirred for 2 h. The mixture was cooled to below 0 ° C, quenched with 20 ml of H20 extracted with 2 x 50 ml of DCM. The combined organics were washed with 50 ml of brine, and dried over anhydrous Na2SO4. After purification by flash chromatography, 5-thiocarbamoyl-2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid tert-butylester was obtained as a pale yellow solid. MS (ES +): 258 (M + H) A Step C: A mixture of 0.19 g (1 mmol) of 2-chloro-1- (2-chloro-pyridin-4-yl) -ethanone and 0.257 g (1 mmol) of 5-thiocarbamoyl-2-tert-butylester , 5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid in 20 ml of ethanol was refluxed under nitrogen in a sealed tube for 2 h. The mixture was cooled below room temperature, all the solvent was removed by vacuum. After purification by flash chromatography, the 2- [4- (2-Chloro-pyridin-4-yl) -thiazol-2-yl] -2,5-diaza-bicyclo [2.2.1] heptane as a pale yellow solid. MS (ES +): 293 (M + H) +. 5- [4- (2-Chloro-pyridin-4-yl) -thiazol-2-yl] -2,5-diaza-bicyclo [2. 2 . l] heptane-2-carboxylic acid, MS (ES +): 393 (M + H) Step D: A mixture of 0.17 g (0.58 mmol) of [4- (2-chloro-pyridin-4-yl) -thiazol-2-yl] -2,5-diaza-bicyclo [2.2. 1] heptane-2-carboxylic acid and 0.089 ml (0.7 mmol) of (S) -a-methylbenzylamine in 50 ml of toluene was degassed by bubbling nitrogen for 1 h. Then Pd (OAc) 2 (13 mg, 0.058 mmol), BINAP (36 mg, 0.058 mmol) and NaOtBu (0.11 g, 1.16 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained in 150 mg as a pale yellow solid. MS (ES +): 378 (M + H) +. Example 40 3-Chloro-l- (2-chloro-pyridin-4-yl) -lH-indazole To a solution of 3-chloroindazole (1 g, 6.6 mmol) in methylene chloride (25 ml) and methanol (25 ml) were added. added 2-chloro-4- (4,4,5, 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyridine (3.6 g, 15 mmol) and copper (II) acetate (1.4 g, 7.5 mmol), followed by triethylamine (2 mL, 15 mmol). The The resulting mixture was stirred vigorously at room temperature for 20 h. The reaction was filtered and the gray solid was discarded. The blue color filtrate was concentrated in vacuo and the residue was dissolved in methylene chloride and washed with saturated sodium bicarbonate and brine and dried over MgSO4. Instantaneous chromatography of the crude product mixture with 25:10:65 and 35:10:55 EtOAc-CH2Cl2-Hexane gave the title compound as a white solid. MS (ES +): 264.0 [M + H] +.

Example 41 (S) - [4- (3-chloro-indazol-1-yl) -pyridin-2-yl] - (1-phenyl-ethyl) -amine To a solution of 3-chloro-l- (2-chloro- pyridin-4-yl) -lH-indazole (0.29 g, 1.1 mmol) in toluene (6 ml) under nitrogen was added palladium acetate (0.025 g, 0.11 mmol), rac-2, 2'-bis (diphenylphosphino) - 1,1'-biphenyl (0.069 g, 0.1 mmol), and (S) - (-) -a-methylbenzylamine (0.18 mL, 1.38 mmol), followed by sodium t-butoxide (0.3 g, 3.1 mmol). Mix The resultant was heated at 70 ° C for 1 h, during which time TLC and CLAR indicated the termination of the reaction. After cooling to room temperature, the reaction was diluted with saturated methylene chloride and washed with saturated sodium bicarbonate and brine and dried over MgSO4. Instantaneous chromatography of the crude product mixture with 25:10:65, 35:10:55, and 50:10:40 EtOAc-CH2Cl2-hexane gave the title compound as a light brown solid. ): 349.3 [M + H] +, 347.1 [MH] ".

Example 42 - Tert-butyl ester. { 1- [2- ((S) -1-phenyl-ethylamino) -pyridin-4-yl] -lH-indazol-3-yl} - (SS, 45) -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid To a solution of 4- (3-chloro-indazol-1-yl) -pyridin-2-yl] - ( 1-phenyl-ethyl) -amine (0.17 g, 0.48 mmol) in toluene (3 ml) under nitrogen was added palladium acetate (0.011 g, 0. 05 mmol), rac-2, 2'-bis (diphenylphosphino) -1,1 '-bubfthyl (0.03 g, 0.05 mmol), and t-butyl (1S, 4S) - (-) -2, 5- diazabicyclo [2.2.1] heptan-2-carboxylate (0.14 g, 0.72 mmol), followed by sodium t-butoxide (0.13 g, 1.3 mmol). The resulting mixture was stirred at 90 ° C for 20 h. After cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate and brine, and dried (MgSO4). Instant chromatography of the crude product mixture with 25:10:65, 40:10:50, 50:10:40, 60:10:30, and 70:10:20 EtOAc-CH2Cl2-Hexane gave the title compound . MS (ES +): 511.4 [M + H] +, 509.2 [M-H] "Example 43 (S) -. { 4- [3- ((Is, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine A tert-butyl ester of 5- acid. { 1- [2- (1-phenyl-ethylamino) -pyridin-4-yl} -lH-indazol-3-il} -2, 5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid (0.044 g, 0.086 mmol) was added 4N HCl in dioxane (1 ml) and a few drops of methanol. After stirring at room temperature for 30 minutes, the reaction was concentrated in vacuo and the residue was partitioned between methylene chloride and stiff sodium bicarbonate; the aqueous layer was extracted again with methylene chloride (2x). The combined organic extract was dried (K2C03), filtered, and concentrated in vacuo. Flash chromatography with 1%, 3%, and 5% 2M NH 3 in MeOH / CHCl 3 gave the title compound as a cream colored solid. MS (ES +): 411.3 [M + H] +, 409.5 [M-H]. " Example 44 (, S) -. { 4- [3- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -undazol-1-yl] pyridin-2-yl} - (1-phenylethyl) -amine To a solution of. { 4- [3- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine (0.03 g, 0.074 mmol) in chloroform (1 ml), acetone (0.5 ml) and sodium triacetoxyborohydride (0.039 g, 0.018 mmol) were added and the solution was stirred at 70 ° C durnate 1 h. After cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate. The aqueous layer was extracted again with methylene chloride (2x). The combined organic extracts were dried (K2C03), filtered, and concentrated in vacuo. Flash chromatography with 1%, 3%, and 5% 2M NH 3 in MeOH / CHCl 3 gave the title compound as an off-white crystal. MS (ES +): 453.3 [M + H] +, 451.4 [M-H]. " Example 45 2,4-dichloro-quinazoline The title compound was synthesized following the procedure described in J. Med. Chem. 1988, 31, 2136. MS (ES +): 199.2 [M + H] A Example 46 - (2-Chloro-quinazolin-4-yl) - (SS, 4S) -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid tert-butyl ester To a solution of 2, 4 Dichloro quinazoline (0.25 g, 1.26 mmol) in isoprapanol (6 ml) was added t-butyl- (1S, 4S) - (-) -2,5-diazabicyclo [2.2.1] heptan-2-carboxilate (0.25 g) g, 1.26 mmol) and the solution was heated at 60 ° C for 4 h.

The reaction was concentrated in vacuo and the residue was chromatographed on silica with 25:10:65, 35:10:55, and 50:10:40 EtOAc-CH2Cl2-Hexane; 1%, 3%, and 5% to give the title compound. MS (ES +): 361.1 [M + H] A Example 47 - [2- (2-Chloro-pyridin-4-yl) -quinazolin-4-yl] - (1S, 4S) -2,5-diaza-bicyclo [2.2.1] heptan- tert -butyl ester 2-carboxylic acid To a solution of 5- (2-chloro-quinazolin-4-yl) -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid tert-butyl ester (0.145 g, in 0.4 mmol) in DME (2 ml) under nitrogen was added palladium acetate (0.0045 g, 0.02 mmol), tri-o-tolylphosphine (0.015 g, 0.048 mmol), and 2-chloro-4- (4,4,5) , 5-tetramethyl- [1,3,2] dioxaborolan-2-yl) pyridine (0.19 g, 0.8 mmol), followed by 2M Na 2 CO 3 (0.6 ml, 1.2 mmol). The resulting mixture was heated at 80 ° C for 20 h. The reaction was diluted with methylene chloride, and washed with saturated sodium bicarbonate and brine and dried (MgSO4).

Instant chromatography of the raw product mixture with :10:65, 35:10:55, and 50:10:40 of EtOAc-CH2Cl2-Hexane gave the title compound. MS (ES +): 438.2 [M + H] +.

Example 48 - Tert-butyl ester. { 2- [2- ((S) -1-phenyl-ethylamino) -pyridin-4-yl} -quinazolin-4-yl] - (1S, 4S) -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid The title compound was synthesized analogously by the procedure described in Example 2 from tert. 5- [2- (2-Chloro-pyridin-4-yl) -quinazolin-4-yl] -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid butyl ester. MS (ES +): 523.3 (M + H) +. Example 49 . { 4- [4- ((ÍS, 4S) -2, 5-diaza-bici.clo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (S) - (1-phenyl-ethyl) -amine The title compound was synthesized analogously by the procedure described in Example 4 starting from tert-bulyl ester of 5- acid. { 2- [2- (1-phenyl-ethylamino) -pyridin-4-yl] -quinazolin-4-yl} 2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid. MS (ES +): 423.3 (M + H) +. Example 50 (S) -. { 4- [2- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -thiazol-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine A mixture of 75 mg (0.2 mmol) of. { 4- [2- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -thiazol-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 5 ml of chloroform was treated with 0.15 ml (2 mmol) of acetone, 120 mg (2 mmol) of NaBH 3 (CN) and 1 ml of methanol consequently. The mixture was stirred at room temperature for 15 h. EM showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3, dried over Na2SO4. After purification by chromatography, it was obtained the title compound as a yellow solid. MS (ES +): 420 (M + H +). Example 51 (S) -. { 4- [4- ((lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl] -quinolin-2-yl] -pyridin-2-yl.} - (1- phenyl-ethyl) -amine Step A: The mixture of 2-chloro-isonicotinic acid (16.8 g, 0.107 mol), 100 ml of absolute ethanol and concentrated H2SO4 (3.28 ml, 0.118 mol) was refluxed under nitrogen for 15 h. After converting all the starting material, the mixture was cooled to room temperature, and all the ethanol was evacuated. The resulting mixture was diluted with 250 ml of ethyl acetate, washed with saturated NaHCO3, dried over anhydrous Na2SO4. Purified by a short column, ethyl ester of 2-chloro-isonicotinic acid was obtained as a pale yellow liquid. MS (ES +): '186 (M + H) Step B: Mix 15 g of 2-chloro-isonicotinic acid ethyl ester (81.4 mmol), and 8.75 ml of ethyl acetate (88 mmol) in 200 ml of THF Anhydrous, was stirred at 0 ° C under nitrogen. The mixture was treated with 100 ml of LHMS (1.0 M in THF) for 30 minutes. The resulting mixture was stirred at 0 ° C-room temperature for 15 h, then rapidly quenched with 200 ml of saturated NH4C1 at 0 ° C and the pH was adjusted to 6-7. The water layer was extracted with ethyl acetate 3 x 50 ml. The combined organics were dried over anhydrous Na2SO4, and purified by column chromatography. Ethyl 3- (2-chloro-pyridin-4-yl) -3-oxo-propionic acid ester was obtained as a pale yellow solid. MS (ES +): 228 (M + H) A Step C: A mixture of 2.2 ml (24.18 mmol) of aniline, 5.49 g (24.18 mmol) of ethyl ester of acid 3- (2-Chloro-pyridin-4-yl) -3-oxo-propionic acid and 0.36 g (2.4 mmol) of TsOH in 100 ml of toluene was refluxed with a Dean-Stark trap for 8 h. 10 ml of diphenyl ether were added and heated at 180 ° C for 2 h. EM showed that all the starting material It was converted to the desired product. The mixture was cooled to room temperature, and a pink solid was precipitated. The solid was filtered and washed with hexane, and was obtained as a brown solid of 2- (2-chloro-pyridin-4-yl) -quinolin-4-ol, MS (ES +): 257 (M + H) Step D: To 250 ml of RBF was added 4.6 g (18 mmol) of 2- (2-chloro-pyridin-4-yl) -quinolin-4-ol and 100 ml of POC13, and the mixture was treated with 3.1 ml of DIEA (18 mmol). The mixture was stirred at room temperature for 1 h, and all the starting material was converted. All P0C13 was subjected to vacuum. The residue was dissolved in 250 ml of DCM, washed with saturated NaHCO3 carefully to pH 8. The organic phase was dried over concentrated Na2SO and purified by column and yielded a pale yellow color of 4-chloro-2- (2-chloro). pyridin-4-yl) -quinoline. MS (ES +): 275 (M + H) A Step E: To 100 ml of RBF was added 1.54 g (5.6 mmol) of 4-chloro-2- (2-chloro-pyridin-4-yl) -quinoline, 1.22 g. (6.16 mmol) of (S) -N-Boc-2, 5-diaza-bicyclo [2.2.1] heptane, 0. 77 g (5.6 mmol) of K2C03 and 20 ml of DMF. The mixture was refluxed under nitrogen for 15 h, and all the Initial material was converted. The reaction mixture was added to 300 ml of ethyl acetate and washed with 3 x 50 ml H20. brine (50 ml), dried over Na 2 SO concentrated and purified by the column, giving a pale yellow color of tert-butyl ester of the acid - [2- (2-Chhoro-pyridin-4-yl) -quinolin-4-yl] -2,5-diaza-bicyclo [2.2.1] hept an-2-carboxylic acid. MS (ES +): 437 (M + H) A Step F: To 250 ml of RBF, 0.6 g (1.38 mmol) of 5- [2- (2-chloro-? Iridin-4-yl) -quinolin tert-butyl ester was added. -4-yl] -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid, 100 ml of toluene, and 0.21 'ml (1.65 mmol) of (S) -io-methylbenzylamine. The mixture was degassed by nitrogen bubbling for 1 h. After Pd (OAc) 2 (15 mg, 0.069 mmol), BINAP (43 mg, 0.069 mmol) and NaOtBu (0.265 g, 2.76 mmol) were added, the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled below room temperature, diluted with 300 ml of DCM, washed with 20 ml of saturated NaHCO3, and dried over anhydrous Na2SO4. After purification by flash chromatography, tert-butyl ester of 5- acid. { 2- [2- (1-f-enyl-ethylamino) -pyridin-4-yl] -quinolin-4-yl} -2, 5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid was obtained as a solid from pale yellow color. MS (ES +): 522 [M + 1] A Step G: To 50 ml of RBF was added 0.35 g (0.67 mmol) of tert-butyl ester of 5- acid. { 2- [2- (1-phenyl-ethylamino) -pyridin-4-yl] -quinolin-4-yl} -2, 5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid, 5 ml of methanol and stirred at room temperature under nitrogen. The mixture was treated with 2.5 ml of 4N HCl in dioxane and was stirred at room temperature for 1 h. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3 and dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as pale yellow colr solid. MS (ES +): 422 (M + H) +. Example 52 (S) -. { 4-. { 4- (5-isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine A mixture of 60 mg (0.14 mmol) of. { 4- [4- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 5 ml of chloroform, was treated with 0. 15 (2 mmol) of acetone, 120 mg (2 mmol) of NaBH 3 (CN) and 1 ml of methanol. The mixture was stirred at room temperature for 15 h. EM showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO 3, dried over anhydrous Na 2 SO.After purification by flash chromatography, the title compound was obtained as a yellow solid MS (ES +) : 464 (M + H) A Example 53 (S) -. { 4- [4- (5-ethyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine A mixture of 60 mg (0.14 mmol) of. { 4- [4- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 5 ml of chloroform, was treated with 0.1 ml (1.8 mmol) of acetaldehyde, 113 mg (1.8 mmol) of NaBH3 (CN) and 1 ml of methanol. The mixture was stirred at room temperature for 15 h. E showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of NaHCO3 saturated and dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES +): 450 (M + H) +.

Example 54 (S) -. { 4-. { 4- (5-methyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenylethyl) -amine A mixture of 60 mg (0.14 mmol) of. { 4- [4- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine in 5 ml of chloroform, was treated with 0.11 ml (1.42 mmol) with formaldehyde with 37% water solution, 113 mg (1.8 mmol) of NaBH3 (CN) and 1 ml of methanol The mixture was stirred at room temperature for 15 h. EM showed that all the starting materials were converted. The mixture was diluted with 100 ml of DCM, washed with 20 ml of saturated NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, the title compound was obtained as a yellow solid. MS (ES +): 436 (M + H) A Example 55 Benzyl- (4- [5- ((1S, 4S) -2-5-diaza-bicyclo [2, 2, l] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] -pyridin-2-yl) -amine Step A: 5- [7- (2-Chloro-pyridin-4-yl) -imidazo [1, 2-c] pyrimidin-5-yl] tert-butyl ester 2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid. To a solution of 5-chloro-7- (2-chloropyridin-4-yl) -imidazo [1,2-c] pyrimidine (3,615 g) in NMP was added tert-butyl ester of the acid 2, 5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid (3 g) followed by potassium carbonate (9.4 g). The reaction mixture was stirred at room temperature overnight. The crude reaction mixture was worked up to give the desired product as a whitish solid. MS (ES +): 497 (M + H) Stage B: 5- tert-butyl ester. { 7- (2-benzylaminopyridin-4-yl) -imidazo [1,2-c] pyrimidin-5-yl] -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid To a solution of tert- 5- [7- (2-chloropyridin-4-yl) imidazo [1, 2-c] pyrimidin-5-yl] -2,5-diaza-bicyclo [2.2. 1] heptan-2-carboxylic acid (1.0 g) in toluene was added benzylamine (0.28 g), palladium acetate (0.16 g), BINAP (0.044 g), and sodium tert-butoxide (0.630 g). The reaction mixture was stirred at 70 ° C under N2 for 2 h. The reaction mixture was cooled below room temperature, then filtered on a pad of celite and chromatographed to give the desired product as a light yellow solid. MS (ES +): 143 (M + H) A Step C: Benzyl- (4- [5- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] ] irimidin-7-yl] -pyridin-2-yl) -amine To a solution of tert-butyl ester of 5- acid. { 7- (2-benzylaminopyridin-4-yl) imidazo [1,2-c] pyrimidin-5-yl] -2,5-diazabicyclo [2.2.1] heptan-2-carboxylic acid (0.207 g) was added MeOH (2 ml) followed by 4N HCl in 1,4-dioxane (5 ml) at room temperature. After 30 minutes, work between dichloromethane and sodium bicarbonate followed by flash column purification afforded the title compound as a whitish solid. MS (ES +): 398 (M + H) A (ES-): 396 (M-H). " Example 56 Bencil- { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] - pyridin-2-yl} -amine Stage D: Bencil-. { 4- [5- (5-isopropyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl} -amine The title compound was synthesized analogously by the method described in Example 55 with the addition of a step. To a solution of benzyl- (4- [5- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl] pyridin-2-yl ) amine (0.400 g) was added chloroform (4 ml) followed by acetone (5 ml), and sodium triacetoxy borohydride (0.600 mg) at 70 ° C. After 30 minutes, work-up between dichloromethane and sodium bicarbonate followed by flash column purification afforded the title compound as an off-white solid. MS (ES +): 440 (M + H) +; (ES-): 438 (M-H) ".

Example 57 . { 4- [5- ((SS, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2- il} - (2-fluorobenzyl) -amine The title compound was synthesized analogously by the method described in Example 1, except that 2-fluorobenzylamine, instead of benzylamine, was used. MS (ES +): 416 (M + H) A (ES-): 414 (M-H). " Example 58 (2-fluoro-benzyl) -. { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] - pyridin-2-yl} -amine The title compound was synthesized analogously by the method described in Example 2, except that 2-Fluorobenzylamine, instead of benzylamine, was used. MS (ES +): 458 (M + H) +; (ES-): 456 (M-H) "Example 59 Benicl. { 4- [5- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl] pyridin-2-yl} methylamine The title compound was synthesized analogously by the method described in Example 1, except that benzylmethylamine, instead of benzylamine, was used. MS (ES +): 412 (M + H) +; (ES-): 410 (M-H). "Example 60 N- (2-carbamoyl-phenyl) -2-chloronic-isonicotinamide To a solution of anthranilamide (2.36 g, 17.33 mmol) in 100 ml of THF at room temperature, 2-chloroisonicotinol chloride (3.35 g, 19.04 mmol) was added. . A Precipitate appeared and the reaction was heated to reflux overnight. The reaction was cooled to room temperature and concentrated. The precipitate was filtered and washed with H20, CH2C12 and Et20 to give N- (2-carbamoyl-phenyl) -2-chloro-isonicotinamide as a light brown solid. MS (ES-): 274 (M-H). "Example 61 2- (2-chloro-pyridin-4-yl) -3H-quinazolin-4-one Sodium hydroxide (5M, 5 ml) was added to a suspension of N- (2-carbamoylphenyl) -2-chloroisonicotinamide in acetone / water (1/1, 100 ml). The reaction was heated to reflux and stirred overnight. The resulting solid was placed in solution with water and adjusted to pH 7 using 5M HCl. The precipitate was filtered and concentrated with toluene (3x) to give 2- (2-chloro-pyridin-4-yl) -3H-quinazolin-4-one as a light brown solid. MS (ES-): 256 (M-H). " Example 62 4-chloro-2- (2-chloro-pyridin-4-yl) -quinazolin To a suspension of 2- (2-chloro-pyridin-4-yl) -3H-quinazolin-4-one (3.20 g, 12.40 mmol ) in POCL3 (32 ml) was added diisopropylethylamine (2.16 ml, 12.40 mmol) at room temperature. The reaction was heated to reflux for 2 h and then cooled and concentrated. The crude product was diluted with CH2C12 and NaHCO3 (saturated) was added. The organic layer was separated, dried over Na 2 SO, filtered and concentrated. The crude product was purified by chromatography on silica gel (3/1 Hex / EtOAc) to give 4-chloro-2- (2-chloro-pyridin-4-yl) -quinazoline as a light yellow solid. MS: 276 (M + H) Example 63 (S) -. { 4- [4- (5-methyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine To a solution of (S) -. { 4- [4- (2,5-diazabicyclo [2.2.1] hept-2-yl) quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine (105 mg, 0.25 mmol) in 2 ml of CHC13 at room temperature, formaldehyde was added (37%, 407 μl, . 00 mmol), NaCNBH3 (47 mg, 0.75 mmol) and MeOH (0.4 ml). The reaction was stirred at room temperature overnight and then NaHCO3 (saturated) was added and the product was extracted with CH2C12. The combined organic layers were dried over Na 2 SO, filtered and concentrated. The crude product was purified by chromatography on silica gel (gradient elution of 1 to 5% MeOH in CH2C12) to give (S) -. { 4-. { 4- (5-methyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-F-enyl-ethyl) -amine as a light yellow solid. MS (ES +): 437 (M + H) +.

Example 64 (S) -. { 4- [4- (5-ethyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine The title compound was synthesized analogously by the method described for (S). { 4-. { 4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine from (S) -. { 4-. { 4- (2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine. The compound was obtained as a white solid. MS (ES +): 451 (M + H) +.

Example 65 (S) -. { 4- [4- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinázolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine The title compound was synthesized analogously by the method described for (S) -. { 4- [4- (5-methyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine from (S) -. { 4- [4- (2, 5-diaza- bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1- phenyl-ethyl) -amine. The compound was obtained as a white solid. MS (ES +): 465 (M + H) A Example 66 (S) -. { 4- [2- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -pyrimidin-4-yl] -pyridin-2-yl} - (1-Phenylethyl) -amino Step A: Ethyl 3- (2-chloro-pyridin-4-yl) -3-oxo-propionic acid ester (0.35 g), 1.54 mmol) was dissolved in aqueous HCl solution (15 ml, 36.5%) and heated to 50 ° C. After 3.5 hours, the reaction mixture was cooled to below room temperature and rapidly cooled with sodium carbonate until no bubbles were generated. The reaction mixture was extracted with EtOAc (3x35 ml) and the organic layers were combined, dried over MgSO and concentrated to give the product 1- (2-chloro-pyridin-4-yl) -ethanone as an off-white solid. Step B: 1- (2-Chloro-pyridin-4-yl) -ethanone (0.22 g, 1.41 mmol) was dissolved in N, N-dimethylacetal (25 ml) and heated reflux overnight. After that, the reaction mixture was cooled to below room temperature. Evaporation of all the solvent under vacuum to give the product 1- (2-chloro-pyridin-4-yl) -3-dimethylamino-propenyone as a yellow solid. MS (ES +): 211 (M + H) A Step C: To a solution of tert-butyl ester of (tert-butoxycarbonylimino-pyrazol-1-yl-methyl) -carbamic acid (0.34 g, 1.09 mmol, 1.00 equivalents) in CH3CN, 2-isopropyl-2,5-diaza-bicyclo [2.2.1] heptane (0.23 g, 1.09 mmol, 1.00 equivalents) and 2.00 equivalents of DIEA were added. The reaction was stirred at room temperature for 13 h, then filtered and extracted with EtOAc (3x50 mL). The combined organic layers were washed with water (1x50 ml) and NaOH (IN, 50 ml), dried over MgSO 4 and concentrated to give the product tert-butyl ester of [t erc-but oxycarbonylimino- (5-isopropyl-2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -methyl] -carbamic acid as a white solid. Step D: To a solution of tert-butyl ester of [tert-butoxycarbonylimino- (5-isopropyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -methyl] -carbamic acid (0.38 g, 0.99 mmol) in methanol was added HCl dioxane (4.0 M, 20 ml). After 30 minutes, the evaporation of all the solvent gave the HCl salt product 5-isopropyl-2,5-diaza-bicyclo [2.2.1] eptan-2-carboxamidine as 280 mg of a yellow solid. MS (ES +): 183 (M + H) A Step E: To a solution of HCl salt 5-isopropyl-2,5-diaza-bicyclo [2.2.1] heptan-2-carboxamidine as a yellow solid ( 0.28 g, 1.10 mmol, 1.00 equivalents) and 1- (2-chloro-? Iridin-4-yl) -3-dimethylamino-propenyone (0.23 g, 1.10 mmol, 1.00 equivalents) in isopropanol, 25 ml of KOH ( 0.19 g, 3.30 mmol, '3.00 equivalents). The reaction mixture was heated to reflux for 2 h, then cooled below room temperature. All the solvent was evaporated and purification by flash chromatography gave the product 2- [4- (2-chloro-pyridin-4-yl) -pyrimidin-2-yl] -5-isopropyl-2,5-diaza-bicyclo [ 2.2.1] -heptane as a yellow solid. Stage F: To a solution of 2-. { 4 - (2-chloro-pyridin-4-yl) -pyrimidin-2-yl] -5-isopropyl-2,5-diazabicyclo [2.2.1] heptane (0.09 g, 0.27 mmol, 1.00 equivalents) in 35 ml of toluene was added (S) -a-methylbenzylamine (0.05 g, 0.41 mmol, 1.50 equivalents). The mixture was degassed by nitrogen bubbling for 15 minutes followed by the addition of Pd (0Ac) 2 (6.13 mg, 0.03 mmol, 0.10 equivalent), BINAP (17.27 mg, 0.03 mmol, 0.10 equivalents) and NaOtBu (0.192 g, 2.0 mmol) were added, The mixture was heated to 70 ° C and stirred during 2. 5 h under nitrogen. The mixture was cooled below temperature. environment, filtered and concentrated. The CLAR purification of Gilson gave the product (S) -. { 4- [2- (5-isopropyl-2,5-diaza-bicyclo [2.2.1] hept-2-yl) -pyrimidin-4-yl] -pyridin-2-yl} - (1-f-enyl-ethyl) -amine as a yellow solid. MS (ES +): 415 (M + H) A Example 67 (S) -benzyl-. { 4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6-fluoro-indazol-1-yl] -pyridin-2-yl} -amine Stage A: Acid. { [chloro (2-bromo-4-fluorophenyl) methylene] hydrazide} -4-methylbenzenesulfonic acid To a solution of 2-bromo-4-fluoro-benzoic acid (10 g), thionyl chloride (50 ml) was added. The reaction mixture was stirred at 80 ° C for 1 h. The mixture of reaction was cooled, and thionyl chloride was removed. To a solution of 2-bromo-4-fluoro-benzoyl chloride (10.87 g) in dichloromethane, p-toluenesulfonyl hydrazide was added. The heterogeneous reaction was stirred for 1 h at 40 ° C. Work by means of suspension gave the desired intermediate as a blaquecino solid. To 2-bromo-4-fluoro-benzoic acid hydrogenate (16.2 g) thionyl chloride (50 ml) was added. The reaction was stirred at 80 ° C for 1 h. Thionyl chloride was removed and the solid was suspended in heptane to yield the title compound as an off-white solid. MS (ES +): 357 (M + H) A Step B: 5- [(2-Bromo-4-fluoro-phenyl) - ((toluene-4-sulfonyl) -hydrazono) -methyl] tert-butyl ester] -2, 5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid solution. { . { chloro (2-bromo-4-fluorophenyl) methylene] hydrazide} -4-methylbenzenesulfonic acid (5.0 g) in THF, 2,5-diaza-bicyclo-tert-butyl ester [2.2. 1] heptan-2-carboxylic acid (5.8 g). The reaction mixture was stirred at 65 ° C under N2 overnight. The reaction mixture was cooled to room temperature. Work between dichloromethane and sodium bicarbonate followed by the flash column purification afforded the title compound as an off-white solid. MS (ES +): 567 (M + H) +; (ES-): 565 (M-H) ".

Step C: 5- [6-f luoro-1- (toluene-4-sulfonyl) -lH'-indazol-3-yl] -2,5-diaza-bicyclo [2.2.1] acid tert-butyl ester Heptan-2-carboxylic acid To a solution of 5 - [(2-bromo-4-fluoro-f-enyl) - ((toluene-4-sulfonyl) -hydrazono) -methyl] - 2,5-tert-butyl ester -diaza-bicyclo [2.2.1] hept an-2-carboxylic acid (3.3 g) in isopropanol (30 ml) potassium carbonate was added (1.0 g), and copper iodide (0.026 g). The reaction mixture was stirred at 84 ° C under N2 for 30 minutes. The reaction was cooled to room temperature, and 60 ml of H20 were added. The reaction was stirred at 0 ° C for 15 minutes, and the solid was filtered and dried under vacuum to yield the title compound as an off-white solid. MS (ES +): 487 (M + H) A Step D: 5- (6-Fluoro-lH-indazol-3-yl) -2,5-diaza-bicyclo [2.2.1] heptan tert-butyl ester -2-carboxylic acid To a solution of 5- [6-fluoro-l-toluene-4-sulfonyl) -lH-indazol-3-yl] -2,5-diaza-bicyclo-tert-butyl ester [2.2.1] ] heptan-2-carboxylic acid (2.5 g) in 20 ml of 1: 1 ethanol: H20, potassium hydroxide (1 g) was added. The reaction was stirred at 78 ° C for 16 h, then cooled to room temperature and acidified to pH 5 with HCl. Ethanol was evaporated, work between dichloromethane "and sodium bicarbonate followed by the flash column purification afforded the title compound as an off-white solid MS (ES +): 333 (M + H) A (ES-): 331 (M-H)". Step E: 5- [1- (2-Chloro-pyridin-4-yl) -6-fluoro-lH-indazol-3-yl] -2,5-diaza-bicyclo-tert-butyl ester [2.2.1] ] heptan-2-carboxylic acid To a solution of 5- (6-fluoro-lH-indazol-3-yl) -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid tert-butyl ester ( 600 mg) in toluene (10 ml), was added 2-chloro-4-iodo-pyridine (519 mg), copper iodide (17 mg), potassium phosphate (807 mg) and cyclohexane-1,2-diamine. The reaction was stirred at 80 ° C overnight, cooled to room temperature, work-up between dichloromethane and sodium bicarbonate followed by flash column purification afforded the title compound as an off-white solid. MS (ES +): 444 (M + H) +. Stage F: 5- Tert-butyl ester. { 6-fluoro-l- [2- (1-phenyl-ethylamino) -pyridin-4-yl} -lH-indazol-3-il} -2, 5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid To a solution of 5- [1- (2-chloro-pyridin-4-yl) -6-fluoro-lH-tert-butyl ester -indazol-3-yl] -2,5-diaza-bicyclo [2.2. l] heptan-2-carboxylic acid (193 mg) in toluene, was added 1-phenylethylamine (0.048 ml), palladium acetate (10 mg), naphthalene biphenyl (27 mg), and sodium tert-butoxide (117 mg). The reaction was stirred at 70 ° C for 2 h, cooled to room temperature, filtered through a pad of celite, and chromatographed to yield the title compound as a white solid. MS (ES +): 529 (M + H) +; (ES-): 527 (MH). "Step G: {. 4- [3- (2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -6-fluoro-indazole-1- il] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine To a solution of 5- {6-fluoro-1- [2- (1-phenyl- ethylamino) -pyridin-4-yl] -lH-indazol-3-yl.} -2,5-diaza-bicyclo [2.2.1] heptan-2-carboxylic acid (160 mg) in MeOH (2 ml) followed by 4N HCl in 1,4-dioxane (5 ml) at room temperature After 30 minutes, work-up between dichloromethane and sodium dicarbonate followed by flash column purification afforded the title compound as an off-white solid MS (ES +) : 429 (M + H) +; (ES-): 427 (MH). " Example 68 Bencil- { 4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6-fluoro-indazol-1-yl] -pyridin-2-yl} -amine The title compound was synthesized analogously by the method described in Example 1, benzylamine, instead of 1-phenylethylamine was used. MS (ES +): 415 (M + H) +; (ES-): 413 (M-H) ". 'Example 69 Bencil- { 4- [3- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl} -pyridin-2-il} -amine The title compound was synthesized analogously by the method described in acid in Example 1. 2-Bromo-benzoic acid, instead of 2-bromo-4-fluoro-benzoic acid was used. MS (ES +): 397 (M + H) +; (ES-): 395 (M-H) A Step A: Synthesis of 4- (2-chloropyridin-4-yl) -6-methyl-2- (methylthio) pyrimidine The mixture of 4-chloro-6- (2-chloropyridin-4-yl) -2- (methylthio pyrimidine (8.7 g, 32 mmol) (for synthesis see Example 1, Step D) in 150 ml of toluene, stirred at room temperature, treated with Pd (PPh3) 4 (0.37 g, 0.32 mmol) and 25.1 ml of 1.4 M MeMgCl in toluene / THF (3: 1). The mixture was heated to 50 ° C and stirred for 2 h. EM showed that all the starting material was converted. The reaction mixture was cooled to below room temperature and quenched with 100 l of saturated NH 4 Cl, extracted with 3 x 100 ml ethyl acetate. The organic The combined extracts were dried over anhydrous NaS0. After purification by flash chromatography, the title compound was obtained. MS (ES +): 252 (M + H) A Step B: Synthesis of 4- (2-chloropyridin-4-yl) -6-methyl-2- (methylsulfonyl) pyrimidine The mixture of 4- (2-chloropyridin-4-yl) -6-methyl-2- (methylthio) pyrimidine (4.9 g, 19.5 mmol), oxone (18 g, 29.3 mmol) in methanol / H20 (9: 1) was stirred at room temperature for 2 h. EM showed that all the starting material was converted. The reaction mixture was quenched rapidly with 100 ml of saturated Na 2 SO 3, extracted with DCM 3 x 100 ml.

The combined organics were dried over anhydrous Na2SO4.

After purification by flash chromatography, the title compound was obtained. MS (ES +): 268 (M + H) A Step C: Synthesis of 5- (4- (2-chloropyridin-4-yl) -6-methylpyrimidin-2-yl) -2,5-diaza-bicyclo [2.2 .1] tere-butyl heptan-2-carboxylate The mixture of 4- (2-chloropyridin-4-yl) -6-methyl-2- (methylsulfonyl) pyrimidine (6.17 g, 23 mmol), 2,5-diaza -bicycle [2.2. l] tert-butyl heptan-2-carboxylate (4.8 g, 24.3 mmol) and potassium carbonate (3.2 g, 23 mmol) in 80 DMF, was stirred at 80 ° C under nitrogen for 1 h. The reaction mixture was cooled to below room temperature and diluted with 300 ml of ethyl acetate. The mixture was washed with 3 x 100 ml of water, and 100 ml of brine. The organic was dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained. MS (ES +): 402 (M + H) +. Step D: Synthesis of 5- (4-methyl-6- (2- ((S) -1-phenylethylamino) pyridin-4-yl) pyrimidin-2-yl) -2,5-diaza-bicyclo [2.2.1 ] tert-butyl heptan-2-carboxylate To 100 ml of RBF, 5- (4- (2-chloropyridin-4-yl) -6-methylpyrimidin-2-yl) -2,5-diaza-bicyclo [ 2.2.1] tert-butyl heptan-2-carboxilate (4.0 g, 10 mmol), 100 ml of toluene, and (S) -a-methylbenzylamine (1.93 ml, 15 mmol). The mixture was degassed by bubbling nitrogen for 1 h. After adding Pd (OAc) 2 (224 mg), BINAP (622 mg, 1.0 mmol) and NaOtBu (1.92 g, 20 mmol), the mixture was heated to 90 ° C and stirred for 2 h under nitrogen. The mixture was cooled to below room temperature, diluted with 300 ml of DCM, washed with 20 ml of saturated NaHCO3 and dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained as a light yellow solid. MS (ES +): 487 (M + H) A Step E: 4- (2- (2,5-diaza-bicyclo [2.2.1] heptan-2-yl) -6-methylpyrimidin-4-yl) -N - ((S) -1-phenylethyl) pyridin-2-amine The mixture of 4.24 g (8.7 mmol) of 5- (4-methyl-6- (2- ((S) -1-phenylethylamino) pyridin-4-yl) pyrimidin-2-yl) -2,5-diaza- bicycles { 2.2.1] tert-butyl heptan-2-carboxilate in 10 ml of methanol stirred at 0 ° C under nitrogen, treated with 20 ml of 4 M HCl in dioxane, and stirred for 1 h at room temperature. EM showed that all the raw material was converted. The reaction mixture was diluted with 300 ml of DCM, and washed carefully with saturated NaHCO 3. The organic was dried over anhydrous Na2SO4. After purification by flash chromatography, the title compound was obtained. MS (ES +): 387 (M + H) +. 10. Example 71 4- (2- (5-isopropyl-2,5-diaza-bicyclo [2.2.1] heptan-2-yl) -6-methylpyrimidin-4-yl) -N- ((S) -1-phenylethyl) pyridine -2-amine A solution of 4- (2- (2, 5-diaza-bicyclo [2.2.1] heptan-2-yl) -6-methylpyrimidin-4-yl) -N- ((S) -1-phenylethyl) pyridin-2-amine (0.23 g, 0.60 mmol ) in chloroform (5 ml), acetone (1 ml) and sodium triacetoxyborohydride (0.45 g, 2.14 mmol) were added and stirred at 70 ° C for 2 h. During cooling to room temperature, the reaction was diluted with methylene chloride and washed with saturated sodium bicarbonate, brine, and dried over anhydrous K2C03.

Flash chromatography of the crude product with 1% 2M NH3 in MeOH / CHCl3 afforded the title compound as a light yellow solid. MS (ES +): 429 [M + H] The following compounds were synthesized according to various procedures provided in the previous examples, particularly those of Examples 1-4, 13, 15, 21, 22, 40-44 and 45- 49: Example 72: 6- (2- (((1S) -1- (4-fluorophenyl) ethyl) amino) -4-pyridinyl) -3-methyl-2- (5-methyl-2, 5-diazabicyclo [ 2.2.1] hept-2-yl) -4 (3H) -pyrimidinone; Example 73: 2- (2,5-diazabicyclo [2.2.1] hept-2-yl) -3-methyl-6- (2- ((2-thienylmethyl) amino) -4-pyridinyl) -4 (3H ) -pyrimidinone; Example 74: A, 1-dimethylethyl-5- (1-methyl-6-oxo-4- (2- (((IR) -1-phenylethyl) amino) -4-pyridinyl) -1,6-dihydro-2 -pyrimidinyl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate; Example 75:? 3-Methyl-2- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -6- (2- (((SS) -1-phenylethyl) amino) - 4-pyridinyl) -4 (3H) -pyrimidinone; Example 76: A-methyl-2- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) -4 (3H) -pyrimidinone; Example 77: M- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) [1,2,4] triazolo [4, 3-c] pyrimidin-7-yl) -N- ( (1S) -1-phenylethyl) -2-pyridinamine; Example 78: A, 1-dimethylethyl-5- (7- (2-amino-4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5-diazabicyclo [2.2.1] heptane- 2-carboxylate; Example 79:? 4- (5- (5- (Methylsulfonyl) -2-, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 80: AIS) -l-methyl-2-oxo-2- (5- (7- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1, 2-c] pyrimidin-5-yl) -2,5-diazabicyclo [2.2.1] hept-2-yl) ethyl acetate; Example 81: A, 1-dimethylethyl-5- (7- (2- (((2S) -2- (acetyloxy) propanoyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl ) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate; Example 82: (2S) -1-oxo-l- (5- (7- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidine-5 -yl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -2-propanol; Example 83: N- ((SS) -1-cyclohexylethyl) -4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl ) -2-pyridinamine; Example 84: M- (5- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; Example 85:? N- ((IR) -1-cyclopropylethyl) -4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7- il) -2-pyridinamine; Example 86:? N- ((1S) -1-cyclohexylethyl) -4- (5- (5- (1- methylethyl) -2,5-diazabicyclo [2.2. l] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; Example 87: 4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1- (1-naphthalenyl) ethyl) -2-pyridinamine; Example 88: - (5- (5- (1-Methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ( 2-thienylmethyl) -2-pyridinamine; Example 89: N- (4- (5- (5- (1-Methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinyl) benzenesulfonamide; Example 90:? N- (4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl ) -2-pyridinyl) benzamide; Example 91:? N- (2-furanylmethyl) -4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; Example 92:? N- ((SS) -1- (4-fluorophenyl) ethyl) -4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl ) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; Example 93: M- (5- (5- (2, 2-difluoroethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) - N- ((1S) -1-phenylethyl) -2-pyridinamine; Example 94: - (5- ((1S, 4S) -5-butyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N - ((1S) -1- phenylethyl) -2-pyridinamine; Example 95:? - ((1S) -1-phenylethyl) -4- (5- ((1S, 4S) -5- ((1S) -2,2,2-trifluoro-1-methylethyl) -2,5-diazabicyclo [2.2 .1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; Example 96: M- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (1-naphthalenylmethyl) -2-pyridinamine; Example 97: M- (2- (2,5-diazabicyclo [2.2.1] hept-2-yl) -1,3-thiazol-4-yl) -N- ((SS) -1-phenylethyl) -2 -pyridinamine; Example 98: 4- (2- (5- (1-Methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1,3-thiazol-4-yl) -N- (( ÍS) -1-phenylethyl) -2- 'pyridinamine; Example 99: M- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((1S) -1- (4- (methyloxy) phenyl) ethyl) -2-pyridinamine; Example 100: M- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1- ( 4-fluorophenyl) ethyl) -2-pyridinamine; Example 101: M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; Example 102: M- (5- (5- ((SS) -1-methylpropyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl ) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 103:? 4- (5- (5- ((IR) -1-methylpropyl) -2, 5- diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] irimidin-7-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 104: M- (5- (5-cyclopentyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 105: A- (5- (7- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2, 5- diazabicyclo [2.2.1] hept-2-yl) -2-propanol; Example 106: 4- (5- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 107: - (3- (5- (1-Methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- ((1S) -1 phenylethyl) -2-pyridinamine; Example 108: N- ((1S) -1-phenylethyl) -4- (5- ((1S, 4S) -5- (2- (phenyloxy) ethyl) -2,5-diazabicyclo [2.2.1] hept- 2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; Example 109: M- (5- ((IR, 4R) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine-7 -yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 110:? N- ((SS) -1-phenylethyl) -4- (5- (5-propyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl) -2-pyridinamine; Example 111: 4- (5- (5- (2-methylpropyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N - ((SS) -1-phenylethyl) -2-pyridinamine; Example 112: M- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (phenylmethyl) -2-pyridinamine; Example 113: M- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N-methyl-N- (phenylmethyl) - 2-pyridinamine; Example 114:? N- ((3-chlorophenyl) ethyl) -4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl ) -2-pyridinamine; Example 115: M- (5- ((SS, 4S) -5- (1,1-dimethylethyl) -2,5-diazabicyclo [2.2.1] ept-2-yl) imidazo [1,2-c] pyrimidine -7-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 116: A, 1-dimethylethyl 5- (7- (2- ((phenylmethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5-diazabicyclo [2.2. 1] heptane-2-carboxylate; Example 117: M- (5- ((IR, 4R) -5- (1,1-dimethylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine -7-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; Example 118: A, 1-dimethylethyl 5- (7- (2- (((2-fluorophenyl) ethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5 -diazabicyclo [2.2.1] heptane-2-carboxylate; Example 119: M- (5- (2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((3-fluorophenyl) ethyl) ) -2-pyridinamine; Example 120: X - ((IS) -1- (4-fluorophenyl) ethyl) -4- (3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1H-indazol-1-yl) -2-pyridinamine; Example 121: M- (4- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-pyrazol-1-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; -Example 122: 2 ~ ((4- (5- (2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinyl) amino ) -2-phenylethanol; Example 123: A, 1-dimethylethyl 5- (1- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) -lH-indazol-3-yl) -2,5-diazabicyclo [2.2 .1] heptane-2-carboxylate; Example 124: - (5- ((SS, 4S, 6S) -6-methyl-5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2- c] pyrimidin-7-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 125: 4- (5- (5-methyl-2, 5-diazabicyclo) [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (phenylmethyl) -2-pyridinamine; Example 126: M- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (phenylmethyl) -2-pyridinamine; Example 127:? N- ((3-fluorophenyl) methyl) -4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2 -c] pyrimidin-7-yl) -2-pyridinamine; Example 128: M- (3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; Example 129:? N- ((1S) -1-phenylethyl) -4- (5- (5- (3- (phenyloxy) propyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl) -2-pyridinamine; Example 130: - ((2-fluorophenyl) methyl) -4- (3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazole-1- il) -2-pyridinamine; Example 131: - (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((2-fluorophenyl) methyl) -2-pyridinamine; Example 132:? N- ((SS) -1-phenylethyl) -4- (5- (5- (phenylmethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2- c] pyrimidin-7-yl) -2-pyridinamine; Example 133: - (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; Example 134: N- ((2-fluorophenyl) methyl) -4- (5- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine- 7-yl) -2-pyridinamine; Example 135: M- (5- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((2- fluorophenyl) methyl) -2-pyridinamine; Example 136: 4- (5- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (phenylmethyl) -2-pyridinamine; Example 137:? Methyl-3- (5- (7- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2 , 5- diazabicyclo [2.2.1] hept-2-yl) propanoate; Example 138: 3- (5- (7- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1, 2-c] pyrimidin-5-yl) -2,5 -diazabicyclo [2.2.1] hept-2-yl) propanic; - Example 139: -? 4- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -5-fluoro-lH-indazol-1-yl) -N- ((SS) -1 phenylethyl) -2-pyridinamine; Example 140: M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((2-fluorophenyl) methyl) -2-pyridinamine; Example 141: - (3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; Example 142: M- (5-Fluoro-3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((SS) - 1-phenylethyl) -2-pyridinamine; Example 143:? N- ((2-fluorophenyl) methyl) .- 4- (3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl ) -2-pyridinamine; Example 144: 4- (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; Example 145: M- (5-Fluoro-3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ( (1S) -1-phenylethyl) -2-pyridinamine; Example 146: A- (7- (2- (3, 4-dihydro-2 (1H) -isoquinolinyl) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] heptane; - Example 147: 4- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N-phenyl-2-pyridinamine; Example 148: 4- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; Example 149:? 4- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((1S) -1- (2-fluorophenyl) ethyl) -2-pyridinamine; Example 150: - (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N- ((1S) -1-phenylethyl) - 2-pyridinamine; Example 151: M- (3- ((1S, 4S) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-pyrazol-1-yl) -N - ((SS) -1-phenylethyl) -2-pyridinamine; Example 152: - (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -7-fluoro-lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) - 2-pyridinamine; Example 153: 4- (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -7-fluoro-lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 154: M- (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; Example 155: 2- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -5- (3,4-difluorophenyl) -3-methyl-6- (2- (( 2- phenylethyl) amino) -4-pyridinyl) -4 (3H) -pyrimidinone; Example 156: M- (6-fluoro-3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ( phenylmethyl) -2-pyridinamine; Example 157: - (6-Fluoro-3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2- pyridinamine; Example 158: ~ (4-chloro-3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) - 2-pyridinamine; Example 159: 4- (4-chloro-3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; Example 160: 4- (4-chloro-3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- ((SS) - 1-phenylethyl) -2-pyridinamine; Example 161: - (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N- (phenylmethyl) -2- pyridinamine; Example 162: M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -6-nitro-lH-indazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; Example 163: - (4-chloro-3- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) - 2-pyridinamine; Example 164: M- (6-chloro-3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((SS ) -1-phenylethyl) -2-pyridinamine; Example 165: M- (3- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N-methyl-N - (phenylmethyl) -2-pyridinemine; Example 166: M- (3- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6-methyl-lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; Example 167: A, 1-dimethylethyl (SS, 4S) -5- (4-chloro-l- (2- ((phenylmethyl) amino) -4-pyridinyl) -lH-indazol-3-yl) -2, 5 -diazabicyclo [2.2.1] heptane-2-carboxylate; Example 168: M- (3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6-methyl-lH-indazol-1-yl) -N- ((IR ) -1-phenylethyl) -2-pyridinamine; Example 169: A, 1-dimethylethyl (SS, 4S) -5- (6-methyl-1- (2- (((IR) -1-phenylethyl) amino) -4-pyridinyl) -lH-indazole-3- il) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate; Example 170: M- (6-methyl-3- ((SS, 4S) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazole-1- il) -N- ((IR) -1-phenylethyl) -2-pyridinamine; Example 171: A- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl ) -1 H -indazol-6-amine; Example 172:? N- (3- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) -1H-indazol-6-yl) acetamide; Example 173:? N- (3- ((1S., 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1- (2- (((SS) -1-phenylethyl) amino ) -4-pyridinyl) -1H- "indazol-6-yl) methanesulfonamide; Example 174: A- ((SS, 4S) -2,5-diazabicyclo [2.2.1] • hept-2-yl) -6- Nitro-L- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) -lH-indazol-7-ol; Example 175:? 4- (3- ((1S, 4S) -2 , 5-diazabicyclo [2.2.1] hept-2-yl) -6- (trifluoromethyl) -lH-indazol-1-yl) -N- ((IR) -1- phenylethyl) -2-pyridinamine; Example 176: A, 1-dimethylethyl (SS, 4S) -5- (1- (2- ((phenylmethyl) amino) -4-pyridinyl) -6- (trifluoromethyl) -1H-indazol-3-yl) -2, 5- diazabicyclo [2.2.1] heptane-2-carboxylate Example 177: M- (3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6- (trifluoromethyl) - 1H-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; and Example 178: A, 1-dimethylethyl (SS, 4S) -5- (1- (2- (((1S) -1- phenylethyl) amino) -4-pyridinyl) -6- (trifluoromethyl) -1H-indazol-3-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate. ions herein are useful for treating a variety of diseases or conditions associated with kinases, and particularly those related to PKCT. The following biological assays were used to measure the activity of the compounds described in I presented.

Homogeneous Time-resolved Fluorescent Kinase (HTRF) Assay with PKCT: The HTRF assay begins with PKCT in the presence of ATP that phosphorylates a biotinylated peptide substrate based on a Thr-substituted pseudosubstrate of Thr-substituted PKCa (YTASQDVANRFAIRKGTLRQKINV). The reaction is incubated for 60 minutes. To rapidly cool the assay, detection reagents are added, which both stop the reaction by diluting the enzyme as well as subjecting the metals to chelation due to the presence of EDTA. Once the detection reagents are added, the assay is incubated for 60 minutes to allow equilibration of the detection reagents. The HTRF assay with PKCT is comprised of 1 μl of compound in 100% DMSO, 10 μl of ATP and biotinylated peptide substrate, and 5 μl of KD with PKCT for a final volume of 50 μl. The final concentration of PKCa pseudosubstrate is 1 μM. The final concentration of ATP is 25 μM (km app = 69 μM) and the final concentration of PKCT is 100 pM. The conditions of the buffer are as follows: 50 mM Tris pH 7.5, 10 mM MgCl2, 10% DMSO, 1.5 M DTT, 0.03% BSA. Five μL of the assay is rapidly cooled by adding it to 45 μL of detection reagent. The detection reagents are as follows: buffer made of 100mM Tris, pH 7.5, 100mM NaCl, 5mM EDTA, 0.1% BSA, 0.1% Tween20. It is added to this buffer before reading, Streptavidin allophycocyanin (SA-APC) at a final concentration in the 25 nM assay, and anti-phospho Treonine Ab europylated (Eu-anti-pT) at a final concentration of 0.3 nM. The test plate is read in Discovery. Eu-anti-pT is excited at 320 nm and emits at 615 nm to excite SA-APC, which in turn is emitted at 655 nm. The ratio of SA-APC at 655 nm (excited due to close proximity to Eu-anti-pT due to phosphorylation of the peptide) with free Eu-anti-pT at 615 nm will give phosphorylation of the substrate. Examples 4-39, 41-44, 48-59, 63-69 and 71-178 exhibit activity better than 50 μM in the HTRF assay with PKCT. Assays for other PKC isoforms or other kinases are done in a similar manner as described above, varying the concentrations of enzyme, peptide substrate, and ATP added to the reaction, depending on the specific activity of the enzyme. kinase and Km 's measured for substrates.

Secretion and proliferation assay of cell IL-2 induced in T-ani-CD3 / an ti -CD28: The purpose of this test is to test the potency of the T-cell receptor (TCR, CD3) and CD28 indicating the path of inhibitors in human T cells. T cells isolated from human peripheral blood lymphocytes (hPBL) are enriched a >90% purity by T cell kit Human pan with MACS columns (Miltenyi Biotec). For stimulations of anti-CD3 and anti-CD28, T cells (lxlO5 T cells / posillo) in the proliferation medium (RPMI supplemented with 10% FCS, 50 μm of β-glutamine, 2 mM L-glutamine and 100 units / ml of penicillin / streptomycin are added in duplicate to 96-well plates pre-coated with anti-CD3 antibody (0.5 μg / ml - Pharmingen) and anti-CD28 (2.0 μg / ml - R &D Systems) overnight at 4 ° C T cells are incubated for 40 h at 37 ° C in 5% C02, then IL-2 secreted in supernatants is quantified by ELISA cytokine (R & D Systems.) The remaining cells in the posillos are then pulsed with [3H ] -thymidine during 16-18 h to determine the proliferative response of T cells. The cells are harvested on glass fiber filters and the incorporation of 3 H-thymidine into DNA is analyzed by the liquid scintillation counter. The production of IL-2 and specific proliferation were calculated as an average count in duplicate posillos after the subtraction of the baseline of syngeneic cultures.The potential inhibitor compounds can be tested for inhibition of this response as described above for antibodies anti-CD3 and -CD28 The following compounds exhibit an activity better than 500 μM in the secretion of IL-2 induced in anti-CD3 / anti-CD28 in whole human blood: (S) - { 4- [4 - (5-isopropyl- (1S, 4S) -2,5-diaza-bi-cyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - - ( 1-f-enyl-ethyl) -amine; {. 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [ 1, 2-c] pyrimidin-7-yl] -pyridin-2-yl.} - (1-f-enyl-ethyl) -amine;. {4- [4- ((SS, 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - - (1-phenyl-ethyl) -amine; (S) -. 4- [4- (5-ethyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -qui Nazolin-2-yl] -pyridin-2-yl} - (1-f-enyl-ethyl) -amine; (S) -. { 4- [4- (5-methyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1- f -yl-ethyl) -amine; . { 4- [5- ((1S, 4S) -2, 5-d? Aza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin- 2-il} - (2-f luorobenzyl) -amine; {. 4- [4- (5-isopropyl- (S, 4 S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - quinolin-2-yl] -pyridin-2-yl.} - (1-f-enyl-ethyl) -amine; {. 4- [3- (5-isopropyl- (1S, 48) -2, 5- diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine;. {4- [4- ( (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine; {. 4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl}. - (1-phenyl-ethyl) -amine; Benzyl-. {4- [3- ((1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6-fluoro -indazol-1-yl] -pyridin-2-yl.} -amine; and Benzyl-. {4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept- 2-yl) -indazol-1-yl] -pyridin-2-yl.} - amine.

Cytokine secretion assay and proliferation of T cells induced in anti-CD3 / B7.2 Fe: The purpose of this test is to test the potency of the T cell receptor (TCR, CD3) and CD28 signaling the pathway of inhibitors in human T cells. Anti-CD3 (Pharmingen) is coated on 96-posillos round bottom tissue culture plates (Falcon) overnight at 4 ° C; the concentration of anti-CD3 depends on the donor. The plates are washed with PBS (Gibco) the next morning, and then 3 μg / ml of human B7.2 Fe (R & D Systems) is coated in for -4 h at 37 ° C. T-cells are purified from human peripheral blood lymphocytes (hPBL) using magnetic granules from Miltenyi Biotec. T cells are added to the plates, then the plates were washed with PBS (IxlO5 T cells / posillo). The test compounds are diluted to 4 M in DMSO, and then record dilutions are made in DMSO using a Precision2000 robot (Bio-Tek Instruments) to produce a 10-dot volume. The compounds are then diluted 1: 100 in RPMI medium 1640 (Gibco) supplemented with 10% FBS (JRH Biosciences), 0.1 mM non-essential amino acids MEM (Gibco), 100 units / ml Penicillin, 0.1 mg / ml Streptomycin, 292 μg / ml of L-glut amicine (Gibco), and 55 μM of 2-mercaptoethanol (Gibco). Then the compounds (4x) are added to the cells. Cells are cultured for -48h at 37 ° C in 5% C02. IL-2, TNFa and IFN? secreted in supernatants are quantified by electrochemiluminescence (MSD). 20 μl of the supernatant are incubated with 110 μl of buffer 2X MSD buffer and 20 μl of antibody diluent (1 μg / ml of each detection antibody) in a 3-point MSD plate (IL-2, TNFa and IFN? ). The plates are covered and incubated overnight at room temperature ambient. A Sector HTS reader (MSD) is used to analyze cytokine levels. The cells are pulsed with H-thymidine (ICN) for 16 h to determine the proliferative response of T cells. The cells are harvested on glass fiber filters (Wallac) and the incorporation of 3 H-thymidine into DNA is analyzed by a counter of liquid scintillation (Perkin Ele r). Lymphocyte Reaction to Human Mix (Single Sense MLR): The purpose of this assay is to test the potency of T cell inhibitors in an in vivo model of allogeneic T cell stimulation. Human peripheral blood lymphocytes (hPBL); lxl05 / posillo) of a donor are incubated with hPBL treated with mitomycin C (30 μg / ml for 1 h); lxloVposillo of another donor as allogeneic stimulators in the presence or absence of dilutions of the compound of potential inhibitor in 96-posillos round bottom tissue culture plates. These cultures are incubated at 37 ° C in 5% C02 for a total of 6 days. The proliferative response of hPBL is measured by the incorporation of 3H-thymidine (0.5uCi / posillo) overnight between 5 and 6 days after the start of culture. The cells are harvested and the incorporation of 3H-thymidine into DNA is analyzed by the liquid scintillation counter.

Supervision of the Jurka t test: The purpose of this test is to test the general cytotoxic / anti-proliferative effect of compounds on the Jurkat T cell line. Jurkat cells (lxl 0 / posillo) are placed in flat-bottom 96-cell tissue culture plates with or without compound dilutions and grown for 72 h at 37 ° C in 5% C02. The viable cell number is determined during the last 4 h of culture, adding 10 μl / posillo of WST-1 dye. The conversion of the WST-1 dye relies on active mitochondrial electron transport for the reduction of tetrazolium dye. The dye conversion is read by OD at 450-600 nm.

Secretion of IL-2 induced in anti-CD3 / anti-CD28 in whole human blood The purpose of this test is to test the potency of the T cell receptor (TCR, CD3) and CD28 that signals the path of inhibitors in whole human blood. Anti-CD3 antibody (10 μg / ml; R & D Systems) is pre-routed in the posillos of 96-posillos plates. The compounds are added in the T cell dilution media (modified Iscoves DMEM), supplemented with 0.1% human serum albumins, μM of Beta-mer captoethanol, and lx Pen / Strep / Glu. Compounds are tested in triplicate. 100 μl of whole human blood (collected in heparinized tubes) is added to each of the dishes and the plates are incubated for 30 minutes at 37 ° C, 5% C02 The anti-CD28 antibody (2 μg / ml; R & D Systems) is diluted in T-cell dilution media and added to the cells. The mixture is incubated for 48 h at 37 ° C, 5% C02. The cells were then granulated, and the supernatant was collected and the production of IL-2 was determined by ELISA (R &D Systems). The following compounds exhibit better activity than 5 μM in the secretion of IL-2 induced by anti-CD3 / anti-CD28 in whole human blood: (S) -. { 4- [4- (5-ethyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [4- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenylethyl) -amine; Bencil- { 4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} -amine; (4- [4- ((1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl}. - (1 phenyl-ethyl) -amine; {. 4- [3- ((SS, 4S) -2, 5-diaza-bicyclo [2.2, 1] liept-2-yl) -indazol-1-yl] -pyridin -2-yl.} - [1- (2-fluoro-phenyl) -ethyl] -amine; {. 4- [4- (5-isopropyl- (S, S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine;. {4- [5- ( 4S) -2, 5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl.} - (1-phenyl) -ethyl) -amine; (S) - { 4- [2- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -pyrimidin- 4-yl] -pyridin-2-yl.} - (1-phenylethyl) -amine;. {4- [3- (5-isopropyl- (S, S) -2,5-diaza-bicyclo] .1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl.} - (1-phenyl-ethyl) -amine; Benzyl-. {4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6-fluoro-indazol-1-yl] -pyridin-2-yl} -amine; . { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] pyrimidin-7-yl] - pyridin-2-yl} - (1- phenyl-etif1-amine; Benzyl-. {4- [3- ((1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6-flu ro -indazol-l-yl] -pyridin-2-yl.}. -amine;. {4- (5- (5-ethyl- (lS, 48) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl} - - (1-phenylethyl) -amine; and. {4- [5- (( 1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] pyrimidin-7-yl] -pyridin-2-yl} - (2-fluorobenzyl) -amine. While the compounds of the invention can be administered as the sole active pharmaceutical agent, the invention or other agents can also be used in combination with one or more compounds. When administered as a combination, the therapeutic agents can be formulated as separate compositions that are given at the same time or at different times, or the therapeutic agents can be given as a single composition. The foregoing is merely illustrative of the invention and it is not desired to limit the invention to the disclosed compounds. Variations and changes that are obvious to the skilled in the art are desired to be within the scope and nature of the invention, which are defined in the appended claims.

From the above description, the person skilled in the art can easily determine the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various uses and conditions. For the treatment of the disease indications described herein, the compounds of the present invention may be administered orally, parentally, by inhalation spray, rectally, or topically in unit dosage formulations containing pharmaceutically carriers, adjuvants, and vehicles. acceptable conventional. The term "parenteral" as used herein includes, subcutaneously, intravenously, intramuscularly, intrasternally, infusion techniques or interperitoneally. The treatment of diseases and disorders herein is also intended to include the prophylactic administration of a compound of the invention, pharmaceutical salt thereof, or a pharmaceutical composition thereof to a subject (i.e., an animal, preferably a mammal, more preferably a human) which is believed to need preventive treatment of, such as, for example, pain, inflammation and the like. The dosing regimen to treat a PKC-mediated disease, cancer, and / or hyperglycemia with the compounds of this invention and / or the compositions of this invention, is based on a variety of factors, including the type of disease, age, weight, sex, patient's medical condition , severity of the condition, route of administration, and of the particular compound used. Thus, the dosage regimen - may vary widely, but can be determined routinely using standard methods. Dosage levels in the range of about 0.01 mg to about 30 mg per kilogram of daily body weight, preferably from about 0.1 mg to 10 mg / kg, more preferably from about 0.25 mg to 1 mg / kg, are useful for all methods of use described herein. The pharmaceutically active compounds of this invention can be processed according to conventional pharmacy methods to produce medicinal agents for administration to patients, including humans and other mammals. For oral administration, the pharmaceutical composition may be in the form of, for example, capsule, tablet, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a given amount of active ingredient. For example, these may contain a quantity of active ingredient of about 1 to 2000 mg, preferably about 1 to 500 mg, more preferably about 5 to 150 mg. A suitable daily dose for a human or other mammal can vary widely depending on the condition of the patient and other factors, but once again can be determined using routine methods. The active ingredient can also be administered by injection as a composition with suitable carriers including saline, dextrose, or water. The daily parenteral dosage regimen will be from about 0.1 to about 30 mg / kg of total body weight, preferably from about 0.1 to about 10 mg / kg, and more preferably from about 0.25 mg to 1 mg / kg. Injectable preparations, such as sterile injectable aqueous or oleaginous suspensions, can be formulated as known, using suitable suitable wetting or dispersing agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parenteral diluent or solvent, for example as a solution in 1,3-butanediol.

Among the vehicles and acceptable solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile oils, stable are conventionally used as solvent or suspension medium. For this purpose any soft stable oil can be used, including synthetic mono- or diglycerides. In addition, fatty acids, such as oleic acid find use in the preparation of injectables. Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures, but liquid at rectal temperatures and will therefore melt in the rectum and they will release the drug. A suitable topical dose of the active ingredient of a compound of the invention is 0.1 mg to 150 mg, administered one to four, preferably once or twice a day. For topical administration, the active ingredient can comprise from 0.001% to 10% w / w, for example, from% to 2% by weight of the formulation, although it can also comprise 10% w / w, but preferably not more than 5% w / w. % p / p, and more preferably from 0.1% to 1% formulation. Formulations suitable for topical administration include liquid or liquid preparations suitable for penetration through the skin (eg, liniments, lotions, ointments, creams, or pastes) and drops suitable for administration to the eye, ear, or nose For administration, the compounds of this invention are ordinarily combined with one or more adjuvants appropriate for the indicated route of administration. The compounds can be mixed with lactose, sucrose, starch powder, cellulose esters of alkanoic acids, stearic acid, talc, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, acacia, gelatin, alginate of sodium, polyvinyl-pyrrolidine, and / or polyvinyl alcohol, and are formed into tablets or encapsulated for conventional administration. Alternatively, the compounds of this invention can be dissolved in saline, water, polyethylene glycol, propylene glycol, ethanol, corn oil, peanut oil, cottonseed oil, sesame oil, tragacanth gum, and / or various buffers. Other adjuvants and modes of administration are good known in the pharmaceutical art. The carrier or diluent may include delay material, such as glyceryl monostearate or glyceryl distearate alone or with a wax, or other materials well known in the art. Pharmaceutical compositions can be made in solid form (including granules, powders or suppositories) or in liquid form (e.g., solutions, suspensions, or emulsions). The pharmaceutical compositions may be subjected to conventional pharmaceutical operations, such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, buffers, etc. Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound can be mixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may also comprise, as in normal practice, additional substances with different inert diluents, for example, lubricating agents, such as magnesium stearate. In the case of capsules, tablets, and pills, the dosage forms may also comprise quenching agents.

Tablets and pills can be prepared additionally with enteric coatings. Liquid dosage forms for oral administration may include emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, pharmaceutically acceptable, such as water. Such compositions may also comprise adjuvants, such as wetting, sweetening, flavoring, and perfuming agents.

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

R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, and where the ring is replaced by 0, 1, 2 or 3 substituents independently selected from Ca-βalkyl, C?-Haloalkyl, halo, cyano, nitro, C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, - 0C (= 0) Rb,

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. Compound of formula I or a pharmaceutically acceptable salt thereof, characterized in that J is NH, N (Rb), O or S; m is independently in each case 0, 1, 2 or 3; n is 1 or 2; R1 is selected from R is a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of the O and S atoms is not greater than 2, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8 alkyl, C? _4 haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaR, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -OCalkyl2_6NRaRa, -0Calkyl2_60Ra, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, S (= 0) 2NRaRa, -S (= 0) 2N ( Ra) C (= 0) Rb, S (= 0) 2N (Ra) C (= 0) OR1 -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rü, N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, - (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra ) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa and -NRaC2_ 6alkyloor; R3 is independently in each case H, C? _ Salkyl, C? _4haloalkyl, halo, cyano, nitro, C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -QC2-6alkylNRaRa, -0C2-6alkyl0Ra, -SRa, -S (= 0) Rb, -S (= 0 ) 2Rb, -S (= 0) 2NRaRa, - S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0 ) 2N (Ra) C (= 0) NRaRa, -NRaRa, - (Ra) C (= 0) R, - (Ra) C (= 0) 0Rb, - (Ra) C (= 0) RaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2-6alkyl0Ra; R4 is independently in each case Cx_ 8alkyl, C? _4haloalkyl, halo, cyano, nitro, C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, OC (= 0) NRaRa, -OC (= 0) N (R) S (= 0) 2Rb, -OC2_6alkylNRaRa, -0C2-6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2Rb , -S (= 0) 2NRaRa, - S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2 (Ra) C (= 0) NRaRa, -NRaRa, - (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, - (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2_6alkylORa; R5 is H or C-L-ealkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; Rd is H, Rc, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf. Ra is independently, in each case, H or Rb; R is independently, in each case, phenyl, benzyl or CL-5alkyl, phenyl, benzyl and C? _6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C? -alkyl, C? _3haloalkyl, -OC ? 4- alkyl, -NH2, -NHC? _ Alkyl, and N (C? -4alkyl) C? _ Alkyl; Rc is independently in each case a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of the O and S atoms is not greater than 2, where the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups, Rd is independently in each case Cx-salkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaR, -C (= NRa) NRaRa , -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2_6alkylNRRa, -OC2_6alkyl? ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) R, -S (= 0) 2N (Ra ) C (= 0) 0R, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (R) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2_6alkyl0Ra; Re is independently in each case Rd or H; and Rf is independently in each case, a 5, 6 or 7 monocyclic or 6, 7, 8, 9, 10 or 11 member saturated, partially saturated or unsaturated bicyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from C? _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C. (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaR, -OC (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkylNRaRa, -OC2_6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, --S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, - N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2_6alkyl0Ra.
2. Compound according to claim 1, characterized in that J is NH or N (Rb); m is independently in each case 0, 1, 2 or 3; n is 1 or 2; R1 is selected from R2 is a 5-, 6- or 7-membered monocyclic ring 0 bicyclic of 6-, 7-, 8-, 9-, 10- or 11-member saturated, partially saturated or unsaturated containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of the atoms of 0 and S is not greater than 2, where the ring carbon atoms are replaced by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8 alkyl, C? _ Haloalkyl, halo, cyano, nitro, -C (= 0) R, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0R, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0Calkyl2-6NRaRa, -0Calkyl2-60Ra, -SRa, -S (= 0) R, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S ( = 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= O) 2N (Ra) C (= 0) NRaRa, -NRaRa , -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, - N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa, and -NRaC2_6alkylore; R3 is independently in each case H, C? _ 8alkyl, C? _4haloalkyl, halo, cyano, nitro, -0Ra, -0C2_6alkylNRRa, -OC2_6alkyloRa, -SRa, -NRaRa, -N (Ra) C (= 0) NRaRa , -NRaC2-6alkylNRaRa or -NRaC2_6alkyloor; R4 is independently in each case Cx-salkyl, C? _4 haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -0Ra, -OC_6alkylNRaRa, -OC2-6alkyloRa, -SRa, -NRaRa, -NRaC2_6alkylNRaRa or -NRaC2_6alkylorA; R5 is' H or C-L-6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H, Rc, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf. Ra is independently, in each case, H or Rb; Rb is independently, in each case, phenyl, benzyl or C6_6alkyl, phenyl, benzyl and C6_6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C4_4alkyl, C3_haloalkyl, -0C1_4alkyl , -NH2, -NHCi-4alkyl, and N (C? _4alkyl) C? _4alkyl; Rc is independently "" in each case a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of the O and S atoms is not greater than 2, where the ring carbon atoms are replaced by 0, 1 or 2 oxo groups , Rd is independently in each case C? _8alkyl, C! _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa ) NRaRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -0C2_6alkyNRaRa, -OC2_6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (- = 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb , -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, - NRaC2-6alkylNRaR or -NRaC2_6alkyl0Ra; Re is independently in each case Rd or H; and Rf is independently in each case, a 5, 6 or 7 monocyclic or 6, 7, 8, 9, 10 or 11 member saturated, partially saturated or unsaturated monocyclic ring that contains 0, 1, 2, 3 or 4 atoms selected from N, O and S, where the ring carbon atoms are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents selected from C? _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, - 0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -OC2-6alkylNRaRa, -OC2_6alkylore, -SRa, -S (- = 0) Rb -S (= 0) 2Rb -S (= 0) 2NRaRa -S (= 0) 2N (Ra) C (= 0) R £ -S (= 0) 2N (Ra) C (= 0) ORb, -S (= 0) 2N (Ra) C (= 0) NRaRa -NRaRa -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2_6alkyl0Ra. Compound according to claim 1, characterized in that J is NH, N (Rb), 0 or S; m is independently in each case 0, 1, 2 or 3; n is 1; R1 is selected from -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2R, -0C2_6alkylNRaRa, -0C2_6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra ) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (- = 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2-6alkyl0Ra. R3 is independently in each case H, C? _8alkyl, C ^ haloalkyl, halo, -0Ra, -SRa or -NRaRa; R4 is C? _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -0Ra, -SRa, -NRaRa, -NRaC2_6alkylNRaRa or -NRaC2_5alkyl0Ra; R5 is H or C6_6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; Re is H, Rc, Rd, or a C ?_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; Ra is independently, in each case, H or Rb; Rb is independently, in each case, phenyl, benzyl or Ci-β alkyl, the phenyl, benzyl and Ci-βalkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C! _4alkyl, C? -3haloalkyl, - 0C? _alkyl, -NH2, -NHC-alkyl, and N (C? _alkyl) C? _4alkyl; R is independently, in each case, phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, where the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups; R is independently in each case, C;? 8 alkyl, C? _4 haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (- = 0) NRaRa, -C (= NRa) NRaRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (- = 0) 2Rb, -OC2_6alkylNRaRa, -OC2_6alkyl? ORa, -SRa, -S (= 0) Rb, -S (= 0 ) 2Rb, - S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0R, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaR, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2_6alkyloor; Re is independently in each case Rd or H; Y R is independently, in each case, phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydroxyl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl ,. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C ? 8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (- = 0) NRaRa, -ORa, -OC2-6alkylNRaRa, -OC2_6alkylore, -SRa, -S (= 0) R, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) NRRa, -N (Ra) S (= 0) 2Rb, -N (R) S (- = 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2_6alkyloRa; 4. Compound according to claim 1, characterized in that J is NH or NCH3; m is independently in each case 0, 1, 2 or 3; n is 1; R is selected from R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the atoms carbon ring are replaced by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C? -4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -0C (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb , -0C2-6alkylNRaRa, -OC2-6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2R, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C ( = 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (R) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NR) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkyNRaRa and -NRaC2_6alkyl0Ra; R3 is independently in each case H, C? _8alkyl, C? _haloalkyl, halo, -0Ra, -SRa or -NRaRa; R4 is C? _8alkyl, C? _haloalkyl, halo, cyano, nitro, -0Ra, -SRa, -NRaRa, -NRaC2_6alkylNRaRa or ~ NRaC2_6alkyl0Ra; R5 is H or C6_6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H, Rc, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R is independently, in each case, H or Rb; Rb is independently, in each case, phenyl, benzyl or C? -6alkyl, phenyl, benzyl and C? _6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C? _alkyl, C? _haloalkyl, -OC? -4alkyl, -NH2, -NHC? _4alkyl, and N (C? _4alkyl) C! -alkyl; Rc is independently, in each case, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the ring carbon atoms they are substituted by 0, 1 or 2 oxo groups; R is independently in each case, C? _8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa ) NRaRa, -ORa, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2_6alkylNRaRa, -OC2_6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2R, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa or -NRaC2_6alkyl0Ra; Re is independently in each case Rd or H; and Rf is independently, in each case, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups; and the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) NRaRa, -0Ra, -0C2_6alkylNRaRa, -0C2_6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) NRaRa , -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2_6alkyl0Ra. Compound according to claim 4, characterized in that R5 is H. 6. Compound according to claim 1, characterized in that J is NH or NCH3; m is independently in each case 0, 1, 2 or 3; n is 1; R1 is selected from R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl,. pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C1_4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, --C (= 0) ORb, -C ( = 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkylNRaRa, -OC2_6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaR, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2_6alkyl0Ra; R3 is independently in each case H, C? _8alkyl, C? _4haloalkyl, halo or 0Ra; R4 is H or C? _8alkyl; R5 is H, or Ci-ealkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H or C? -6alkyl; Ra is independently in each case, H or Rb; Rb is independently in each case, phenyl, benzyl or Cx-galkyl, phenyl, benzyl and C6-6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C1_alkyl, C? _3haloalkyl, -0C? _4alkyl, -NH2, -NHC? _4alkyl and N (C? _4alkyl) C? _4alkyl; Rd is independently in each case, C? -8alkyl C! _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) R -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2_6alkylNRaRa -OC2_6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, - S (= 0) 2NRaRa -S (= 0) 2N (Ra) C (- = 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa or -NRaC2_6alkyl0Ra; Re is independently in each case, Rd or H; and Rf is independently, in each case, phenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl. indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 , 1, 2 or 3 substituents selected from C? _8alkyl, C? -haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) NRaRa, -ORa, -OC2_6alkylNRaRa, -OC2_6alkyloor, - SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) ) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRC2_5alkyl0Ra. 7. Compound according to claim 1, characterized in that J is NH or NCH3; m is independently in each case 0, 1, 2 or 3; n is 1; R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the atoms of the ring carbon are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (- = 0) NRaR, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0 ) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2-6alkylNRaRa, -OC2_6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S ( = 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) ORb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -'N (Ra) C (= 0) ORb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaR, -NRaC2_6alkylNRaRa and -NRaC2_6alkyl0Ra. R3 is independently, in each case H, -CH3, -CH2CH3 or -0Ra; R4 is absent; R5 is H, -CH3, - -CH2CH3, -C (= 0) CH (OH) CH3, -S02CH3, -C (= 0) CH (CH3) OC (= 0) CH3, propyl, -isopropyl, -CH2CHCF2 , -n-butyl, -t-butyl, -isobutyl, - (CH2) 2C00H, - (CH2) 2C0ÓCH3, (CH2) 2OPh, -CH (CH3) ethyl, -CH (CH3) CF3, -cyclopentyl or 0Ra; R6 is H, -CH3, or -CH2CH3; Ra is independently, in each case, H or Rb; and Rb is independently in each case, phenyl, benzyl or C ?_6alkyl, phenyl, benzyl and C? -6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C 4 alkyl, C 3 haloalkyl, C 0 alkyl, -NH 2, -NHC α -alkyl and N (Ca_ alkyl) C 1 _ alkyl. 8. Compound according to claim 1, characterized in that J is NH or NCH3; m is independently in each case 0, 1, 2 or 3; n is 1; R, 1? is R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the atoms of the ring carbon are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (- = 0) 0Rb, -C (= 0) NRaRa, -C (- = NRa) NRaRa, -0Ra, -0C (= Q) Rb, -OC ( = 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2_6alkyl? NRaRa, -OC2-6alkylore, -SRa, -S (= 0) Rb, -S (= 0) 2Rb , -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0R, -N (Ra) C (= 0) NRRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2R, -N (Ra) S (= 0) 2NRaRa, -NRaC2-6alkylNRaRa and -NRaC2_6alkyloor. R3 is independently, in each case H, -CH3, -CH2CH3 or -0Ra; R4 is absent; R5 is H, -CH3, -CH2CH3, -C (= 0) CH (OH) CH3, -S02CH3, -C (= 0) CH (CH3) 0C (= 0) CH3, propyl,. -isopropyl, -CH2CHCF2, -n-butyl, -t-butyl, -isobutyl, - (CH2) 2C00H, - (CH2) 2C00CH3, (CH2) 20Ph, -CH (CH3) ethyl, -CH (CH3) CF3, -cyclopentyl or 0Ra; R6 is H, -CH3, or -CH2CH3; Ra is independently, in each case, H or Rb; and R is independently in each case, phenyl, benzyl or Cx-galkyl, the phenyl, benzyl and C6-6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C1_alkyl, C? _3haloalkyl, -0C? _alkyl, -NH2, -NHC? _alkyl and N (C? _alkyl) C? -4alkyl; and Re is independently in each case, H, Cl, F, Br, I, CH3, N02, NHS02CH3, OH, CF3 or N-Acetyl. 9. Compound according to claim 1, characterized in that J is NH or NCH3; m is independently in each case 0, 1, 2 or 3; n is 1; R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (R) S (= 0) 2Rb, -OC2 -6alkylNRRa, -OC2-6alkyloRa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, - NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2_6alkyl0Ra. R3 is independently, in each case H, -CH3, -CH2CH3 or -0Ra; R4 is absent; R5 is H, -CH3, -CH2CH3, -C (= 0) CH (0H) CH3, -S02CH3, -C (= 0) CH (CH3) 0C (= 0) CH3, propyl, -isopropyl, -CH2CHCF2, -n-butyl, -t-butyl, -isobutyl, - (CH2) 2C00H, - (CH2) 2COOCH3, (CH2) 2OPh, -CH (CH3) ethyl, -CH (CH3) CF3, -cyclopentyl or 0Ra; R6 is H, -CH3, or -CH2CH3; R is independently, in each case, H or Rb; R b is independently in each case phenyl, benzyl or C 6 alkyl, phenyl, benzyl and C 6 alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C 1 alkyl, C 3 haloalkyl, -OC ? alkyl, -NH2, -NHC1_alkyl and N (C? _4alkyl) C? _ alkyl; and Re is independently in each case, H, Cl, F, Br, I, CH3, N02, NHS02CH3, OH, CF3 or N-Acetyl. 10. Compound according to claim 1, characterized in that J is NH or NCH3; m is independently in each case 0, 1, 2 or 3; n is 1; R1 is selected from R2 is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? -8alkyl, C? -4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, - C (= 0) NRaRa, -C (= NRa) NRaRa, -ORa, -OC (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb , -OC2-6alkylNRaRa, -OC2_6alkylORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (- = 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa ) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2_6alkyl0Ra. R3 is independently, in each case H, -CH3, -CH2CH3 or -0Ra; R4 is absent; R5 is H, -CH3, -CH2CH3, -C (= 0) CH (OH) CH3, -S02CH3, -C (= 0) CH (CH3) OC (= 0) CH3, propyl, -isopropyl, -CH2CHCF2, -n-butyl, -t-butyl, -isobutyl, - (CH2) 2C00H, - (CH2) 2C00CH3, (CH2) 20Ph, -CH (CH3) ethyl, -CH (CH3) CF3, -cyclopentyl or 0Ra; R6 is H, -CH3, or -CH2CH3; Ra is independently, in each case, H or Rb; Rb is independently in each case, phenyl, benzyl or The alkyl, the phenyl, the benzyl and the C, 6 alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C 4 alkyl, C 3 haloalkyl, 0 C 4 alkyl, -NH 2, -NHC ??? alkyl and N (C? _4alkyl) C? -4alkyl; and Re is independently in each case, H, Cl, F, Br, I, CH3, N02, NHS02CH3, OH, CF3 or N-Acetyl. 11. Compound according to claim 1, characterized in that it is selected from: 5- [7- (2-chloro-pyridin-4-yl) -imidazo [1, 2-c] -pyrimidin-5-tere-butyl ester. -yl] - (SS, 4S) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid; (S) -. { 4- [5- ((1S, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2 -il} - (1-phenylethyl) -amine; (S) -. { 4- [5- (5-Isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} - (1-phenyl-ethyl) -amine; (S) -. { 4- [5- (5-Ethyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} - (1-phenyl-ethyl) -amine; (R) -. { 4- [5- ((lS, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2 -il} - (1-phenyl-ethyl) -amine; (R) -. { 4- [5- (5-Isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} - (1-phenyl-ethyl) -amine; . { 4- [5- ((lS, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2 -il} - (1,2-dimethyl-propyl) -amine; (1,2-Dimethyl-propyl) -. { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} -amine; . { 4- [5- ((SS, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2 -il} -naphthalen-l-ylmethyl-amine; . { 4- [5- (5-Isopropyl- (SS, 4S) -2, 5'-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] -pyrimidin-7-yl ] -pyridin-2-il} -naphthalen-1-ylmethyl-amine; (S) -. { 4- [6- ((1S, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -2-methylsulfanyl-pyrimidin-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [6- (5-Isopropyl- (1S, 4S) -2,5-diaza bicyclo [2.2.1] hept-2-yl) -2-methylsulfanyl-pyrimidin-4-yl] -pyridin-2-yl } - (1-phenyl-ethyl) -amine; (S) - (2, 2-Dimethoxy-ethyl) -. { 2- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6- [2- (1-f-enyl-ethylamino) -pyridin-4- il] -pyrimidin-4-il} -amine; (S) -. { 4- [5- ((lS, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl) - [1, 2, 4] triazolo [1, 5-c] -pyrimidin-7 -yl] -pyridin-2-il} - (1-f-enyl-ethyl) -amine; (S) -. { 4- [5- (5-Isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - [1, 2, 4] triazolo [1, 5-c] -pyrimidin-7-yl] -pyridin-2-yl} - (1-f-enyl-ethyl) -amine; (S) -. { 4- [5- ((1S, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) - [1,2, 4] triazolo [1, 5-c] -pyrimidin-7 -yl] -pyridin-2-il} - (1-naphthalen-1-yl-ethyl) -amine; (S) -. { 4- [5- (5-Isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - [1, 2, 4] triazolo [1, 5-c] -pyrimidin-7-yl] -pyridin-2-yl} - (1-naphthalen-1-yl-ethyl) -amine; (S) - [2 '- ((lS, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl) - [4, 4'] bipyridinyl-2-yl] - (1- f-ethyl-ethyl) -amine; (S) - [2 '- (5-Isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) - [4,4'] bipyridinyl-2-yl] - (1-f-enyl-ethyl) -amine; 3-Methyl-2- (5-methyl- (lS, 4S) -2,5-d-iaza-bicyclo [2.2.1] hept-2-yl) -6- [2- (S) - (1- f-enyl-ethylamino) -pyridin-4-yl] -3H-pyrimidin-4-one; 2- ((1S, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -3-methyl-6- [2- ((S) -1-f-enyl-ethylamino) -pyridin-4-yl] -3H-pyrimidin-4-one; (S) -. { 4- [5- (5-tert-Butyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7- il] -pyridin-2 ~ il} - (1- f -yl-ethyl) -amine; (S) -. { 4- [3- ((SS, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} - [1- (2-f luoro-f-enyl) -ethyl] -amine; (S) -. { 4- [5- (5-Isopropyl-6-methyl ~ (IS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] -pyrimidin- 7-yl] -pyridin-2-yl} - (1-f-enyl-ethyl) -amine; 2-. { 2- (5-Isopropyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6- [2- (S) - (1-f-enyl-ethylamino) - pyridin-4-yl] -pyr__nridin-4-ylamino} -ethanol; (S) -. { 4- [5- (5-n-Butyl- (IS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7- il] -pyridin-2 ~ il} - (1-f-enyl-ethyl) -amine; (S) -. { 4- [5- (5- (2, 2,2-Trifluoro-l-methyl-ethyl) - (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-yl} - (1-f-enyl-ethyl) -amine; (S) -. { 4- [5- (5-sec-Butyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1,2-c] -pyrimidin-7- il] -pyridin-2-il} - (1-f-enyl-ethyl) -amine; (S) -. { 4- [5- (5-Cyclopentyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} - (1-f-enyl-ethyl) -amine; (S) -. { 4- [5- (5-Methyl- (1S, 4S) -2,5-diaza- bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [5- (5-Propyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} - (1-phenyl-ethyl) -amine; • (S) -. { 4- [5- (5-Isobutyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} - (1-phenyl-ethyl) -amine; - (S) -. { 4- [5- (5-Benzyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} - (1-phenyl-ethyl) -amine; (S) -. { 4- [5- (5- (2-Phenoxy-ethyl) - (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] - pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [5- (5- (2-Phenoxy-propyl) - (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] - pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [5- (5- (2-Phenoxy-propyl) - (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] - pyrimidin-7-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) - (4- { 5- [5- (2,2-Difluoro-ethyl) - (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl] - imidazo [1, 2-c] -pyrimidin-7-yl.} - pyridin-4-yl) - (1-phenyl-ethyl) -amine; (S) -. { 4- [2- ((1S, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl) -thiazol-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; Tere butyl ester of 5- acid. { l- [2- ((S) -l-Phenylethylamino) -pyridin-4-yl] -lH-indazol-3-yl} - (SS, 4S) -2,5-diaza-bicyclo [2.2.1] heptane-2-carboxylic acid; (S) -. { 4- [3- ((ls, -4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [3- (5-Isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; . { 4- [4- ((SS, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (S) - (1-phenyl-ethyl) -amine; (S) -. { 4- [2- (5-Isopropyl- (SS, S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -thiazol-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [4- ((1S, 4S) -2,5-Diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [4- (5-Isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [4- (5-Ethyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [4- (5-Methyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; Benzyl- (4- [5- ((lS, 4S) -2-5-diaza-bicyclo [2.2, l] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl ] -pyridin-2-yl) -amine; Benzil- { 4- [5- (5-isopropyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} -amine; . { 4- [5- ((SS, 4S) -2, 5-Diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2 -il} - (2-fluoro-benzyl) -amine; (2-Fluoro-benzyl) -. { 4- [5- (5-isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-il} -amine; Benzil { 4- [5- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] -pyrimidin-7-yl] -pyridin-2-yl} methylamine; (S) -. { 4- [4- (5-Methyl- (lS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl-) -amine; (S) -. { 4- [4- (5-Ethyl- (SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [4- (5-Isopropyl- (1S, S) -2,5-diaza-bicyclo [2.2.l] hept-2-yl) -quinazolin-2-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -. { 4- [2- (5-Isopropyl- (1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -pifimidin-4-yl] -pyridin-2-yl} - (1-phenyl-ethyl) -amine; (S) -Benzil-. { 4- [3- ((1S, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6-fluoro-indazol-1-yl] -pyridin-2-yl} -amine; Benzil- { 4- [3- ((SS, 4S) -2,5-diaza-bicyclo [2.2.1] hept-2-yl) -6-fluoro-indazol-1-yl] -pyridin-2-yl} -amine; and Benzil-. { 4- [3- (SS, 4S) -2, 5-diaza-bicyclo [2. 2 . 1] hept-2-yl) -indazol-1-yl] -pyridin-2-yl} -amine 12 Compound of formula II or a pharmaceutically acceptable salt thereof, characterized in that J is NH, N (Rb), O "or -S; K is -C (R3R3) m, -C (= 0), -C (= 0) 0- , -C (= 0) N (R) -, -C (= NRa) N (Ra) -, -0-, -0C (= 0) -, -0C (= 0) N (Ra) -, "-0C2-6alkylN (Ra), -0C2-6alkyl0- , -S-, -S (= 0) -, -S (= 0) 2-, -S (= 0) 2N (Ra) -, -N (Ra) -, -N (Ra) C (= 0) -, -N (Ra) C (= 0) O-, -N (Ra) C (= 0) N (Ra) -, -N (Ra) C (= NRa) N (Ra) -, -N (Ra) S (= 0) 2-, -N (Ra) S (= 0) 2N (Ra) - or -N (Ra) C2_6alkylN (Ra); R1 is selected from R is a 5-, 6- or 7-membered monocyclic ring or 6-, 7-, 8-, 9-, 10- or 11-membered bicyclic saturated, partially saturated or unsaturated containing 1, 2, 3 or 4 atoms selected from N, O and S, as long as the combination of O and S atoms is not greater than 2, where the ring carbon atoms are replaced by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? _ Salkyl, C-L_4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NR R \ -C (= NRa) NRaRa, 0Ra, -OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra ) S (= 0) 2Rb, -OCalkyl2-6NRaRa, -OCalkyl2_6ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S ( = 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NR) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa and -NRaC2_6alkyl0Ra; R3 is independently in each case H, Ci-galkyl, C -?. _ 8 alkylRa, C1_4haloalkyl, C1_4haloalkyloRa, halo, cyano, nitro, oxo, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NR) NRaRa, -0Ra, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2 -5alkylNRaRa, -OC2_6alkyloor, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa or -NRaC2 6alkyl0Ra; R4 is independently in each case C? _8alkyl, C? -haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) -Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2_6alkylNRaR, -0C2_6alkyl0Ra, -SRa, -S (= 0) Rb, -S ( = 0) 2Rb, - -S (- = 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, - S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C ( = 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa or -NRaC2 5alkyl0Ra; R5 is H, C (= 0) Rb, -S (0) pRb, C (= 0) Rc, -S (0) pRc, or C? _6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H, Rc, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; Ra is independently, in each case, H or Rb; Rb is independently, in each case, phenyl, benzyl or C6-6alkyl, the phenyl, benzyl and C6-6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C 4 alkyl, C 3 haloalkyl, C 1 4 alkyl, -NH 2, -NHC 6 alkyl, and N (C 4 alkyl) C 4 alkyl; Rc is independently in each case, a 5-, 6-6- or 7-membered monocyclic or 6-7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated containing 1, 2, 3 or 4 atoms selected from N, O and S, provided that the combination of the atoms of 0 and S is not greater than 2, where the ring carbon atoms are replaced by 0, 1 or 2 oxo groups; Rd is independently in each case C? _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -0C (= 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -0C2-6alkylNRaRa, -OC2_6alkylore, -SRa, - S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb , -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa or -NRaC2-6alkyloRa; Re is independently in each case Rd or H; Rf is independently, in each case, a 5-, 6- or 7-membered or 6-, 7-, 8-, 9-, 10- or 11-membered saturated, partially saturated or unsaturated monocyclic ring containing 0, 1, 2, 3 or 4 atoms selected from N, O and S, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and the ring is substituted by 0, 1, 2 or 3 selected substituents Ci-galkyl, C ^ haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0R, -0C (= 0) Rb, -0C (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OCalkyl2_6NRaRa, -OCalkyl2-6ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (- = 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) ORb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) ORb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2 6alkylNRaRa and -NRaC2_6alkyloor; m is independently in each case 0, 1, 2 or 3; n is 1; and p is 0, 1 or 2. 13. Compound according to claim 12, characterized in that J is NH or NCH3; K is C (R3R3) m, -C (= 0), -C (= 0) 0-, -C (= 0) N (Ra) -, -C (= NRa) N (Ra) -, -S (= 0) -, -S (= 0) 2, -S (= 0) 2N (Ra) ~ or -N (Ra) -; R1 is selected from R is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0, 1, 2 or 3 substituents independently selected from C? -8alkyl , C? -haloalkyl, halo, cyano, nitro, -C (= 0) R, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -ORa, -0C ( - = 0) Rb, -OC (= 0) NRaRa, -0C (= 0) N (Ra) S (= 0) 2Rb, -OC2_6alkylNRaRa, -OC2_6alkyl? ORa, -SRa, -S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2_6alkyloor. R3 is independently in each case H, C? _8alkyl, C1_haloalkyl, halo, -0Ra, -SRa or -NRaRa; R4 is independently in each case C? _8alkyl, C? _4haloalkyl, halo, cyano, nitro, -0Ra, -SRa, -NRR, -NRaC2_6alkylNRaRa or -NRaC2_6alkyloRa; R5 is H, C (= 0) Rb, S (0) pRb, C (= 0) Rc, S (0) pRc, or C? _6alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H, Rc, Rd, or a C6_6alkyl substituted by 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; Ra is independently in each case, H or Rb; Rb is independently in each case, phenyl, benzyl or C6-6alkyl, the phenyl, benzyl or C6-6alkyl are substituted by 0, 1, 2 or 3 substituents selected from halo, C? -4alkyl, C? -3haloalkyl, -OC? _4alkyl, -NH2, -NHC? -4alkyl and N (C? -4alkyl) C? _4alkyl; Rc is independently, in each case, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the carbon of the ring are substituted by 0, 1 or 2 oxo groups; Rd is independently in each case, C? -8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) 0Rb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -0Ra, -OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (-0) 2Rb, -OC2_6alkylNRaRa, -OC2_6alkylore, -SRa, - S (= 0) Rb, -S (= 0) 2Rb, -S (= 0) 2NRaRa, -S (= 0) 2N (Ra) C (= 0) Rb, -S (= 0) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2N (Ra) C (= 0) NRaRa, -NRaRa, -N (Ra) C (= 0) Rb, -N (Ra) C (= 0) 0Rb, -N (R) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa or -NRaC2_6alkyloor; Re is independently in each case Rd or H; Rf is independently at each instance, phenyl, naphthyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, - isoquinazolinyl, tetrahydroquinazolinyl, tetrahidroisoquinazolinilo, morpholinyl, thiophenyl, pyranyl, furyl, I dihydrofuryl , tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups; and the ring is replaced by 0, 1, 2 or 3 substituents independently selected from Ci-salquilo, C? _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) NRaRa, -ORa, -OC2-6alkylNRaRa, -OC2_6alkylore, -SRa, -S (= 0) Rc -S (= 0) 2R -S (= 0) 2NRaRa -NRaRa -N (Ra) C (= 0) Rb -N (Ra) C (= 0) NRaRa, -N (Ra) S (= 0) 2Rü, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNR Ra and -NRaC2_6alkyloor; m is independently in each case 0, 1, 2 or 3; n is 1; and p is 0, 1 or 2. 14. Compound according to claim 12, characterized in that J is NH or NCH3; K is C (R3R3) m, -C (= 0), -C (= 0) N (Ra) -, -S (= 0) -, -s (= 0) 2- or S (= 0) 2N (Ra) -; R is selected from R is a ring selected from phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, t-tetrahydxoquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl and benzimidazolyl, wherein the ring carbon atoms are substituted by 0, 1 or 2 oxo groups, and wherein the ring is substituted by 0 , 1, 2 or 3 substituents independently selected from C ?_8alkyl, C ?haloalkyl, halo, cyano, nitro, C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NRaRa, -ORa, - OC (= 0) Rb, -OC (= 0) NRaRa, -OC (= 0) N (Ra) S (= 0) 2Rb, -OC2-6alkylNRaRa, -OC2_6alkylOR, -SRa, -S (= 0) Rb , -S (= 0) 2Rb, S (= 0) 2NRaRa, -S (= 0) 2 (Ra) C (= 0) Rb, -S (= 0) 2 (Ra) C (= 0) 0Rb, -S (= 0) 2 (Ra) C (= 0) NRaRa, -NRaRa, - (Ra) C (= 0) Rb, N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NRaRa, -N (Ra) C (= NRa) NRaRa, -N (R) S (= 0) 2R, -N (Ra> S (= 0) 2NRaRa, -NRaC2-6alkyNRaRa and -NRaC2_ 6alkyloor; R3 is independently in each case H, C? _ Alkyl, C? _4 haloalkyl, halo or 0Ra; R4 is H or C? _6 alkyl; R5 is H, C (= 0) Rb, S (0) pRb, C (= 0) Rc, S (0) pRc, or C? _alkyl substituted by 0, 1, 2 or 3 substituents independently selected from Rd and further substituted by 0 or 1 substituents selected from Rf; R6 is H or C? _6 alkyl; Ra is independently in each case, H or Rb; Rb is independently in each case, phenyl, benzyl or Cx-βalkyl, the phenyl, benzyl or C i -alkyl are substituted by 0, 1, 2 or 3 substituents selected from • halo, C? _ Alkyl, C? _ Haloalkyl, -OC? _4 alkyl, -NH2, -NHCi-4alkyl and N (C? _4alkyl) C? _4alkyl; Rc is independently, at each instance, phenyl, dihydroindenyl, naphthyl, tetrahydronaphthalenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, triazinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinazolinyl, isoquinazolinyl, tetrahydroquinazolinyl, tetrahydroisoquinazolinyl, morpholinyl, thiophenyl, pyranyl, furanyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, indolinyl, benzodioxyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl , cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, benzothiophenyl or benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups; Rd is independently in each case, C? _ Salkyl, C! _4haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) ORb, -C (= 0) NRaRa, -C (= NRa) NR a R, -0Ra, -0C (= 0) Rb, -OC (= 0) NR a R, -OC (= 0) N (Ra) .S (= 0) 2 R b, -OC2-6alquiloNRaRa, -OC2_6alkylOR, -SRa, -S (= 0) Rr -S (= 0) 2R £ S (= 0) 2NRaRa, -S (= 0) 2 (Ra) C (= 0) Rb, • S (= 0 ) 2N (Ra) C (= 0) 0Rb, -S (= 0) 2 (Ra) C (= 0) NRaRa, -NRaRc -N (Ra) C (= 0) R £ N (Ra) C (= 0) 0Rb, -N (Ra) C (= 0) NR a R, -N (Ra) C (= NR) NR a R, -N (Ra) S (= 0) 2 R b, -N (Ra) S (= 0) 2 NR, -NRaC2-.6alquiloNRaRa or -NRaC2_ 6alquilo0Ra; Re is independently in each case, H, Cl, F, Br, I, CH3, N02, NHS02CH3, OH, CF3 or N-Acetyl; Rf is independently at each instance, phenyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl, piperazinyl, 'triazinyl, morpholinyl, thiophenyl, pyranyl, furyl, dihydrofuryl, tetrahydrofuryl, pyrrolyl, piazolilo, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl , indolyl, isoindolyl, indolinyl, benzofuranyl, dihydrobenzofuranyl, cyclopropyl, cyclobutyl, cyclopentyl, ciciohexilo, cicioheptilo, benzothiophenyl or benzimidazolyl, wherein the carbon atoms of the ring are substituted by 0, 1 or 2 oxo groups and the ring is substituted by 0 , 1, 2 or 3 substituents independently selected from C? _ 8alkyl, C? _haloalkyl, halo, cyano, nitro, -C (= 0) Rb, -C (= 0) NRaRa, -0Ra, -OC2_6alkylNRaRa, -OC2-6alkyloor, -SRa, -S (= 0) Rb, -S (= 0) 2R, -S (= 0) 2NRaRa, -NRaRa, N (Ra) C (= 0) Rb, -N (Ra) C (= 0) ) NRaRa, -N (Ra) S (= 0) 2Rb, -N (Ra) S (= 0) 2NRaRa, -NRaC2_6alkylNRaRa and -NRaC2-6alkyloor; m is independently in each case 0, 1, 2 or 3; n is 1; and p is 0, 1 or 2. 15. Compound according to claim 12, characterized in that it is selected from: -? 6- (2- (((1S) -1- (4-fluorophenyl) ethyl) amino) -4-pyridinyl) -3-methyl-2 - (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -4 (3H) -pyrimidinone; 2- (2,5-diazabicyclo [2.2.1] hept-2-yl) -3-methyl-6- (2- ((2-thienylmethyl) amino) -4-pyridinyl) -4 (3H) -pyrimidinone; A, 1-dimethylethyl-5- (1-methyl-6-oxo-4- (2- (((IR) -1-phenylethyl) amino) -4-pyridinyl) -1,6-dihydro-2-pyrimidinyl) -2, 5-diazabicyclo [2.2.1] heptane-2-carboxylate; 3-Methyl-2- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -6- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl ) -4 (3H) -pyrimidinone; 3-Methyl-2- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl) -4 (3H) -pyrimidinone; - (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) [1,2,4] triazolo [4, 3-c] pyrimidin-7-yl) -N- ((ÍS) - 1-phenylethyl) -2-pyridinamine; A, 1-dimethylethyl-5- (7- (2-amino-4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate; 4- (5- (5- (methylsulfonyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) - 1- phenylethyl) -2-pyridinamine; x (SS) -l-methyl-2-oxo-2- (5- (7- (2- (((SS) -1- phenylethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidine -5-yl) - '2,5-diazabicyclo [2.2.1] hept-2-yl) ethyl acetate; A, 1-dimethylethyl-5- (7- (2- (((2S) -2- (acetyloxy) propanoyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2 , 5-diazabicyclo [2.2.1] heptane-2-carboxylate; - (2S) -1-oxo-l- (5- (7- (2- (((S) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl ) -2,5-diazabicyclo [2.2.1] hept-2-yl) -2-propanol; N- ((iS) -l-cyclohexylethyl) -4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) - 2- pyridinamine; M- (5- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1- phenylethyl) -2- pyridinamine; N- ((IR) -1-cyclopropylethyl) -4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) - 2-pyridinamine; N- ((1S) -1-cyclohexylethyl) -4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] ] pyrimidin-7-yl) -2-pyridinamine; - (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1- (1-naphthalenyl) ethyl) -2-pyridinamine; - M- (5- (5- (1-Methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (2 -thienylmethyl) -2-pyridinamine; N- (4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2 pyridinyl) benzenesulfonamide; N- (4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2 pyridinyl) benzamide; N '(2-furanylmethyl) -4- (' 5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine- 7-yl) -2-pyridinamine; N- ((1S) -1- (4-fluorophenyl) ethyl) -4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [ 1,2-c] pyrimidin-7-yl) -2-pyridinamine; - (5- (5- (2, 2-difluoroethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2- c] pyrimidin-7-yl) -N- (( 1 S) -1-phenylethyl) -2-pyridinamine; M- (5- ((1S, 4S) -5-butyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl) -N- ( (SS) -1-phenylethyl) -2-pyridinamine; N- ((1S) -l-phenylethyl) -4- (5- ((1S, 4S) -5- ((SS) -2,2,2-trifluoro-1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; - (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (1-naphthalenylmethyl) -2-pyridinamine; 4- (2- (2,5-diazabicyclo [2.2.1] hept-2-yl) -1,3-thiazol-4-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; M- (2- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1,3-thiazol-4-yl) -N- ((SS) -1 phenylethyl) -2-pyridinamine; M- (5- (5- (1-Methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((1S ) -1- (4- (methyloxy) phenyl) ethyl) -2-pyridinamine; M- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1- (4-fluorophenyl) ethyl) -2-pyridinamine; - (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -1H-indazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; M- (5- (5- ((SS) -1-methylpropyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N - ((1S) -1-phenylethyl) -2-pyridinamine; M- (5- (5- ((IR) -1-methylpropyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N - ((1S) -1-phenylethyl) -2-pyridinamine; M- (5- (5-cyclopentyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1- phenylethyl) -2-pyridinamine; 1- (5- (7- (2- (((SS) -1-phenylethyl) amino) -4- pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -2-propanol; 4- (5- (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1 phenylethyl) -2-pyridinamine; - (3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; N- ((SS) -1-phenylethyl) -4- (5- ((SS, 4S) -5- (2- (phenyloxy) ethyl) -2,5-diazabicyclo [2.2.1] hept-2 il) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; - (5- ((IR, 4R) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) - N- ((1S) -1-phenylethyl) -2-pyridinamine; N- ((1S) -l-phenylethyl) -4- (5- (5-propyl-2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine-7 -yl) -2-pyridinamine; M- (5- (5- (2-methylpropyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((ΔS ) -1-phenylethyl) -2-pyridinamine; 4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl) -N- (phenylmethyl) -2-pyridinamine; M- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N-methyl-N- (phenylmethyl) -2-pyridinamine; N- ((3-chlorophenyl) methyl) -4- (5- (2,5-diazabicyclo) [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; 4- (5- ((SS, 4S) -5- (1,1-dimethylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine-7 -yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; A, 1-dimethylethyl 5- (7- (2- ((phenylmethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5-diazabicyclo [2.2.1] heptane -2-carboxylate; 4- (5- ((IR, 4R) -5- (1,1-dimethylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7- il) -N- ((ÍS) -1-phenylethyl) -2-pyridinamine; A, 1-dimethylethyl 5- (7- (2- (((2-fluorophenyl) ethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5-diazabicyclo [ 2.2.1] eptane-2-carboxylate; M- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((3-fluorophenyl) methyl) -2- pyridinamine; N- ((1S) -1- (4-fluorophenyl) ethyl) -4- (3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH -indazol-1-yl) -2-pyridinamine; M- (4- (2,5-diazabicyclo [2.2.1] hept-2-yl) -1H-pyrazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; 2- ((4- (5- (2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinyl) amino) -2- phenylethanol; A, 1-dimethylethyl 5- (1- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl) -lH-indazol-3-yl) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate; M- (5- ((SS, 4S, 6S) -6-methyl-5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; - (5- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl) -N- (phenylmethyl) -2-pyridinamine; - (5- (5- (1-Methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (phenylmethyl) - 2-pyridinamine; N- ((3-fluorophenyl) methyl) -4- (5- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -2-pyridinamine; M- (3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; N- ((SS) -1-phenylethyl) -4- (5- (5- (3- (phenyloxy) propyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1, 2-c] pyrimidin-7-yl) -2-pyridinamine; N- ((2-fluorophenyl) methyl) -4- (3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl ) -2-pyridinamine; M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -1H-indazol-1-yl) -N- ((2-fluorophenyl) methyl) -2-pyridinamine; N- ((SS) -1-phenylethyl) -4- (5- (5- (phenylmethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine -7-yl) -2-pyridinamine; M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -1 H -indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; N- ((2-fluorophenyl) methyl) -4- (5- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidine-7- il) -2-pyridinamine; M- (5- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- ((2-fluorophenyl) methyl) ) -2-pyridinamine; M- (5- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) imidazo [1,2-c] pyrimidin-7-yl) -N- (phenylmethyl) -2-pyridinamine; Methyl-3- (5- (7- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2, 5- diazabicyclo [2.2.1] hept-2-yl) propanoate; 3- (5- (7- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -2,5-diazabicyclo [ 2.2.1] hept-2-yl) propanic; M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -5-fluoro-lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) -2- pyridinamine; M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -1H-indazol-1-yl) -N- ((2-fluorophenyl) methyl) -2-pyridinamine; M- (3- (5-methyl-2,5-diazabicyclo [2.2.1] hept-2-yl) - lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; M- (5-fluoro-3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- ((SS) -1-phenylethyl ) -2-pyridinamine; - ((2-fluorophenyl) methyl) -4- (3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -2-pyridinamine; - (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; M- (5-fluoro-3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; 2- (7- (2- (3, 4-dihydro-2 (1H) -isoquinolinyl) -4-pyridinyl) imidazo [1,2-c] pyrimidin-5-yl) -5- (1-methylethyl) -2, 5-diazabicyclo [2.2.1] heptane; M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -1 H -indazol-1-yl) -N-phenyl-2-pyridinamine; M- (3- (2,5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; - (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -1H-indazol-1-yl) -N- ((1S) -1- (2-fluorophenyl) ethyl) -2- pyridinamine; M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) -2- pyridinamine; M- (3- ((1S, 4S) -5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-pyrazol-1-yl) -N- (( ÍS) -1-phenylethyl) -2- pyridinamine; M- (3- (2,5-diazabicyclo [2.2.1] hept-2-yl) -7-fluoro-H-indazole-lyryl) -N- ((SS) -1-phenylethyl) -2-pyridinamine; M- (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -7-fluoro-lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) ) -2-pyridinamine; M- (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- ((SS) -1-phenylethyl) -2- pyridinamine; A- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -5- (3,4-difluorophenyl) -3-methyl-6- (2- ((2-phenylethyl) amino) -4-pyridinyl) -4 (3H) -pyrimidinone; M- (6-Fluoro-3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- (phenylmethyl) - 2-pyridinamine; M- (6-fluoro-3- (5-methyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; M- (4-chloro-3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) -2- pyridinamine; 4- (4-chloro-3- (5- (1-methylethyl) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((S ) -1-phenylethyl) -2-pyridinamine; - (4-chloro-3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -IH-indazol-1-yl) -N- ((1S) -1-phenylethyl) -2-pyridinamine; 4- (3- (5-ethyl-2, 5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; M- (3- (2, 5-diazabicyclo [2.2.1] hept-2-yl) -6-nitro-lH-indazol-1-yl) -N- ((SS) -1-phenylethyl) -2- pyridinamine; - (4-chloro-3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- (phenylmethyl) -2-pyridinamine; - (6-chloro-3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -lH-indazol-1-yl) -N- ((SS) -1- phenylethyl) -2-pyridinamine; 4- (3- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6-fluoro-lH-indazol-1-yl) -N-methyl-N- (phenylmethyl) ) -2-pyridinamine; 4- (3- ((lS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6-methyl-lH-indazol-1-yl) -N- (phenylmethyl) -2- pyridinamine; A, 1-dimethylethyl (SS, 4S) -5- (4-chloro-l- (2- ((phenylmethyl) amino) -4-pyridinyl) -lH-indazol-3-yl) -2,5-diazabicyclo [ 2.2.1] heptane-2-carboxylate; M- (3- ((lS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6-methyl-lH-indazol-1-yl) -N- ((IR) -1 phenylethyl) -2-pyridinamine; A, 1-dimethylethyl (1S, 4S) -5- (6-methyl-l- (2- (((1R) -1-phenylethyl) amino) -4-pyridinyl) -lH-indazol-3-yl) - 2,5-diazabicyclo [2.2.1] heptane-2-carboxylate; M- (6-methyl-3- ((SS, 4S) -5- (1-methylethyl) -2,5-diazabicyclo [2.2..1] hept-2-yl) -IH-indazol-1-yl) -N- ((IR) -1-phenylethyl) -2-pyridinamine; 3- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -l- (2- (((1S) -1-phenylethyl) amino) -4-pyridinyl) -lH -indazole-6-amine; N- (3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1- (2- (((1S) -1-phenylethyl) amino) -4- pyridinyl) -lH-indazol-6-yl) acetamide; N- (3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -1- (2- (((SS) -1-phenylethyl) amino) -4- pyridinyl) -lH-indazol-6-yl) methanesulfonamide; 3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6-nitro-1- (2- (((SS) -1-phenylethyl) amino) -4 -pyridinyl) -iH-indazol-7-ol; 4- (3- ((1S, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6- (trifluoromethyl) -lH-indazol-1-yl) -N- ((IR ) -1-phenylethyl) -2-pyridinamine; A, 1-dimethylethyl (SS, 4S) -5- (1- (2- ((phenylmethyl) amino) -4-pyridinyl) -6- (trifluoromethyl) -lH-indazol-3-yl) -2, 5- diazabicyclo [2.2.1] heptane-2-carboxylate; - (3- ((SS, 4S) -2,5-diazabicyclo [2.2.1] hept-2-yl) -6- (trifluoromethyl) -lH-indazol-1-yl) -N- (phenylmethyl) -2 -pyridinamine; and A, 1-dimethylethyl (SS, 4S) -5- (1- (2- (((SS) -1-phenylethyl) amino) -4-pyridinyl) -6- (trifluoromethyl) -lH-indazole-3- il) -2,5-diazabicyclo [2.2.1] heptane-2-carboxylate. 16. Pharmaceutical composition, characterized in that it comprises a compound according to claim 1 and a pharmaceutically acceptable carrier. 17. Pharmaceutical composition, characterized in that it comprises a compound according to claim 12 and a pharmaceutically acceptable carrier. 18. Use of a medicament for the treatment of inflammation, the medicament comprises a compound according to claim 1. 19. Use of a medicament for the treatment of inflammation, the medicament comprises a compound according to claim 12. 20. Use of a medicament for treating a disease or disorder mediated by PKC theta, the medicament comprises a compound according to claim 1. 21. Use of a medicament for treating a -disease or disorder mediated by PKC theta, the medicament comprises a compound according to claim 12. 22. Use of a medicament for treating a disease or disorder associated with the activation of T cells, the medicament comprises a compound according to claim 1. 23. Use of a medicament to treat a disease or disorder associated with the activation of T cells, the medicament comprises a compound in accordance with the claim 12 24. Use of a medication for the treatment of arthritis, rheumatoid arthritis, psoriatic arthritis or osteoarthritis, organ transplantation, acute rejection to transplantation or heterograft and homograft, ischemic and reperfusion injury, induction of tolerance- transplantation, multiple sclerosis, inflammatory disease of the intestine, ulcerative colitis, Crohn's disease, lupus, graft against host diseases, T-cell mediated hypersensitivity diseases, contact hypersensitivity, late type hypersensitivity, Gluten-sensitive enteropathy, type 1 diabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, Graves' disease, Addison, autoimmune polyglandular disease, autoimmune alopecia, pernicious anemia, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, autoimmune diseases, glomerulonephritis, serum sickness, urticaria, respiratory allergies, asthma, hay fever, allergic rhinitis, skin allergies , sclera, mycosis fungoides, acute inflammatory responses, acute respiratory anxiety syndrome, dermatomyositis, alopecia areata, actinic dermatosis, eczema, Behcet's disease, Palmoplantaris pustulosis, Pyoderma gangrenosum, Sezary's syndrome, atopic dermatitis, systemic sclerosis, morphea, Type II diabetes, resistance to insulin, diabetic retinopathy, diabetic macular edema, diabetic neuropathy; cardiovascular disease related to diabetes or a combination thereof in a mammal, the medicament comprises a compound according to any of claims 1-15. 25. Use of a drug for the treatment of cancer where PKC theta or other kinases of the PKC family are activated, overexpress or facilitate tumor growth or survival of tumor cells, T cell leukemia, thymoma, lymphoma T and B cells, colon carcinoma, breast carcinoma, or lung carcinoma or provide resistance to chemotherapeutic drugs or therapeutic radiation, the medicament comprises a compound according to any of claims 1-15. SUMMARY OF THE INVENTION The present invention relates to therapeutic diazobicyclic pyridines and their use in the treatment of arthritis, rheumatoid arthritis, psoriatic arthritis or osteoarthritis, organ transplantation, acute rejection to transplantation or heterograft and homograft, ischemic and reperfusion injury, induction of tolerance to transplant, multiple sclerosis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, lupus, graft against host diseases, T cell-mediated hypersensitivity diseases, contact hypersensitivity, late type hypersensitivity, Gluten-sensitive enteropathy, type 1 diabetes , psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, Graves' disease, Addison's disease, autoimmune polyglandular disease, autoimmune alopecia, pernicious anemia, vitiligo, autoimmune hypopituitarism, Guillain-Barre syndrome, autoimmune diseases, glomer ullephritis, serum sickness, urticaria, respiratory allergies, asthma, hay fever, allergic rhinitis, skin allergies, sclera, mycosis fungoides, acute inflammatory responses, acute respiratory anxiety syndrome, dermatomyositis, alopecia areata, chronic actinic dermatitis, eczema , disease Behcet, Pustulosis palmoplantaris, Pyoderma gangrenosum, Sezary syndrome, atopic dermatitis, systemic sclerosis, morphea, type II diabetes and cancers where PKC theta or other kinases of the PKC family are activated, 'overexpress or facilitate tumor growth or the survival of tumor cells, T-cell leukemia, thymoma, T-cell and B-cell lymphoma, colon carcinoma, breast carcinoma and lung carcinoma or provide resistance to chemotherapeutic drugs.