ES2470291T3 - Bis-arylamide compounds and methods of use - Google Patents

Abstract

Compound of formula I: **Formula** N /R2 A, 0 A2 83 or stereoisomer, solvate or pharmaceutically acceptable salt thereof, wherein A1 is CR4; A2 is CR5; A3 is CR6; A4 is CR7; provided that when L is -NHC(0)-, then R6 is H; L is -C(0)NR7-, -NR7C(0)-, -NR7C(0)NR7-, -NR7C(0)0-, -S(0)2NR7-, -NR7S(0)2NR7- or NR7S(0)2-; R1 is pyrimidyl or pyrazinyl, each ring of which is optionally substituted -8-R9, independently with one or more substituents of R8, NREIR8, NR OR8, OR9, SR8, SR9, C(0)R8, C(0)R9 , OC(0)R8, C(0)0R8, C(0)NR8R8, C(0)NR8R9, NR8C(0)R8, NR8C(0)R9, NR8C(0)NR8R8, NR8C(0)NR8R9, NR8C (0)0R8, NR8C(0)0R9, S(0)2R8, S(0)2R9, S(0)2NFeR8, S(0)2NR8R9, NR8S(0)2NR8R8, NR8S(0)2NR8R9, NR8S(0 )2R8 or NR8S(0)2R9; R2 is H or C1-10 alkyl;

Description

Bis-arylamide compounds and methods of use

The present invention relates generally to bis-arylamide compounds, to pharmaceutical compositions comprising the same and to the use for the treatment of disorders mediated by kinases.

 Autoinrnunitary inflammatory diseases, such as rheumatoid arthritis, scleroderma polyarthritis, inflammatory bowel disease, type I diabetes, multiple sclerosis, ulcerative colitis, Crohn's disease, Sjogren's disease, polymyositis, dermatomyositis, vasculitis, myasthenia gravis, psoriasis and lupus, usually they activate various inflammatory factors, including T cells. T cells play a central role in the regulation of immune responses and are important to establish immunity against pathogens. The

 T cell activation is also an important component of organ transplant rejection, reactions Allergic and asthma.

T cells are activated by specific antigens through T cell receptors (TCR) that are expressed on the cell surface. This activation triggers a series of mediated intracellular serialization cascades by enzymes expressed inside the cell (Kane, LP et al. Current Opinion in lmmunol. 2000, 12, 242). These

 waterfalls lead to gene regulation events that result in the production of cytokines, which include interleukin-2 (IL-2). IL-2 is a critical cytokine in the activation of T cells, which leads to proliferation and amplification of specific immune responses.

It has been shown that kinase enzymes are important in the transduction of intracellular signals. A class of Kinase enzymes involved in signal transduction is the Src family of protein tyrosine kinases (PTK), which  includes, for example: Lck, Fyn (B), Fyn (T), Lyn, Src, Yes, Hck, Fgr and Blk (for review see: Bolen, JB, and Brugge, JS Annu Rev. Immunol 1997, 15, 371). Studies of genetic alteration suggest that the inhibition of some members of the Src family of kinases would possibly lead to therapeutic benefit. Src (- / -) mice have osteoporosis abnormalities or bone remodeling (Soriano, P. Cell 1991, 64, 693), suggesting that the inhibition of Src kinase can be ON in bone resorption diseases, such as osteoporosis. Lck (- / -) mice have

 defects in maturation and activation of T cells (Anderson, SJ et al. Adv. Immunol. 1994, 56, 151), which suggests that the inhibition of Lek kinase may be useful in inflammatory diseases caused by T cells. In addition, human patients have been identified with mutations that affect the activity of the Lck kinase (Goldman, FD et al. J. Clin. Invest-1998, 102, 421). These patients suffer from an immunodeficiency disorder. combined serious (SCID).

 Src family kinases are also important for the subsequent signaling of other receptors of immune cells Fyn, like Lek, is involved in signaling TCR in T cells (Appleby, MW et al. Cell 1992, 70, 751). Hck and Fgr are involved in the serialization of the Fey receiver that leads to activation of neutrophils (Vicentini, L. etal. J. Immunol. 2002, 168, 6446). Lyn and Src also participate in the signaling of

Fey receptor that leads to the release of histamine and other allergic mediators (Turner, H. and Kinet, J-P  Nature 1999, 402, B24). These findings suggest that Src family kinase inhibitors may be Useful in the treatment of asthma and allergic diseases.

It has also been found that Src kinases are activated in tumors that include sarcoma, melanoma, breast and colon cancers suggesting that Src kinase inhibitors may be anticancer agents Useful (Abram, CL and Courtneidge, SA Exp. Cell Res. 2000, 254, 1). It has also been reported that inhibitors of

 Src kinase are effective in an animal model of cerebral ischemia (R. Paul etal. Nature Medicine 2001, 7, 222), which suggests that Src kinase inhibitors may be effective by limiting brain damage after an accident cerebrovascular

Another protein kinase that is believed to cause autoimmune disease is c-Kit. C-kit is a tyrosine kinase receptor expressed on the surface of mast cells, for which the stem cell factor (SCF) is a ligand. Be  He believes that aberrant c-kit signaling is a mediator of certain autoimmune diseases. The SCF binding to the c-kit media receptor in various mast cell functions. As an important mediator of the function of mast cells, it is believed that c-kit also plays a role in pathologies associated with mast cells (MC).

C-kit works through mast cell generation, which plays an important role in triggering of autoimmune diseases. Mast cells are tissue elements derived from a particular subset

 hematopoietic stem cells that express CD34, c-kit and CD13 antigens (Kirshenbaum et al., Blood 94: 2333-2342, 1999 and lshizaka etal, Curr. Opinion lmmunol. 5: 937-943, 1993). Mast cells are characterized by its heterogeneity, not only with respect to tissue location and structure but also at functional levels and

histochemistry (Aldenberg and Enerback, Histochem. J. 26: 587-596, 1994; Bradding et al., J. lmmunol. 155: 297-307, nineteen ninety five; Irani etal. J. Immunol. 147: 247-253, 1991).

 It is believed that mast cells participate in tissue destruction by releasing various proteases and mediators classified into three groups: mediators associated with preformed granules (histamine, proteoglycans and proteases) neutral), mediators derived from lipids (prostaglandins, thromboxanes and leueotriennes) and various cytokines, including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, TNFa, GM-CSF, MIP-1 a, MIP-1b, MIP-2 and IFNy. The liberation of

these mediators induce and activate various immune response components involved in diseases autoimmune, and also promotes the tissue destruction procedure.

It is postulated that the activation of the autoimmune response is caused by, or stimulated from, the mast cell degranulation. Immature MC progenitors circulate in the bloodstream and differ in  the tissues. These differentiation and proffered processes are influenced by various cytokines. Cell factor Mother (SCF) and IFNy are two cytokines that are important in influencing such processes. The SCF receiver is encoded by the proto-oncogen c-kit, which belongs to the receptor tyrosine kinase subfamily type III (Boissan and Arock, J. Leukoc. Biol. 67: 135-148, 2000), together with PDGF and cFMS. C-kit receptor binding by SCF induces its dimerization followed by its transphosphorylation, which leads to the recruitment and activation of various

 intracytoplasmic substrates. IFNy is another cytokine secreted by mast cells. It has been reported that IFNy is responsible for the major histocompatibility complex associated with autoimmune diseases (Hooks etal., New England J. de Med., 301: 5-8, 1979). These activated substrates induce multiple serialized routes intracellular responsible for the proffered & and cellular activation (Boissan and Arock, 2000).

TNF is another cytokine produced by mast cells. More recently, it has been reported that TNF produced by  Mast cells are involved in the pathogenesis of autoantibody-mediated vasculitis (Watanabe et al., Blood 11: 3855-3866, 1994). It was also shown that mast cells control the recruitment of neutrophils during delayed type hypersensitivity reactions mediated by T cells through TNF and inflammatory protein of macrophages 2 (MIP-2). Therefore, c-kit regulation can be useful in various types of inflammation that

they include without limitation, rheumatoid arthritis, severe asthma, chronic allergy-associated rhinitis, and the like.

 Mast cells have also been implicated in liver allograft rejection (Yammaguchi etal., Hematology 29: 133-139, 1999) and in hepatic fibrosis, in which hepatic star cells produce the SCF that recruits the mast cells (Gaca etal., J. Hematology 30: 850-858, 1999). These observations suggest that the inhibitors of C-kit kinase can help prevent rejection and organ fibrosis. Some possible therapeutic indications Related c-kit mediated include idiopathic pulmonary fibrosis (IPF) and scleroderma. The mast cells too

 have been implicated in the pathology of multiple sclerosis (Secor et al., J. Experimental Medicine 191: 813-822, 1999) and lesion due to ischemia-reperfusi & (Andoh et al, Clinical & Experimental Immunology 116: 90-93, 1999) in models Experiments using mice with mutant c-kit receptors that are mast cell deficient. In both cases, the disease pathology was significantly attenuated with respect to mice with populations of c-kit and normal mast cells. Therefore, the role of mast cells in these diseases suggests

 c-kit modulators may be useful therapeutic agents.

The serialized & c-kit is also important for gonadal fetal development, and plays a role in fertility in the adult (Mauduit et al, Human Rep. Update 5: 535-545, 1999). Spermatogenesis is inhibited through a reduction of c-Kit activity in the c-kit serialized & through the path of the PI3 kinase (Blume-Jensen et al, Nature Genetics 24: 157-162, 2000). It has been observed that c-kit expression was lower in subfertile testicles

 than in normal testicular tissue (Feng et al, Fertility and Sterility 71: 85-89, 1999). The c-kit serialized & also It is important for ovogenesis and folliculogenesis (Parrott and Skinner, Endocrinology 140: 4262-4271, 1999). These reports suggest that modulation of the enzymatic activity of c-kit may be a method to reduce the fertility both male and female.

WO-A-0055120 discloses amide derivatives for use in the treatment of diseases or  medical states mediated by cytokines.

While various groups have published on c-kit kinase inhibitors, disclosing various compounds Chemicals, including 2-phenylamino-imidazo [4,5-Nisoquinolin-9-ones (Snow, RJ et al, J. Med. Chem. 2002, 45, 3394), pyrazolo [3,4-d] pyrimidines (Burchat, AF et al, Bioorganic and Med. Chem. Letters 2002, 12, 1987 and Henke, JH eta !, J. Biol. Chem. 1996, 271, 695), pyrrolo [2,3-d] pyrimidines (Altmann., E eta !, Bioorganic and Med. Chem. Letters 2001,  11, 853), anilinoquinazolines (Wang, YD et al, Bioorganic and Med. Chem. Letters 2000, 10, 2477), imidazoquinoxalines (Chen, P. eta!, Bioorganic and Med. Chem. Letters 2002, 12, 3153), the PCT publication entitled, quot; Methods of Modulating C-kit Tirosine Protein Kinase Function with lndoline Compoundsquot; and the PCT publication titled, "Use of Tirosine Kinase Inhibitors for Treating Autoimmune Diseasesquot ;, none of these groups describe the compounds of the present invention, and particularly as kinase enzyme modulators such as c-kit, and

 Useful for the regulation of autoimmune disease (s), allergies, asthma, cancer and the like.

The present invention provides compounds that can modulate the activity of one or more kinase enzymes, thereby regulating various disorders associated with kinases that include inflamed & disease Autoimmune

The compounds of the present invention, including stereoisomers, solvates and pharmaceutically salts  acceptable thereof, are represented by general formula I:

wherein Al, A2, A3, A4, L, R1, R2 and R3 are defined in the detailed description below. The compounds of formula I can modulate protein tyrosine kinase enzymes of the Src family, such as Lck, as well as other protein kinase enzymes such as c-kit. Therefore, these compounds are useful in the treatment,

 including preventive, prophylactic and therapeutic treatment of disorders associated with or mediated by protein tyrosine kinase, including inflammatory disorders mediated by T cells and autoimmune diseases regulated by mast cells and other disorders associated with or mediated by c-kit.

quot; Disorders associated with protein kinasequot; they are disorders that result from aberrant kinase activity, and / or that they are palliated by the regulation, and inhibition in particular, of one or more of these kinase enzymes. By

 For example, Lck inhibitors are valuable in the treatment of several such disorders (for example, treatment of autoimmune diseases), since Lck inhibition blocks the activation of T cells. compounds of formula I modulate the activation of T cells by inhibiting one or more of the multiple protein tyrosine kinases involved in the early serial transduction stages that lead to T cell activation, for example, by the inhibition of Lck kinase.

 Therefore, the compounds of formula I are useful for the treatment of cell-mediated diseases T, including the inhibition of the activation and proliferation of T cells. In addition, the compounds can block the activation of tyrosine kinase protein from endothelial cells by oxidative stress thereby limiting the surface expression of adhesion molecules that induce neutrophil binding, and may also inhibit the protein tyrosine kinase necessary for the activation of neutrophils. The compounds will be useful, therefore, in the

 Ischemia and reperfusion injury treatment. In addition, the present specification discloses a method for the treatment of protein tyrosine kinase associated disorder, the method comprising administering to a subject at least one compound of formula I in an amount effective to treat the disorder.

Additional disorders associated with tyrosine kinase, or in which the compound (s) of the present invention is / are Citil (s) include, arthritis (such as rheumatoid arthritis, psoriasis arthritis or osteoarthritis); transplant rejection (such

 as organ transplant, acute transplant or heterograft or homograft (as used in the treatment of Burns)); protection against reperfusion or ischemic injury such as reperfusion or ischemic injury which occurs during organ transplantation, myocardial infarction, stroke or other causes; induction of transplant tolerance; multiple sclerosis; inflammatory bowel disease, including colitis ulcerative and Crohn's disease; lupus (sisternic lupus erythematosus); graft versus host diseases;  T-cell mediated hypersensitivity diseases, including contact hypersensitivity, delayed type hypersensitivity and gluten-sensitive enteropathy (celiac disease); type I diabetes; psoriasis; contact dermatitis (including that due to poison ivy); Hashimoto's thyroiditis; Sjogren's syndrome; autoimmune hyperthyroidism, such as Grave's disease; Addison's disease (disease autoimmune adrenal glands); autoimmune polyglandular disease (also known as  autoimmune polyglandular syndrome); autoimmune alopecia; pernicious anemia; vitiligo; insufficiency autoimmune adenohypophyseal; Gulllain-Barre syndrome; other autoimmune diseases; cancel in that Lck or other kinases of the Src family such as Src are activated or overexpressed, such as colon carcinoma and thymoma, or cancers in which the kinase activity of the Src family facilitates the tumor growth or survival; glomerulonephritis, serum sickness; urticaria; allergic diseases  such as respiratory allergies (asthma, hay fever, allergic rhinitis) or skin allergies; scleracielma; mycosis fungoid; acute inflammatory responses (such as acute respiratory distress syndrome and injury from ischemia / reperfusion); dermatomyositis; alopecia areata; chronic actinic dermatitis; eczema; Behcet's disease;

pustulosis of the palms of the hands and the soles of the feet; gangrenous pyoderma; Sezary syndrome; atopic dermatitis; sisternic sclerosis; And morphea The present specification also discloses methods  for

 the treatment of the aforementioned disorders such as atopic dermatitis by administration of a therapeutically effective amount of a compound of the present invention, which is a protein tyrosine kinase inhibitor, to a patient suffering from dermatitis and potentially in need of such

treatment.

The compounds of the invention can also modulate the protein kinase c-kit activity and, therefore, can  regulate various disorders related to c-kit. More specifically, these compounds are useful in the treatment, including preventive, prophylactic and therapeutic treatment of disorders associated with or mediated for c-kit kinase including autoimmune disorders regulated by mast cells and fibrotic diseases,

10

fifteen

twenty

25

30

35

40

including idiopathic pulmonary fibrosis. The convention of the invention are useful for the treatment of

mast cell production, tumors related to mast cell proliferation and mastocytosis, reactions allergies that include severe asthma, rheumatoid arthritis, scleroderma, multiple sclerosis and chronic rhinitis associated with allergy, and fibrotic and auto-mediated disease mediated by c-kit.

The compounds of the invention are useful for the treatment of an anomalous state associated with transduction. of inappropriate c-kit kinase mediated signals in a subject, the method of treatment comprising the stage of administer to the subject an effective dosage amount of a compound according to the invention.

To treat patients of such disorders and conditions, another embodiment of the invention provides a composition that It comprises a compound of formula I and a pharmaceutically acceptable carrier. A pharmaceutical composition

of this type, or medication, can be administered to the subject, such as a human being, for the purpose of treating the disorder. Other therapeutic agents such as those described below may be used in combination with the compounds of the invention, such as in a combined composition. Alternatively, such or such others therapeutic agents can be administered before, simultaneously with, or after administration of the compound (s) of the present invention.

The present invention provides a compound of formula I:

R2

P.

A4 A3

R3

or a stereoisomer, solvate or pharmaceutically acceptable salt thereof, in which

A1 is CR4;

A2 is CR8;

A3es CR8;

A4 is CR7; provided that when L is -NHC (0) -, then R8 is H;

L is -C (0) NR7-, -NR7C (0) -, -NR7C (0) NR7-, -NR7C (0) 0-, -S (0) 2NR7-, -NR7S (0) 2NR7-o - NR7S (0) 2-;

R1 is pyrimidyl or pyrazinyl, each ring of which is optionally independently substituted with one or more substituents of R8, R9, NR8R8, NR8R9, OR8, OR9, SR8, SR9, C (0) R8, C (0) R9, OC (0) R8,

C (0) 0R8, C (0) NR8R8, Cp) NR8R9, NR�C (0) R8, NR8C (0) R9, NR8C (0) NR8Ru, NR8C (0) NR6R9, NR8C (0) 0R8, NR8C (0) 0R, S (0) 2R8, S (0) 2R, S (0) 2NR8R8, S (0) 2NR8R9, NR8S (0) 2NR8R8, NR8S (0) 2NRcR9, NR8S (0) 2R8 0 NR8S (0) 2R8;

R2 is H or C1-10 alkyl;

R3 is C1-10 alkyl, C2_10 alkenyl, C210 alkynyl, C3-10 cycloalkyl, heterocyclic ring system no 5-6 member monocyclic aromatic� or 9-10 member bicyclic or an aromatic� ring system

5-6 member monocyclic or 9-10 member bicyclic, optionally including said system of rings consisting of carbon atoms 1-3 heteroatoms if it is monocyclic or 1-6 heteroatoms if it is bicyclic, said heteroatoms of 0, N or S being selected, wherein said 01-10 alkyl, C2-1o alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, non-aromatic heterocyclic ring system and aromatic ring system

R12 R13, NR11R11,

optionally independently substituted with one or more Rquot substituents;

NR11R12, oR11, sR11 oR12, sR12, c (oR11, c (s ,, Rti

 CN (CN) R11, C (0) R12, C (S) 0, CN (CN) R12,

iii I1'i-ii, C (0) C (0) R11, OC (0) R i 7 COOR, C (0) SR1'1, C (0) C (0) R 2 A OC (0) R12, C00R12, C (0) SR12, C (0) NR1 R

NRc (o) R1

C (S) NR11R11.11 12

 C (0) NR R, C (S) NR1IR12, OC (0) NR �RI ', 11 11NR11C (0) R12, NR11C (S) R11, NR11C (0) NR1IRii,. N.-iiC (0) NR11R12, -11C (S) NRil, e. N.-11C (S.) NR11R12, ..- ii

NKC (0) 0R11 S (0) 2R11,

NR11C (S) R12, I.lt; NKK

 NRquot; C (0) 0R12, NR'1C (0) C (0) R11, NR11C (0) C (0) R12, NR11C (0) C (0) NR11R 2, S (0) 2R12,

12  K

1-11, -,

S (0) 2NR1 S (0) 2NR11NR11S (0) 2NR11R1`, NR11S (0) 2R11 0 NR11S (0) 2R12;

one-<

each of R4, R5, R8 and R7, independently, is H, halo, haloalkyl, NO2, CN, NR8R8, NR8R9, OR8,

OR9, SR8, SR9, C (0) R8, C (0) R9, OC (0) R8, C (0) 0R8, C (9NR8R8, C (0) NR8R9, NR8C (0) R9, NR8C (9R9,

NR8C (0) NR8R8, NR8C (0) NR8R9, NR8C (0) 0R8, NR8C (0) OR, S (0) 2R8, S (0) 2R9, S (0) 2NR R8, S (0) 2NR R9,

NR8S (0) 2NR8R8, NR8S (0) 2NR8R9, NR8S (0) 2R�, NR8S (0) 2R9, C110 alkyl, C2_10 alkenyl, C2-10 alkynyl,

 C3-10 cycloalkyl or C4_10 cycloalkenyl, each comprising C110 alkyl, C2-10 alkenyl, alkynyl C2-10, C3_10 cycloalkyl and C4_10 cycloalkenyl optionally 1-4 heteroatoms selected from N, OySy optionally substituted with one or more substituents of R9 or R10;

alternatively, R5 and R8 taken together form a saturated or partially or completely unsaturated ring 5-6 monocyclic carbon atom members that optionally include 1-3 heteroatoms  selected from 0, N or S, and the ring is optionally independently substituted with 1-3 substituents of R8.8 R9 or R10;

R 8 is H, halo, haloalkyl, CN, NO 2, acetyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 3-10 cycloalkyl, each comprising C1IO alkyl, C2_10 alkenyl, C2_10 alkynyl and C3_10 cycloalkyl optionally 1-4 heteroatoms selected from N, OyS and optionally substituted with one or more substituents of  NR8R9, NR9R9, OR8, SR8, OR9, SR9, C (0) R8, OC (0) R8, COOR8, C (0) R9, OC (0) R9, COOR9, C (0) NR8R9, C (0) NR9R9, NR9C (0) R8, NR9C (0) R9, NR9C (0) NR8R9, NR9C (0) NR9R9, NR9 (COOR8), NR9 (COOR1, OCO) NR8R9, OC (0) NR9R9, S (0) 2R8, S (0) 2NR8R9, S (0) 2R9, S (0) 2NR9R9, NR9S (0) 2NR8R,

NR9S (0) 2NR9R9, NR9S (0) 2R8, NR9S (0) 2R9 or R9;

R9 is a 3-8-membered partially or completely saturated or unsaturated monocyclic ring system,

 bicyclic of 6-12 members or tricyclic of 7-14 members, optionally including said ring system formed by carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms If it is tricyclic, said heteroatoms of 0, N or S being selected, and in which each ring of said ring system is optionally independently substituted with 1-3 R10 substituents,

R, cryo, 10 NR1uC (0) NRoRio, oxo, NR1010 SR10, C (0) R10, COOR10, C (0) NR R10, NR10C (0) R10.1  OC (0) NR10R10, s (0) 2-0 S (0) 2NR10R10 NR10s (0) 2R10; K

R1� is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1_10 alkyl, C2_10 alkenyl, alkynyl C3-10 cycloalkyl, C4_10 cycloalkenyl, alkylamino dialkylamino alkoxy

 C110, C1_10 thioalkoxy or a saturated or partially or completely unsaturated 5-8-membered monocyclic ring system, bicyclic of 6-12 members or tricyclic of 7-14 members, optionally including said ring system  formed by carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9

heteroatoms if it is tricyclic, said heteroatoms of 0, N or S being selected, in which each of the C1.10 alkyl, C2.10 alkenyl, C2-10 alkynyl, C3_10 cycloalkyl, C4_10 cycloalkenyl, alkylamino dialkylamino C1.10 alkoxy, C1-10 thioalkoxy and ring of said ring system is optionally independently substituted with 1-3 halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl substituents,

 methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl;

R 11 is H, halo, haloalkyl, CN, NO 2, acetyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl or C 3-10 cycloalkyl, each comprising C110 alkyl, C2_10 alkenyl, C2_10 alkynyl and C3-10 cycloalkyl optionally  1-4 heteroatoms selected from N, OyS and optionally substituted with one or more substituents of NR12-13

NR13R13, OR12, SR12, OR13 .; SR13, C (0) R12 OC (0) R12, C00R12, C (0) R13, OC (0) R13, COOR13,

,

1213

C (TRR13, C (9NRR13, NR1T (0) R12, NRI3C (0) R13, NR13C (0) NR12R13, NR13C (0) NR13R13, NR1 C (0) 0R12, NR 3C (0) 0R13, OC (0) NR12R13, 0C (0? NR1 "; R13, S (012R12, S (0) 2NR12R13, S (0) 2R13, S (0) 2NRI3R13, NR13S (0) 2NR12R'3, NR1'S (0) 2NR13R13, NR 3S (0) 2R12, NR1 S (0) 2R13 or R13;

 R12 is a partially or completely saturated or unsaturated monocyclic ring system of 3-8 members, bicyclic of 6-12 members or tricyclic of 7-14 members, optionally including said ring system formed by carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heterottoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, said heteroatoms of 0, N or S being selected, and in which each ring of said ring system is optionally independently substituted with 1-3 substituents of R13,

 oxo, NR13R13, OR13, 5R13, C (0) R13, C00R13, C (0) NR13R13, NR13C (0) R13, NiR1'C (0) NR13R13,

OC (0) NR13R13, S (0) 2R13, S (0) 2NR13R13 or NR13S (0) 2R13;

alternatively, R11 and R12 taken together form a partially or fully saturated or unsaturated ring of 56 carbon atom members that optionally includes 1-3 heteroatoms selected from 0, N or S, and the ring is optionally independently substituted with 1-5 R13 substituents; Y

 R13 is H, halo, haloalkyl, CN, OH, NO2, NH2, OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, oxo,

acetyl, benzyl, cyclopropyl, cyclobutyl or a partially or completely saturated ring system or unsaturated monocyclic 3-8 members or bicyclic 6-12 members, optionally including said ring system consisting of carbon atoms 1-3 heteroatoms if it is monocyclic or 1-6 heteroatoms

if it is bicyclic, said heteroatoms of 0, N or S being selected, and optionally substituted independently with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, benzyl or phenyl.

In another embodiment, the present invention relates to a pharmaceutical composition comprising a carrier pharmaceutically acceptable and a compound according to the invention.

In another embodiment, the present invention relates to a compound according to the invention for use in the treatment. of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute myelogenous leukemia or Chronic, destruction of pancreatic cells 1, osteoarthritis, rheumatoid spondylitis, gouty arthritis, disease 10 inflammatory bowel syndrome, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, syndrome Reiter, type I diabetes, type II diabetes, bone resorption diseases, graft versus host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia-reperfusion injury,

atherosclerosis, craniocerebral trauma, multiple sclerosis, cerebral malaria, septicemia, septicemic shock, 15 toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses, herpes zoster infection or a combination thereof in a subject.

In another embodiment, the present invention relates to a compound according to the invention for use in the treatment. of fibrotic disease, mastocytosis, the presence of one or more mast cell tumors, severe asthma, arthritis rheumatoid, scleroderma, multiple sclerosis and chronic allergic rhinitis.

In another embodiment, the present invention relates to a compound according to the invention for use in the treatment. of idiopathic pulmonary fibrosis.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a medication for the treatment of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute or chronic myelogenous leukemia, destruction of pancreatic f3 cells, osteoarthritis, spondylitis 25 rheumatoid, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, resorption diseases bone, graft versus host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia-reperfusion injury, atherosclerosis, craniocerebral trauma, multiple sclerosis, cerebral malaria,

30 septicemia, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes virus, herpes zoster infection or a combination of The same in a subject.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a medication for the treatment of fibrotic disease, mastocytosis, the presence of one or more tumors of 35 mast cells, severe asthma, rheumatoid arthritis, scleroderma, multiple sclerosis and chronic allergic rhinitis.

In another embodiment, the present invention relates to the use of a compound according to the invention for the preparation of a medication for the treatment of idiopathic pulmonary fibrosis.

In another embodiment, the present invention relates to a method of preparing a compound according to the invention, the method comprising the step of reacting a compound 51

R2

Ri``.N /

 A3

A4

51

40

1, A2, m3, A412

wherein A, R and R are as defined in claim 1 and L1 is NH2, COOH, C (0) CI, SO2CI, OC (0) 0H or OC (0) CI, with a compound having a general formula L2-R3, wherein L2 is NH2, COOH, C (0) CI, SO2CI, OC (0) 0H or OC (0) CI, to prepare a compound according to the invention.

Preferred embodiments are set forth in the dependent claims.

The groups and subgroups of the compound described hereinbelow disclose various embodiments of the present invention in which the compounds in that embodiment include the variables

specified as defined in that embodiment. The scope of each defined variable can be taken with Any other embodiment described herein to form a compound of the present invention. For example, the embodiment immediately below describes compounds in which A1 is CR4, which may be combined with compounds in which the remaining variables are as defined in any of the

 Additional embodiments described herein. All compounds resulting from such combinations of embodiments are contemplated herein and included in the invention.

In another embodiment, together with any of the preceding or following embodiments, A1 is CR4, wherein R4 is halo, haloalkyl, NO2, CN, NRBRB, Ole, SRB, C (0) R8 or C1_10 alkyl; A2 is CH; AB is CH; and A4 is CH.

In another embodiment, together with any of the preceding or following embodiments, L is -C (0) NH-, -NHC (0) -,  -NHC (0) NH-, -NHC (0) 0-, -S (0) 2NH-, -NHS (0) 2NH-or -NHS (0) 2-.

In another embodiment, together with any of the preceding or following embodiments, RB is C1_10 alkyl, C210 alkenyl, C2-10 alkynyl, C3_10 cycloalkyl, 5-6 membered monocyclic non-aromatic heterocyclic ring system or bicyclic of 9-10 members or a system of aromatic rings monocyclic of 5-6 members or bicyclic of 9-10 members, optionally including said ring system consisting of carbon atoms 1-3 heteroatoms Si  it is monocyclic or 1-6 heteroatoms if it is bicyclic, said heteroatoms of 0, N, or S being selected, in which said Cmo alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl, non-aromatic heterocyclic ring system and aromatic ring system is optionally independently substituted with one or more substituents there

11i2iR oe, se, 0R12, sR12, c (o) R11, (alkyl), R12 (ring), R, C (S) R11 CN (CN) Rquot ;, C (0) R12,

13, NRR1I, NRi

ii Ri2,

C (S) R12 CN (CN) R1, C (0) C (0) R11, OC (0) R, COOR11, C (0) SR11, C (0) C (0) R12, OC (0) R12 , COOR12, C (0) S ii ii C (S) NR1111-, ec (o) R12.11R12 N Nec (s) e,

 C (0) NR R, 11 C (0? NR11K .- '12, C (S) NR11R12, OC (0) NR NR11C (0) R11, NR11c (s) R12, R12, R11,

 NR11C (0) NR11R 1, NR1 IC (0) NR11 NR1IC (S) NR1 NR11C (S) NR11R12, NR11C (0) 0R11,

NR11C (010R12,. N ..-. 11 11.11 R12, s (0) 2R1i, R11,

K C (0) C (0) R NR C (0) C (0) R12, NR11C (0) C (0) NR11 S (0) 2R12, S (0) 2NR11 1R12, .01 Ri2, NRils (0) 2.-1,

S (0) 2NRi 1

S (0) 2NR N ..- K K0 NR11S (0) 2R1`.

In another embodiment, together with any of the preceding or following embodiments, R3 is Cmo alkyl, cycloalkyl  C3_10, phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, benzimidazolyl, benzoxazolyl, bencisoxazolyl or benzothiazolyl, each of the which is optionally substituted as defined in the first described embodiment of the detailed description in the present document.

 In another embodiment, together with any of the preceding or following embodiments, R4 is H, halo, haloalkyl, NO2, NR8R8,

CN, NR6R9, ORB, OR9, SRB, SR9, C (0) R8, C (0) R9, OC (0) R8, C (0) OR8, C (0) NR8R8, C (0) NR8R9, NRBC ( 0.1R8, NR8C (0) R9 NR8 C (0) NRBRB, NR8C (0) NR8R9, NR C (0) OR8, NR8 C (0) 0R9, S (0) 2R8, S (0) 2R9, S (0) 2NR RB , S (0) 2NR8R9, NR8S (0) 2NR8R8, NR8S (0) 2NR8R9, NR8S (0) 2R8, NR8S (0) 2R9, C2_10 alkenyl alkyl, C2_ alkynyl

10, C3-10 cycloalkyl or C4_10 cycloalkenyl, each comprising C1_10 alkyl, C2_10 alkenyl, C2-10 alkynyl,  C3-10 cycloalkyl and C4_10 cycloalkenyl optionally 1-4 heteroatoms selected from N, OyS and optionally substituted with one or more substituents of R9 or R19.

In another embodiment, the compounds of the present invention include compounds in which R 4 is halo, haloalkyl, CN, NRBRB, ORB, SRB, C (0) R8 or C1-10 alkyl, together with any of the preceding or following embodiments.

In another embodiment, together with any of the preceding or following embodiments, R 6 is H, halo, haloalkyl, NO 2,  CN, NRBRB NR8R9, ORB, OR9, SR� SR9, C (0) R8, C (0) R9, OC (0) R8, C (0) 0R6, C (0) NR8R8, C (0) NR8R9, NRBC (Or

8 88 8 9

NRBC (0) Rd NR8C (0) NRR ', NR C (0) NRR, NR C (0) 0R8, NR8C (0) 0R9, S (0) 2R8, S (0) 2R9, S (0) 2NR R8 , S (0) 2NR81 = e, NR8S (0) 2NR8R8, NR8S (0) 2NR8R9, NR8S (0) 2R8, NR8S (0) 2R9, C1.10 alkyl, C2_10 alkenyl, C2_ alkynyl 10, C3_10 cycloalkyl or C4_10 cycloalkenyl, each comprising C110 alkyl, C2-10 alkenyl, C2_10 alkynyl, C3_10 cycloalkyl and C4_10 cycloalkenyl optionally 1-4 heteroatoms selected from N, 0 and S and optionally

 substituted with one or more substituents of R9 or R10.

In another embodiment, the compounds of the present invention include compounds in which R 6 is H, together with any of the previous or following embodiments.

In another embodiment, together with any of the preceding or following embodiments, R 6 is H, halo, haloalkyl, NO 2, CN NR8R8 NR8R9 OR8, OR9, SR, SR9, C (0) 1e, C (0) R9, OC (0) 1e, C (0) 01:28, C (0) NR8R8, C (0) NR81-19 , NRBC (Or,  NRC (0) R9A NR8C (0) NR8R8, NR8C (0) NR8R9 NR C (0) ORB, NR8C (0) 0R9, S (0) 21e, S (0) 2R9, S (0) 2NR RB,

S (0) 2NR8W, NR8S (0) 2NR8R8, NRBS (0) 2NR8R9, 'NRBS (0) 2RB, NR8S (0) 2R9, Cmo alkyl, C2_10 alkenyl, C210 alkynyl, C3_10 cycloalkyl or C4-10 cycloalkenyl, each comprising one of the Cmo alkyl, C2.10 alkenyl, C2-10 alkynyl, C3-10 cycloalkyl and C4_10 cycloalkenyl optionally 1-4 heteroatoms selected from N, O and Sy optionally substituted with one or more substituents of R9 or R10.

 In another embodiment, the compounds of the present invention include compounds in which R 6 is H, together with any of the previous or following embodiments.

In another embodiment, together with any of the previous or following embodiments, R6 and R6 taken together form

a saturated or partially or completely unsaturated monocyclic ring of 5-6 carbon atom members that optionally includes 1-3 heteroatoms selected from 0, N or S, and the ring is optionally substituted independently with 1-3 substituents of R8, R9 or R10.

In another embodiment, together with any of the preceding or following embodiments, R7 is H, halo, haloalkyl, NO2,  CN NR8R8, NR8R9 OR8 OR9 SW 'SR9 C (0) R8 C (0) R9, OC (0) R8, C (0) 0R8, C (0) NR8R8, C (0) NR8R9, NR8C (0e8, NReC (0) R9, NR86 (0) NiR8R8: ''

NR8C (0) NR8R9, NR8C (0) 0R8, NR8C (0) 0R9, S (0) 2R8, S (0) 2R9, S (0) 2NR R8, S (0) 2NR8Fe, NR8S (0) 2NR8R8, NR8S (0) 2NR8R9, NR8S (0) 2R8, NR8S (0) 2R9, C1_10 alkyl, C2_10 alkenyl, C210 alkynyl, C3-10 cycloalkyl each C4_10, each comprising Ci_io alkyl, C2_10 alkenyl, C2-10 alkynyl, C3_10 cycloalkyl and C4-10 cycloalkenyl optionally 1-4 heteroatoms selected from N, 0 and S and optionally

 substituted with one or more substituents of R9 or R10.

In another embodiment, the compounds of the present invention include compounds in which R7 is H, together with any of the previous or following embodiments.

In another embodiment, together with any of the preceding or following embodiments, R8 is H, halo, haloalkyl, CN, NO2, acetyl, C1.10 alkyl, C2_10 alkenyl, C2_10 alkynyl or C3_10 cycloalkyl, each comprising C1_ alkyl  10, C2_10 alkenyl, C2_10 alkynyl and C3_10 cycloalkyl optionally 1-4 heteroatoms selected from N, 0 and S% optionally-substituted with one or more substituents of NR8R9, NR9R9, OR8, SR8, OR9, SR9, C (0) R8, OC (0) W, COOR8, C (0) R9, OC (0) R9 COOR8, C (0) NR8R8, C (0) NR8R9, NR9C (0) R8, NR9C (0) W, NR9C (0) NR8R9,

NR C (0) NR R, NR9 (COORh), NR9 (COOR9, OC (0) NR8R9, OC (0) NR9R9 S (0) 2R8, S (0) 2NR8R9, S (0) 2R9, S (0) 2NR9R9, NR9S (0) 2NR8R9, NR9S (0) 2NR9R, NR9S (0) 2R8, NR9S (0) 2R9 or R9. '

 In another embodiment, together with any of the previous or following embodiments, R9 is a ring system partially or completely saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic or tricyclic 7-14 members, optionally including said ring system consisting of carbon atoms 1-3

heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, selecting said heteroatoms of 0, N or S, and in which each ring of said ring system is optionally substituted -10, sRio,

C (0) R10, COOR1�, C (0) NR10R1�, 10R10,10R1010

independently with 1-3 substituents of R1�, oxo NR10R OR1�,

NR1uC (0) R10, NR10C (0) K OC (0) NR S (0) 2NR or NR S (0) 2R10.

In another embodiment, together with any of the preceding or following embodiments, R1� is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C110 alkyl, C2_10 alkenyl, C2_10 alkynyl, C3_10 cycloalkyl, C4_10 cycloalkenyl, alkylamino C1_10- dialkylamino, C110 alkoxy, C1-10 thioalkoxy or a saturated or partially or completely saturated ring system  unsaturated monocyclic 5-8 members, bicyclic 6-12 members or tricyclic 7-14 members, including optionally said ring system formed by carbon atoms () 1-3 heteroatoms If it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, said heteroatoms being selected from 0, N, or S, wherein each of the C110 alkyl, C2_10 alkenyl, C2_10 alkynyl, C3_10 cycloalkyl, C4_10 cycloalkenyl, alkylamino C1_10-, C110 alkyloxy dialkylamino, C10 thioalkoxy and ring of said ring system is optionally

 independently substituted with 1-3 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl.

In another embodiment, together with any of the preceding or following embodiments, R 11 is H, halo, haloalkyl, CN, NO2, acetyl, C110 alkyl, C2_10 alkenyl, C2.10 alkynyl or C3_10 cycloalkyl, each comprising C1 alkyl.  10, C2_10 alkenyl, C2_10 alkynyl and C3-10 cycloalkyl optionally 1-4 heteroatoms selected from N, 0 and S and optionally substituted with one or more substituents of NR12R13, NR13R13, OR12, SR12, OR13, SR13, C (0) R14, 0Cf0) R12, C00R12, C (0) R13, OC (0) R13 C00R13, C (OpR12R13, C (0) NR13R13, NR13C (0) R1`, NR13C (0) R13, NRI3C (9NR12R13, NR13C (0) NR13R1 NR43C (0) 0R14, NR1 90) OR13, OC (0) NR12R13, OC (0) NR13R13, S (0) 2R12, S (0) 2NR 2R13, S (0) 2R13, S (0) 2NR13 R1, NR13 S (0) 2NR1`R13, NR 3S (0) 2NR13R13, NR13S (0) 2R12, NR13S (0) 2R13 or R13.

 In another embodiment, together with any of the preceding or following embodiments, R12 is a ring system partially or completely saturated or unsaturated 5-8 membered monocyclic, 6-12 membered bicyclic or tricyclic 7-14 members, optionally including said ring system consisting of carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, selecting said heteroatoms of 0, N or S, and in which each ring of said ring system is optionally substituted

 undesirably with 1-3 substituents of R13, oxo NR13R13, OR13, SR13, C (0) R13, COOR13, C (0) NR13R13,

131313 C (0) NR13-13, 13,

OC (0) NR13-r (S (0) 2R, S (0) 2NR13R13 or NR13S (0) 2R13.

C (0) RNR, NR

In another embodiment, together with any of the preceding or following embodiments, R11 and R12 taken together they form a partially or totally saturated or unsaturated ring of 5-6 members of carbon atoms that includes optionally 1-3 heteroatoms selected from 0, N or S, and the ring is optionally substituted  independently with 1-5 substituents of R13.

In another embodiment, together with any of the preceding or following embodiments, R13 is H, halo, haloalkyl, CN, OH, NO2, NH2, OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, oxo, acetyl, benzyl, cyclopropyl, cyclobutyl or a

partially or completely saturated or unsaturated 5-8 membered monocyclic or 6-12 bicyclic ring system members, optionally including said ring system consisting of carbon atoms 1-3 heteroatoms if is = noddle� or 1-6 heteroatoms if it is bicyclic, said heteroatoms being selected from 0, N or S, and optionally independently substituted with 1-5 substituents of halo, haloalkyl, CN, NO2, NH2, OH, methyl,

5 methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, benzyl or phenyl.

In another embodiment, the compounds of formula I include compounds in which L is -C (0) NR7-or -S (0) 2NR7-, together with any of the previous or following embodiments.

In another embodiment, the compounds of formula I include compounds in which Al is CR4, in which R4 is halo, Haloalkyl, NO2, CN, NR8W, OR8, SR8, C (0) R8 or C1-10 alkyl;

A2 is CH;

A3 is CH;

A4 is CH;

L is -C (0) NR7-or -S (0) 2NR7-; Y

R2 is H or C1_10 alkyl, together with any of the preceding or following embodiments.

In another embodiment, the compounds of examples 1-2 and 6-140 described herein are provided. document, or a pharmaceutically acceptable salt thereof, selected from:

The compounds of formula I and stereoisomers, solvates and pharmaceutically acceptable salts thereof compounds, are useful for treating subjects, usually mammals such as humans, with various

20 diseases and / or pathological conditions, as described above. To this end, and in another embodiment, the The invention provides pharmaceutical compositions comprising one or more of the compounds of formula I, including compounds according to any of the various embodiments described above, and a carrier or pharmaceutically acceptable diluent.

The compounds of formula I or the pharmaceutical composition comprising such / such compound (s), may

25 administered in an effective amount to the subject to modulate one or more target proteins, including receptors and / or kinase enzymes, in the subject thus treating the disease or the state mediated by target.

The present specification also discloses a method for treating a protein-mediated disorder. kinase in a marnifero, which comprises administering to the mammal a therapeutically effective amount of a compound according to any one of the above embodiments. The protein kinase can be one of Lck or c-Kit.

This specification also discloses methods to treat conditions, disorders or diseases related to the modulation of protein kinase activity. This includes a method of treating inflammation in a mammal, a method of inhibiting the activation of T cells in a mammal, a method of decreasing plasma concentrations of any one or a combination of TNF-a, IL-1, IL-6 or IL-8 in a subject, a method of treating overproduction of histamine in a subject, a method of treating a 35 autoimmune disease, mastocytosis, mast cell tumors, asthma, chronic rhinitis, cell lung cancer small, acute myelocytic leukemia, acute lymphocytic leukemia, myelodysplastic syndrome, myelogenous leukemia Chronic, colorectal carcinoma, gastric carcinoma, gastrointestinal stromal tumor, testicular cancer, glioblastoma, astrocytoma or a combination thereof in a subject and a method of arthritis treatment rheumatoid, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute or chronic myelogenous leukemia, 40 destruction of pancreatic f3 cells, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory disease of the intestine, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft versus host reaction, disease of

Alzheimer's, stroke, myocardial infarction, ischemia-reperfusion injury, atherosclerosis,

45 head trauma, multiple sclerosis, cerebral malaria, septicemia, septicemic shock, syndrome Toxic shock, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes virus, herpes zoster infection or a combination thereof in a subject, in which each of The above methods, independently, comprise administering to the subject or mammal a quantity Therapeutically effective, or a therapeutically effective dosage amount, of a compound according to a 50 any of the above embodiments in relation to formula I.

30 The

The present specification also discloses a method of treating an associated abnormal state with inappropriate transduction of serials mediated by kinase c-kit in a subject, the method comprising the stage of administering to the subject an effective dosage amount of a compound according to any one of the previous embodiments.

The present specification also discloses a method of the immediately preceding embodiment in the that the state is selected from the group consisting of fibrotic disease, mastocytosis, the presence of one or more mast cell tumors, severe asthma, rheumatoid arthritis, scleroderma, multiple sclerosis and chronic rhinitis associated with allergy.

 The present specification also discloses a method of treating idiopathic pulmonary fibrosis in a mammal, the method comprising administering to the marnifero a therapeutically effective amount of a compound according to any one of the above embodiments.

The present specification also discloses a method of treatment of multiple sclerosis, disease inflammatory bowel, including ulcerative colitis, Crohn's disease, lupus, contact hypersensitivity,  delayed type hypersensitivity, and gluten-sensitive enteropathy, type I diabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, autoimmune hyperthyroidism, Addison's disease, disease autoimmune polyglandular, autoimmune alopecia, pernicious anemia, vitiligo, adenohypophyseal insufficiency autoimmune, Guillain-Barre syndrome, glonnerulonephritis, serum sickness, hives, diseases allergic, asthma, hay fever, allergic rhinitis, scleracielma, fungoid mycosis, dermatomyositis, alopecia areata,

 Chronic actinic dermatitis, eczema, Behcet's disease, pustulosis of the palms and soles of feet, gangrenous pyoderma, Sezary syndrome, atypical dermatitis, sisternic sclerosis, morphea or dermatitis Atopic in a mammal, understanding the method of administering to the mammal a therapeutically effective amount of a compound follows any one of the preceding embodiments.

The present specification also discloses a method of treatment of a proliferative disease in  a mammal, the method comprising administering to the mammal a therapeutically effective amount of a compound according to any one of the above embodiments.

The present specification also discloses the manufacture of a medicament for the purposes of administering the compound of formula I, or the pharmaceutical composition comprising the same, to the mammal for the treatment thereof, as described herein.

 The present specification also discloses the manufacture of a medicament comprising a compound follow any one of the above embodiments in relation to formula I.

The present specification also discloses a method of manufacturing a medicament for treatment of a protein kinase mediated disease, for the inhibition of the activation and proliferation of T cells, for the treatment of cancer, for the treatment of colon carcinoma or thymoma in a mammal, for the  treatment of autoimmune disease (s), for the treatment of inflammation, for the treatment of arthritis, rheumatoid arthritis, psoriasis arthritis or osteoarthritis in a mammal, for the treatment of organ transplants, transplant rejection or acute graft or homograft, or induction of transplant tolerance in a mammal, for the treatment of reperfusion or isquernica injury, myocardial infarction, or stroke in a mammal, each of the methods, independently, comprises combining a compound according to any one

 of the above embodiments with a pharmaceutically acceptable carrier to form the medicament.

The present specification also discloses a method of manufacturing a medicament for mCiltiple sclerosis treatment, inflammatory bowel disease, including ulcerative colitis, disease Crohn, lupus, contact hypersensitivity, delayed type hypersensitivity and gluten-sensitive enteropathy, type I diabetes, psoriasis, contact dermatitis, Hashimoto's thyroiditis, Sjogren's syndrome, hyperthyroidism  autoimmune, Addison's disease, autoimmune polyglandular disease, autoimmune alopecia, pernicious anemia, vitiligo, autoimmune adenohypophyseal insufficiency, Guillain-Barre syndrome, glomerulonephritis, serum sickness, hives, allergic diseases, asthma, hay fever, allergic rhinitis,

scleracielma, fungoid mycosis, dermatonniositis, alopecia areata, chronic actinic dermatitis, eczema, disease of Behcet, pustulosis of the palms and soles of the feet, gangrenous pyoderma,  Sezary, atopic dermatitis, systemic sclerosis, morphea or atopic dermatitis in a mammal, comprising the method of combining a compound according to any one of the above embodiments with a carrier pharmaceutically acceptable to form the medication.

how described herein, comprising the step of reacting a compound 51

Another embodiment of the invention relates to a method of preparing a compound according to Formula I, such

(quot; 31k2

A4 A3

Li

51

wherein A1, A2, A3, A4, R1 and R2 are as defined in claim 1 and L1 is NH2, COOH, C (0) CI, SO2CI,

OC (0) 0H or OC (0) CI, with a compound having a general formula L2-R3, wherein L2 is NH2, COOH, C (0) CI,

SO2CI, OC (0) 0H or OC (0) CI, to prepare a compound of formula I.

5 Meanings and definitions Unless otherwise specified, the following terms found in the specification and the

Claims have the following meanings and / or definitions: ac .: Aqueous ATP: Adenosine triphosphate BSA: Bovine Alburninaserica DBU: 1,8-diazabicyclo [5.4.0] undec-7-eno

DCE: Dichloroethane DCM: Dichloromethane DIEA: Diisopropylethylamine DMA: N, N-Dimethylacetamide DME: Dimethoxyethane DMF: N, N-Dimethylformamide DMSO: Dimethylsulfoxide dppf: 1,1 '- (diphenylphosphino) ferrocene DTT: Dithiothreitol EDTA: Acidoethendiaminetetraacetic Et0Ac: Ethyl Acetate Et0H: Ethanol FCS: Fetal Calf Suerode

g: gram (s)

h: hour (s) HBTU: 0-benzotriazol-1-11-N, N, N ', N'-tetramethyluronium hexafluorophosphate

Hepes: N- [2-Hydroxyethyl] piperazin-N '- [2-ethanesulfonic acid]

IC50 value: The concentration of an inhibitor that causes a 50% reduction in a measured activity.

IPA Alcoholisopropyl

Lck: Specific lymphocyte tyrosine kinase LiHMDS: Lithium bis (trimethylsilyl) amide

Mel: Methyl iodide

MeCN: Acetonitrile

MeOH: Methanol

min: Minute (s)

mmol: Milimol (s)

NBS: N-Bronze-succinimide

Ni-NTA: Nickel-nitrileacetic acid

NIS: N-Iodosuccininnide

NMP: N-methylpyrrolidone

TA, ta: Ambient temperature

TFA: Acidotrifluoroacetic

THF: Tetrahydrofuran

Generally, the reference to a certain tat element as hydrogen or H is intended to include all isOtopos of that element. For example, if an R group is defined to include hydrogen or H also includes Deuterium and tritium. Compounds that include radiois, such as tritium, C14, P32, and S3� are per se within the scope of the invention. The procedures for inserting such markers into the compounds of the

The invention will be readily apparent to those skilled in the art based on the description herein. document.

In general, quot; replacedquot; as used herein refers to a group, as defined by then, in which one or more bonds to a hydrogen atom contained in the same are replaced by a bond to non-hydrogen or non-carbon atoms including, a halogen atom such as F, CI, Br and I; a Oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups and ester groups; an atom� of sulfur in groups such as thiol groups, alkyl and arylsulfide groups, sulfoxide groups, sulfone groups and groups sulfonyl such as sulfonyl halides and sulfonamides; a nitrogen atom in groups such as amines, amides, alkylamines, dialkylamines, arylamines, alkylamines, diarylamines, N-oxides, ureas, imines, imides and enamines; a silicon atom in groups such as trialkylsilyl groups, dialkylarylsilyl groups, groups Alkyldiarylsilyl and triarylsilyl groups; and other heteroatoms in various other groups. Substituted alkyl groups and

also substituted cycloalkyl groups and others also include groups in which one or more links to a carbon or hydrogen atom / atoms is substituted by a bond to a heteroatom such as oxygen in acid� carboxylic, ester and carbamate groups; and nitrogen� in groups such as imines, oximes, hydrazones and nitriles.

Substituents, including alkyl and ring groups, can be either monovalent or polyvalent

20 depending on the context of its use. For example, if the description contained the group R1-R2-R3 and R2 was defined as C1-6 alkyl, then R2 alkyl would be considered polyvalent because it must be attached to at least R1 and R3.

Alternatively, if R 1 was defined as C 6 alkyl, then the R 1 alkyl would be monovalent (except any

additional substitution expression).

In general, "not substituted"; tat as used herein with reference to a group, means that the

25 group does not have one or more bonds to a hydrogen or carbon atom contained therein substituted by a bonding to a hydrogen or non-carbon atom, as described above.

The term "optionally substituted"; such as is used herein with reference to a group, means that the group may be substituted with a specified number of defined substituents or the group may remain unsubstituted

30 In general, quot; alkylquot; tat come is used herein either alone or within other terms such come quot; haloalquiloquot ;, quot; alkylaminoquot; and "cycloalkyl" refers to linear, branched or cyclic radicals having one to about twelve carbon atoms. quot; Cycloalkylquot; It is also used exclusively here document to refer specifically to fully or partially saturated cyclic alkyl radicals. Examples of radicals quot; alkylquot; include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,

Isoamyl, hexyl, cyclopropyl, cyclopentyl and cyclohexyl.

In general, quot; alkyl Ca-bquot; such as used herein refers to an alkyl group comprising from a to b 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 alkyl C1-8 include the following:

In general, quot; aralquiloquot; as used herein refers to radicals containing linear aryl or branched each having alkyl parts of one to about ten carbon atoms. Examples of such Radicals include benzyl and 2-phenyl propane.

 In general, "halogenoquot; and quot; haloquot; tat as used herein, refers to halogen atoms� selected from F, Cl, Br and I.

In general, "haloalkyl" as used herein refers to radicals in which any one

or more of the alkyl carbon atoms is substituted by halo as defined above. Specifically, monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals including perhaloalkyl are included. A  monohaloalkyl radical, for example, may have either an iodine, bromine, chlorine or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl,

chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl.

 quot; Perfluoroalkylquot; means alkyl radicals that have all the hydrogen atoms substituted by atoms of fluoro Examples include trifluoromethyl and pentafluoroethyl.

In general, "haloalkyl Ca-bquot; tat as used herein refers to an alkyl group, as described above, in which any number, at least one, of the hydrogen atoms attached to the chain alkyl are substituted by F, Cl, Br or I. Examples of haloalkyl include, trifluoromethyl and pentafluoroethyl.

 In general, "heteroalkyl"; as used herein refers to an alkyl having one or wings of carbon atoms substituted by a heteroatom, selected from nitrogen, oxygen and sulfur. For example, a heteroalkyl would include an ether or thioether chain, or an alkoxy moiety, in which the heteroatom is in the region linear of the rest. The term also includes residues in which the heteroatom is in a branched region. By example, the term includes 2-amino-n-hexane or 5-hydroxy-pentane.

 In general, "hydroxyalkyl"; as used herein refers to linear alkyl radicals or branched that have one to about ten carbon atoms any one of which can ester substituted with one or more hydroxyl radicals. Examples of such radicals include hydroxymethyl, hydroxyethyl,

hydroxypropyl, hydroxybutyl and hydroxyhexyl.

In general, quot; alkoxyloquot; as used herein refers to radicals containing linear oxy or

 branched each having alkyl parts from one to about ten carbon atoms. The examples of such radicals include methoxy, ethoxy, propoxy, butoxy and tert-butoxy. The alkoxy radicals may be additionally substituted with one or more halo atoms, such as fluoro, chloro or bromo, to provide radicals; haloalkoxyquot; Examples of lower haloalkoxy radicals having one to three carbon atoms they include fluoronnethoxy, chloromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy and fluoropropoxy.

 In general, "sulfoniloquot;" as used herein either alone or in conjunction with other terms such as alkylsulfonyl, it refers respectively to divalent radicals -SO2-.

In general, the term "aminoquot;" as used herein either alone or in conjunction with other terms, refers to a nitrogen radical that contains two hydrogen atoms (NH2), a nitrogen radical that this monosubstituted such as an alkylamine (methylamine for example), or a nitrogen radical that is disubstituted such

 as a dialkylamine (dimethylamine for example). Generally, amine nitrogen is the point of attachment to group in question. Therefore, the term quot; alkylaminoquot; or dialkylaminoquot; as used herein document, means a group linked to mono-alkyl or bis-substituted alkyl amine. The term quot; cycloalkylaminoquot; be

refers to a cycloalkyl group attached to amine. The term "arylamino"; refers to an aryl group attached to amine. He term quot; heteroarylaminoquot; refers to a heteroaryl group linked to amine. The termini "heterocyclylamino"; refers to  a heterocyclyl group attached to amino.

In general, "ariloquot;" as used herein alone or in combination, refers to a system

aromatic carbocyclic containing one, two or three rings in which such rings may be joined together of fused nanny. The term "ariloquot; includes aromatic radicals such as phenyl, naphthyl, indenyl, tetrahydronaphthyl and indanyl. The group "ariloquot; it can have 1 to 3 substituents such as alkyl, hydroxyl, halo, haloalkyl, nitro,  cyano, alkoxy and alkylamino. quot; Ariloquot; it also includes the rest in which the aromatic carbocycle is condensed with a cycloalkyl bridge Cm, in which the bridge optionally includes 1, 2 6 3 heteroatoms selected from N, 0 and

S. For example, phenyl substituted with -0-CH2-0-forms the aryl benzodioxolyl substituent.

In general, "heterocyclic"; tat as used herein, refers to full ring radicals or partially saturated containing heteroatoms, in which the heteroatom (s) can be selected from nitrogen, sulfur and oxygen. quot; Heterocycloquot; it is used herein as a synonym with heterocycloalkyl.

In general, "heterocycloalkyl"; tat as used herein, refers to saturated ring radicals

 and partially saturated (or partially unsaturated) containing heteroatoms, in which the heteroatoms They can be selected from nitrogen, sulfur and oxygen. Does not include rings containing bread -0-0-, -0-S-or -S-S-. Said group "heterocycloalkyl"; it can have 1 to 3 substituents such as hydroxyl, Boc, halo, haloalkyl, cyano, lower alkyl, oxo, alkoxy, amino and alkylamino.

Examples of saturated heterocycloalkyl radicals include saturated heteromonocyclic groups of 3 to 6

 members containing 1 to 4 nitrogen atoms [eg, pyrrolidinyl, imidazolidinyl, piperidinyl, pyrrolinyl, piperazinyl]; saturated heteromonocyclic group of 3 to 6 members containing 1 to 2 atoms of oxygen and 1 to 3 nitrogen atoms [eg morpholinyl]; saturated heteromonocyclic group from 3 to 6 members containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms [for example, thiazolidinyl]. The Examples of partially saturated heterocyclyl radicals include dihydrotienyl, dihydropyranyl, dihydrofuryl and

 dihydrotiazolyl.

In general, quot; heteroaryloquot; tat as used herein, refers to ring radicals containing completely unsaturated or aromatic heteroatoms, in which the heteroatoms can be selected from nitrogen, sulfur and oxygen. Examples of heteroaryl radicals include unsaturated heteromonocyclyl groups of 5 to 6 members containing 1 to 4 nitrogen atoms, for example, pyrrolyl, imidazolyl, pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl [eg, 4H-1,2, 4-triazolyl, 1H-1,2,3-triazolyl, 2H1,2,3-triazolyl]; unsaturated heteromonocyclic group of 5 to 6 members containing an oxygen atom, by example, pyranyl, 2-furyl, 3-furyl, etc .; unsaturated heteromonocyclic group of 5 to 6 members that contains a

sulfur atom, for example, 2-thienyl, 3-thienyl, etc .; unsaturated heteromonocyclic group of 5 to 6 members that contains 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, for example, oxazolyl, isoxazolyl, oxadiazolyl  [eg., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl]; unsaturated heteromonocyclic group from 5 to 6 members containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, for example, thiazolyl, thiadiazolyl [for example, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl].

The tannin� quot; heteroaryloquot; it also encompasses radicals in which heterocyclic radicals are fused / condensed with aryl radicals (also referred to herein  quot; arylheterocycloalkylquot;); unsaturated condensed heterocyclic group containing 1 to 5 nitrogen atoms�, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl, benzotriazolyl, tetrazolopyridazinyl [eg, tetrazolo [1,5-b] pyridazinyl]; unsaturated condensed heterocyclic group that it contains 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms [for example benzoxazolyl, benzoxadiazolyl];

unsaturated condensed heterocyclic group containing 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms�

 [for example, benzothiazolyl, benzothiadiazolyl]; and saturated heterocyclic group, partially unsaturated and unsaturated condensate containing 1 to 2 oxygen or sulfur atoms [eg benzofuryl, benzothienyl, 2,3-dihydrobenzo [1,4] dioxinyl and dihydrobenzofuryl]. Preferred heterocyclic radicals include fused or non-fused radicals. merged from five to ten members. More preferred examples of heteroaryl radicals include quinolyl,

isoquinolyl, imidazolyl, pyridyl, thienyl, thiazolyl, oxazolyl, furyl and pyrazinyl. Other preferred heteroaryl radicals

 they are 5-6-membered heteroaryl, which contains one or two heteroatoms selected from sulfur, nitrogen and oxygen, selected from thienyl, furyl, pyrrolyl, indazolyl, pyrazolyl, oxazolyl, triazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridyl, piperidinyl and pyrazinyl.

Additional examples of suitable heterocyclic and heteroaryl radicals, some of which have been described previously, they include the following:

91

LNKN 'LNIfsr ) ‘I 1‘1

0

� \: N

S N N

NI, I ()

0 --- N 0 N is-3 Q

"Saturated or unsaturated"; with reference to a group or substitution means a substituent that is completely saturated, completely unsaturated or has any degree of intermediate unsaturation. The examples of a 6-membered saturated or unsaturated ring carbocycle will include phenyl, cyclohexyl, cyclohexenyl and cidohexadienyl.

In general, the term quot; salquot; refers to a salt form of a free base compound of the present invention, such  as the usual experts in the art will appreciate. The salts can be prepared by conventional means, known to those skilled in the art. In general, "pharmaceutically acceptable" when used in reference to a salt, refers to salt forms of a given compound, which are within the safety guidelines government regulators for ingestion and / or administration to a subject. The term quot; salts pharmaceutically acceptablequot; encompasses salts commonly used to form alkali metal salts and to form addition salts of

 free acids or free bases. The nature of salt is not critical, as long as it is safe and considered Pharmaceutically acceptable.

Suitable pharmaceutically acceptable acid addition salts of compounds of formula I can be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids are acid. hydrochloric, bromhydric, iodhydric, nitric, carbonic, sulfuric and phosphoric. Organic acids can be selected  appropriate of the aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic acid classes organic, examples of which are acidic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malico, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyrovic, aspartic, glutamic, benzoic, anthranilic, mesilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethanesulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic,

 sulfanilic, cyclohexylaminosulfonic, camphoric, camphorsulfOnico, digluconic, cyclopentanepropionic, dodecylsulfonic, glucoheptanoic, glycerophosphonic, heptanoic, hexanoic, 2-hydroxy-ethanesulfonic, nicotinic, 2-naphthalenesulfOnico, oxalic, palnnoic, pectinic, persulfuric, 2-phenylpropionic, picric, pivalic, propionic, succinic, tartaric, thiocyanic, mesilic, undecanoic, stearic, algenetic, 13-hydroxybutyric, salicylic, galactarian and galacturonic.

Suitable pharmaceutically acceptable base addition salts of compounds of formula I include salts

 metal, such as salts prepared from aluminum, calcium, lithium, magnesium, potassium, sodium and zinc, or salts prepared from organic bases including primary, secondary and tertiary amines, substituted amines which include cyclic amines, such as caffeine, arginine, diethylamine, N-ethylpiperidine, aistidine, glucamine, isopropylamine, lysine, morpholine, N-ethylnnorpholine, piperazine, piperidine, triethylamine, trimethylamine.

Additional examples of such acid and base addition salts can be found in Berge et al. , J.Pharm. Sci.,

 66, 1 (1977). All these salts can be prepared by conventional means from the compound corresponding of the invention by reacting, for example, the appropriate acid or base with the compound of Formula I.

In addition, the basic nitrogen-containing groups of compounds of formula I can be quaternized with such agents such as lower alkyl halides including chlorides, bromides and iodides of methyl, ethyl, propyl and butyl;  dialkyl sulfates including dinnetyl, diethyl, dibutyl and diamyl sulfates, large chain halides such as chlorides, bromides and iodides of decyl, lauryl, myristyl and stearyl, aralkyl halides such as bronnides of benzyl and phenethyl, and others. Products soluble or dispersible in water or oil can be obtained by quaternizing such basic nitrogen groups in compounds of formula I. Certain quaternized nitrogen compounds of the This invention is not included in the invention, as specified herein in the

 claims.

In general, "pharmaceutically acceptable"; when used with reference to a derivative, it matches the meaning with reference to a salt, and refers to a derivative that is pharmacologically safe for consumption, generally as determined by an authorized or governmental regulatory body.

In general, quot; outgoing group; tat as used herein, refers to groups that can move  easily by a nucleophile, such as an amine, a thiol nucleophile or alcohol. Such outgoing groups are They know well in the art. Examples of such leaving groups include N-hydroxysuccinimide, Nhydroxybenzotriazole, halides, triflates and tosylates. Preferred leaving groups are indicated herein. where appropriate.

In general, quot; protective group; as used herein, refers to groups well known in the  technique that are used to prevent selected reactive groups, such as carboxyl, amino, hydroxyl, mercapto and the like, experience unwanted reactions, such as nucleophiles, electrophiles, oxidation and reduction. Preferred protecting groups are indicated herein when appropriate. The Examples of amino protecting groups include, aralkyl, substituted aralkyl, cycloalkenyl alkyl and

substituted cycloalkenyl alkyl, allyl, self substituted, acyl, alkoxycarbonyl, aralkoxycarbonyl and silyl. The examples of  aralkyl include, benzyl, ortho-methylbenzyl, trityl and benzhydryl, which may be optionally substituted with halogen, alkyl, alkoxy, hydroxyl, nitro, acylamino, acyl and the like, and salts, such as phosphonium salts and ammonium. Examples of aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9- (9-phenylfluorenyl), phenanthrenyl and durenyl Examples of cycloalkenyl alkyl or substituted cycloalkylene alkyl radicals, which have preferably 6-10 carbon atoms, include cyclohexenylmethyl. The acyl, alkoxycarbonyl and

Suitable aralkoxycarbonyl include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, benzoyl substituted, butyryl, acetyl, tri-fluoroacetyl, tri-chloroacetyl and phthaloyl. A mixture of protecting groups may be used. to protect the same amino group, such as a primary amino group can be protected by both a group aralkyl as an aralkoxycarbonyl group.

5 The amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example, 1,2-bis (methylene) benzene, phthalimidyl, succinimidyl and maleimidyl and in which these heterocyclic groups may also include adjacent aryl and cycloalkyl rings. In addition, heterocyclic groups may be mono, di

or trisubstituted, such as nitroftalimidyl. Amino groups can also be protected against non-reactions. desired, such as oxidation, by forming an addition salt, such as hydrochloride, acid

10 toluenesulfonic and trifluoroacetic acid. Many of the amino protecting groups, including aralkyl groups by For example, they are also suitable for protecting carboxyl, hydroxyl and mercapto groups. Rent groups are also Suitable groups to protect hydroxyl and mercapto groups, such as tert-butyl.

Silyl protecting groups are groups containing silicon atoms that are optionally substituted with one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, trimethylsilyl, Triethylsilyl, tri-isopropylsilyl, tert-butyldimethylsilyl, dimethylphenylsilyl, 1,2-bis (dimethylsilyl) benzene, 1,2-bis (dimethylsilyl) ethane and diphenylmethylsilyl. Silylation of amino groups provides mono or disilylamino groups. The silylation of compounds Amino alcohol can lead to a derivative of N, N, 0-tri-silyl. The elimination of the silyl function from a fund & suit ether is easily achieved by treatment with, for example, a metal hydroxide reagent or ammonium fluoride, either as a differentiated reaction stage or in situ during a reaction with the group 20 alcohol Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl dimethylsilyl chloride, phenyldimethylsilyl chloride, diphenylmethylsilyl chloride or its combination products with imidazole or DMF. The Those skilled in the art are well aware of methods for silylation of amines and removal of protective groups of silyl Those skilled in the art of organic chemistry, including amino acid chemistry / amino acid esters or Amino alcohol, they also know well methods of preparing these amine derivatives from

25 amino acids, amino acid amides or corresponding amino acid esters.

Protective groups are removed under conditions that will not affect the remaining part of the molecule. These Methods are well known in the art and include acid hydrolysis and hydrogenolysis. A preferred method involves the removal of a protective group, such as the removal of a benzyloxycarbonyl group by hydrogenolysis using palladium on carbon in a suitable solvent system such as an alcohol and acetic acid

30 mixtures thereof. A t-butoxycarbonyl protecting group can be removed using an inorganic acid I organized, such as HCI or trifluoroacetic acid, in a suitable solvent system, such as dioxane or chloride Methylene The resulting amino salt can be easily neutralized to provide the free amine. The group carboxyl protector, such as methyl, ethyl, benzyl, tert-butyl and 4-methoxyphenylmethyl, can be removed in Hydrolysis and hydrogenation conditions well known to those skilled in the art.

It should be noted that the compounds of the invention may contain groups that may exist in forms. tautomerics, such as cyclic and acyclic amidine and guanidine groups and heteroaryl groups substituted with heteroatoms (Y '= 0, S, NR), which are illustrated in the following examples:

NR '

 NHR '

II

NH R '

Item

R

 NHRquot;  RNRquot;

RHNLNRquot;

Y 'Y1-H

NR '

NH

RHN NHRquot; RN NHR "

OH

R 'R' Ft '

and although a form is named, described, presented and / or claimed in this document, it is intended that all 40 the

 ester tautonic forms inherently included in such name, description, presentation and / or claim.

In general, the term "stereoisomer"; such conno used herein refers to a compound that It has one or more asymmetric centers. The chiral centers in a compound generally cause the compound exists in many different conformations or stereoisomers. The term quot; stereoisomerosquot; It includes

enantiomers, diastereOrneros, atropoisomeros and geometric isomers.

 Stereoisomers generally have different chemical properties and / or biological activity, such as the experts in the art will appreciate. For example, a stereoisomer may be more active and / or may present beneficial effects compared to the other stereoisomer (s) or when separated from the other (s) Stereois Number (s). However, it is completely within the knowledge of the usual expert separate, and / or selectively prepare said stereoisomers. Therefore, quot; stereolsomerosquot; of the present

 Invention necessarily includes mixtures of stereoisomers, including racemic mixtures, stereoisomers individual and optically active forms.

In general, the term quot; solvatoquot; when used with reference to a compound it refers to a compound, which associated with one or more molecules of a solvent, such as an organic solvent, inorganic solvent, solvent aqueous or mixtures thereof. The compounds of formula I may also be solvated, especially

 hydrated Hydration can occur during the manufacture of the compounds or compositions that They comprise the compounds, or hydration can occur over time due to nature hygroscopic of the compounds. The compounds of the invention may exist as organic solvates as well as, including DMF solvates, ether and alcohol among others. The identification and preparation of any particular solvate It is within the knowledge of the usual expert of synthetic organic or medical chemistry.

 In general, the term quot; citocinaquot; as used herein, refers to a secreted protein that affects the functions of other cells, particularly as regards the modulation of interactions between immune system cells or cells involved in the inflammatory response. Examples of cytokines include interleukin 1 (IL-1), preferably 1L-13, interleukin 6 (IL-6), interleukin 8 (IL-8) and TNF, preferably TNF-a

(tumor necrosis factor alpha-a).

 In general, the term "treatment"; as used herein, includes therapeutic treatment as well as a prophylactic treatment (either preventing the onset of disorders completely or delaying the onset of a preclinically evident stage of disorders in individuals).

In general, the term "therapeutically effective"; as used herein, it is intended to determine the amount of each compound of formula I, which will achieve the treatment goal, for example, improvement in severity  of the disorder and the frequency of incidence throughout the treatment of each agent by itself, while avoiding Adverse side effects normally associated with alternative therapies.

In general, "disease or disease states mediated by Lck or C-kitquot; refers to all pathological states in which Lck or C-kit unpack a paper, either directly as Lck and / or C-kit by themselves, or by Lck and / or C-kit inducing other proteins, cytokines, enzymes or disease-causing agents to be released,

 activate or on the contrary regulate directly or indirectly.

The specification and claims contain a list of species that use the expression "selected" of ... and ... quot; and "is ... or ..."; (sometimes called Markush groups). When this expression is used in this application, Unless stated otherwise, it is intended to include the group as a whole, or any individual member of the same, or any subgroup thereof. The use of this expression is simply for the purpose of abbreviation and is not

 It is intended in no way to limit the elimination of individual elements or subgroups of the genre.

1. Synthesis

The compounds of formula I can be synthesized according to one or more of the following schematic procedures and specific methods in which the substituents are as defined in formula I, above, except when be indicated additionally. The procedures and methods as shown refer to the preparation of

 compounds that have unspecified stereochemistry. However, such procedures and methods may generally applied to compounds of a specific stereochemistry, for example, when stereochemistry about a group is (S) or (R). In addition, compounds that have a stereochemistry (for example, (R)) can often used to produce those with the opposite, are named or with the nomenclature system of the

Conventional IUPAC either with the naming system used in ChemDraw, software version 8.0, or  the convention used by MDL.

Scheme 1

STAGE A

2a 2b

VARA B

4

Compound 5b is a reference compound

5a 5b

R3

Scheme 1 describes a general method for preparing meta-substituted compounds 5a, of formula I. As sample, an amine 1 can be reacted with an aromatic carboxylic acid 2a or 2b to generate the amide corresponding 3a or 3b by known methods (step A), such as in the presence of a reagent of 5 conventional coupling, in a suitable basic medium or solvent. Methods that are suitable and that can used to form the amide are described in more detail in scheme 2 below, which generally describes various methods of forming the union element ";" in compounds 5a and 5b above, from parts of the joining element L1 and L2, as shown in compounds 3a and 3b and 4, respectively. Note that intermediate products 3a and 3b already have in place the part of the joining element L1 that can 10 be reacted with the part of the joint element L2 in a desired ring R3. As shown, a product intermediate with R3 4 can be reacted with a compound 3a or a compound 3b using methods

known (step B), such as those described in more detail in scheme 3 below, to prepare a

meta-substituted bis-arylamide compound 5a or para-substituted 5b, of formula I.

Scheme 2

coupling reagent of amide

7a 7b

(i)

 CO, M Pd

(2)

 Li0} 1.1120

10

Compound 1113 is a reference compound

Scheme 2 describes a general method for preparing meta-substituted compounds 11a, of formula I. As shown, an amine 6 can be reacted with an aromatic iodine-carboxylic acid 7a or 7b to generate the corresponding amide 8a or 8b by known methods, such as in the presence of a reagent of 5 conventional coupling, in a suitable basic medium or solvent. Methods that are suitable and that can used to form the amide are described in more detail in scheme 3 below. This way they can first install desired R1 groups or rings. The iodine-aromatic amides 8a or 8b can be made react with carbon monoxide and methanol in the presence of a palladium catalyst to generate the adduct of corresponding methyl ester, aster which can then be hydrolyzed by conventional methods, such

10 as with a suitable base, such as aqueous LiOH, to provide the corresponding carboxylic acids 9a and 9b. As shown, an amine substituted with R3 10 can be reacted with compound 9a or 9b using known methods (scheme 3), to prepare a meta-substituted bis-arylamide compound 11a or para-substituted, of formula I.

Scheme 3

twenty-one

(FOn

(R) n

4. M0) 0

S (0) 2X

(R) n

protected-pc

iprotected- (0) C

5.

0

(R) n

n

 protected-pc

protected-i- (0) C

6.

c0tegidaq0 C

protected 0) C

7.

S (0) 2X

Scheme 3 describes various exemplary coupling methods by which they can

prepare or form the desired joining elements quot; Lquot; between the 6-member center ring and a desired ring

R3, as illustrated in formula I herein. The 6-member center ring, illustrated in the

5 Formula I, is designated and referred to in general in scheme 3, and throughout the entire memory descriptive, like the ring "Bquot ;. R3 rings, illustrated in formula I, are designated and referred to as general way in scheme 3, and throughout the entire specification as the ring quot; Aquot ;.

Each of the seven sub-schemes, numbered 1-7 above and described below, use the following meanings for R ', (R) ,, X, Nu', E +, W and m: R 'in subschemes 1-4 represents R1R2N-as defined in the 10 formulaI; (R) a refers to n nOrders of substitutions R4, R5, R6 and R7 where n is an integer from 0-4; X se generally refers to a quotient; outgoing group; such as a halide (bromine, chlorine, iodine or fluorine), alkyl sulfonate and other known leaving groups (see also definitions in this document); Nu refers to general manner to a nucleophile or nucleophilic species such as a primary or secondary amine, an oxygen, a sulfur or a kind of anionic carbon, examples of nucleophiles include, amines, hydroxides and alkoxides; E + 15 refers generally to an electrophilic or electrophilic species, such as the carbon atom of a carbonyl or the carbon atom attached to an activated leaving group, whose carbon atom is susceptible to nucleophilic attack

or is easily removed, examples of suitable electrophilic carbonyl species include, acid halides, rnixtos anhydrides, aldehydes, carbamoyl chlorides, sulfonyl chlorides (sulfonyl electrophile), acid carbonyls activated with activation reagents such as TBTU, HBTU, HATU, HOBT, BOP, PyBOP, carbodiimides (DCC and EDC), pentafluorophenyl and other electrophilic species including halides, isocyanates (see ring A reagent

 of sub-scheme 3) and diazonium ions; W is either 0 or S; and m is either 0 6 1. The protected carbonyl, as shown in subschemes 5-7, allows to take an intermediate product of ring A attached to desired B and bind various intermediate ring products "Dquot; or primary or secondary amines coupled to selected R1. This It allows the advantage of modifying the R1 group in a single stage.

The coupling of rings B and A, as shown as products in subschemes 1-7, can

 caused by using various conventional methods to join rings B and A together. For example, an item of amide or sulfonamide binding ";" as shown in subscheme 1 (where m = 0), 2, 4, 5, 6 and 7 in those that Nu-is an amine, respectively, can be prepared using an amine in any of the B rings

or A and an acid chloride or sulfonyl chloride in the other of any of rings A or B. The reaction proceeds from generally in the presence of a suitable solvent and / or base. The reaction progresses generally in  presence of a suitable solvent and / or base. Suitable solvents generally include solvents. non-nucleophiles, aprotics such as toluene, CH2Cl2, THF, DMF, DMSO and N, N-dimethylacetamide, and combinations of solvents thereof. The solvent (s) may vary in polarity, as the technical experts. Suitable bases include, for example, soft bases such as amine bases. tertiary including, DIEA, TEA, N-methylmorpholine; and stronger bases such as carbonate bases including,  Na2CO3, K2CO3, Cs2CO3; hydrides including, NaH, KH, borohydrides and cyanoborohydrides; and alkoxides including, NaOCH3. The base itself can also serve as a solvent. The reaction can be executed optionally pure, that is, without any base and / or solvent. For structurally simple non-hindered substrates, these

coupling reactions are generally rapid and the conversion normally occurs in conditions environmental. However, depending on the particular substrate, the steric hindrance, the concentration and others  stoichiometric factors, such reactions may be slow and may require an adjustment of basicity or heat, such as the experts in the art will appreciate.

As another example, a urea binding element (or a sulfonylurea binding element), as shown in Sub-scheme 3 can be prepared by reacting an amine with a desired isocyanate. Like the Isocyanates are generally highly reactive species, urea formation progresses generally

 fast, at ambient temperatures with a minimum amount of solvent, as experts will appreciate usual in the art. The reaction can be optionally executed pure, that is, without any basis and / or solvent

Similarly, carbamate binding elements are illustrated in subscheme 1 (in which m = 1) in which Nuseria an amine, the anhydride binding elements are illustrated in subscheme 1 in which Nu-would be a  oxygen, the inverse amide binding elements are generally illustrated in sub-scheme 6 in which Nuseria would be an amine and E + would be an acid chloride, the urea binding elements are illustrated in sub-scheme 3, Thioamide and thiourea binding elements are illustrated in subschemes 2 and 3 in which carbonyl oxygen respective is a sulfur, and the thiocarbamates are illustrated in subscheme 1 in which carbonyl oxygen and / or the respective carbamate oxygen is a sulfur. Although the above methods are described in this way, they are not

 exhaustive, and other methods can be used to join A and B rings together as those skilled in the art will appreciate technique.

Although it is illustrated that subschemes 1-7 have nucleophilic and electrophilic coupling groups, such as the amino group and the acid chloride groups illustrated in subscheme 2, attached directly to the substrate, the ring either A or B, in question, the invention is not limited in this way. This document includes

 that these nucleophilic and / or electrophilic coupling groups may be indirectly attached to their ring respective. For example, the amine group in ring B, and / or the acid halide group in ring A, such

 how I know illustrated in sub-scheme 2, they can be removed from direct union to the ring by one or more spacers of atoms, such as by means of a methylene, ethylene, propylene or similar spacer. As you will appreciate the Experts in the art, tat spacer may or may not affect the coupling reactions described  previously, and therefore, it may be necessary to modify such reaction conditions to effect the desired transformation.

The coupling methods described in subschemes 1-7 can also be applied to couple A rings. desired to intermediate products R1-N (R2) C (0)-desired ring B (subschemes 1-4), to synthesize compounds desired of formula I. For example, an amine-protected B-ring intermediate can be coupled into  first to an R1R2N-desired group, tat as illustrated in formula I and as R 'in subschemes 1-4, for form intermediate R1-N (R2) C (0) -B. The protected amine can then be deprotected and used for forming an amide binding element, or becoming an isocyanate, for example, or any other desired group for coupling ring A by means of the desired joining element. The amino protecting groups of ring B Suitable include t-butoxycarbonyl group, which can be prepared with BOC-ON, they exist as they will

 skilled in the art and are further described herein.

The specific methods and examples described in detail a continued & show by way of example

additionally the synthesis of compounds of formula I, described generally in Schemes 1-3 previously.

Analytical methods:

Unless otherwise indicated, all LC-MS sample analyzes and / or HPLC analyzes of compounds a  As an example, intermediates and starting materials described herein were made using one of the following methods:

They run on an HP-1000 or HP-1050 system with an HP Zorbax SB-C18 inverse phase column (5 p.) (4.6 x 150 mm) executed at 30�C with a flow rate of 1.00 ml / min. The mobile phase used solvent A (H201e1 0.1% of TFA) and solvent B (CH3CN / 0.1% TFA) with a gradient of 20 min. from 10% to 90% of

 CH3CN. The gradient was followed by a 2 min return. 10% CH3CN and a 3 min wash.

Method A (CL-MS):

Samples were run on an HP-1100 system with an HP Zorbax SB-C8 inverse phase column (5 (4.6 x 50 mm) executed at 30�C with a flow velocity of 0.75 ml / min. The mobile phase used solvent A (H20 / 0.1% of AcOH) and solvent B (CH3CN / 0.1% AcOH) with a gradient of 10 min. from 10% to 90% of

 CH3CN. The gradient was followed by a 1 min return. 10% CH3CN and a 2 min wash.

Method B (CL-MS):

Samples were run on an HP-1100 system with an HP Zorbax SB-C8 inverse phase column (5 p.) (4.6 x 50 mm) executed at 30�C with a flow rate of 1.5 ml / min. The mobile phase used solvent A (H20 / 0.1% of AcOH) and solvent B (CH3CN / 0.1% AcOH) with a gradient of 5 min. from 10% to 90% of

 CH3CN. The gradient was followed by a 0.5 min return. 10% CH3CN and a 1.5 min wash.

Method C:

Samples were run on an Agilent-1100 system with a Fenomenex Luna C8 inverse phase column (5 1.1) (4.6 x 100 mm) executed at 40�C with a flow rate of 1.0 ml / min. The mobile phase used solvent A (H20 / el 0.1% TFA) and solvent B (CH3CN / 0.1% TFA) with a gradient of 7 min. from 10% to 100% of

 CH3CN, and kept 2.5 min. 100% CH3CN. The gradient was followed by a 1 min return. at 10% of CH3CN and a 2 min wash.

Method D:

Samples were run on an Agilent 1100 system with a Fenomenex-Synergy MAX inverse phase column

(4 1.1) (2.0 x 50 mm) executed at 40�C with a flow rate of 0.8 nnl / min. The mobile phase use) solvent A

 (H201e1 0.1% TFA) and solvent B (CH3CN / 0.1% TFA) with a gradient of 3 min. from 10% to 100% CH3CN. The gradient was followed by a 0.5 min return. 10% CH3CN and a 1.5 min wash.

Proton NMR spectra:

Unless otherwise indicated, all 1 H-NMR spectra were performed with a Varian series instrument. Mercury 300 or 400 MHz or with a Bruker 400 MHz instrument. All observed protons, when notified,  are as parts per million (ppm) downstream of tetramethylsilane (TMS) or other internal reference in the solvent appropriate indicated.

Example 1 (method A)

H2 Raniey} 12NyN.,

Neither of

NO2 Et0H 7

NO2

H214

NH

H210% Pd / C

N NH CF3

Et0Ac / Me0H

0 NEt3 0  NH

CH2C12

NO2

 9 NH2

FaC

10

Synthesis of N- (2-amino-5-pyrimidiniI) -2-methyl-5 - (((3- (trifluoromethyl) phenyl) carbonyl) amino) benzamide

Stage 1. Pyrimidin-2,5-diamine

A round bottom flask equipped with a stir bar with 5-nitropyrimidin-2-amine 6 (3.0 g, 5 21.4 mmol), wet Raney Ni (-8 g) and Et0H (30 ml). The mixture was purged with H2 (3 vacuum and fill cycles), then it was allowed to stir under an H2 balloon. The reaction was monitored by TLC and LC-MS to determine the complete consumption of the starting material, which occurred after approximately 20 h. I filter the Mix through a layer of Celite with Et0H and CH2Cl2. The raw material was purified on a short bed

using automated medium pressure chromatography (Ism -40 g column; eluting with a linear gradient of 10 from 100% CH2C12 (lane A) to 100% CH2C12 / Me0H / NH3 90/10/1 (lane B) on silica gel) to provide pyrimidin-2,5-diamine 7 as an orange solid.

Stage 2. N- (2-aminopyrimidin-5-iI) -2-methyl-5-nitrobenzamide

2-methyl-5-nitrobenzoic acid (659 mg, 3.64 mmol) was heated to reflux in SOCl2 (6 ml) for 1 h. After cooling until room temperature and concentrate to dryness, the acid chloride in crude is snowed to CH2Cl2 (25 ml). Be 15 ariadi6 pyrimidin-2,5-diamine 7 (400 mg, 3.64 mmol) at dissolution and the mixture was allowed to stir at rt overnight. The mixture became a thick white suspension. NEt3 (700 01, 4.73 mmol) was added. After 2 h, a thick white suspension remained. The mixture was filtered through a Buchner funnel and washed

with abundant amounts of CH2Cl2 to remove the salt of NEt3HCI, providing N- (2-aminopyrimidin-5-11) -2methyl-5-nitrobenzamide 8 eats an off-white solid.

20 Step 3. 5-amino-N- (2-aminopyrimidin-5-iI) -2-rnetylbenzamide

A round bottom flask equipped with a stir bar with N- (2-aminopyrimidin-5-iI) -2-methyl-5 was charged

nitrobenzamide 8 (300 mg, 1.1 mmol), 10% Pd / C (-150 mg), Et0Ac (24 ml) and Me0H (6 ml). The mixture was purged

with H2 (3x evacuation and filling cycles), then it was allowed to stir under an H2 balloon. After 24 h, CCF

and LC-MS indicated that the starting material was completely consumed. The mixture was filtered after one 25 layer of Celite, washing with Me0H and CH2Cl2. Recrystallization from Me0H / CH2C12 provided 5-amino-N- (2

Aminopyrimidin-54) -2-methylbenzamide 9 eats a pale yellow crystalline solid.

Step 4. N- (2-amino-5-pyrimidiniI) -2-methyl-5 - (((3- (trifluoromethyl) phenyl) carbonyl) amino) benzamide

5-Amino-N- (2-aminopyrimidin-5-iI) -2-methylbenzamide 9 (86 mg, 0.353 mmol) was added to CH2Cl2 (3 mL) and added 3- (trifluoromethyl) benzoyl chloride (0.052 ml, 0.353 mmol). The mixture was allowed to stir at rt for 2 h, 30 becoming a thick yellow suspension. NEt3 was added (0.064 ml, 0.459 mnnol). After 0.5 h, it remained

a thick yellow suspension. The complete consumption of the amine starting material was indicated by LC-MS. The crude reaction mixture was concentrated and the title compound purified using medium chromatography. Automated pressure (Isco - 40 g column; eluting with a linear gradient of 100% CH2Cl2 (lane A) up to 100% CH2C12 / Me0H / NH3 90/10/1 (lane B) on silica gel) to provide N- (2-amino-5

5 pyrimidiniI) -2-methyl-5 - (((3- (trifluoromethyl) phenyl) carbonyl) amino) benzamide 10 as an off-white solid (). MS: m / z found 416 [MHf1 (by ESI, positive ion); MS calculated for C20H16F3N502 = 415.13.

Alternatively, compound 10 can be obtained using the following conditions: step 1. H2, Pt02; stage 2. Acid Chloride, NEt3, THF; stage 3; H2, 10% Pd / C, 2-methoxyethanol; and stage 4: same as before.

Example 2 (method Q)

Cul, CH2Cl2

isoaryl nitrite

THF, 70 '0

THE 2

NN 10% Pd / CNEt3

Et0Ac / Me0H fN CH2C12

r

13 NH2

F3C

14

10

Synthesis of 2-methyl-N- (24 (2- (4-morpholino) ethyl) amino) -5-pyrimidini1) -5 - ((((3-trifluorometinphenyl) carboniflamino) benzamide

Stage 1. N- (2-iodopyrinnidin-5-iI) -2-methyl-5-nitrobenzamide

N- (2-Aminoopyrimidin-5-11) -2-methyl-5-nitrobenzamide [prepared according to specific method 1] (200 mg, 0.732 mmol), Cul (140 mg, 0.732 mmol) and CH2I2 (0.30 ml, 3.73 mmol) to THF (3.7 ml) in a resealable Pyrex tube

15 of 16 x 100 mm. The tube was sent and the mixture was heated at 70 ° C for 2 h. After cooling to rt, the mixture is devolved of crude reaction to Et0Ac: HCI 1 N 1: 1 and the phases were separated. The organic phases were washed with NH4C1 saturated, then dried over Na2SO4. Purification by MPLC (Ism - 100% Et0Ac eluent) provided N- (2-iodopyrimidin-5-0-2-methyl-5-nitrobenzamide as a pale yellow solid.

Step 2. 2-methyl-N- (2- (2-morpholinoethylamino) pyrimidin-5-iI) -5-nitrobenzamide

20 N- (2-iodopyrimidin-5-iI) -2-methyl-5-nitrobenzamide (60 mg, 0.156 mmol), 2-morpholinoethanamine (-200 mg, 1.5 mmol) and DIEA (0.041 ml, 0.234 mmol) to IPA (2.5 ml) in a 16 x 100 mm resealable Pyrex tube and heated at 70�C for 4 h. The mixture was concentrated and purified by preparative TLC (2.5% Me0H / CH2Cl2) to

provide 2-methyl-N- (2- (2-morpholinoethylamino) pyrimidin-5-iI) -5-nitrobenzamide.

Step 3. 5-amino-2-methyl-N- (2- (2-morpholinoethylamino) pyrimidin-5-yl) benzamide

The intermediate product of the title was prepared in a manner analogous to the method described in step 3 of example 1.

Step 4. 2-methyl-N- (2 - ((2- (4-morpholino) ethyl) amino) -5-pyrimidiniI) -5 - (((3-trifluoromethyl) phenyl) carbonyl) amino) benzamide

The title compound was prepared in a manner analogous to the method described in step 4 of Example 1. MS: m / z found 529.0 [MH1-] (by ESI, positive ion); MS calculated for C26H27F3N603 = 528.

R1 groups of diamino-pyrimidine 2-NR8R9-substituted can be obtained using the methods described in the 30 examples 3-8

Example 3

26

1) (--N .----, ---, NH2

01.,)

H

IPA, DIEA

N N, ..

NO2 2) H2, 10% Pd / Cf (

MOM, Me0H

 N

15 16

C0)

Synthesis of N2- (3-morpholinopropyl) pyrimidin-2,5-diamine 16

Stage 1.

2-Chloro-5-nitropyrimidine 15 (500 mg, 3.13 mmol), 3-morpholinopropan-1-amine (1.35 g, 9.39 mmol) and DIEA were taken

5 (3.4 ml, 4.7 mmol) to IPA (20 ml) to a resealable Pyrex tube and heated at 70 ° C for 20 h. After cooling to ta, precipitate N- (3-morpholinopropyl) -5-nitropyrimidin-2-amine of the solution and was collected by filtration through a Buchner micromembrane and wash) with Me0H, then dried to provide the 5-nitro intermediate as a pale yellow solid.

Stage 2.

The crude N- (3-morpholinopropyl) -5-nitropyrimidin-2-amine was combined with 10% Pd / C (500 mg) in Et0Ac (20 ml) and Me0H (10 ml) was added. The mixture was purged with H2 and allowed to stir at 1 atm of H2 overnight. The filtration through a layer of Celite and the concentration provided N2- (1-methylpiperidin-4-yl) pyrimidin-2,5-diamine 16 as a reddish brown oil, which was used without further purification. MS: m / z found 270 [MH +].

Example 4

NH2 fifteen

Synthesis of N2-cycloprooylpyrimidin-2,5-diamine

The title compound was prepared by a method similar to that described in example 3, starting from 2-chloro-5-nitropyrimidine 15, MS: m / z found 151 [MH +].

Eiemolo 5

NaH, THF

NO2

NH2

2) H2, 10% Pd / C

fifteen Et0Ad, Me0H

twenty

Synthesis of N2- (1-methylpioeridin-4-yl) pyrimidin-2,5-diamine 17

Stage 1.

1-Methylpiperidin-4-amine (358 mg, 3.13 mmol) and NaH (60% dispersion in mineral oil) (126 mg,

3.13 mmol) to THF (16 ml) at an atmosphere of dry N2. After stirring at rt for 10 min, 2-chloro-5-nitropyrimidine 15 (500 mg, 3.13 mmol) was added. The mixture was allowed to stir at rt for 1 h, then quenched with 1N HCI and concentrated to dryness.

Stage 2.

The crude N- (1-methylpiperidin-4-11) -5-nitropyrimidin-2-amine was combined with 10% Pd / C (500 mg) in Et0Ac (8 ml) and Me0H (20 m1) was fitted. The mixture was purged with H2 and allowed to stir at 1 atm of H2 overnight. The filtration through a layer of Celite and the concentration provided N2- (1-methylpiperidin-4-11) pyrimidin-2,5-diamine 17 as a roasted solid, which was used without further purification, MS: m / z found 285 [MH-F].

2-Chloro-pyrimidin-5-yl compounds can be synthesized from the 2-amino-pyrimidine intermediate 10 directly in one step (mica step using the method described in example 6 below).

Example 6

Bu4NC1 TiVISC1 tE3u0NO DCE / DMF

18

19

Synthesis of 2-methyl-N-M2-chloro) -5-pyrimidini1) -5 - ((((2-methyl) -3-trifluoromethyl) phenyl) carboninaminobenzamide

In a 16 x 120 mm resealable Pyrex tube, 2-methyl-N - (((2-amino) -5-pyrimidini1) -5 - ((((2-methyl) -315 trifluoromethyl) phenyl) carbonyl ) aminobenzamide 18 (0.100 g, 0.23 mmol) at DCE (2.0 ml) and DMF (0.2 ml). solution in one portion with tetrabutylammonium chloride (0.065 g, 0.23 mmol). After 5 min, it was added slowly trimethylsilyl chloride (0.030 ml, 0.23 mmol). After 15 min, tert-butyl nitrite (0.028 ml, was added dropwise) 0.23 mmol) and the mixture was purged with N2, then the tube was sealed and the mixture was heated at 50 ° C for 7 h. After cooling, the crude reaction mixture was brought to a minimum amount of CH2C12 and purified by MPLC (lsco -

20 column of previously filled Redi-Sep� silica gel (40 g); eluent gradient: 5-80% Et0Ac in hexanes over 20 min) to provide the title compound 19 as a white solid. MS: m / z found 449 [MH-1].

Example 7 (method 1)

19

Synthesis of 2-methyl-N- (4-methyl-3-W2- (3-pyridinylamino) -5-pyrimidinipamino) carboninfeni1) -3-arifluoromethyl) benzamide

A small microwave reaction vessel was charged with N- (3 - (((2-chloro-5-pyrimidinyl) amino) carboni1) -4methylpheni1) -2-methyl-3- (trifluoromethyl) benzamide 19 (0.100 g, 0 , 22 mmol) and pyridin-3-amine (0.10 g, 1.1 mmol) in IPA

(1.0 ml). Trifluoroacetic acid (0.034 ml, 0.45 mmol) was added and the vessel sealed. The mixture was stirred Reaction and heating in a Smith Synthesizer microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) to 140�C for 10 min. The reaction was monitored by LC-MS and a 50% conversion was found. Be another 105 mg of aniline and 0.05 ml of TFA were added and microwave heating of the reaction to

5 140�C for 15 min. Once a conversion of approximately> 90% was found by LC-MS, the raw reaction mixture through a Buchner apparatus with a micromembrane filter and the filtrate is washed with Abundant amounts of Me0H to provide 2-methyl-N- (4-methyl-3 - (((2- (3-pyridinylamino) -5-pyrimidinyl) amino) carbonyl) feni1) -3- (trifluoromethyl) benzamide 20 as an off-white solid after drying. MS m / z found 507.1 [MH +], calc. for C26H21F3N602 = 506.17.

10 Example8 (method J)

NH

19 21

Synthesis of 2-methyl-N- (4-methyl-3 - ((((24 (2-pyridinylmethyl) amino) -5-pyrimidinyl) amino) carboniffeni1) -3 (trifluoromethyl) benzamide

A small microwave reaction vessel was charged with N- (3 - (((2-chloro-5-pyrimidinyl) amino) carboni1) -4

15 methylpheni1) -2-methyl-3- (trifluoromethyl) benzamide 19 (0.100 g, 0.22 mmol), pyridin-3-ylmethanamine (0.091 ml, 0.89 mmol) and IPA (1 m1). DIEA (0.058 ml, 0.33 mmol) was added and the vessel sealed. The reaction mixture was stirred and heating in a Smith Synthesizer� microwave reactor (Personal Chemistry, Inc., Upssala, Sweden) at 140�C for 30 min. After monitoring the reaction by LC-MS and finding a conversion> 95%, the concentration was concentrated.

Reacted to dryness and brought to a minimum amount of CH2C12 / Me0H. The reaction solution was injected into

20 crude on Isco {column of previously filled Redi-Sep� silica gel (40 g); eluent gradient: 3-80% of CH2C12 / Me0H / NH3 90/10/1 in CH2C12 over 20 min) to provide 2-methyl-N- (4-methyl-3 - (((24 (2-pyridinylmethyl) amino) -5-pyrimidinipamino) carbonyl) Pheni1) -3- (trifluoromethyl) benzamide 21 pure as a white solid. EM m / z found 521.1 [MH +]; calc. for C2 + 123F311602 = 520.18.

The following compounds, examples 9-86 were obtained using a procedure similar to that described in the examples 25 1-8.

Ex.

Structure Name EM Method

n�

N

.

NH

H3

H3C, N

0

N- (4meti l-3 ((2 (4 (4meti l pi perazi n-1 -

9

0yNH i l) feni l ami no) pi ri mi di n-5i l) carbamoi l) feni I -2 61 1, 1 TO

(ti ofen-2i l) ti azol-4-carboxy da

N'S

d-s

li

N

1 0

N .., NH CH3 0 * 0 NH N- (4meti l -3 ((2 (4 (4meti l pi perazi n1 -1 1) feni l ami no) pi ri mi di n-51 1) carbamoi l) feni 1 -5feni l oxazol-4carboxami da 589, 2 TO

. - #

N.

NyN,

eleven

NH CH3 or 'lam AP' O NH 2meti l -N- (24 - (4 ( -5pi ri mi di ni I) -5 (((3tri fluorometi l) feni l) carboni l) ami no) benzami da 543 TO

F F F

1 2

0 * Th C ./N•••.quot;-../ YN '' 'N NH H or 1100 0 NH F abh F Rip 2-fluoro-N- (4meti l -3 (((2 ((3 (4morfol i ni l) propi Dami no) -5pi ri mi di ni l) ami no) carboni l) feni 1) 3 (tri fluorometi l ) benzami da 561 TO

1 3

5 (((3-fluoro-5 (tri fluorometi l) feni l) carboni l) ami no-2meti l -N- (24 (3 (4morfol i ni l) propi l) ami no) -5pi ri mi di ni pbenzami da 561, 2 TO

1 4

H3C .N 40 H N N N. ' NH H or 0 O NH 2meti l -N- (2 ((4 (4meti l -1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni 1) -5 (((3tri fluorometi l) feni l) carboni l) ami no) benzami da 590, 2 TO

F F F

,

Cl '

fifteen

N., ... 4 .. NH CH, or 0 0 NH H C air, 2meti l -N- (4meti l -3 (((2 ((3 (4morfol i ni l) propi l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni 1) -3 (tri fluorometi l) benzami da 557, 1 TO

F3 F F

RP

1 6

H ' 11y l ■ (..- N NH or 110 or NH 2meti l -N- (24 - ( -4pi peri di ni l) ami no) -5pi ri mi di ni 1) -5 (((3 (tri fluorometi l) feni l) carboni l) ami no) benzami d a 51 3, 2 TO

F F F

.

I.1

1 7

H3C 11101 0 NH N- (2-ami no5pi ri mi di ni I) -2-meti l -5 ((feni l carboni l) ami no) benzami da 348 TO

I NI-12

H3c

„I H N SW

1 8

0 NH N- (2-ami no-5pi ri mi di ni I) -2meti l -5 ((feni l aceti l) ami no) benzami da 362, 0 TO

N N 1 NH2

H N N2 ■ TI 4 • 4.1

N ...... ..) .., NH

1 9

0 40 NH proH, N- (3 (((2-ami no-5pi ri mi di ni l) arni no) carboni 1) -4meti l feni 1 -3 (1, 1 -di meti l eti l) -1 -meti l -1 H-pi razol -5-carboxami da 407, 8 TO

H3C

—N

H3C

CH3

H .2 Ny

N

..... NH CH3

twenty

0 110 O NH is F N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni l and 4meti lfeni 1 -3-cl oro-2, 6-di fl uorobenzami da 41 7, 8 TO

CI

H2N ,,, .. I I N ...,

NH CH3

or

twenty-one

0 NH N- (2-ami nopi ri mi di n-50-5 (ci cl ohexanocarboxami do) -2meti l benzami da 353, 9 TO

H2N

N, t

11., ... To NH

CH,

0

0

22

0 NH N- (2-ami nopi ri mi di n-50-2-meti l -5 (3feni l propanami do) benzami da 375, 9 TO

11101

Hp

I

N

NH

CH3

0

110

2. 3

NH N- (2-ami nopi ri mi di n-54) -5 (3ci cl openti l propanami do) -2meti l benzami da 367.9 TO

H2N N., and * 1 N ,, .. „) .-, NH

CH3

24

or or 0 NH N- (2-ami nopi ri mi di n-50-5 (3-yodobenzoi l ami no) -2meti l -benzami da 473, 7 TO

0

H 2 N and

N

--- NH CH3

25

0 1101 NH N- (2-ami nopi ri mi di n-50-5 (3bromobenzoi l ami no) -2meti l -benzami da 425, 8 TO

#

Br

H2N, and, .., .... i l N, • - •

NH CH3

0

26

0 1110 NH N- (2-ami nopi ri mi di n-50-5 (3-cl orobenzoi l ami no) -2-nneti l -benzami da 381, 8 TO

CI

IP

H2N ,,,. I N

NH CH3

0

10 N- (3 (((2-ami no-5pi ri mi di ni pami no) carboni 1) -

27

4meti l feni I) -2-fluoro-5 433, 8 TO

0

NH (tri fluorometi l) benzami da

0

F

F

F

H2N

NN

N

one

'.7.

NH CH,

or 10

N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni I) -

28

4meti lfeni I) -2-cl gold5 449, 8 TO

Or NH 40 ci

(tri fluorometi l) benzami da

F

F

H2N

N ..

N

one CH,

29

0 0 • NH N- (2-ami no-5pi ri mi di ni I) -5 (((3-fluoro-5 (tri fluorometi l) feni l) carboni l) ami no) -2meti l benzami da 433, 8 TO

F

is

F F vo..T, R , d „.0,1-. ., NH

CH3

30

GONE 11 # 1 NH N- (2-ami no-5pi ri mi di ni I) -5 (((3, 5bi s (methi oxy) phenyl) carbonyl) ami no) -2-methyla benzami 407.9 TO

H3C, 0

H2N .... quot; I I N ..-

NH CH3

31

0 or * NH N- (2-ami no-5pi ri mi di ni I) -5 (((3, 5di fluoropheni l) carboni l) ami no) -2meti l benzami da 383, 8 TO

F

1 1 10 1

F

NEITHER

. ,, NH CH,

32

or I * 0 NH 10 N- (2-ami no-5pi ri mi di ni 1) -2-meti l -5 (((4 (methyloxy) -3 (trifluorometi pfeni l) carboni l) ami no) benzami d a 445, 8 TO

HN N

2

) r 1 NN ...

7 ■ NH CH3

0.

N- (2-amino-5-pyrimidini I) -5 - (((4-fluoro-3

33

0 NH (tri fluorometi l) feni l) carboni l) ami no) -2meti l benzami da 433, 8 TO

*

F

H2N .... ,, N, ... 1 1 J. N NH

CF-I3

3. 4

0 0 * NH N- (3 (((2-ami no5pi ri mi di ni l) anni no) carboni I) -4meti lfeni I) -2-fluoro3 (trifluorometi l) benzami da 433, 8 TO

F

0

F

F

35

rib ,. 111, MyN 4: NH H., 0 10 0 NH H C. 4.16, 2-meti l -N- (4meti l -3 (((2 ((4 (4meti l1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni I ) -3 (tri fluoronneti l) benzami da 604, 3 TO

F

RIP

36

H3C, N 41.6. up NH H 0. 0 NH 5 (((3, 5bi s (meti l oxy) feni l) carboni l) ami no) -2-meti l -N- (2 ((4 (4 (4meti l1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) benzami da) 582, 3 TO

41.11

cH,

37

10 M N., 'r N LNH H3 or [10 0 NH 5 (((3-fluoro-5 (tri fluorometi l) feni l) carboni l) ami no) -2meti l -N- (2 ((4 (4 (4-meti l -1 -pi perazi ni l) feni l) ami no-5pi ri mi di ni l) benzami da 608, 1 TO

F

0

F F

io

ifN .;

38

H, C N NH H3 or io 0 NH F d.o. , 2-fluoro-N- (4meti l -3 (((2 ((4 (4meti l -1 -pi perazi ni l) feni l) ami no-5pi ri mi di rqami no) carbonfl) feni 1) 3 (tri fluorometi l) benzami da 608, 2 TO

F F F

9/1

39

H3C -NI 101 N , NH H � 101 0 NH 5 (((4 (1-1 meti l eti l) feni l) carboni l) ami no) -2meti l -N- (2 ((4 (4 (4meti l -1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) benzami da 578, 2 TO

14 0

H3C

3 3

40

H3C-N 0 one M N IN). NH CH3 0 110 0 NH 2, 2-di fluoro-N- (4meti l -3 ((2 (4 (4nneti l pi perazi n1 -Ofenflami no) pi ri mi di n-5i l) carbamoi l) feni l) benzo [d] [1 , 3] di oxol5carboxami da 602, 2 TO

4

HN.I .

2 N ... 0

NH CH3

00

41

Or NH

11111 CI H NI,

2

N /

NH CH3

0 42

OH

HN N

2 and

NN: ffr'qu; NH CH3

0 43 110 0 NH

IP

FlN N

2 ••• if 4; 1

TO.

N ... 6

N1-1 CH3 or 44

0 NH H3C F FF

N- (2ami no-5pi ri mi di ni I) -5 (((4cl oro-3 (tri fluorometi l) feni l) carboni l) ami no) -2-meti l benzami da

449, 8 TO

N- (2-ami nopi ri mi di n51 1) -5 (ci cl opentanocarboxami do) -2-meti l benzami da

340, 2 TO

N- (2-ami nopi ri mi di n-51 1) -5 (3fluorobenzoi l ami no) -2-meti l -benzami da

366, 2 TO

N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni I) -4meti l feni I) -2meti l-3 (tri fluorometi l) benzami da

429, 8 TO

N- (3 - (((2-amino-5-pyrimidinyl) amino) carboniI) -415.7

TO

4-methylpheniI) -2,3-dichlorobenzamide

H N N 2 ..fr ....

NH

CH3

46

0 * NH N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni I) -4meti lfeni I) -3cl oro-2-fl uorobenzami da 399, 8 TO

CI

01

H2N .. ,, I I N

NH CH3

47

0 OR 10 NH N- (3 ((2-ami nopi ri mi di n-5i l) carbamoi l) -4meti l feni 1) -2, 2-di fluorobenzo [d] [1, 3] di oxo1 -4caboxami da 428, 1 TO

FF

� ip

H2N

r N N .. • NH CH3

48

0 OR IP NH N- (3 ((2-ami nopi ri mi di n-5i l) carbamoi l) -4meti l feni I) -1 -naftami da 398, 2 TO

Ow

H N N 2 ■ if * • ■ •• .1

N ..... 11.-NH

CH3

0

1101

49

0 NH N- (2-ami nopi ri mi di n-5-i I) -2-meti l 5- (4-tri fluorometi l benzoi l ami no) -benzami da 41 6, 1 TO

1.1

F

H N N 2 .... f. ., N .......... A, NH CH, 0 0

fifty

NH N- (2-ami nopi dmi di n-50-2meti l5 (4tri fl uoromethoxy-benzoi l ami no) -benzamide 432, 1 TO

ON

F

F

H 2 N) 1, N ...- •

NH

or

.

51

NH N- (2-ami nopi ri mi di n-5i I) -5 (4-tercbuti lbenzoi lami no) -2-meti l -benzami da 404, 3 TO

1101 H, C CH, CH,

H2N. ,,. N ..... 1 1 3 N ...- • ... NH CH3 0 40,

52

0 NH N- (2-ami nopi ri mi di n-5i I) -5 (4-eti l -benzoi lami no) -2meti l -benzami da 376, 2 TO

IP

N- (2-aminopyrimidin-5-i I) -5- (4-cyano

373.2 A

benzoi lamino) -2-meti l-benzamide

54

N H2Y. N ../ NH H3

0 *

55

0 NH

F.

SW

F F VI N ,.

eleven )

INI., 7 •%.

NH CH,

40 /

0

56

NH

110

CI

H, N li ,.

1st 1

N., / ,,,, NH CH,

0 *

57

or NH

A101 lir

H2NyN. N / NH CH3 0 1110

58 NH

IP

[3 (2-ami nopi ri mi di n-5i l carbamoi l) -4meti l -feni l] -ami da aci dé bi feni 1 -4-carboxy l i co

424, 2 TO

N- [3 (2-ami nopi ri mi di n-5i l carbamoi l) -4meti l -feni 1] -2, 3di fluoro-4-tri fluorometi lbenzami da

452, 2 TO

N- [3 (2-ami nopi ri mi di n-5i l carbamoi l) -4meti l -feni I] -3-cl oro-2, 4-difluorobenzami da

41 8, 1 TO

N- (3 ((2-ami nopi ri mi di n-5i l) carbamoi l) -4meti l feni 1) -2naftami da

398, 2 TO

N- [3 (2-ami nopi ri mi di n-5i l carbamoi l) -4meti l -feni I] -3, 4, 5-tri fluorobenzami da

402, 2 TO

H2Ny.N. ,, .. 1 N „., 4. one...

NH

59

0 0 110 NH N- [3 (2-ami nopi ri mi di n-5i l carbamoi l) -4meti l -feni I] -2, 4-di cl oro-5-fluorobenzami da 434, 2 TO

rail

ci

4.--

CI

H2NyN * 1

N ,,, „) -. NH

CH3

60

0 or NH N- [3 (2-ami no-pi ri mi di n-5i l carbamoi l) -4meti l -feni I] -4-cl gold-2, 5-difluorobenzamide 41 7, 4 TO

say h

F

1.'11

H2NyN.

CI

N

.., NH

61

or YES 0 NH N- [3 (2-ami nopi ri mi di n5-i l carbamoi l) -4meti l-feni I] -2-cl oro-6-fluoro-3meti l -benzami da 41 4, 2 TO

CI

46.6 F

H3C H N N -2 ..... r, .,

14Y1

N ...... A, NH

62

or 0 * NH N- [3 (2-ami nopi ri mi di n-5-i l carbamoi l) -4meti l -feni I] -6-cl oro-2-fluoro-3meti l -benzamide 41 4, 2 TO

ils

CI

H2NyN

63

N „) / ■ NH CH, 0 10/0. .. NH N- (2ami nopi ri mi di n-5i I) -2meti l -5 ((1 S, 2S) -2-feni l ci cl opropanocarboxami do) benzami da 387, 5 TO

TO

1101

64

* K1 NI NH H, 41.-or NH N- (4meti l -3 ((2- (4 (4meti l pi perazi n-1 -i l) feni l ami no) pi ri mi di n-51 1) carbamoi l) feni 1) -1 naftami da 572, 3 TO

041

ii. ..

keN

lillr

Nil ..: NH H3

65

H3V CI 'O rip IV� NH 5benzoi l ami no-2meti l -N- {2- [4 (4meti l -pi perazi n-1 -1 1) -feni l ami nojpi ri mi di n-5i l and benzami da 522, 2 TO

1411

66

HP 1101 N I NH CH3 or '* I 0, NH 7 oli ,, 5acetami do-2meti l -N- (2 (4 (4meti l pi perazi n-1 -i l) feni l ami no) pi ri mi di n-5i l) benzami da 460, 2 TO

67

' , d IP ' eleven N I NH H3 or ao 0 NH CH3 -0 5meti l -N- (4meti l -3 ((2- (4 (4meti l pi perazi n1 -i l) feni l ami no) pi ri mi di n-5i l) carbamoi l) feni pi soxazol-4-carboxami da 527, 2 TO

68

one 40 11 N TJNH CH30-o NH F F Olt 2-fluoro-N- (4-meti l -3 (((24 (4 (4meti l 1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni I) -5 (tri fluorometi l) benzami da 608, 1 TO

kl

...

69

H3C ... N # I NH H 0 110 0 NH 2-meti l -N- {244 (4meti l -pi perazi n-1 41) -feni l ami no] -pi ri mi di n-54} 5 (4-trifluoromethoxy -benzoi l ami no) -benzami da 606, 2 TO

0

0

F

70

H, C, N SW N .A.NN H, 0 Os or NH (4meti l -3- {2- [4 (4meti l -pi perazi n1 -i 1) -feni l ami no] -pi ri mi di n-5i l carbamoi lHeni ly and ami da aci dé bifeni l -4- carboxy li co 598, 2 TO

41

4

71

H3C ..N rig., 6 / I lir N N I NH or * or NH N- (4meti l -3 ((2 (4 (4-4-mei l pi perazi n1 i l) feni l ami no) pi ri mi di n-5i l) carbamoi l) feni I-2naftami da 572, 3 TO

AP

lir

72

H 3C -N il , NI I NH 0 0 H NH 3, 4, 5-tri fluoro-N- (4meti l -3- {244 (4meti l pi perazin-1 -i l) -feni l ami no] pi ri mi di n-5i l carbamoi lyfeni 1) -benzami da 576, 2 TO

F

m

F

F

N

73

CININ, N - / H3d - '31 N— 1.0 H3C NH or ill F F F 2, 6di meti l-N- {214 (4meti l -pi perazi n-1 -i l) -feni l ami nol-pi ri mi di n-5i 1} 3 (3-trifluorometi l -benzoi l ami no) -benzami da 604, 2 TO

74

H3C, N Il N SO Y 'NH H or * HN 0 or F Ilk 2, 2di fluoro-N (4meti l -3 ((2 (4 (4meti l pi perazi n1 -il) feni l ami no) pi ri mi di n-5i l) carbamoi l) feni l) benzo [d] [ 1, 3] di oxo1 -4carboxami da 602, 2 TO

eleven

N

i

NH H

75

- or Yes HN 0 4-fluoro-N- (4meti l-3 (((2 ((4 (4meti l -1 pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni I ) -3- (tri fluorometi l) benzami da 608, 2 TO

F

4 0 1

F

F

76

H3c, N 0 Y'L NH H 0 * HN or CI so 2-cl gold-N- (4meti l -3 (((2 ((4 (4meti l -1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni I) -3 (trifluorometi l) benzami da 624, 1 TO

F

F F

M

N

77

H30, N N .., NH H or 1101 0 NH 2methoxy -N- (4meti l -3 (((2 - ((4 (4meti l -1 pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni l) benzami da 552 TO

Hsc

4

*

Ilyl‘L

N

/ NH H

78

NC ' 0 1101 HN 0 3-ci ano-N- (4meti l -3 (((2 - ((4 (4meti l 1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni l) benzami da 547 TO

411

ICI

Ns.

79

401 i .. • NH 0 0 H3 NH N- (4meti l -3 (((2 - ((4 (4meti l -1 pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni 1) 3ni tro -5 (tri fluorometi l) benzami da 635 TO

o7w * 41 F 0 F F

*

14 N AND N .... NH

80

H3C� 0 110 NOI, NH 4meti l -34 (2 (4 (4meti l pi perazi n-1 -i l) feni l ami no) pi ri mi di n-5i l) carbamoi l) feni l carbamate of mesi ti l o 580 TO

rail

or

H3C

IP CH3

81

Ho c .N SW 11 Rs UNH CH3 0 • or NH 3-iodo-N- (4meti l3 (((2 ((4 (4meti l -1 pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni l) benzami gives 648 TO

0

06. go

eleven N

82

H3C .N 0 0 110 NH 3bromo-N- (4meti l 3 (((2 - ((4 (4meti l -1 -pi perazi ni l) feni l) ami no) -5pi ri mi di ni l) ami no) carboni l) feni l) benz ami da 601 TO

0

Br

H

N

N

401

N A .., NH H3

H3

- 0 0 3cl gold-N- (4meti l -3 (((2 - ((4 (4meti l -1 -

83

pi perazi ni l) feni l) ami no) -5 557 TO

or

NH pi ri mi di ni l) ami no) carboni l) feni l) benzami da

4111

ci

11, N

'7'And I

NH CH3

SW

0

N- (3 - (((2- (cycloolopropyl amino) -584 pyrimidinipamino) carboni1) -4-methylfeni1) -2-470 A

0 NH

meti l-3- (trifluoromethyl) benzamide

HC

F 'lel FF

H NN

0 ', U.

NH CH3

0 [110

2-Methyl-N- (4-Methyl-3 - ((((2- (3-Phenylamino) -585 pyrimidinyl) amino) carbonyl) feniI) -3-505.1 1 Or NH

(trifluoromethyl) benzamide

CH *

F

FF

I

■

NH CH3

2-meti l-N- (4-meti l-3 - (((2 - ((2

0 10

pyridini lmeti l) amino) -5

86 521.1 J

pyrimidini l) amino) carboni l) feni I) -3

0 NH

(trifluorometi l) benzamide

H3C Is

F

FF

Union elements can be synthesized "; urea between rings B and groups R3 from products N-R1R2-5-amino-2-methylbenzamide intermediates directly in one (single stage using desired isocyanates, as described in example 87 below.

Example 87 illustrates how desired -NR8R9 groups can be obtained in a pyrimidyl ring R1. The methodology 5 described in example 87 is also applicable to amino substitutions of other R 1 heterocyclic rings as well, including those defined by R1 in this document.

Example 87

NO2

2. 3

24 25

Synthesis of 5-amino-2-methyl-N- (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5-yl) benzamide

Step 1. Preparation of 5-nitro-N- (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidine

5 A mixture of 4- (4-methylpiperazino) aniline (57.7 g, 302 mmol), 2-chloro-5-nitropyrimidine (48.1 g, 302 mmol) in IPA (500 ml) Trifluoroacetic acid (46 ml, 603 mmol) was added. The mixture was heated to 80 ° C for 4 h, then it was allowed to cool to room temperature. The solid was collected by filtration by suction, washed twice with IPA (80 ml), methanol (100 ml), then dried in vacuo. The compound of the Title 22 as a yellowish solid. MS m / z found 315 [MA]; calc. for C15H18N602: 314.35.

10 Stage 2. Preparation of N2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2,5-diamine

A mixture of salt 22 from step 1 (96 g, 224 mmol) was suspended in water (400 ml) and 2N NaOH was added until

that the aqueous phase had pH = 14. The solid tile color was collected by suction filtration and dried in vacuo overnight. The compound was taken to Et0H (500 ml) and palladium on carbon (10 g, 10% by weight) was added hymedo). The mixture was placed in a pressure vessel with stirring under a hydrogen atmosphere of 50 psi

15 for 48 h. The catalyst was removed by suction filtration and washed) with Et0H. The phases were concentrated organic under reduced pressure and dried in vacuo. N2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidin-2,5-diamine was used 23 raw without any further purification.

Step 3- Preparation of 5-nitro-2-methyl-N- (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5-yl) benzamide

To a mixture of 2-methyl-5-nitrobenzoic acid (46.0 g, 181 mmol) in methylene chloride (2 I) EDC was added 20 (61.0 g, 318 mmol). The mixture was allowed to stir for 30 min at rt.

 N2- (4- (4-methylpiperazin-1yl) phenyl) pyrimidin-2,5-diamine 23 (60 g, 211 mmol) was added and the mixture was allowed to stir 70 h. Water (2 I) was added and

2N NaOH was added until pH = 14. The organic phases were extracted in Et0Ac (4 I). The aqueous phase was extracted with Additional Et0Ac (2 I). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Neve) the residue at 1 I of methylene chloride. The solid formed was collected

25 by suction filtration and washed twice with methylene chloride (250 ml). The solid was dried under vacuum to obtain the title compound 24. MS m / z found 448 [MH-11; calc. for C23H25N703: 447.5.

Step 4. 5-amino-2-methyl-N- (2- (4- (4-methylpiperazin-1-11) phenylamino) pyrimidin-5-inbenzamide

In a 2 I stainless steel pressure vessel with superior agitation, a mixture of product 24 of

step C (25 g, 55.9 mmol,) absolute ethanol (300 ml), Et0Ac (200 ml) and palladium on carbon (15 g, 10% by weight 30 hOmedo). The reactor was charged with a nitrogen atmosphere at 65 psi for 72 h. The catalyst was removed by

Suction filtration and washed with Et0H. The organic phases were concentrated under reduced pressure and dried at empty. The solid was sealed in vacuo to obtain 5-amino-2-methyl-N- (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5

il) benzamide 25. MS m / z found 418 [MH +]; calc. for C23H27N701: 417.5. Example 88 (method B)

1- (4-methyl-3- (pyrimidin-5-ylcarbamoyl) pheny1) -3- (3- (trifluoromethyl) phenyl) urea

5 A suspension of 5-amino-2-methyl-N- (pyrimidin-5-yl) benzamide 26 (0.068 g, 0.30 mmol) in benzene (5 ml) is given afiadi6 1-isocyanate-3- (trifluoromethyl) benzene (0.046 ml, 0.33 mmol). The reaction was heated at 75 ° C for 2 hours, producing a solid precipitate. The mixture was concentrated and chromatographed on silica gel with CH2C12 / Me0H 94/6 to provide 1- (4-methyl-3- (pyrimidin-5-ylcarbamoyl) feni1) -3- (3- (trifluoromethyl) phenyl) urea 27 as a white solid. MS m / z: found 416 [MH-1], calc. for C20H16F3N502 = 415.13.

The following compounds, examples 89-91 were obtained using a procedure similar to that described in the Examples 87 and 88.

Ex. n� Structure Name EM M6 method

ii.6 1 ■ 1N

Mr N s, .LNH

, N 0 1-eti l-3- (4-meti l-3 - ((2- (4- (4- H3C 0

meti lpiperazin-1

89 489.1 B

1) phenylamino) pyrimidin-50, NH

l) carbamoyl) phenyl) urea one , .NH

I CH3

H2N, _, N,

YOU N ..---

NH CH3

0 •

N- (2-amino-5-pyrimidini I) -2meti l-5 - ((((3

431 B

90 0. .... NH

(trifl ino) car

luoromethyl) feni) am one

boni l) amino) benzamide

NH

1101

eleven ,

-1Nr.3, .-%

10 i43

NH c

- so

0 2-meti l-N- (2 - ((4- (4-meti l-1piperazini l) phenyl) amino) -591 pyrimidiniI) -5 - (((3-605.1 B

0,., NH 1 (trifyl) phenyl) amino) car

luoromet Ail NH

boni l) amino) benzamide

1111r

F

Example 92 (method C)

H2

NEM, CH2Cl2

29

Synthesis of N- (2-aminopyrimidin-5-iI) -2-methyl-5- (3- (trifluoromethyl) phenylsulfonamido) benzamide

At a solution of 5-amino-N- (2-aminopyrimidin-5-iI) -2-methylbenzamide 28 (85 mg, 0.349 mmol) in CHCI3 (2 ml),

5 were added triethylamine (0.453 mmol) and 3- (trifluoromethyl) benzene-1-sulfonyl chloride (0.064 ml, 0.401 mmol). Be the reaction mixture was heated to reflux for 12 h, cooled to rt and concentrated in vacuo. The adsorbed crude residue on Si02 and purified by flash chromatography (CH2C12 / Me0H 99: 1) on Si02 to provide N- (2-aminopyrimidin-5-0-2-methyl-5- (3- (trifluoromethylphenyl sulfonamido) benzannide 29. MS m / z found 452

[MH +]; calc. for C19H16F3N5033 = 451.09.

The following compounds, examples 93-95 were obtained using a procedure similar to that described in the example

92.

Ex. N� Structure Name EM M6 method

46 11 114

N- (2-amino-5-pyrimidiniI) -

H, C 2-meti l-5

93 384.0 c

or NH ((feni lsulfoni l) amino) benz r5-4.1 amide

NN

I NH,

H, NyN: 4.1

.

NH CH, N- (2-aminopyrimidin-5-iI)

io 5- (3

94 or 408.8C cyanopheni lsulfonamido) -2

0 meti lbenzamide HN, TO

oo

95

H2N „TI N , .. NH CH, or 0 HN. .P. o o N- (2ami nopi ri mi di n-5i 1) -5 (ci cl opropanosul fonami do) -2meti l benzami da 347.5 C

Example 96 (method D)

HATU, DIEA DMF

Synthesis of 1-methyl-N- (4-methyl-34 (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5-yl) carbamoyl) phenyl) -1H-indole-2carboxamide.

5 In a 16 x 120 mm resealable Pyrex tube, 1-methyl-1H-indo1-2-carboxylic acid (0.11 g, 0.62 mmol) was taken, HATU (0.24 g, 0.62 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.17 ml, 0.96 mmol) to DMF (5 ml) and allowed to Shake at rt for 30 min. 5-amino-2-meth-N- (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5 was added

il) benzamide 30 (0.200 g, 0.48 mmol) and the mixture was stirred at rt overnight. It hey () the reaction mixture in crude at a minimum amount of Me0H / DMS0 and purified by preparative HPLC (Acid Shimadzu column: 1510 85% (0.1% TFA in CH3CN) in H20 over 20 min). The clean fractions were combined and neutralized with saturated NaHCO3, then extracted with CH2C12, dried over Na2SO4, filtered and filtered. concentrated to provide 1-methyl-N- (4-methyl-3 - ((2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5

il) carbamoyl) feni1) -1H-indole-2-carboxamide 31 as a roasted solid. MS m / z found 575.2 [MH +]; calc. For C33H34N802 = 574.28. .

Alternatively, compound 31 can be obtained using the following various conditions:

a) desired ring A acid (RCO2H), EDC.HC1, HOBt.H20, D1EA, DMF;

b) desired ring A acid (RCO2H), HATU, HOAt, DIEA, DMF; or

c) desired ring A acid (RCO2H), EDC, HOAt, D1EA, DMF

The following compounds, examples 97-113 were obtained using a procedure similar to that described in the 20 example 96.

Ex.

Structure Name EM Method

no

H2N .. „_„

I I

N

NH

CH3

0

N- (2-amino-5-pyrimidiniI) -2-methyl-5 - ((3-329.9

D

97 1101

(methyloxy) propanoyl) amino) benzamide

0 NH

... '

C-.r

H3

H2N „, ... ,,, 1 1 N /

NH CH3

98

. 0 1111 NH N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti l feni 1) -4cl oro-2-pi ri di ncarboxami da 383, 0 D

CI

H N 2 "; Tr

.....

N

... • NH

99

or • NH N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti lfeni 1) -1-benzofuran-2-carboxyam 387, 8 D

H2N) 1 'N ../

NH CH,

1 00

or 40 O NH N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti l feni 1) -2-meti li mi dazo [1,2-a] pi ri di n- 3carboxami gives 402 D

�

CH3

H N N 2 ■ fi, ■ • .;)

N

A. NH CH,

1 01

0 0 io NH N- (3 (((2ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti l feni 1) 3, 5di meti l-4 (meti l oxi) benzami da 406 D

H, C

40 CH, 0. CH,

H 2 N ,,,, .. I I

...

NH

1 02

0 110 N- (2-ami no-5pi ri mi di ni 1) -5 ((ci cl opropi l carboni l) ami no) -2meti l benzami da 31 1, 9 D

NH

N, go

H

2

N, •••

NH CH3

0 IP

103 Or NH

ISO HN N

twenty-one :,•).

Neither•

... i,

NH CH3 0 0 NH

, '• .. one CI

I-1

N, r

2 NH CH,

0 •

105 NH

or

N

NH CH,

0 40

106

hey NH

FN • H3

F 1-1211, (N, t)

N „.1) ',.

NH H 00

107

or NH

z * H, C —14 H, C CHs

N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti lfeni l and 1, 2, 3, 4-tetrahi dro1 naftal enocarboxami da

401, 9 D

N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti l feni 1) -5cl oro-3pi ri di ncarboxami da

382, 8 D

N- (3 (((2-ami no-5pi ri mi di ni pami no) carboni 1) -4meti l feni 1) -1 -meti l -1 H-i ndo1 -2-carboxami da

400, 8 D

N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti l feni 1) -1 meti l -3 (tri fluorometi l) -1 H-ti eno [2 , 3c] pi razol -5-carboxami da

476 D

N- (3 (((2-ami no-5pi ri mi di ni l) ami no) carboni 1) -4meti l feni 1) -3 (1, 1 -di meti l eti l) -1-feni 11 H -pi razol -5carboxami da

469.9 D

H2N N, YN 1

N- (3 - (((2-amino-5

*

0

1 08

pi ri mi di ni l) ami no) carboni 1) -4meti l feni 1) -4 487, 7 D

or

NH bromo-3, 5bi s (meti l oxi) benzami da

113C0

Br

H

N

2

Nr

N

... / NH CH3

1 09

0 or . NH N- (3 ((2-ami nopi ri mi di n-5i l) carbamoi l) -4meti l feni l) benzo [d] ti azol -6-carboxami da 404, 8 D

'

S

N /

H2N, riN., 1

N „,

1 ■

NH

H

0

*

1 1 0

OR NH N- (3 ((2-ami nopi ri nni di n-5-i l) carbamoi l) -4meti l feni 1) -1 H-i ndol -5-carboxami da 387, 2 D

110

uo1

N NTa

NH

CH3

H

quot; 0 101 N- (4meti l -3 ((2 (4 (4meti l pi perazi n1

1 1 1

i l) feni l ami no) pi ri mi di n-5 573 D

0

NH i l) carbamoi l) feni l) qui nol i n-4carboxami da

0 I

Iiii6

eleven N

'N

IP

N ..quot; NH

H3C, N

0 0 2-hi droxi5-iodo-N- (4meti l -3 (((2 ((4 (4

1 1 2

meti l -1 -pi perazi ni l) feni l) ami no) -5 664 D

0

NH pi ri mi di ni l) ami no) carboni l) feni l) benzami da

HO Aii

114,

11 N

0N

H, c'N o0 4-chloro-N- (4-methyl-3 - (((2 - ((4- (4-methyl-1piperazini l) feni l) amino) -5

1 13 625 D

pyrimidini l) amino) carboni l) feni I) -3

0 NH

(triluforomethyl) benzamide

4 FF

Cl F

Example 114 (method

N Et3

H2, 10% Pd / C Et0Ac / Me0H CH2Cl2

OCI

NH2

NO2

HATU, DIEA DMF

33

Synthesis of 2-fluoro-N- (4-methyl-3 - (((2- (phenylamino) -5-pyrimidinyl) amino) carbonyl) feni1) -5- (trifluoromethyl) benzamide 33

Step 1. Preparation of 5- (2-fluoro-5- (trifluoromethyl) benzamido) -2-methylbenzoic acid

5 A 250 ml round bottom flask was added with 2-methyl-5-nitrobenzoic acid (5.0 g, 28 mmol) and palladium al 10% on carbon (1.5 g, 14 nmol). The mixture is snowed to Et0Ac (30 ml), then Et0H (70 ml) is added. It is purged) mixture with H2, then allowed to stir at 1 atm of H2 for 24 h. CL-EM indicated a conversion of approximately 10% to product. Approximately 0.5 g of 10% Pd / C and —30 ml of Me0H were added to the reaction. The reaction was purged, cyan with H2 and allowed to stir at 1 atm of H2 for 20 h. The reaction was monitored

10 to determine the complete conversion using LC-MS. The mixture was passed through a layer of Celite, washing with Me0H and concentrated to provide 5-amino-2-methylbenzoic acid as an off-white solid. MS m / z found 152.1 (ESI, negative ion).

Stage 2.

To a 100 ml round bottom flask containing 2-fluoro-5- (trifluoromethyl) benzoyl chloride (0.44 ml,

2.9 mmol) in CH2Cl2 (30 ml) was added triethylamine (0.48 ml, 3.4 mmol). After 10 min, 5-amino-2-methylbenzoic acid (0.400 g, 2.6 mmol) was added. The solution was stirred at rt overnight. After cooling, the mixture was concentrated of crude reaction to remove excess NEt3, then diluted with CH2Cl2 and washed with 1N HCI once and brine and

 Salt once, then dry over Na2SO4 to provide 5- (2-fluoro-5 (trifluoromethyl) benzamido) -2-methylbenzoic acid 32 as an off-white solid. MS m / z found: 342.1 (ESI, positive ion).

20 Stage 3:

Acid 5- (2-fluoro-5- (trifluoromethyl) benzamido) -2-methylbenzoic acid 32 (0.25 g, 0.73 mmol), HATU (0.28 g, 0.73 mmol) and N-ethyl-N-isopropylpropan-2-amine (0.20 ml, 1.1 mmol) to DMF (6 ml). The solution was stirred at rt for 30 min, then N2-phenylpyrimidin-2,5-diamine (0.105 g, 0.56 mmol) was added and the mixture was allowed to stir to Ta during the night. The crude reaction mixture is snowed to a minimum amount of Me0H / DMS0 and purified 25 through preparative HPLC (Gilson acid column: 10-90% (0.1% TFA in CH3CN) in H20 over 15 min) The clean fractions were combined and allowed to stand for 2 h. Precipitate part of the product TFA salt and

was collected and neutralized with saturated NaHCO3, then extracted with CH2Cl2, semi-Na2SO4, filtered!) and concentrate to provide 2-fluoro-N- (4-methyl-3 - (((2- (phenylamino) -5-pyrimidinyl) amino) carbonyl) phenyl1) -5 (trifluoromethyl) benzamide 33 as a white solid. MS m / z found 510.1 [MH +]; calc. for C261-119F4N502 = 509.15.

The following compounds, examples 115-126 were obtained using a procedure similar to that described in the 5 exercises 114.

Ex.

Structure Name EM Method

n�

1 ■ 1N

.N

...

NH N- (4-chloro-3 - ((2- (4- (4- H, cA 0-40 methylpiperazin-1i) phenylamino) pyrimidin-5

1 15 622 E

0 NH il) carbamoyl) feni1) -2,2-dilophorebenzo [d] [1, 3] dioxo1-5carboxamide

FF

.41, h

11, and, N

ipi

NH I

.. N

2cl gold-N- (2 - ((4 (4meti l -1 -

H3C

0 SW pi perazi ni l) feni l) ami no) -5

1 1 6

pi ri mi di ni I) -5 (((3 61 0, 2 AND

0

NH (tri fl uorometi l) feni l) carboni l) ami

no) benzami da

F

011

F F

to

xN ,.

NH I , N

2-meti l-N- (4-chloro-3 - (((2 - ((4- (4-

H, C 0 #

methyl-1-piperazini l) phenyl) amino) 117 5-624.1 E

or NH pyrimidinyl) amino) carbonyl) feniI)

3- (one way trip

luorometi) benzam

H30

w

F

FF

SW

NH

143Cquot; 0 IS

2-Chloro-5 - (((4- (1, 1-dimethyl-methyl) phenyl) carbonyl) amino) 11 8 0 NH N- (2 - ((4- (4-methyl-1-598.3 E piperazini l) feni l) amino) -5pyrimidini l) benzamide IS

HaC ci.e14.

,

i rquot; 11N

iur NI

NH 10) 2-luphorus-N- (4-chloro-3 - (((2 - ((4- (4-

H3C-0

meti l-1-piperazinyl) phenyl) amino) 11 9 5-628.2 E 0 NH pyrimidinipamino) carboni l) feni 1) 5- (trilfuorometi l) benzamide

F

F kii

9H,

0

ara

W 9 CH,

NH H, 0 '. N (3 ((6, 7 di methoxy qui nol i n3

1 20

HN 0 i l) carbamoi l) -4meti lfeni 1) -2-meti l -3 524 AND

CH,

(tri fluorometi l) benzami da

4

F

F

(Reference compound)

9143 or

1 21

or 40 OH, NH or 10 HN 0 N- (3 ((6, 7-di methoxy qui nol i n-3i l) carbamoi l) -4meti l feni 1) -2, 2difluorobenzo [d] [1, 3] di oxo1 -4carboxami da 522, 1 AND

F, 40 F '‘0

fai

(Reference compound)

943 or „rob

1 22

or IP 6H3 NH 413 0 0 MN 0 N- (3 ((6, 7 di methoxy qui nol i n-3i l) carbamoi l) -4meti l feni 1) -2, 2-difluorobenzo [d] [1, 3] di oxo1 -5carboxami da 522, 1 AND

410

F

F

(Reference compound) 91-1. or 0ri,

1 23

4 NH H3 0-so HN or ci .. ,, c / h., 2-cl gold-N- (3 ((6, 7di methoxy qui nol i n-3i l) carbamoi l) -4meti l feni 1) -3 (tri fluorometi l) benzami da 544 AND

F

WI

F

(Reference compound) CH3 0 cam

1 24

0 1111 61-13 '.. N CH 0 110 MN 0 H3C 01 N- (3 ((6, 7-di methoxy qui nol i n-3i l) carbamoi l) -4eti l feni 1) -2-meti l -3 (tri fluorometi l) benzamide 538, 2 AND

F

F

F

(Reference compound)

I

110

NH CH3

Hpquot;

or to 2meti l -N- (4-eti l -3 (((24 (4 (4meti l -1 -pi perazi ni l) feni l) ami no

1 25

5 61 8, 2 AND

HN

pi ri mi di ni pami no) carboni l) feni l -

NC

3 (trifluorometi l) benzami da

F

I

.

416

/one N

IP '

1.1 s' NH CH3 4meti l -N3 (2 (4 (4

1 26

' or IS meti l pi perazi n1 - 572 AND

i l) feni l ami no) pi ri mi di n-51 1) N1

(naftal in-1 -1 1) and softal ami da

IP

Example 127 (method F)

CO (g), Me0H

Pd (OAc) 2, dppp

Uoh

DIPEA

H20

THF

36

EDC, HOBt DIPEA, DMF

36

Synthesis of N1- (2-fluoro-5- (trifluorometipfeni1) -4-methyl-N3- (2- (4- (4-methylpiperazin-1-11) phenylamino) pyrimidin-511) isophthalamide

5 Stage 1. N- (2-fluoro-5- (trifluoromethyl) feniI) -3-iodo-4-methylbenzamide

A solution of 3-iodo-4-methylbenzoic acid (10.0 g, 38.2 mmol) in thionyl chloride (30.0 ml) was heated to reflux for 3 hours. The resulting yellow solution was cooled to room temperature and concentrated to reduced pressure to provide 3-iodo-4-methylbenzoyl chloride. A solution of slowly added 3-iodo-4-methylbenzoyl chloride (1 g, 4 mmol) in dichloronnethane (10 ml) at a 0 ° C solution of 3-amino-4

10 fluorobenzotrifluoride (0.7 ml, 4 mmol) and diisopropylethylamine (0.9 ml, 5 mmol) in dichloromethane (10 ml). The stirring was stirred Reaction at 0 ° C and heated to room temperature over 20 hours. The reaction mixture was purified by column chromatography on silica gel (gradient elution with 0 to 100% hexane ethyl acetate) to provide N- (2-fluoro-5- (trifluoromethyl) feniI) -3-iodo-4-methylbenzamide 34. MS m / z found 423.9 [MH-F]; calc. for C15F110F4INO = 423.14.

Step 2. 5 - ((2-Fluoro-5- (trifluoromethyl) phenyl) carbamoyl) -2-methylbenzoate

A stainless steel cylinder equipped with a glass coating with N- (2-fluoro-5 (trifluoromethyl) feni1) -3-iodo-4-methylbenzamide 34 (1.089 g, 2.57 mmol), methanol (20 ml) was charged ) and a stir bar magnetic Argon gas was bubbled after this solution for one minute and then triethylamine was added

(0.358 ml, 2.57 mmol), 1,3-bis (diphenylphosphino) propane (0.0584 g, 0.142 mmol) and palladium acetate (11) (0.0289 g, 0.129 mmol). The cylinder was sealed, charged to 200 psi of CO gas, placed in a 75 ° C oil slurry and stirred for 2 hours. The reaction was cooled to room temperature and palladium acetate (11) was added. (0.0289 g, 0.129 mmol), DMF (2 ml), 1,3-bis (diphenylphosphino) propane (0.0584 g, 0.142 mmol) and triethylamine (0.358 ml,

5 2.57 mmol). The cylinder was sealed, up to 200 psi of CO gas was loaded, placed in an oil pan at 75 ° C and stirred 48 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified by column chromatography on silica gel (gradient elution with 0 to 100% ethyl acetate in hexane) to provide methyl 5 - ((2-fluoro-5- (trifluoromethyl) phenyl) carbamoyl) -2-methylbenzoate as a solid yellow 'I walk. MS m / z found 356 [MH +]; calc. for C17H13F4NO3 = 355.28.

10 Stage 3. acid� 5 - ((2-fluoro-5- (trifluoromethyl) phenyl) carbamoyl) -2-methylbenzoic acid

A solution of methyl 5 - ((2-fluoro-5- (trifluoromethyl) phenyl) carbamoyl) -2-methylbenzoate 35 (0.904 g, 2.5 mmol), THF (20 ml), lithium hydroxide (0.18 g, 7.6 mmol) and water (5 ml) at 55 ° C for 24 hours and then cooled up to room temperature The aqueous phase was separated, cooled in a barium of ice water and acidified with HCI. 6 M (aq.) To pH 1. This solution was extracted with ethyl acetate (3 x 10 ml) and the organic phases were dried

Combined over anhydrous sodium sulfate, filtered and concentrated to provide 54 (2-fluoro-5 (trifluoromethyl) phenyl) carbamoyl) -2-methylbenzoic acid 36. MS m / z found 342 [MH +]; calc. for C161-113F4NO3 = 341.26.

Step 4. N1- (2-fluoro-5- (trifluoromethyl) feni1) -4-methyl-N3- (2- (4- (4-methylpiperazin-1-11) phenylamino) pyrimidin-5-inisophthalamide

A 16 x 100 mm vial was loaded with 5 - ((2-fluoro-5- (trifluoromethyl) phenyl) carbamoyl) -2-methylbenzoic acid 36 (0.100 g, 0.293 mmol), dichloromethane (3 ml), diisopropylethylamine (0.200 ml, 1.15 mmol), 1-hydroxybenzotriazole (0.0396 g, 20 0.293 mmol), EDC.HCI (0.0562 g, 0.293 mmol) and N2- (4- (4-methylpiperazin-1-yl) phenyl) pyrimidine-2,5-diamine (0.0875 g, 0.308 mmol) and the mixture was stirred at room temperature for 24 hours. The reaction mixture was purified by column chronoatography on silica gel (gradient elution with 0 to 20% methanol in dichloromethane) to provide N1- (2-fluoro-5- (trifluoromethyl) feni1) -4-methyl-N3- (2- (4- (4-methylpiperazin-1yl) phenylamino) pyrimidin-5-ipisophthalamide 37 as a solid� light yellow MS m / z found 608 [MH +]; calc.

25 C31H29F4N702 = 607.60.

The following compounds, examples 128-134 were obtained using a procedure similar to that described in examples 127.

Ex. N�

Structure Name EM Method

CH3

6 a.

„W Y

NH H3

CH,

0

10 N3 (6, 7-di methoxy qui nol i n-3i 1) -

1 28

4meti l -N1 - (3 ((4meti l pi perazi n-1 i l) meti l) -5 622, 2 F

or

NH (tri fluorometi l) feni l) i softal ami da

lisc-N-quot;)

4

(Compound of reference) 9H,

or there „111111

NH

Y

CH3

0 0 N3- (6,7-dimethoxyquinoline in-3-i 1) - N1 - (2-fluoro-5

129 528.1 F

(triluforomethyl) feni1) -4-

NH

meti l isophthalamide

F MO

F

F (Reference compound)

N

1 30

H3C 'N • I NH ei 0-0, 4meti l -N3 (2- (4 (4meti l pi perazi n1 -i l) feni l ami no) pi ri mi di n-5i I) -N1 - (3 (tri fluorometi l) feni l) i softal ami da 590, 2 F

011

F

F F

I

1 31

I NH 043 0quot; jii 'W I 1-13c-v ^ .., 411..11 F 4meti l -N1 - (3 ((4meti l pi perazi n1 -i pmeti l) -5 (tri fluorometi l) feni I) -N3 (2 (4 (4meti l pi perazi n-1 -il) feni l ami no ) pi ri mi di n-5i l) i softal ami da 351, 7 F

00

NH CH3

1 32

0 io HN 0 4meti l-N3 (qui nol i n-31 1) -N1 - (3 (tri fluorometi l) feni l) i softal ami da 450, 1 F

4 F

F F

(Reference compound)

OP

NH

1 33

0 H3d. N, - „, SO HN 0 • F F F 4meti l-N1 - (3 ((4meti l pi perazi n1 -i l) meti l) -5 (tri fluorometi l) feni 1) -N3 (qui nol i n-3i l) i softal ami da 562 F

(Reference compound)

10

NH H3

1 34

0 F 40 HN 0 deik N1 - (2-fluoro5 (trifluorometi l) feni I) -4-meti l -N3 (qui nol i n-31 1) i softal ami da 468 F

W.

F (Reference compound)

Example 135 (method

EtaB

Pd (OAc) 2 S-Phos K3PO4

38 39

Synthesis of N- (4-ethyl-34 (2- (4- (4-methylpiperazin-1 -11) phenylamino) pyrimidin-5-i0carbamoiffeni0-2,2difluorobenzoldlf1,31 dioxol-5-carboxamide

5 A resealable tube was charged with N- (4-chloro-3 - ((2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5-yl) carbamoyl) feni1) -2,2difluorobenzo [d ] [1,3] dioxol-5-carboxamide 38 (0.050 g, 0.080 mmol), palladium (II) acetate (0.0018 g, 0.0080 mmol), 2- (dicyclohexylphosphino) -2 ', 6'-dimethoxy-1,1'-biphenyl (0.0066 g, 0.016 mmol), potassium phosphate (0.068 g, 0.32 mmol) and DMF (2.0 m1). A solution of triethylborane (0.12 ml, 0.12 mmol) (1 M in THF) was added. The tube was emptied reaction and purged with argon and then sealed & The mixture was stirred at 100 ° C for 6 h. The mixture was filtered

10 reaction through a layer of Celite and concentrated to provide a solid green-yellow. I purified this material by preparative thin layer chromatography (eluting three times with dichloromethane / methanol / hydroxide of ammonium 95: 5: 0.5,) to provide N- (4-ethyl-3 - ((2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5yl) carbamoyl) feni1) -2 , 2-difluorobenzo [d] [1,3] dioxol-5-carboxamide 39 as an off-white solid. MS m / z found 616.2 [MH-f-]; calc. for C32H31F2N704 = 615.63.

Example 136 (method H)

HO

KOtBu

F3C

41

40

Synthesis of 2-methyl-5-a (2 - ((1-methyl-4-piperidini0oxy) -5- (trifluorometiOphenecarbonyl) amino) -N- (2- (phenylamino) -5-pyrimidiniftenzamide

To a suspension of potassium t-butOxide (17 mg, 0.151 mmol) in THF (2 ml) was added 1-methylpiperidin-4-ol

20 (15 mg, 0.130 mmol). The mixture was allowed to stir at rt for 15 min, at which time 2fluoro-N- (4-methyl-3 - ((((2- (phenylamino) -5-pyrimidinyl) amino) carbonyl) phenyl1) - 5- (trifluoromethyl) benzamide 40 (55 mg, 0.108 mmol). The reaction mixture was stirred at room temperature for 24 h, at which time LC-MS showed complete conversion. The reaction mixture was diluted with CH2C12, washed. with water (3 x 20 ml), seat ' over Na2SO4 and concentrated. The crude residue was brought to Me0H / DMS0 and purified on reverse phase HPLC

25 Shimadzu with a gradient of 15-85%. The pure fractions were combined, basified with bicarbonate of

saturated sodium and extracted with CH2C12 (4 x 20 ml). The combined organic extracts were dried over sulfate sodium and concentrated to provide 2-methyl-5 - (((2 - ((1-methyl-4-piperidinyl) oxy) -5 (trifluoromethyl) phenyl) carbonyl) amino) -N- (2- (phenylamino) -5-pyrimidinyl) benzamide 41. MS m / z found 605.3 [MH-1-]; calc. for C32H31F3N603 = 604.24.

30 Example 137 (method K)

0 Cl

F3C

NH

0

F30

NEt3

0 NH CH2C12: Pyridine

NH2

F30 F3C

42 43 44

Synthesis of N- (2-amino-5-pyrimidini1) -2-methyl-3 - (((3- (trifluoromethyl) phenyl) carbonipamino) benzamide

It flew ') 3-amino-N- (2-aminopyrimidin-5-0-2-methylbenzannide 42 (113 mg, 0.464 mmol) [prepared according to procedure described for 5-amino-N- (2-aminopyrimidin-5-iI) -2-methylbenzamide in example 1] to CH2Cl2 (4 ml) and 5 pyridine (3 ml) and 3- (trifluoromethyl) benzollo chloride (0.31 ml, 2.09 mmol) followed by NEt3 (0.13 ml, 0.928 mmol). The complete consumption of the amine starting material was indicated by LC-MS. The crude reaction mixture and the product was purified using automated medium pressure chromatography (40 g column, eluting with a linear gradient from 97% CH2Cl2 (lane A) to 100% of CH2C12 / Me0H / NH3 90/10/1 (lane B) on silica gel) to provide N- (2-amino-5-pyrimidiniI) -2-methyl-3 - (((3

10 (trifluoromethyl) phenyl) carbonyl) amino) benzamide 43 as an off-white solid. MS m / z found 416 [MH +]; calc. for C20H16F3N502 = 415.13; and 2-methyl-3 - (((3- (trifluoromethyl) phenyl) carbonyl) amino) -N- (2 - (((3 (trifluoromethyl) phenyl) carbonyl) amino) -5-pyrimidinyl) benzamide 44 as a solid� whitish MS m / z found 588 [MH +]; calc. for C28H19F6N503 = 587.14.

Example 138 (method L)

CI

M2

Pd / C NH2 NO2

H2

Pd / C

Et0Ac Me0h

NO2

48

45 47

fifteen

Synthesis of 2-methyl-N- (5-pyrimidiniI) -5 - (((3- (trifluoromethyl) phenyl) carbonyl) amino) benzamide

Stage 1.

The method followed in step 1 was analogous to that described in Can. J. Chem. Vol. 77, 216-222 (1999). It is loaded) a 1 I high pressure reaction vessel with ether (300 ml) and a catalyst was added, 10% palladium on 20 boiled carbon (50% water) (1.68 g), followed by 4, 6-dichloropyrimidin-5-amine (21 g). A solution was diluted of 50% sodium hydroxide (168 ml) with water (150 ml) and added to the previous mixture. The mixture was pressurized biphasic at 35 psi of H2 and stirred mechanically for 24 h. More catalyst was added at this point (1.5 g) and He returned the reaction to H2 for 24 h. The reaction is completed as monitored by LC-MS and

filtered through Celite and rinsed with water. The biphasic mixture was separated and the aqueous phase was extracted 3 times with

25 ether The organic phases were combined, dried over MgSO4, filtered and concentrated to provide the crude 5-amino-pyrimidine product as a yellow solid. It was recrystallized from toluene / Me0H. Turned to Extract the aqueous phase twice using Et0Ac, the organic phases were dried over MgSO4, filtered and

concentrated to provide more desired product. All solids were combined to give the product pyrimidin-5-amine.

Stage 2.

A round bottom flask of 2 Icon mechanical stirring with 2-methyl-5-nitrobenzoic acid (20 g), HATU was charged (38 g) and diisopropylamine (32 ml) in DMF (90 ml). This mixture was stirred for 30 min, then pyrimidin-5amine was added and the reaction was stirred for 18 h. LC-MS showed complete conversion. The DMF was removed in vacuo

5 maximum possible, then water was added and a solid precipitated (use of mechanical agitation). The roasted solid was filtered and rinsed with water, then brought to Et0Ac, washed) with brine, dried over MgSO4, filtered and concentrated. Be I bring the crude product to Et0Ac and precipitate the product 45. This was filtered and the filtrate was concentrated and brought to Et0Ac / Hex. After standing overnight, more solids were filtered and combined with the first material picked up 2-Methyl-5-nitro-N- (pyrimidin-5-yl) benzamide was obtained as a light yellow solid.

10 Step 3. 5-amino-2-methyl-N- (pyrimidin-5-ipbenzamide

A 2 1 high pressure vessel with 10% palladium on wet carbon (50% water) and Et0Ac was loaded (50 ml). 2-Methyl-5-nitro-N- (pyrimidin-5-yl) benzamide 45 (18.79g) was dissolved in methanol (400 ml) and added to the above mixture. The reaction vessel was pressurized to 30 psi of H2 and stirred mechanically until it was stopped the entry of hydrogen. It was determined that the reduction of the nitro group was complete by LC-MS and

15 the mixture was filtered through paper and glass paper. The crude 5-amino-2-methyl-N- (pyrimidin-5yl) benzamide 46 was obtained as a yellow solid and was used without further purification.

Stage 4

The title compound, 2-methyl-N- (5-pyrimidini1) -5 - (((3- (trifluoromethyl) phenyl) carbonyl) amino) benzamide, is prepared starting from compound 46 obtained in step 3 according to the procedure described in step 4 of example 1. MS m / z

20 found 400.7 [MH +]; calc. for C20H15F3N402 = 400.11.

Example 139 (method N)

DMAP (i-P02NEt CH2Cl2

47

30

Synthesis of 4-methyl-34 (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5-ipcarbamoyl) phenylearbamate of mesityl

A 16 x 100 mm vial was charged with 5-amino-2-methyl-N- (2- (4- (4-methylpiperazin-1-11) phenylannino) pyrimidin-5

25 il) benzamide 30 (0.100 g, 0.24 mmol), 4- (dimethylamino) pyridine (0.0059 g, 0.048 mmol), dichloromethane (2 ml) and diisopropylethylamine (0.050 ml, 0.29 mmol). A solution of mesityl hydrochloride was added dropwise (0.048 g, 0.24 mmol) in dichloromethane (1 ml) and the reaction mixture was stirred at room temperature for 20 hours. The reaction mixture was purified by column chromatography on silica gel (elution in gradient with 0-20% methanol in dichloromethane) to provide 4-methyl-3 - ((2- (4- (4-methylpiperazin-1

30 il) phenylamino) pyrimidin-5-yl) carbamoyl) phenylcarbamate of mesityl 47 eat a bright yellow solid. MS m / z found 580 [MH +]; calc. for C33H371 \ 1703 = 579.69.

Example 140 (method 0)

NO2

NT, NO2

'

HN NH2

CI N I

48

H2 10% Pd / C

Ii

HN

DMAC, 120�C

4950

5% Pd (PPI-19) C12

Synthesis of N3- (4-amino-2- (methylamino) pyrimidin-5-0-4-methyl-N1- (2-methyl-3- (trifluoromethyl) phenylisphthalamide

Stage 1. 2-Chloro-5-nitropyrimidin-4-amine

At a rapid stirring solution of saturated aqueous ammonium hydroxide (50 ml) and ice in a 0�C bath,

5-aryadium 2,4-dichloro-5-nitropyrimidine (6.0 g, 31 mmol) in portions. The foamy mixture was allowed to stir resulting yellow for 30 min, at which point the precipitate is isolated by filtration. The solid was clarified several times with ice water and once with icy ethanol to give a solid peach color. It was purified crude solid by adsorption on 18 g of silica gel, followed by silica gel chromatography, eluting with 0-20% Me0H / dichloromethane to give 2-chloro-5-nitropyrimidin-4-amine as an off-white solid. MS (ES):

10 175 (M + H) +; calc. for C4H3CIN402 = 174.55.

Stage 2. N2-methyl-5-nitropyrimidine-2,4-diamine

A mixture of 2-chloro-5-nitropyrimidin-4-amine (1.0 g, 5.8 mmol) and methylamine (solution) was allowed to stir 2.0 M in THF, 14 ml, 28 mmol) in a sealed container for 1 h. Then the mixture was heated to 60�C for 30 min. The reaction was cooled to room temperature and an additional amount of methylamine was added. 15 (2.0 M solution in THF, 8 ml, 16 mmol) and the reaction was sealed and heated to 60 ° C for 30 min. It cooled The reaction was diluted with water and the precipitate was collected by filtration. The solid was clarified with small portions of water followed by diethyl ether. The material was dried under reduced pressure to give N2-methyl-5-nitropyrimidine-2,4-diamine 48

like a light yellow solid. MS (ESquot;): 170 (M + H) +; calc. for C5H7N502 = 169.14.

Stage 3. N2-methylpyrimidin-2,4,5-triamine

20 N2-methyl-5-nitropyrimidine-2,4-diamine 48 (0.83 g, 4.9 mmol) and 10% palladium on carbon (0.52 g, 0.49 mmol) under nitrogen. Methanol was added (16 ml) and the atmosphere was replaced with hydrogen from a balloon. The reaction was stirred rapidly for 6 h, at which point the atmosphere was replaced with nitrogen and the atmosphere was filtered. reaction mixture through Celite, rinsing with methanol. The filtrate was concentrated in vacuo to give N2methylpyrimidin-2,4,5-triamine 49 as a light pink solid, MS (ES +): 140 (M + H) +; calc. for C5H9N5 = 139.16.

Step 4. N3- (4-amino-2- (methylamino) pyrimidin-5-0-4-methyl-N1- (2-methyl-3- (trifluoromethyl) phenylisphthalamide

To a small glass vessel was added N2-methylpyrimidin-2,4,5-triamine 49 (0.050 g, 0.36 mmol), 3-iodo-4methyl-N- (2-methyl-3- (trifluoromethyl) phenyl ) benzamide (0.15 g, 0.36 mmol) [prepared from 3-iodo-4-methylbenzoic acid and 2-methyl-3- (trifluoromethyl) bencenamine as shown in the first stage of Example 1271 and bis (triphenylphosphine) palladium (II) dichloride (0.013 g, 0.018 mmol). A septum was joined and the mixture was purged with N2. Be Ariadium 2,6-lutidine (0.054 ml, 0.47 mmol) by syringe and purged) the mixture with CO (g) in a container of Pressure reaction and placed under 95 psi, then heated at 120 ° C for 24 h. The reaction was allowed to be cooled to rt, then the pressure was released and the tacky red residue was analyzed by LC-MS. It was found that the MS for the title compound was (ESI, positive ion) m / z: 459.1 [M + 1]. The crude residue was triturated with Me0H and He was allowed to stir at rt overnight. The crude reaction mixture was filtered through an apparatus 35 Buchner with micromembrane filter and the filtrate was washed with copious amounts of Me0H. The mother liquor until a sticky dark red solid is obtained after drying. This material was taken to a minimum quantity of CH2Cl2 and the solution was injected into the Isco column {previously filled Redi-Sepe silica gel column (40 g); gradient eluent: 3-80% CH2C12 / Me0H / NH3 90/10/1 in CH2Cl2 over 20 min} to provide N3- (4-amino-2- (methylamino) pyrimidin-5-0-4-methyl-N1- (2-methyl-3- (trifluoromethyl) phenyl) isophthalamide 50 as

40 off-white solid. MS m / z found 459.1 [M +]; calc. for C22H21F3N602 = 459.17.

Additional examples 141-143 were prepared by methods described above.

Example 141

N..ir N NHcl-13

Example 142

N N

) r

6N NH

 c1-13 0

0 NH

CH

5 Example 143

Example 144

Pd (0A (52, �PPP

EDC CO, BA AileOH DCM, CAW 75 • C

(Compound of reference)

H2N-0 — NH2

 H2N t4quot; -

WC HOER

93% yield

51

Synthesis of N3- (6-aminopyridin-3-iI) -N1- (2-cyclopentylethyl) -4-methylisophthalamide (51)

10 Stage 1:

It was charged in a round bottom flask acid-3-iodo-4-methylbenzoic acid (1.4 g, 5.4 mmol), dichloromethane (4 ml) and DMF

 (2 ml). This mixture was cooled to 0 ° C and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added (1.2 g, 6.3 mmol). The reaction mixture was stirred for 10 min before introducing 2-cyclopentylethanamine (0.47 g,

4.2 mmol). The reaction mixture was stirred at 0 ° C for 1 h, then at RT under N2 for 16 h. The reaction between DCM (60 ml) and brine (50 ml). The aqueous phase was extracted again with DCM (4 x 20 ml) and dried () the combined phase with DCM (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography through a previously filled Redi-sep silica gel column (330 g), eluting

5 with a gradient of 5% to 5% Et0Ac in hexane, to provide N- (2-cyclopentylethyl) -3-iodo-4-methylbenzamide Like a white solid. MS (ESI, positive ion) m / z: 358.1 (M + 1).

Stage 2.

It was placed in a 120 ml pressure cylinder with glass coating N- (2-cyclopentylethyl) -3-iodo-4-methylbenzamide (1.7 g, 4.9 mmol) and methanol (25 ml). Nitrogen was bubbled through this mixture, then 10 added palladium acetate (55 mg, 0.24 mmol), 1,3-bis (diphenylphosphino) propane (0.11 g, 0.27 mmol) and triethylamine (1.6 ml, 11.6 mmol). The cylinder was covered with a pressure gauge and charged to 40 psi of CO gas. The reaction was heated in an oil level at 75�C for 20 h. The orange precipitate was filtered off and the filtrate was concentrated to empty. The red residue was dissolved in DCM and purified by chromatography through a gel column of Redi-Sepe pre-filled silica (120 g), eluting with a gradient of 10% to 25% Et0Ac in hexane,

15 to provide methyl 5 - ((2-cyclopentylethyl) carbamoyl) -2-methylbenzoate as a white solid. EM (ESI, iOn positive) m / z: 290.2 (M + 1).

Stage 3:

Methyl 5 - ((2-cyclopentylethyl) carbamoyl) -2-methylbenzoate (1.2 g, 4.3 mmol) dissolved in THF (15 ml) was added a solution of L10H, monohydrate (0.27 g, 6.4 mmol) in water (15 ml). The reaction mixture was stirred at RT

20 for 18 h. THF was removed, the residue was extracted with ether (5 ml) and the phases were separated. The aqueous phase is HC1 2N atiadium until pH 4-5 (form) much precipitate). The solid was collected by filtration, washed with water, Dry to give 5 - ((2-cyclopentylethyl) carbamoyl) -2-methylbenzoic acid as a white solid, MS (ESI, pos, ion) m / z: 276.2 (M + 1).

Stage 4:

25 An MFR was charged with 5 - ((2-cyclopentylethyl) carbamoyl) -2-methylbenzoic acid (0.25 g, 0.91 mmol), DCM (3 ml), N, Ndiisopropylethylamine (0.6 ml, 3 , 5 mmol), HOBt (0.14 g, 1.0 mmol), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (0.21 g, 1.1 mmol) and 2,5-diaminopyridine (0.1 g, 0.91 mmol) in that order. This mixture was stirred at RT under N2 for 18 h. The reaction was partitioned between DCM (30 ml) and brine (20 ml). The precipitate was collected formed, washed, with water, dried in a vacuum oven overnight to give N3- (6-aminopyridin-3-iI) -N1- (2

30 cyclopentylethyl) -4-methylisophthalamide as a solid. MS (ESI, positive ion) m / z: 367.2 (M + 1).

Example 145

Synthesis of N1 - (2-cyclopentylethyl) -4-methyl-N3- (6- (3-methylbutanamido) pyridin-3-inisophthalamide (52)

(Compound nde reference)

Et3N.0.0

N3- (6-aminopyridin-3-iI) -N1- (2-cyclopentylethyl) -435 methylisophthalamide (0.19 g, 0.52 mmol) and triethylamine (0, were added to a 25 ml round bottom flask. 18 ml, 1.3 mmol) to stir at 0 ° C. It was added drop by drop isovaleryl chloride (0.14 ml, 1.0 mmol) at dissolution. The reaction was allowed to stir for one hour. In that moment was shown to have been completed by LC-MS. DI water was added to the reaction. The reaction to a separatory funnel, where the aqueous phase was extracted 3 times with DCM. The phases were washed Organics combined with brine, saturated NaHCO3, dried with MgSO4, filtered and concentrated. Be The crude product was adsorbed on a bed of silica gel and chromatographed through a column

of previously filled Biotage silica gel (25 M), eluting with a gradient of 1% to 10% Me0H in CH2C12, to provide N1- (2-cyclopentylethyl) -4-methyl-N3- (6- (3-methylbutanamido) pyridin-3-11) isophthalamide as a solid white. MS (ESI, positive ion) m / z: 451.3 (M + 1).

Example 146

to.

 H2N .t.1) .NH2

Pd (OAc) 2, Ph3P

EDC, HOBt, iPr2h1Eit

0

Bu3N, Cs0Ac H2O, Co DMF, 90�C  0 b. UCH, THF

53

(Compound

of reference)

Synthesis of N3- (6-aminopyridin-3-11) -N1- (cyclopropylmethyl) -4-methylisophthalamide (53)

Stage 1:

5 A pressure vessel was charged with methyl 3-bromo-4-methylbenzoate (5.0 g, 22 mmol), DMF (20 ml), water (1.25 ml) and tributylamine (8 ml, 34 mmol). Then cesium acetate (2.1 g, 11 mmol) was added and the flask was purged with N2. Palladium acetate (0.25 g, 1.0 mmol) and triphenylphosphine (2.9 g, 11 mmol) were added and the flask was purged with CO gas. The reaction mixture was then heated to 90 ° C under 20 psi of CO gas with vigorous stirring during the night. The reaction mixture was diluted with 50 ml of toluene and extracted with saturated NaHCO3 (3 x 50 ml). Wash.

10 the aqueous phase combined with Et0Ac (10 ml), then acidified using 2N HCI to pH 5. The volume was reduced to about 50 ml and the resulting precipitate was collected by filtration, washed with water and dried for give 5- (methoxycarboni) -2-methylbenzoic acid as a white solid. MS (ESI, positive ion) m / z: 193.1 (M-1).

Stage 2:

It was charged in a round bottom flask acid 5- (nnethoxycarboni) -2-methylbenzoic acid (0.2 g, 1.0 mmol), dichloromethane

15 (3ml), N, N-diisopropylethylamine (0.7 ml, 4.0 mmol), HOBt (0.16 g, 1.2 mmol), 1- (3-dimethylaminopropyl) 3-ethylcarbodiimide hydrochloride (0, 24 g, 1.2 mmol) and 2,5-diaminopyridine (0.11 g, 1.0 mmol) in that order. The mixture was stirred reaction at RT under N2 for 18 h. The reaction was partitioned between DCM (30 ml) and brine (20 ml). It was extracted from again the aqueous phase with DCM (3 x 15 ml) and the combined phase was dried with DCM (Na2SO4) and concentrated. Be dissolved in crude product in Me0H and absorbed on silica gel, purified by chromatography through

20 of a 40 g Redi-Sep column, eluting with a gradient of Me0H from 0% to 10% in CH2Cl2, for provide methyl 3 - ((6-aminopyridin-3-yl) carbamoyl) -4-methylbenzoate as a tan solid. MS (ESI, ion positive) m / z: 286.2 (M + 1).

Stage 3:

A 3 - ((6-Aminopyridin-3-yl) carbamoyl) -4-methylbenzoate methyl (0.11 g, 0.39 mmol) dissolved in tetrahydrofuran

25 (1.5 ml) was added a solution of lithium hydroxide monohydrate (24 mg, 0.58 mmol) in water (1.5 ml). Be Stir the reaction mixture at RT for 4 h. THF was removed in vacuo and 2N HCI was added to the aqueous phase up to pH 4-5. The precipitate formed was filtered off, washed with water, dried to give 3- (3- aminopyridin-3-11) carbamoyl) -4-methylbenzoic acid as a tan solid. MS (ESI, positive ion) m / z: 272.1 (M + 1).

Stage 4:

30 Charged in a round bottom flask acid� 3 - ((6-aminopyridin-3-yl) carbamoyl) -4-methylbenzoic acid (70 mg, 0.26 mmol), DCM (1 ml) and DMF (1 ml). Then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride was added (74 mg, 0.39 mmol). The reaction mixture was stirred for 10 min before introducing (aminomethyl) cyclopropane. (27 p1, 0.31 mmol). The reaction mixture was stirred at RT under N2 for 16 h. The reaction was shared between DCM

(15 ml) and brine (10 ml). The aqueous phase was extracted again with DCM (3 x 10 ml) and the combined phase was dried

35 with DCM (Na2SO4) and concentrated. The crude product was dissolved in DCM and purified by chromatography to through a column of previously filled Redi-Sepe silica gel (40 g), eluting with a gradient of Me0H from 0% to 10% in CH2Cl2, to provide N3- (6-aminopyridin-34) -N1- (cyclopropylmethyl) -4-methylisophthalamide

as an off-white solid, m / z: 325.2 (M + 1).

Examples 147 and 148, materials as main elements for the compounds of formula 1, were prepared 40 according to bibliographic references provided below.

Example 147

NI-12

US patent application publication. (2005), 43 pp. CODE: USXXCO US 2005256125 To 20051117 CAN 143: 460185 AN 2005: 1224270

Example148

Synthesis 2005, 15, 2503-2506.

Each of the following examples 149-221 of formula 1 were obtained using a procedure analogous to described in examples 1, 2, 88, 96, 114, 127, 136-1400 144-146. The compounds of examples No. 155 to 158, 10 162, 164a 166, 169, 170, 172, 173, 175, 178 to 216, 218 and 219 are reference compounds.

Ex.n.� M + H Compound Name 149 421, 1 2-Chloro-N-5-pyrimidini 1-5 - (((3- (triluforomethyl) phenyl) carbonyl) amino) benzamide 150 452.2 2-Chloro-5 - (((4- (4-morpholinylmethyl) phenyl) carbonyl) amino) -N-5-pyrimidinylbenzamide 151 381, 1 2-chloro-5 - (((4-ethylphenyl) carbonyl) amino) -N-5-pyrimidinylbenzamide 152 2-Chloro-5 - ((3-cyclopentylpropanoyl) amino) -N-5-pyrimidinylbenzamide 153 5- (acetylamino) -2-chloro-N-5-pyrimidinylbenzamide 154 2-Chloro-N-5-pyrimidini 1-54 (3- (1-pyrrolidinyl) propanoyl) amino) benzamide 155 400.1 4-methyl-N-3--3-pyridinyl-N-1 - (3- (trifluoromethyl) feni1) -1, 3-benzenedicarboxamide 156 434 N-3 - (6-chloro-3-pyridini1) -4-methyl-N-1 - (3- (trifluoromethyl) feni1) -1, 3-benzenedicarboxamide 157 418 N-1 - (2-fluoro-5- (trilfuoromethyl) feni1) -4-methyl-N-3--3-pyridini1-1, 3-benzenedicarboxamide 158 433 N-3 - (6-amino-3-pyridini1) -N-1 - (2-fluoro-5- (trilfuoromethyl) feni1) -4-methyl-1, 3

benzenedicarboxamide

159 401, 1 4-methyl-N-3--5-pyrimidinyl-N-1 - (3- (trilfuoromethyl) feniI) -1, 3-benzenedicarboxamide 160 401, 1 4-methyl-N-3--2-pyrimidinyl-N-1 - (3- (trilfuoromethyl) feni1) -1, 3-benzenedicarboxamide 161 401, 1 4-methyl-N-3--2-pyrazinyl-N-1 - (3- (trifluoromethyl) feni1) -1, 3-benzenedicarboxamide 162 415.1 N-3 - (6-amino-3-pyridini1) -4-methyl-N-1 - (3- (trifluorometipfeni1) -1, 3-benzenedicarboxamide 163 416.1 N-3 - (2-amino-5-pyrimidini1) -4-methyl-N-1 - (3- (trifluoromethyl) feni1) -1, 3

benzenedicarboxamide 164 401, 1 4-methyl-N-3--4-pyridazinyl-N-1 - (3- (trifluoromethyl) feniI) -1, 3-benzenedicarboxamide 165 418.1 N-3 - (3,5-dimethyl-4-isoxazoli1) -4-methyl-N-1 - (3- (triluforomethyl) feni1) -1, 3

benzenedicarboxamide 166 457.1 N-3 - (6- (acetylamino) -3-pyridini1) -4-methyl-N-1 - (3- (trifluoromethyl) feni1) -1, 3-benzenedicarboxyamide 167 458.2 N-3 - (2- (aceti l amino) -5-pyrimidini 1) -4-meti l -N-1 - (3- (trifluorometiVeni 1) -1, 3

benzenedicarboxamide 168 353.2 N-1-42-cyclopentylethyl) -4-methyl-N-3--5-pyrimidini1-1, 3-benzenedicarboxamide 169 367.2 N-3 - (6-amino-3-pyridini1) -N-1 - (2-cyclopentylethyl) -4-methyl-1, 3-benzenedicarboxyamide 170 415.1 N (6-amno-pyridini1) -4-methyl-N1 - (trfi i 1, 3-i

-3 - i 3 - (4-iluorometpfen1) -benzenedicarboxamda 171 401, 1 4-methyl-N-3--5-pyrimidinyl-N-1 - (4- (trifl i) -i i

luorometi) fen1 1,3-benzenecarboxamda 172 445.1 N-3 - (6-amino-3-pyridini1) -4-methyl-N-1 - (4- (methyloxy) -3- (trifluoromethyl) feni1) -1, 3

benzenedicarboxamide 173 409.2 N-3 - (6- (acetylamino) -3-pyridini1) -N-1 - (2-cyclopentylethyl) -4-methyl-1, 3-benzenedicarboxamide 174 431, 1 4-methyl-N-1 - (4- (methyloxy) -3- (trifluoromethyl) feni1) -N-3--5-pyrimidini1-1, 3

benzenedicarboxamide

175 395.2 N-1 - (2-cyclopentylethyl) -N-3 - (6- (ethylamino) -3-pyridini1) -4-methyl-1, 3-benzenedicarboxamide 176 368.2 N-3 - (2-amino-5-pyrimidini1) -N-1 - (2-cyclopentylethyl) -4-methyl-1, 3-benzenedicarboxyamide 177 410.2 N-3 - (2- (acetylamino) -5-pyrimidinip-N-1 - (2-cyclopentylethyl) -4-methyl-1, 3

benzenedicarboxamide 178 381, 2 N-3 - (6-amino-5-methyl-3-pyridini1) -N-1 - (2-cyclopentylethyl) -4-methyl-1, 3-benzenedicarboxyamide

179 382.2 N-1 - (2-cyclopentylethyl) -4-methyl-N-3 - (6- (methyloxy) -3-pyridini1) -1, 3-benzenedicarboxamide 180 391, 3 N-1 - (2-cyclopentylethyl) -4-methyl-N-3--1H-pyrrolo [2,3-b] pyridin-54-1, 3-benzenedicarboxamide 181 420.2 N-1 - (2-cyclopentylethyl) -4-methyl-N-3 - (6- (triluforomethyl) -3-pyridini1) -1, 3

benzenedicarboxamide

1 82

381, 3 N-3- (6ami no-3pi ri di ni I) -N-1 - (2-ci cl ohexi l eti l) -4meti l -1, 3bencenodi carboxami da

1 83

451, 3 N-1 - (2-ci cl openti l eti l) -N-3- (6 ((2, 2-di meti l propanoi l) ami no) -3pi ri di ni 1) -4meti l -1, 3

bencenodi carboxami da

1 84

435, 2 N-1 - (2-ci cl openti l eti l) -N-3- (6 ((ci cl opropi l carboni l) ami no) -3pi ri di ni l) -4meti l -1, 3

bencenodi carboxami da

1 85

449, 2 N-1 - (2-ci cl openti l eti l) -4meti l-N-3- (6 ((3meti l -2-butenoi l) ami no) -3pi ri di ni 1) -1, 3

bencenodi carboxami da

1 86

393, 3 N-1 - (2-ci cl openti l eti l) -N-3- (2, 3di hi dro1 H-pi rrol o [2, 3-b] pi ridi n-51 1) -4meti l -1, 3

bencenodi carboxami da

1 87

424, 2 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 (((mei l ami no) carboni l) ami no) -3pi ri di ni 1) 1, 3

bencenodi carboxami da

1 88

368, 3 N-3- (6-ami no3pi ri di ni I) -4meti l -N-1 - (2 (1 -pi rrol i di ni l) eti l) 1, 3bencenodi carboxami da

1 89

449, 3 N-3- (6 (ci cl ohexi l ami no) -3pi ri di ni I) -N-1 - (2-ci cl openti l eti l) -4meti l -1, 3

bencenodi carboxami da

1 90

402, 2 N-1 - (2-ci cl openti l eti l) -4meti l -N-3-3-qui nol i ni 1 -1, 3bencenodi carboxami da

1 91

395, 2 N-1 - (2-ci cl openti l eti l) -N-3- (6 (di meti l ami no) -3pi ri di ni 1) -4meti l1, 3

bencenodi carboxami da

1 92

381, 2 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 (methyl ami no) -3pi ri di ni 1) -1, 3bencenodi carboxami da

1 93

463, 2 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 ((tri fluoroaceti l) ami no) -3pi ri di ni 1) -1, 3

bencenodi carboxami da

1 94

451, 3 N-1 - (2ci cl openti l eti l) -4meti l -N-3- (64 (3meti l butanoi l) ami no) -3pi ri di ni 1) -1, 3

bencenodi carboxami da

1 95

461, 2 N-1 - (2-ci cl openti l eti l) -N-3- (6 ((2-furani l carboni pami no) -3-pi ri di ni 1) -4meti l -1, 3

bencenodi carboxami da

1 96

407, 3 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (2-oxo-2, 3di hi dro1 H-pi rrol o [2, 3b] pi ri di n-51 1) 1, 3

bencenodi carboxami da

1 97

421, 3 N-1 - (2-ci cl openti l eti l) -N-3- (6 ((ci cl opropi l meti l) ami no) -3pi ri di ni 1) -4-meti l1, 3

bencenodi carboxami da

1 98

370, 2 N-1 - (2-ci cl openti l eti l) -N-3- (6-fluoro-3pi ri di ni 1) -4meti l -1, 3bencenodi carboxami da

1 99

452, 3 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 (W1 -meti l eti l) ami no) carboni l) ami no) -3pi ri di ni I) -1 , 3

bencenodi carboxami da

200

471, 2 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 ((feni l carboni l) ami no) -3pi ridi ni 1) -1, 3

bencenodi carboxami da

201

477, 2 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 ((2-ti eni l carboni l) ami no) -3pi ri di ni 1) -1, 3

bencenodi carboxami da

202

449, 2 N-3- (6 ((ci cl obuti l carboni pami no) -3pi ri di ni 1) -N-1 - (2-ci cl openti l eti l) -4meti l -1, 3

bencenodi carboxami da

203

501, 2 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 (((3 (methyloxy) feni l) carboni l) ami no) -3pi ri di ni 1) - 1, 3

bencenodi carboxami da

204

366, 3 N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6meti l -3pi ri di ni 1) -1, 3bencenodi carboxami da

205

463, 3 N-3- (6 ((ci cl openti l carboni l) ami no) -3pi ri di ni I) -N-1 - (2-cycle openti l eti l) -4meti l -1, 3

bencenodi carboxami da

206

461, 2 N-1 - (2-ci cl openti l eti l) -N-3- (64 (1 H-i mi dazol -4i lcarboni l) ami no) -3pi ri di ni l) -4meti l1, 3

bencenodi carboxami da

207

464, 2 N-1 - (2-ci cl openti l eti l) -4meti l-N-3- (6 (D-prol i l ami no) -3pi ri di ni 1) -1, 3

bencenodi carboxami da

208

355, 2 N-3- (6-ami no-3pi ri di ni I) -4meti l -N-1 - (tetrahi dro-2-furani l meti l) -1, 3

bencenodi carboxami da

209

396, 2 N-3- (6ami no-3pi ri di ni I) -4meti l -N-1 - (3 (2-oxo1 -pi rrol idi ni l) propi l) 1, 3

bencenodi carboxami da

21 0

325, 2 N-3- (6ami no-3pi ri di ni I) -N-1 - (ci cl opropi l meti l) -4meti l1, 3bencenodi carboxami da

21 1

371, 3 N-3- (6ami no3pi ri di ni I) -4meti l -N-1 - (3 ((1 -meti l eti l) oxy) propi l) -1, 3

bencenodi carboxami da

21 2

N-1 - (2-ci cl openti l eti l) -4meti l -N-3- (6 ((((1 R, 2R) -2-feni l ci cl opropi l) carboni l) ami no) - 3

pi ri di ni 1) -1, 3-benzenedi carboxy

21 3

379, 3 N-3- (6ami no3pi ri di ni p-N-1 - (2- (1 -ci cl ohexen1 -1 1) eti l) -4meti l1, 3

bencenodi carboxami da

21 4

381, 2 N-3- (6-ami no3pi ri di ni 1) -4meti l-N-1 - (2 (2-ti eni l) eti l) -1, 3bencenodi carboxami da

21 5

355, 2 N-3- (6-ami no3pi ri di ni I) -N-1 - (3, 3-di methi butyl) -4-methi -1, 3-benzenedi carboxy

21 6

401, 2 N-3- (6-ami no-3pi ri di ni I) -N-1 - (2, 3-di hi dro1 H-i nden-2-i l meti l) -4-meti l1, 3

bencenodi carboxami da

21 7

421 4-cl gold-N-3--5pi ri mi di ni l -N-1 - (3 (trifluorometi l) feni I) -1, 3bencenodi carboxami da

21 8

387, 2 N-3- (6ami no-3pi ri di ni 1) -4-cl gold-N-1 - (2-cycle openti l eti l) -1, 3bencenodi carboxami da

219 469.2 4-Chloro-N-1 - (2-cyclopentylethyl) -N-3 - (6 - ((3-methyl-2-butenoyl) amino) -3-pyridini1) -1,3-benzenedicarboxyamide

The following compounds in Tables 1 and 2 are additional representative examples of the compounds of

formula 1, as provided by the present invention. Table 1

(Compound reference)

Ex. n. �

R ' L R4 RJ

220

ci cl ohexi l-HN- (CH2) 2pi ri di n- -NHCO- Meti l o aceti l i ndol i na

21 1 -

221

pi peri di n- (CH2) 2pi ri di mi di ni l - -NHCO cl gold say met l i ndol i na

222

NH2pi ri di n-3i l - -CONH- Meti l o pi ri mi di na

223

pi ri mi di n-51 1 - -CONH- Methyl or chlorine 2CH3-feni l o

224

NH2pi ri mi di n-5i l - -CONH- Meti l o o cl gold 4-CF3-feni l o

225

1 -pi peri di ni l -N-pi ri di n-31 1 - -CONH- Meti l o o cl gold 3-CF3-feni l o

226

ci cl ohexi l-N-pi ri di n-31 1 - -NHCO- Meti l o o cl gold 6-CH3-feni l o

227

morphol i n (CH2) 2-N-pi ri di n3-1 1 - -NHCONH- Meti l o o cl gold 20CH3-feni lo

228

(CH3) 2N- (CH2) 2-N-pi ri di n-3i l -NHCONH- Meti l o o cl gold 40CH3-feni lo

229

(C2H5) 2N- (CH2) 2pi ri mi di n-5 -NHCO- Meti l o o cl gold pi ri di na

1230 3-0H-pyrimidin-5-yl-NHCO-Methylchloro indole 231 3-amido-pyridinyl -CONH-Methylochloro indoline 232 4-amido-2-pyridinyl -CONH-Methylchlorobenzofuran 233 3-amido-5-pyrimidinyl -CONH-Methylchloro-2-F-phenyl 234 4-CH3-pyridazinyl -CONH-Methylchloro 4-F-phenyl 235 NH2-pyrazinyl -NHCO-Methylchloro dihydrobenzofuran 236 NH2-quinazolinyl -NHCONH-Methylochlorocyclohexyl- (CH2) 2237 CH3-isoquinazolinyl -NHCONH-Methylchlorocyclopropyl- (CH2) 2238 cyclohexyl-HN- (CH2) 2-pyridin - NHCO-Methylchloro-2-CH3-phenyl

2-1 1239 piperidin- (CH2) 2-pyrimidinyl - NHCO-Methyl chloro 4-CF3-phenyl 240 NH2-pyridin-3-yl - CONH-Methyl chloro 3-CF3-phenyl 241 pyrimidin-5-yl -CONH-Methylchloro 6-CH3-phenyl 242 NH2-pyrimidin-5-yl - CONH-Methyl chloro 2-0CH3-phenyl

243 1-piperidinyl-N-pyridin-3-11 - CONH-Methylchloro 4-0CH3-phenyl 244 cyclohexy l-N-pyridin-3-1 1 - NHCO-Mel loocloro pyridine 245 morpholin- (CH2) 2-N-pyridin-3-11 - NHCONH-Methylchloro indole 246 (CH3) 2N- (CH2) 2-N-pyridin-3-yl - NHCO-Methylochloro indoline

247 (C2H5) 2N- (CH2) 2-pyrimidin-5 - NHCO-Methylchlorobenzofuran

l248 3-0H-pyrimidin-5-yl -CONH-Methylchloro-2-F-phenyl 249 3-amido-pyridinyl -CONH-Methyl or chloro 4-F-phenyl

250 4-amido-2-pyridinyl -CONH-Methylchloro dihydrobenzofuran 251 3-amido-5-pyrimidini lo -CONH-Meti loocloro 2-CH3-feni lo 251 4-CH3-pyridazinyl -NHCO-Methylchloro 4-CF3-phenyl 253 cyclohexyl-HN- (CH2) 2-pyridine - NHCONH-Methylchloro-3-CF3-phenyl

2-1 1254 piperidin- (CH2) 2-pyrimidinyl - NHCONH-Methylchloro 6-CH3-phenyl 255 NH2-pyridin-3-yl - NHCO-Methylchloro 2-0CH3-phenyl 256 pyrimidin-5-yl-NHCO-Methyl chloro 4-0CH3-phenyl 257 NH2-pyrimidin-5-yl - CONH-Methylchloro pyridine 258 1-piperidinyl-N-pyridin-3-11 - CONH-Methylchloro indole 259 cyclohexyl-N-pyridin-3-11 - CONH-Methylchlorochlorine 260 morpholin- (CH2) 2-N-pyridin-3-yl - CONH-Methylchlorobenzofuran

261

(CH3) 2N- (CH2) 2-N-pi ri di n3i l - -NHCO- Methyl or chlorine 2-F-feni l o

262

(C2H5) 2N- (CH2) 2pi ri mi di n-5 -NHCONH- Methyl or chlorine 4F-feni l o

i l -

263

30H-pi ri mi di n-5i l o -NHCONH- Methyl or chlorine say hi drobenzofuran

264

3ami dopi ri di ni l o -NHCO- Methyl or chlorine ci cl ohexi l (CH2) 2

265

4ami do-2-pi ri di ni l o -NHCO- Methyl or chlorine ci cl opropi l (CH2) 2

266

3ami do-5pi ri mi di ni l o -CONH- Methyl or chlorine 2CH3-feni l o

267

4-CH3pi ri dazi ni l o -CONH- Meti l o o dor� 4CF3-feni l o

268

ci cl ohexi l -HN- (CH2) 2pi ri di n- -CONH- Methyl or chlorine 3CF3-feni l o

2-i l -

269

pi peri di n- (CH2) 2pi ri mi di ni l - -CONH- Methyl or chlorine 6CH3-feni l o

270

NH2pi ri di n3i l - -NHCO- Methyl or chlorine 2-0CH3-feni l o

271

pi ri mi di n-5i l o -NHCONH- Methyl or chlorine 40CH3-feni l o

272

NH2pi ri mi di n-5h l - -NHCONH- Meti l o o cl gold pi ri di na

273

1 -pi peri di ni l -N-pi ri di n-3i l - -NHCO- Methyl or chlorine i ndol

274

ci cl ohexi l-N-pi ri di n-3i l - -NHCO- Methyl or chlorine i ndol i na

275

morphol i n (CH2) 2-N-pi ri di n-3i l - -CONH- Meti l o o cl gold benzofuran

276

(CH3) 2N- (CH2) 2-N-pi ri di n-3i l - -CONH- Meti l o o cl gold 2-F-feni l o

277

(C2H5) 2N- (CH2) 2pi ri mi di n-5 -CONH- Meti l o o cl gold 4F-feni l o

i l -

278

30H-pi ri mi di n-5i l o -CONH- Meti l o o cl gold say hi drobenzofuran

279

3pi ri di ni l -ami do-pi ri di n-3i l o -NHCO- Meti l o o cl gold ci cl ohexi l (CH2) 2

280

N-feni l -ami do3pi ri di ni l o -NHCONH- Meti l o o cl gold ci cl opropi l (CH2) 2

281

3ami do5-pi ri mi di ni l o -NHCONH- Meti l o o cl gold 2-you offense

282

4-CH3pi ri dazi ni l o -NHCO- Meti l o o cl gold 3-you offense

283

ci cl ohexi l -HN- (CH2) 2pi ndi n- -NHCO- Meti l o o cl gold 2-pi ri di na

2-i l -

284

pi peri di n- (CH2) 2pi ri mi di ni l - -CONH- Meti l o o cl gold 1 -ofofol i ni l o

285

NH2pi ri di n-3i l - -CONH- Methyl or chlorine 1 -pi perazi ni l o

286

pi ri mi di n-5i l o -CONH- Methyl or chlorine 1 -pi eri di ni l o

Table 2

R ,.

The compounds in which

A5 is CH are examples of

refer

Ex. n. �

Rl a TO 5 L R3

287

ci cl ohexi l -HN- (CH2) 2pi ri di n-2-i l - N -NHCO- 2CH3-feni l o

288

pi peri di n- (CH2) 2pi ri mi di ni l - N -NHCO 4CF3-feni l o

289

NH2pi ri di n-3i l - N -CONH- 3CF3-feni l o

290

pi ri mi di n-5i l o N -CONH- 6CH3-feni l o

291

NH2pi ri mi di n5i l - CH -CONH- 20CH3-feni l o

292

1 -pi peri di ni l -N-pi ri di n-3i l - CH -CONH- 40CH3-feni l o

293

ci cl ohexi l -N-pi ri di n-3i l - CH -NHCO pi ri di na

294

morfol i n- (CH2) 2-N-pi ri di n-3i l - CH -NHCONH- i ndol

295

(CH3) 2N- (CH2) 2-N-pi ri di n-3i l- CH -NHCONH- i ndol i na

296

(C2H5) 2N- (CH2) 2pi ri mi di n-5i l- CH -NHCO- benzofuran

297

30H-pi ri mi di n-5i l o CH -NHCO- 2-F-feni l o

298

3ami dopi ri di ni l o CH -CONH- 4F-feni l o

299

4ami do-2-pi ri di ni l o N -CONH- di hydrobenzofuran

300

3-ami do-5pi ri mi di ni l o N -CONH- ci cl ohexi l - (CH2) 2

301

4-CH3pi ri dazi ni l o N -CONH- ci cl opropi l - (CH2) 2

302

NH2pi razi ni l o N -NHCO 2CH3-feni l o

303

NH2qui nazol i ni l o N -NHCONH- 4CF3-feni l o

304

CH3i soqui nazol i ni l o CH -NHCONH- 3-CF3-feni l o

305

ci cl ohexi l-HN- (CH2) 2pi ri di n-2h l- CH -NHCO- 6CH3-feni l o

68

306

pi peri di n- (CH2) 2pi ri mi di ni l - CH -NHCO 2-0CH3-feni l o

307

NH2pi ri di n-3i l - CH -CONH- 40CH3-feni l o

308

pi ri mi di n-5i l o CH -CONH- pi ri di na

309

NH2pi ri mi di n5i l - CH -CONH- i ndol

31 0

1 -pi peri di ni l -N-pi ri di n-3i l - CH -CONH- i ndol i na

31 1

ci cl ohexi l -N-pi ri di n-3i l - CH -NHCO- benzofuran

31 2

morfol i n- (CH2) 2-N-pi ri di n-3-i l - N -NHCONH- 2F-feni l o

31 3

(CH3) 2N- (CH2) 2-N-pi ri di n-3i l - N -NHCO- 4F-feni l o

31 4

(C2H5) 2N- (CH2) 2pi ri mi di n-5i l- N -NHCO say hi drobenzofuran

31 5

30H-pi ri mi di n-5i l o N -CONH- 2-CH3-feni l o

31 6

3-ami dopi ri di ni l o N -CONH- 4CF3-feni l o

31 7

4ami do-2-pi ridi ni l o N -CONH- 3CF3-feni l o

31 8

3ami do-5pi ri mi di ni l o N -CONH- 6CH3-feni l o

31 9

4-CH3pi ri dazi ni l o N -NHCO 20CH3-feni lo

320

ci cl ohexi l -HN- (CH2) 2pi ri di n-2i l - N -NHCONH- 40CH3-feni lo

321

pi peri di n- (CH2) 2pi ri mi di ni l - N -NHCONH- pi ri di na

322

NH2pi ri di n-3i l- N -NHCO i ndol

323

pi ri mi di n-5i l o N -NHCO i ndol i na

324

NH2pi ri mi di n-5i l - CH -CONH- benzofuran

325

1 -pi peri di ni l -N-pi ridi n-3-i l - CH -CONH- 2-F-feni l o

326

ci cl ohexi l-N-pi ri di n-3i l- CH -CONH- 4-F-feni l o

327

morfol i n (CH2) 2-N-pi ri di n3-i l - CH -CONH- say hi drobenzofuran

328

(CH3) 2N- (CH2) 2-N-pi ri di n-3i l- CH -NHCO- ci cl ohexi l - (CH2) 2

329

(C2H5) 2N- (CH2) 2pi ri mi di n-5i l - CH -NHCONH- ci cl opropi l (CH2) 2

330

30H-pi ri mi di n5i l o CH -NHCONH- 2-CH3-feni l o

331

3-ami dopi ri di ni l o CH -NHCO 4CF3-feni l o

332

4-ami do-2-pi ri di ni l o CH -NHCO 3CF3-feni l o

333

3-ami do-5-pi ri mi di ni l o CH -CONH- 6CH3-feni l o

334

4-CH3pi ri dazi ni l o CH -CONH- 2-0CH3-feni lo

335

ci cl ohexi l-HN- (CH2) 2pi ri di n-2i l - CH -CONH- 4-0CH3-feni l o

336

pi peri di n- (CH2) 2pi ri mi di ni l - N -CONH- pi ri di na

337

NH2pi ri di n-3i l - N -NHCO i ndol

338

pi ri mi di n-5i l o N -NHCONH- i ndol i na

339

NH2pi ri mi di n-5i l- N -NHSO2NH- benzofuran

340

1 -pi peri di ni l -N-pi ri di n-3i l - N -NHCO 2-F-feni l o

341

ci cl ohexi l -N-pi ri di n-3i l - N -NHCO 4F-feni l o

342

morfol i n- (CH2) 2-N-pi ri di n-3i l - N -CONH- say hi drobenzofuran

343

(CH3) 2N- (CH2) 2-N-pi ri di n-3i l - N -CONH- ci cl ohexi l (CH2) 2

344

(C2H5) 2N- (CH2) 2pi ri mi di n-5i l - N -CONH- ci cl opropi l (CH2) 2

3. 4. 5

30H-pi ri mi di n-5i l o N -SO2NH- 2-you offense

346

3pi ri di ni l -ami dopi ri di n-3i l o N -NHS02 3-you offense

347

N-feni l -ami do3pi ri di ni l o N -NHCONH- 2-pi ri di na

348

3ami do-5pi ri mi di ni l o N -NHCONH- 1 -ofofol i ni l o

349

4-CH3pi ri dazi ni l o CH -NHCO- 1 -pi perazi ni l o

350

ci cl ohexi l -HN- (CH2) 2pi ri di n-2i l - N -NHS02 1 -pi peri di ni l o

The following compounds are additional representative examples of the compounds of the present invention:

All the procedural steps described herein can be carried out under conditions of known reactions, preferably those specifically mentioned, in the absence of or usually in presence of solvents or diluents, preferably such as those that are inert for the reagents used and 5 can dissolve them, in the absence or presence of catalysts, condensing agents or neutralization, for example single exchangers, normally cation exchangers, for example in H + form, depending on the type of reaction and / or reactant at reduced, normal or elevated temperature, for example in the range from about -100�C to about 190�C, preferably from about -80�C to about 150�C, for example at about -80 to

10 at about 60 ° C, at RT, at about -20 to about 40 ° C or at the boiling point of the solvent used, at atmospheric pressure or in a closed container, when appropriate under pressure and / or in a inert atmosphere, for example, under argon or nitrogen.

Salts may be present in all starting and transient compounds, if they contain formation groups of Salt. Salts may also be present during the reaction of such compounds, provided that the reaction is not 15 alter this way.

In certain cases, normally in hydrogenation procedures, it is possible to achieve reactions Stereoselective, allowing for easier recovery of individual isomers.

Solvents from which those suitable for the reaction in question can be selected include, by for example, water, esters, usually lower alkyl lower alkanoates, for example Et0Ac, ethers,  normally aliphatic ethers, for example Et20 or cyclic ethers, for example THF, aromatic hydrocarbons liquids, usually benzene or toluene, alcohols, usually Me0H, Et0H, IPA or 1-propanol, nitriles, Normally AcCN, halogenated hydrocarbons, normally CH2Cl2, acid amides, usually DMF, bases, normally heterocyclic nitrogen bases, for example pyridine, carboxylic acids, normally acids lower alkanocarboxylic acids, for example HOAc, carboxylic acid anhydrides, normally anhydrides of

 lower alkano acid, for example acetic anhydride, cyclic, linear or branched hydrocarbons, normally cyclohexane, hexane or isopentane or mixtures of these solvents, for example aqueous solutions, unless otherwise indicated in the description of the procedure.

The compounds of formula I, including their salts, can also be obtained in the form of hydrates, or their crystals they can include for example the solvent used for crystallization (present as solvates).

 The starting materials of the invention are known, commercially available or can be synthesized in analogy with or according to methods that are known in the art.

In the preparation of starting materials, existing functional groups should be protected, if necessary who do not participate in the reaction. Preferred protecting groups, their introduction and removal were described. above or in the examples.

 All remaining starting materials are known, can be prepared according to known procedures or they can be obtained commercially, in particular, they can be prepared using procedures as described In the examples.

The above examples serve to illustrate various embodiments of the invention. The tables also contain the method by which these examples were prepared, with respect to the various schemes and examples presented

 previously. The schematic illustrations, the detailed description of the methods and the preparation of the compounds of formula I and the compounds described above are within the scope and serve to exemplify the scope of the compounds contemplated in the invention. These detailed method descriptions They are presented cynically for illustrative purposes.

BIOLOGICAL TESTS

 The following tests can be used to determine the degree of activity of a compound as an inhibitor of protein kinase. The compounds described herein have been tested in one or more of these trials and have shown activity. Compounds representative of the invention were tested and

found that they showed IC50 values of at least lt; 101.1M in any of the described trials, demonstrating and thereby confirming the usefulness of the compounds of the invention as protein kinase inhibitors and in  prophylaxis and treatment of autoimmune diseases, hyperproliferative disorders, etc.

Time-resolved homogeneous fluorescence kinase assay (HTRF) for LCK:

The HTRF assay for LCK begins with LCK in the presence of ATP that phosphorylates the biotinylated gastrin peptide. The reaction is incubated for 90 min. To extinguish the assay, detection reagents are added that stop the reaction both by diluting the enzyme and chelating the metals due to the presence of EDTA. Once they have

 added detection reagents, the assay is incubated for 30 min to allow reagent equilibration of detection.

The HTRF assay for LCK comprises 10 pi of compound in 100% DMSO, 15 JAI of ATP and biotinylated gastrin and 15 AI of LCK KD GST (225-509) for a final volume of 40 jil. The final gastrin concentration is 1.2 pl.M. The Final ATP concentration is 0.5 1AM (Km app = 0.6 OA + 1-0.1) and the final LCK concentration is 250 pM. The

 Buffer conditions are as follows: 50 mM HEPES pH 7.5, 50 mM NaCl, 20 mM MgCl, 5 mM MnCI, DTT 2 mM, 0.05% BSA.

The test is extinguished and stopped with 160 1.11 detection reagent. The detection reagents are as follows: Buffer composed of 50 mM Iris, pH 7.5, 100 mM NaCl, 3 mM EDTA, 0.05% BSA, 0.1% Tween 20. Prior to the reading is added to this streptavidin-allophycocyanin buffer (SA-APC) at a conc. final in the essay of  0.0004 mg / ml and Europium-labeled anti-phosphotyrosine Ac (Eu-anti-PY) at one conc. 0.025 nM final.

The test plate is read in a reader either Discovery or RubyStar. Eu-anti-PY is excited at 320 nm and emits at

615 nm to excite SA-APC which in turn emits at 655 nm. The SA-APC ratio at 655 nm (excited due to the close proximity with Eu-anti-PY by phosphorylation of the peptide) with respect to free EU-anti-PY at 615 nm will give phosphorylation of the substrate.

Assays for other kinase are performed in a similar manner as described above, varying the Enzyme, peptide substrate and ATP concentrations added to the reaction, depending on the specific activity of the kinase and Km measured for the substrates.

Of the compounds that were tested, the compounds by way of example 1, 2, 11-20, 22-72, 74-86, 88,

 90-94, 96, 98-101, 103-136 and 140-143 showed an average IC50 value of 10 uM or less in a trial of HTRF in humans, for the inhibition of the enzyme kinase Lek. Most of the compounds by way of example tested showed an average C150 value of 1 uM or less in the HTRF test for the Lck kinase in humans.

Human mixed lymphocyte reaction (huMLR):

 The purpose of this test is to test the potency of cell activation inhibitors. Have an in vitro model. of stimulation of allogenic T cells. Human peripheral blood lymphocytes are incubated (hPBL; 2x105 / well) with lymphoblast B cells treated with mitomycin C (JY cell line; 1x105 / well) as stimulators allogens in the presence or absence of dilutions of potential inhibitor compound in tissue culture sites of 96-well round bottom. These cultures are incubated at 37�C in 5% CO2 for a total of 6 dies. The

 proliferative response of hPBL by incorporating 31-1-thymidine overnight between days 5 and 6 after start of cultivation The cells are collected on glass fiber filters and the incorporation of 3H-thymidine is analyzed in DNA by liquid scintillation counter.

Jurkat proliferation / survival test.

The purpose of this test is to test the general antiproliferative / cytotoxic effect of the compounds in the line

 Jurkat human T cells. Jurkat cells (1x105 / well) are planted in place of tissue culture of 96-well piano bottom with or without compound dilutions and grown for 72 h at 37 ° C in 5% CO2. Be determine the number of viable cells during the last 4 h of culture by adding 10 1.11 / well of WST dye

1. The conversion of the WST-1 dye is based on active mitochondrial electron transport for the reduction of tetrazolium dye. The dye conversion is read by OD at 450-600 nm.

 Assay of proffered & secretion of IL-2 by T cells induced by anti-CD3 / CD28 antibody:

The purpose of this test is to test the potency of inhibitors of the CD28 signaling pathway and the T cell receptor (TCR; CD3) in human T cells. T cells are purified from blood lymphocytes Human peripheral (hPBL) and pre-incubated with or without compound before stimulation with a combination of an anti-CD3 and anti-CD28 antibody in 96-well cell culture sites (1x105 T cells / well). They are cultivated

 the cells for —20 h at 37�C in 5% CO2, then the IL-2 secreted in the supernatants is quantified by ELISA for cytokines (Pierce / Endogen). The remaining cells in the wells are then pulsed with 3Htimidine overnight to evaluate the proliferative response of the T cells. The cells are collected on filters. of fiberglass and the incorporation of 31-1-thymidine in the DNA is analyzed by liquid scintillation counter. For For comparison purposes, forbolmiristatic acid (PMA) and calcium ionophore can be used in combined & to induce

 secretion of IL-2 from purified T cells. Potential inhibitor compounds may be tested to determine the inhibition of this response as described above for anti-CD3 antibodies and anti-CD28.

Time-resolved homogenous fluorescence kinase assay (HTRF) for cKIT:

The purpose of this test is to measure the inhibition of the enzymatic activity of cKIT (autophosphorylation and phosphorylation of

 substrate) using small molecule test compounds. The HTRF test for cKIT begins with the cKIT catalyzed phosphorylation of the biotinylated peptide Her-2 (N-GGMEDIYFEFMGGKKK-C) in the presence of ATP. The cKIT enzymatic reaction comprises 1 [LI of compound in 100% DMSO, 15 g of 2X substrate mixture

(ATP 50 1AM TP and biotinylated Her-2 2 1.1M) and 15 III of 2X cKIT (6.25 12M) (catalytic domain, labeled with GST Nterminal, not phosphorylated) in 4 mM DTT all diluted in enzyme buffer (HEPES 25 mM pH 7-5, 12.5 mM NaCl,

 50 mM MgCI, 0.05% BSA). The reaction is incubated for 90 min at room temperature. Then they add One hundred seventy microliters of detection mixture containing streptavidin-allophycocyanin 0.47 prg / m1 and Ac 29.7 pM labeled antiphosphotyrosine with Europium (PT66, Perkin Elmer) in HTRF buffer (100 mM Hepes pH 7.5, NaCI

100 mM, 0.1% BSA, 0.05% Tween 20) to stop the reaction by diluting the enzyme also to allow quantification of phosphorylated Her-2. After 3 h at room temperature, the detection reaction is read in a reader

 places Packard DiscoveryTM (BD1000 model). The wells are excited with a coherent light at 320 nM and the razor, of delayed emissions (50 ms after excitation) at 620 nM (native europium fluorescence) and 665 nm (Europium fluorescence transferred to allophycocyanin - an index of substrate phosphorylation). The

provide phosphorylated substrate in the kinase reaction in the presence of compound compared to the phosphorylated substrate in the presence of DMSO vehicle alone (HI control) using the formula:% control (POC) =

 (comp. - LO average) / (HI average - LO average) * 100. The data (consisting of inhibitor concentration and POC in piN / 1) conform to an equation of 4 parameters (y = A + ((B-A) / (1 + ((x / C) AD))), where A is the value minimum y (POC), B is the maxim� and (POC), C is x (comp. concentration) at the inflection point and D is the factor

of slope) using a non-linear regression algorithm of Levenburg-Marquardt.

Of the compounds tested, the compounds by way of example 1, 2, 11-40, 22-40, 42-46, 48-63, 69-72, 74-76, 81-86, 88, 90, 96, 98-100, 102-105, 109, 110, 112, 113, 120-130, 134-138, 141, 144-146, 149-152, 154- 159, 161-164, 166-174, 176-180, 182, 184-190, 192-204, 206 and 217-219 showed an average IC50 value of 10 uM or less in an HTRF assay in humans, for the inhibition of the enzyme kinase c-kit. Most of the

 Exemplary compounds tested above showed an average IC50 value of 1 µM or less in the HTRF assay for c-kit kinase in humans.

Electrochemiluminescent immunoassay of phosphorylated c-kit (Tyr721) in M07e:

The purpose of this test is to test the potency of biological and small molecule compounds over the phosphorylation of the c-kit receptor stimulated by tyrosine SCF 721 (Tyr721) in M07e cells. The activation of  c-kit after binding with its ligand, the stem cell factor (SCF), leads to dimerization / oligomerization and autophosphorylation.

The activation of c-kit results in the recruitment and tyrosine phosphorylation of components of signaling containing subsequent SH2, such as the p85 subunit of the PI3 kinase (Sattler, M.etal. (1997) J, Biol. Chem. 272, 10248-10253). Phosphorylated C-kit in Tyr721 binds to the p85 subunit of PI3 kinase (BlumeJensen, P et a /. (2000) Nature Genet. 24, 157-162). M07e cells are a leukemia cell line Factor-dependent human megakaryoblastic (it has been confirmed that these cells carry the c-kit receptor wild). The cells are maintained in growth medium (IMDM, 10% HI-FBS, 1XPGS, GM-CSF 5 ng / ml). To measure SCF-induced c-kit phosphorylation, the cells are washed and resuspended to 3.3E5c. / M1 in test medium (RPM! 1640/4% HI-FBS, 1XPGS) and plated at 30 ul / well for 10,000 c / well. Be  dilute small molecule compounds in 100% DMSO, antibodies and other biological molecules are diluted in test medium only. Cells are pre-incubated with 0.5-2 I.tl of compound for 1 h at temperature ambient. Then ten microliters of 4XSCF (100 ng / ml) are added in test medium at room temperature. After 30 min incubation at room temperature, the cells are lysed with the addition of 20 0 of 3X lysis buffer ice cream (20 mM Tris-CI, 1 mM EDTA, 150 mM NaCI, 1% NP-40, 2 mM NaF, 20 mM D-glycerophosphate, 1 mM Na3VO4  and 1 complete proteinase inhibitor tablet / 50 ml of 1X lysis buffer (Roche Cat. No. 1697498, in warehouse)). Twenty-five microliters of lysate are transferred to blocked MSD plates (blocked with 5% BSA in saline solution buffered with Tris, 0.01% Tween (TBS-T) for 1 h with stirring, then washed 3X with TBS- T) coated with anti-c-kit antibody (Labvision EM-289). Once the plates were incubated with shaking for 1 h at ambient temperature, 25 0 of 10 nM rutenylated detection antibody (Zymed 34-9400) are added and  incubate the plates again with stirring for 1 h at room temperature. Then the 3X plates are washed with TBS-T, 150 0 of MSD reading buffer are added and the electrochemiluminescence reaction (ECL) is read in the Sector lmagerTM 6000 device. A low voltage is applied to the inborn complexes rutenylated antibody-c-kit phosphorylated (Tyr721), which in the presence of TPA (the active component of the ECL reaction buffer, Read Buffer T), results in a cyclic redox reaction that generates light at 620 nm. The amount of phosphorylated c-kit is calculated  (Tyr721) in the presence of compounds compared to the amount in the presence of a vehicle alone (HI control) using the formula:% control (POC) = (comp. -LO average) / (HI average -LO average) * 100. The data (which consist of inhibitor concentration and POC in iiM) conform to an equation of 4 parameters (y = A + ((B-A) / (1 + ((x / CD))), where A is the minimum value and (POC), B is the maximum and (POC), C is x (concentration of comp.) In the inflection point and D is the slope factor) using a non-linear regression algorithm of Levenburg-Marquardt.

 UT7 proliferation / survival assay stimulated by SCF and GM-CSP:

The purpose of this test is to test the general antiproliferative / cytotoxic effect of biological compounds of small molecule on UT-7 cells stimulated by SCF or GM-CSF. The prevention of SCF-stimulated proliferation / survival agrees with an effect on the mechanism while the GM-CSF-directed proliferation / survival inhibition is indicative of effects other than those desired.  UT-7 is a factor-dependent human megakaryoblastic leukemia cell line that can be grown in either IL-3, GM-CSF, EPO or SCF (it has been confirmed that these cells carry the wild c-kit receptor). The cells are maintained in growth medium (IMDM, 10% HI-FBS, 1XPGS, GM-CSF 1 ng / ml). To measure the SCF or GM-CSF induced proliferation, cells are washed and resuspended up to 5e4c / m1 in assay medium (RPM! 1640/4% HI-FBS, 1XPGS) and plated at 50 uUpocillo for 2500 c / well. First of all it  dilute small molecule compounds in 100% DMSO, then dilute 1: 4 in test medium to room temperature. Antibodies and other biological molecules are diluted in assay medium only. Be add five microliters of 11X SCF (55 ng / ml) or 11X GM-CSF (11 ng / ml) in test medium plus 1 III of drug diluted to cell plates. The treated cells are incubated in a humidified incubator at 37�C with 5% CO2 for 3 days. The amount of ATP is then measured as a substitute marker for cell viability. This is  Carry out 50 pl of 1-stage ATP reagent from Perkin Elmer (according to the instructions in the manual of reagent, cat. 6016739), incubating at room temperature for 15 min and reading the luminescence with a NXTTmHTS Topcount plate reader from Perkin Elmer (model c384). The amount of viable cells is calculated stimulated by SCF or GM-CSF in the presence of compound compared to the amount in the presence of vehicle only (control HI control) using the formula:% control (POC) = (comp. -LO average) / (average HI

The average) * 100. The data (consisting of inhibitor concentration and POC in gM) fit an equation of 4 parameters (y = A + ((B-A) / (1 + ((x / C) AD))), where A is the minimum value and (POC), B is the maximum and (POC), C

is x (concentration of comp.) at the inflection point and D is the slope factor) using an algorithm of nonlinear regression of Levenburg-Marguardt.

Methods of use

For the treatment of diseases mediated by Lck, diseases mediated by c-kit and / or other diseases

 listed above, the compounds of the present invention can be administered by several ways different, including oral, parental administration, by spray, rectal or topical inhalation, as Comment in this document. The parenteral term as used herein includes subcutaneous, intravenous, intramuscular, intrasternal, infusion or intraperitoneal administration.

It is intended that the treatment of diseases and disorders in this document also include the

 therapeutic administration of a compound of the invention (or a pharmaceutical salt, derivative or prodrug of the same) or a pharmaceutical composition containing said compound to a subject (i.e. an animal, preferably a mammal, most preferably a human being) that is believed to need treatment preventive, such as, for example, for pain and inflammation. The treatment also includes the administration of compound or pharmaceutical composition to subjects who have not been diagnosed as needing it, is

 that is, prophylactic administration to the subject. Generally, an accredited physician and / or authorized physician diagnoses initially to the subject and it is suggested, recommended or prescribed a regimen for prophylactic and / or therapeutic treatment to through the administration of the compound (s) or compositions of the invention.

quot; Tratarquot; or quot; dequot treatment; within the context of the present invention, it means relief, in whole or in part, of the symptoms associated with a disorder or disease, or the arrest of progression or worsening  additional of these symptoms, or the prevention or prophylaxis of the disease or disorder. Similarly, as is use herein an "effective amount"; or "therapeutically effective amount"; of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, the symptoms associated with a disorder or disease, or stops further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disease or disorder. For example, within the context of patient treatment  In need of a c-kit inhibitor, satisfactory treatment may include a reduction in adhesion and tumor anchoring; relief of symptoms related to a cancerous growth or tumor or the proliferation of diseased tissue; a stop in the progression of a disease such as cancer or cell growth

cancerous

Although it may be possible to administer a compound of the invention alone, in the methods described, the compound

 administered generally present as an active ingredient in a desired unit dosage formulation, such as a pharmaceutically acceptable composition containing pharmaceutically acceptable carriers conventional. Therefore, in another embodiment of the invention, a pharmaceutical composition is provided that It comprises a compound of this invention in combination with a pharmaceutically acceptable carrier. The Pharmaceutically acceptable carriers generally include diluents, excipients and adjuvants such as

 described in this document.

A pharmaceutical composition of the invention may comprise an effective amount of a compound of the invention or an effective dosage amount of a compound of the invention. A dosage amount Effective of a compound of the invention includes an amount less than, equal to or greater than an effective amount of the compound. For example, a pharmaceutical composition in which two or more dosages are required

 units, such as tablets and capsules, to administer an effective amount of the compound, or alternatively, a multi-dose pharmaceutical composition, such as powders and liquids, in which you can an effective amount of the compound is administered by administering a portion of the composition.

Pharmaceutical compositions can generally be prepared by mixing one or more compounds of Formula I, including stereoisomers, tautOmeres, solvates, pharmaceutically acceptable salts thereof, with

 carriers, excipients, binders, adjuvants and pharmaceutically acceptable diluents to form a Desirable administrable formulation to treat or improve a variety of disorders related to the activity of Lck, particularly inflammation, or related to c-kit activity, particularly disease Autoimmune

Pharmaceutical compositions can be manufactured by methods well known in the art such as  granulation, mixing, dissolution, encapsulation, lyophilization, emulsion or levigation procedures conventional, among others. The compositions may be in the form of, for example, granules, powders, tablets, capsules, syrup, suppositories, injections, emulsions, elixirs, suspensions or solutions. The present compositions may be formulated for various routes of administration, for example, by oral administration, by transmucosal administration, by rectal administration or by administration

 subcutaneous, as well as intrathecal, intravenous, intramuscular, intraperitoneal, intranasal, intraocular or intraventricular The compound or compounds of the present invention can also be administered in a manner local rather than systematic, such as injection as a sustained release formulation.

In addition to those representative pharmaceutical forms described herein, experts in the

technique generally know pharmaceutically acceptable excipients and carriers and therefore are included in the present invention. Such excipients and carriers are described, for example, in "Remingtons Pharmaceutical Sciencesquot; Mack Pub. Co., New Jersey (2000); &quot; Pharmaceutics The Science of Dosage Form Design, 2nd Ed. (AuIton, ed.) Churchill Livingstone (2002). The following pharmaceutical forms are administered by way of example and

 They should not be considered as limiting the invention.

For oral, oral and sublingual administration, powders, suspensions, granules, tablets, are acceptable. pills, capsules, gelatin capsules and oblong tablets as solid pharmaceutical forms. These can be prepared, for example, by mixing one or more compounds of the present invention, or stereoisomers, solvates, prodrugs, pharmaceutically acceptable salts or tautomers thereof, with at least one additive or excipient  such as a starch or other additive and give rise to tablets, encapsulate or transform into other forms desirable for conventional administration. Suitable additives or excipients are sucrose, lactose, cellulose, sugar, mannitol, maltitol, dextran, sorbitol, starch, agar, alginates, chitins, chitosans, pectins, gum tragacanth, gum arabic, gelatines, collagen, casein, albumin, synthetic or semi-synthetic polymers or glycerides, methylcellulose, hydroxypropylmethylcellulose and / or polyvinylpyrrolidone. Optionally, oral pharmaceutical forms  may contain other components to aid in administration, such as an inactive diluent or lubricants such as magnesium stearate, or preservatives such as paraben or ascorbic acid, or antioxidants such as ascorbic acid, tocopherol or cysteine, a disintegrating agent, binders, thickeners, buffers, sweeteners, flavoring agents or perfuming agents. Additionally, dyes or pigments for identification. The tablets and pills can be further treated with

 suitable coating known in the art.

Liquid pharmaceutical forms for oral administration may be in the form of emulsions, syrups, elixirs, suspensions, thick suspensions and pharmaceutically acceptable solutions, which may contain a inactive diluent, such as water. Pharmaceutical formulations can be prepared as suspensions or liquid solutions using a sterile liquid, such as an oil, water, an alcohol and combinations thereof.

 Surfactants, suspending agents and pharmaceutically suitable emulsifying agents may be added for oral or parenteral administration.

For nasal administration, the pharmaceutical formulations may be a spray or aerosol containing a appropriate solvent and optionally other compounds such as stabilizers, antimicrobial agents, antioxidants, pH modifiers, surfactants, bioavailability modifiers and combinations thereof.

 A propellant for an aerosol formulation may include compressed air, nitrogen, carbon dioxide or a low boiling solvent based on hydrocarbon. The compound or compounds of the present invention it is conveniently administered in the form of an aerosol spray presentation from a nebulizer

Injectable pharmaceutical forms for parenteral administration generally include aqueous suspensions.

 oil suspensions, which can be prepared using a suitable dispersing or wetting agent and an agent of suspension. Injectable forms may be in the dissolution phase or a powder suitable for reconstitution as a solution. Both are prepared with a solvent or diluent. Solvents or vehicles Acceptable include sterile water, Ringer's solution or an isotonic aqueous saline solution. Alternatively, Sterile oils can be used as solvents or suspending agents. Normally, the oil or acid�

 Fat is non-volatile, including oils, fatty acids, mono, di or natural or synthetic triglycerides. For the Injection, the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations thereof. The compounds can be formulated to parenteral administration by injection such as by bolus injection or continuous infusion. Form Unitary pharmaceutical for injection can be in ampoules or in multi-dose containers.

 For rectal administration, pharmaceutical formulations may be in the form of a suppository, a ointment, an enema, a tablet or a cream for the release of the compound in the intestines, sigmoid colon and / or straight. Rectal suppositories are prepared by mixing one or more compounds of the present invention, or salts pharmaceutically acceptable or tautomers of the compound, with acceptable vehicles, for example, butter cocoa or polyethylene glycol, which are in solid phase at room temperature but in liquid phase at those

 adequate temperatures to release a farmed) inside the body, tab as in the rectum. Others can be used various agents and additives in the prepared & suppositories tab as those skilled in the art know well.

The formulations of the invention can be designed to be coda action, rapid release, prolonged action and Sustained release tab as described below. Therefore, pharmaceutical formulations can also formulated for controlled release or for slow release. The present compositions can also

 comprise, for example, micelles or liposomes, or some other encapsulated form, or they can be administered in a sustained release form to provide storage and / or prolonged administration effect. By Thus, pharmaceutical formulations can be compressed into granules or cylinders and implanted via intramuscularly or subcutaneously as slow-release injections or as implants such as stents. Such Implants can employ known inert materials such as silicones and biodegradable polymers.

 Specific dosages can be adjusted depending on the pathological conditions, age, body weight,

the general health conditions, the sex and theta of the subject, the dose intervals, the routes of administration, the Excretion rate and drug combinations. Any of the previous pharmaceutical forms that they contain effective amounts that are completely within the limits of routine experimentation and therefore, completely within the scope of the present invention.

 A therapeutically effective dosage amount or dose may vary depending on the route of administration. and in the pharmaceutical way. Normally, the compound or compounds of the present invention is selected (n) to provide a formulation that has a high therapeutic index. The therapeutic index is the dose ratio between toxic and therapeutic effects that can be expressed as the ratio between DI-so and DE50. The LD50 is the lethal dose for 50% of the population and the ED50 is the therapeutically effective dose in 50% of the population. The LD50 and the

 DE50 are determined by conventional pharmaceutical procedures in animal cell cultures or in experimental animals

The dosing regimen to treat diseases mediated by Lck, diseases mediated by C-kit and others diseases listed above with the compounds of this invention and / or compositions of this invention is based on a variety of factors, including the type of illness, age, weight, sex, status  doctor of the patient, the severity of the condition, the route of administration and the particular compound employed. So, The dosage regimen can vary widely, but can be determined routinely using methods conventional. Dosage levels of the order of approximately 0.01 mg to 30 mg per kilogram of body weight per day, preferably from about 0.1 mg to 10 mg / kg, more preferably from about 0.25 mg to 1 mg / kg are useful for all methods of use disclosed in the

 present document

For oral administration, the pharmaceutical composition may be in the form of, for example, a capsule, a tablet, suspension or liquid. The pharmaceutical composition is preferably prepared in the form of a dosage unit containing a given amount of the active substance. For example, this may contain a amount of an active ingredient from about 1 to 2000 mg, preferably from

 about 1 to 500 mg, more preferably from about 5 to 150 mg. A daily dose suitable for a human being or other mammal may vary widely depending on the patient's condition and Other factors, but again, can be determined using routine methods.

The active substance can also be administered by injection as a composition with carriers suitable including saline, dextrose or water solution. The daily parenteral dosing regimen will be from  about 0.1 to about 30 mg / kg total body weight, preferably from about 0.1 to about 10 mg / kg and more preferably from about 0.25 mg up to 1 mg / kg

Formulations suitable for typical administration include suitable liquid or semi-liquid preparations for penetration through the skin (eg liniments, lotions, ointments, creams or pastes) and drops  suitable for administration to the eye, ear or nose.

A suitable topical dose of the active substance of a compound of the invention is 0.1 mg to 150 mg. administered one to four, preferably once or twice daily. For typical administration, the principle active may comprise from 0.001% to 10% w / w, for example, from 1% to 2% by weight of the formulation, although it may comprise up to 10% w / w, but preferably not more than 5% w / w and more

 preferably from 0.1% to 1% of the formulation.

Pharmaceutical compositions may be subjected to conventional pharmaceutical operations such as sterilization and / or may contain conventional adjuvants, such as preservatives, stabilizers, agents moisturizers, emulsifiers, buffers, etc. The pharmaceutically active compounds of this invention can be processed according to conventional pharmacy methods to produce pharmaceutical agents for administration

 Apparent, including humans and other mammals.

Although the compounds of the present invention can be administered as the only active pharmaceutical agent, They can also be used in combination with one or more compounds of the invention or with one or more others. Agents When administered as a combination, therapeutic agents can be formulated and administered to the subject as a single composition or the combination of therapeutic agents can be formulated and  administered to the subject as separate compositions that are administered at the same time or at different times.

For example, the compounds of the invention can be used in combination with a second therapeutic agent such how

 those described in this document. Therefore, in some embodiments, compositions are provided. therapeutics that include a compound of the invention and a second therapeutic agent as a preparation combined for simultaneous, separate or sequential use in the treatment of a subject with a disease or condition

 Modulated by Lck kinase or c-kit kinase. In some embodiments, therapeutic compositions are provided that include a compound of the invention and a second therapeutic agent as a combined preparation for use simultaneous, separate or sequential in the prophylactic treatment of a subject at risk of suffering a disease

In some of such embodiments, the components are

or been modulated by Lck kinase or c-kit kinase.

they provide as a single composition. In other embodiments, the compound and the second therapeutic agent are provided separately as parts of a kit.

Treatment may also include administering the pharmaceutical formulations of the present invention in combined & with other therapies. For example, the compounds and pharmaceutical formulations of the present

 The invention can be administered before, during or after the surgical procedure and / or radiotherapy. Alternatively, the compounds of the invention can also be co-administered with other agents. antiproliferatives including those used in gene therapy and antisense.

A category of suitable antiproliferative agents useful in the present invention are alkylating agents, a group of highly reactive chemotherapeutic agents that form covalent bonds with nucleophilic centers  (for example, hydroxyl and carboxyl). Chemically, alkylating agents can be divided into five groups: nitrogen mustards, ethyleninins, alkylsulfonates, triazenos and nitrosoureas. The nitrogen mustards they are often useful in, for example, the treatment of chronic lymphocytic leukemia, Hodgkin's disease, malignant lymphoma, small cell lung cancer and breast and testicular cancer. The nitrogen mustards Examples include chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan and uracil mustard.  Ethylenimines, being the best known thiotepa, can be useful in bladder tumors and adenocarcinomas of breast and ovary Alkylsulfonates are useful in the treatment of chronic myelogenous leukemia and other disorders Myeloproliferative Exemplary alkyl sulfonates include busulfan and piposulfan. The triazines, which they include, for example, dacarbazine, they are useful in the treatment of sarcomas and malignant melanomas. The Temozolomide, a dacarbazine analog, can also be used in the methods and compositions of the

 present invention. Finally, nitrosoureas are especially useful against brain tumors, but also they are effective for, for example, milltiple myeloma, malignant melanoma and lymphoma. Nitrosoureas as an example They include carmustine and lomustine.

Another category of antiproliferative agents suitable for use in the present invention are antimetabolites, Structural analogs of metabolites that normally occur that interfere with the normal biosynthesis of  nucleic acids. This category of agents can be subdivided into the analogs of acid� folic�, analogs of purine and pyrimidine analogs based on the fund & of the metabolite with which the agent interferes. The acid� analog The most common type is methotrexate, 01 in the treatment of choriocarcinoma, leukemia, malignancies and psoriasis. The Purine analogs, such as mercaptopurine, thioguanine and azathioprine, may be useful in leukemia. The Pyrimidine analogs are useful in the treatment of, for example, leukemia and carcinomas of the gastrointestinal tract,

 the mammary gland and the bladder. Exemplary pyrimidine analogs include fluorouracil (5-FU), UFT (uracil and ftorefur), capecitabine, genncitabine and cytarabine.

Vinca alkaloids, agents based on natural products that exert their cytotoxicity by binding to tubulin, represent another category of antiproliferative agents suitable for use in the present invention. Vinca alkaloids are useful in, for example, the treatment of lymphomas, leukemia and lung cancers,  breast, testicle, bladder and head and neck. Exemplary agents include vinblastine, vincristine, vinorelbine and vindesine. Taxanes, agents that promote the assembly of microtobots, and podophyllotoxins, agents that inhibit topoisomerases, represent related categories of antiproliferative agents that can be useful in the methods and compositions of the present invention. Exemplary taxanes include Paclitaxel and docetaxel, which are useful in breast and lung cancers, among others. Podophyllotoxins by way of

 Examples include Etoposide Mil in, for example, lymphoma and Hodgkin's disease), teniposide, irinotecan (Otil in, for example, colon, rectal and lung cancer) and topotecan, these last two acting after inhibition of topoisomerase I.

Antineoplastic antibiotics represent another category of antiproliferative agents useful in methods and methods. Compositions of the present invention. These agents exert their effects by binding to complexing with DNA.

 Exemplary agents include daunorubicin, doxorubicin, epirubicin, mitoxantrone, mitomycin, dactinomycin, plicamycin and bleomycin. Antibiotics are useful in a diverse variety of disorders, including Hodgkin's disease, leukemia, lymphoma and lung cancer.

The methods and compositions of the present invention may comprise other antiproliferative agents, including platinum complexes (for example, cisplatin and carboplatin, which are especially useful in the  cancer treatment of lung, head and neck, ovary and breast); enzymes (for example, L-asparaginase);

hormone-related therapy hormones (e.g., tamoxifen, leuprolide, flutamide, acetate megesterol, diethylstilbestrol, prednisone and estradiol cypionate); hydroxyurea; methylhydrazine derivatives such as procarbazine; adrenocortical suppressors, for example, mitotane, aminoglutethimide; aromatase inhibitors (for example, anastrozole); and biological response modifiers (for example, interferon-A).

 In addition, the methods and compositions of the present invention may comprise antiproliferative agents. resulting from the combination of two or more agents including, for example, prednimustine (a conjugate of prednisone and chlorambucil) and estramustine (a conjugate of nomitrogenated mustard and estradiol).

The methods and compositions of the present invention may comprise a combined & with another inhibitor of kinase Although the present invention is not limited to any particular kinase, kinase inhibitors

contemplated for use include thyrostin AG490 (2-cyano-3- (3,4-dihydroxyphenyl) -N- (benzyl) -2-propenamide), lressa (ZD1839; Astra Zeneca); Gleevec (STI-571 or imatinib mesylate; Novartis); SU5416 (Pharmacia Corp. / Sugen); Y Tarceva (OSI-774; Roche / Genentech / OSI Pharmaceuticals).

Claims (7)

1. Compound of formula I: / R2 N TO, 0 A2 83 or stereoisomer, solvate or pharmaceutically acceptable salt thereof, in which 5 A1 is CR4; A2 is CR5; A3 is CR6; A4 is CR7; provided that when L is -NHC (0) -, then R6 is H; L is -C (0) NR7-, -NR7C (0) -, -NR7C (0) NR7-, -NR7C (0) 0-, -S (0) 2NR7-, -NR7S (0) 2NR7-o 10 NR7S (0) 2-; R1 is pyrimidyl or pyrazinyl, each ring of which is optionally substituted NREIR8, -8-9, independently with one or more substituents of R8, NR ROR8, OR9, SR8, SR9, C (0) R8, C (0) R9, OC (0) R8, C (0) 0R8, C (0) NR8R8, C (0) NR8R9, NR8C (0) R8, NR8C (0) R9, NR8C (0) NR8R8, NR8C (0) NR8R9, NR8C (0) 0R8, NR8C (0) 0R9, S (0) 2R8, S (0) 2R9, S (0) 2NFeR8,  15 S (0) 2NR8R9, NR8S (0) 2NR8R8, NR8S (0) 2NR8R9, NR8S (0) 2R8 or NR8S (0) 2R9;   R2 is H or C1-10 alkyl; R3  it is C1_10 alkyl, C2_10 alkenyl, C2_10 alkynyl, C3_10 cycloalkyl, heterocyclic ring system non-aromatic 5-6-member monocyclic or 9-10-member bicyclic, or a ring system 5-6 member monocyclic aromatic� or 9-10 member bicyclic, optionally including 20 said aromatic ring system consisting of carbon atoms 1-3 heteroatoms If it is monocyclic or 1-6 heteroatoms if it is bicyclic, said heteroatoms being selected from 0, N or S, wherein said C1_10 alkyl, C2-10 alkenyl, C2_10 alkynyl, C3_10 cycloalkyl, ring system non-aromatic heterocyclic and aromatic ring system is optionally substituted 11 R12, R13, NR11R11, NR11R12, 0R11, sR11, independently with one or more R substituents c (0) .-- 1, k 25 OR12, SR12, C (0) R11, C (S) R11, CN (CN) R C (S) R12, CN (CN) R12, C (0) C (0) R11, OC (0) R11, COOR'1, C (0) SR11, C (0) C (0) R12, OC (0) R12, C00R12, C (0) SR12, C (0) NR1 R11, C (S) NR11R11, C (0) NR11R12, C (S) NR11R12, OC (0) NR11R12, NR11C (0) R11, NR11C (0) R12, NR11C (S) R11, NR11C (S) R1`, NR11C (0) NR11R11, NR11C (0) NR11R12, NR11C (S) NR1 IR11, R12, NR11C (S) NRI1 NR11C (0) 0R11, NR11C (0) 0R12, NR11C (0) C (0) R1 NR11C (0) C (0) R12, 11.02, S (0) 2NR11R11, 30 NR11C (0) C (0) NRS (012R11, S (0) 2R12, S (0) 2NFV1R1, NR11S (0) 2NR1IR12, NR11s (0) 2R11 NR11s (D) 2R1; each of R4, R5, R6 and R7, independently, is H, halo, haloalkyl, NO2, CN, NR8R8, NR8R9, OR8, OR9, SR8, SR9, C (0) R8, C (0) R9, OC (0) R8, C (0) 0R8, C (0) NR8R8, C (0) NR8R9, NWC (0) R8, NR8C (0) R9, NR8C (0) NR�R8, NR�C (0) NR�Fe, NR8C (0) 0R8, NR8C (0) 0R9, S (0) 2R8, S (0) 2R9, 35 S (0) 2NR8Fe, S (0) 2NR8R9, NR8S (0) 2NR8R8, NR8S (0) 2NWR9, NR8S (0) 2R8, NR8S (0) 2R9, C1 alkyl 10, C2_10 alkenyl, C2_10 alkynyl, C3_10 cycloalkyl or C4-10 cycloalkenyl, each comprising of C1_10 alkyl, C2-10 alkenyl, C2_10 alkynyl, C3_10 cycloalkyl and C4_10 cycloalkenyl optionally 1-4 heteroatoms selected from N, OyS and optionally substituted with one or more substituents of R9 or R10; Alternatively, R5 and R6 taken together form a saturated or partially or completely ring monocyclic unsaturated 5-6 carbon atom members that optionally include 1-3 heteroatoms selected from 0, N or S, and the ring is optionally substituted independently with 1-3 substituents of R8.8 R9 or R10; Rs  it is H, halo, haloalkyl, CN, NO2, acetyl, Ciio alkyl, C2-10 alkenyl, C2-10 alkynyl or cycloalkyl Co, each comprising C110 alkyl, C2_10 alkenyl, C2-10 alkynyl and Cycloalkyl Co optionally 1-4 heteroatoms selected from N, 0 and S and optionally substituted with one or more substituents of NR8R9, NR9R9, OR8, SR8, OR9, SR9, C (0) R8, OC (0) R8, COOR8, OC (0) R9, COOR9, C (0) NR8R9, C (0) NR9W, NR9C (0) R8, NR9C (0) R9, NR9C (0) NR8W, NR9C (0) NR9R9, NR9 (COOR8), NR9 (COOR), OC (0) NR8R9, OC (0) NRIR9, S (0) 2R8, S (0) 2NR8R9, S (0) 2R9, S (0) 2NR9R9, NR9S (0) 2NR8R, NR9S (0) 2NR9R9, NR9S (0) 2R8, NR9S (0) 2R9 or R9; R9 is a partially or completely saturated or unsaturated monocyclic ring system of 3-8 members, 6-12 member bicyclic or 7-14 tricyclic, optionally including said ring system formed by carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, selecting said heteroatoms of 0, N or S, and in which each ring of said ring system is optionally Rio, 0R10 independently substituted with 1-3 substituents of R10, oxo, NR1SR10, C (0) R1� C (0) NR10R10, NR10c (0) R10, NR10c (0) NR10-10, ioRid COOR10, OC (0) NR10R10, S (0) 2R10, S (0) 2NR or NR10S (0) 2R10; R1� is H, halo, haloalkyl, CN, OH, NO2, NH2, acetyl, C1.10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C310 cycloalkyl, C410 cycloalkenyl, C1-10- alkylamino dialkylamino, alkoxy C1-10 thioalkoxy or a saturated or partially or completely unsaturated monocyclic ring system 5-8 members, 6-12 members bicyclic or 7-14 members tricyclic, including optionally said ring system formed by carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, selecting said heteroatoms of 0, N or S, in which each of the C1_10 alkyl, C210 alkenyl, alkynyl C2_10, Cycloalkyl Co, C4-10 cycloalkenyl, C 1-10 alkylamino dialkylamino, alkoxy C1-10 thioalkoxy and ring of said ring system is optionally substituted independently with 1-3 substituents of halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl or phenyl; R11 is H, halo, haloalkyl, CN, NO2, acetyl, C110 alkyl, C210 alkenyl, C2-10 alkynyl or C310 cycloalkyl, each comprising C1_10 alkyl, C2-10 alkenyl, C2_10 alkynyl and C3_10 cycloalkyl optionally 1-4 heteroatoms selected from N, 0 and S and optionally 12R13, NRisRis, 0R12, sR12, sRis c (0) R12, substituted with one or more NR substituents  C (0) NR12R13 3 090) R12, C00R12, C (0) R13, OC (0) R13, COOR13, C (0) NR13R15, NR1 C (0) R12, NR13C (0) NR12R13, NR 3C (0) R13, NR13C (0) NR13R13, NR1JC (0) 0R12, NR13C (0) 0R13, OC (0) NR12R13  OC (0) NR13R13, S (0) 2R12, S (0) 2NR12R13, S (0) 2R13, S (0) 2NR13R13, NRI3S (0) 2NR1.13, 135 (0) 2NR13R13, NR13s (0) 2 NR NR13S (0) 2R13 or R13; R12 is a partially or completely saturated or unsaturated monocyclic ring system of 3-8 members, 6-12 member bicyclic or 7-14 tricyclic, optionally including said ring system formed by carbon atoms 1-3 heteroatoms if it is monocyclic, 1-6 heteroatoms if it is bicyclic or 1-9 heteroatoms if it is tricyclic, selecting said heteroatoms of 0, N or S, and in which each ring of said ring system is optionally independently substituted with 1-3 substituents of R13, oxo, NR13R13, OR13, SR13, C (0) R13, C (0) NR13R13,, 13 C00R13, NRi3c (0) .- 1- ‹NR13C (0) NR13R13, OC (0) NR13R13, S (0) 2RI3, S (0) 2NR13R1 ' or NR13S (0) 2R13; alternatively, R11 and R12 taken together form a partially or fully saturated ring or unsaturated 5-6 carbon atom members that optionally include 1-3 heteroatoms selected from 0, N or S, and the ring is optionally independently substituted with 1-5 R13 substituents; Y R13 is H, halo, haloalkyl, CN, OH, NO2, NH2, OH, methyl, methoxy, ethyl, ethoxy, propyl, Propoxy, isopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, oxo, acetyl, benzyl, cyclopropyl, cyclobutyl or a partial ring system or completely saturated or unsaturated monocyclic 3-8 members or bicyclic 6-12 members, optionally including said ring system formed by carbon atoms 1-3 heteroatoms if it is monocyclic or 1-6 heteroatoms if it is bicyclic, selecting said 0, N or S heteroatoms, and optionally independently substituted with 1-5 substituents halo, haloalkyl, CN, NO2, NH2, OH, methyl, methoxy, ethyl, ethoxy, propyl, propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamino, dimethylamino, ethylamino, diethylamino, isopropylamino, benzyl or phenyl.  2. Compound according to claim 1, wherein A1 is CR4, where R4 is halo, haloalkyl, NO2, CN, NR8R8, OR8, SR8, C (0) R8 or alkyl A2 is CH; A3 is CH; Y A4 is CH. 5 3. Compound according to claim 1 wherein 2 N N ss, R1 is, where Z is H, CN, NH2, acetyl, C1_10 alkyl, C2_10 alkenyl, alkynyl C2_10, C3-10 cycloalkyl, alkylamino dialkylamino C3-10 cycloalkylamino, aryl-amino-, heteroarylamino- or heterocyclylamino-, in which each of the Ciio alkyl, C2-10 alkenyl, alkynyl Co, C3-10 cycloalkyl, C1_10 alkylamino, C1_10 dialkylamino, C3-10 cycloalkylamino, aryl amino, Heteroarylamino-and heterocyclylamino-is optionally substituted independently with 1-3 halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl substituents, Propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl, R9, NR8R8, NR8R9, OR8, OR9, SR8, SR, C (0) R8, C (0) W, OC (0) R8, C (0) 0R8, C (0) NR8R8, C (0) NR8R9,  15 NR8C (0) R8, NR8C (0) R9, NR8C (0) NR8R8, NR8CSO) NR8R9, NR8C (0) 0R8, NR8C (0) 0R9, S (0) 2R8, S (0) 2R9, S (0) 2NR8R8, S (0) 2NR8W, NR8S (0) 2NRI5Ru, NR8S (0) 2NRI5W, NR8S (0) 2R8 or NR�S (0) 2R9.   4. Compound according to claim 1, wherein R3 is C1_10 alkyl, C3_10 cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl, 20 benzothiophenyl, benzimidazolyl, benzoxazolyl, bencisoxazolyl or benzothiazolyl, each of which is optionally substituted according to claim 1. 5. Compound according to claim 1 wherein A1 is CR4, where R4 is halo, haloalkyl, CN, NR8R8, OR8, SR8, C (0) R8 or alkyl A2 is CH; 25 A3 is CH; A4 is CH; L is -C (0) NR7-, -NR7C (0) -, -NR7C (0) NR7-, -NR7C (0) 0-, -S (0) 2NR7-, -NR7S (0) 2NR7-o - NR7S (0) 2- ZN N R1 is, where Z is H, CN, NH2, acetyl, C110 alkyl, C2-10 alkenyl, alkynyl C2-10, C3_10 cycloalkyl, C3_10- alkylamino dialkylamino, aryl-amino-, heteroarylamino- or heterocyclylamino-, in which each of the C1-10 alkyl, C2-10 alkenyl, alkynyl C2_10, C3_10 cycloalkyl, C1-10- alkylamino dialkylamino, C3-10- cycloalkylamino, aryl amino, heteroarylamino-and heterocyclylamino-is optionally independently substituted with 1-3 halo, haloalkyl, CN, NO2, NH2, OH, oxo, methyl, methoxy, ethyl, ethoxy, propyl substituents, Propoxy, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, methylamine, dimethylamine, ethylamine, diethylamine, propylamine, isopropylamine, dipropylamine, diisopropylamine, benzyl, R9 (ring), NR8R8, NR8R9, OR8, OR9, SR8, SR9, C (0) R8, C (0) R9, OC (0) R8, C (0) 0R8, Co (0) NR8W, C (0) NR8R9, NR8C (0) R8, NR8C (0) R9, NR8C (0) NR8R8, NR8C (0) NR8R9, NRI5C (0) 0R8, NR8C (0) 0R9, S (0) 2R8, S (0) 2R9, S (0) 2NR8R8, S (0) 2NR8R9, NR8S (0) 2NR8R8, NR8S (0) 2NR8R9, 40 NR8S (0) 2R8 or NR8S (0) 2R9; R2 is H or C1-6 alkyl; Y R3 is C1-10 alkyl, C3-10 cycloalkyl, phenyl, naphthyl, pyridyl, pyrimidyl, triazinyl, quinolinyl, isoquinolinyl, quinazolinyl, isoquinazolinyl, thiophenyl, furyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl, isoxazolyl, isothiazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, 3-iodo-N- (4-methyl-3 - (((2 - ((4- (4-methyl-1-piperazinyl) phenyl) amino) -5-pyrimidinyl) amino) carbonyl) phenyl) benzamide; 3-Bromo-N- (4-methyl-3 - (((2 - ((4- (4-methyl-1-piperazinyl) phenyl) amino) -5-pyrimidinyl) amino) carbonyl) phenyl) benzamide; 3-Chloro-N- (4-methyl-3 - (((2 - ((4- (4-methyl-1-piperazinyl) phenyl) amino) -5-pyrimidinyl) amino) carbonyl) phenyl) benzamide; 4-Chloro-N- (4-methyl-3 - (((2 - ((4- (4-methyl-1-piperazinyl) phenyl) amino) -5-pyrimidinyl) amino) carbonyl) phenyl) -3 5 (trifluoromethyl) benzamide; 4-nnetyl-N3- (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-54) -N1- (naphthalen-1-ipisophthalamide; 5- (isoquinolin-1-ylamino) -2-methyl-N- (2- (4- (4-methylpiperazin-1-yl) phenylamino) pyrimidin-5-yl) benzamide; 2-methyl-5 - (((24 (1-methyl-4-piperidinyl) oxy) -5- (trifluoromethyl) phenyl) carbonipamino) -N- (2- (phenylamino) -5 pyrinnidinyl) benzamide; 10 4-methyl-N-3-5-pyrimidinyl-N-1 - (3- (trifluoromethyl) feni1) -1,3-benzenedicarboxyamide; 4-methyl-N-3--2-pyrimidinyl-N-1 - (3- (trifluoromethyl) feniI) -1,3-benzenedicarboxyamide; 4-methyl-N-3--2-pyrazinyl-N-1 - (3- (trifluoromethyl) feniI) -1,3-benzenedicarboxamide; N-3 - (2-amino-5-pyrimidini1) -4-methyl-N-1 - (3- (trifluoromethyl) feni1) -1,3-benzenedicarboxamide; N-3 - (2- (acetylamino) -5-pyrimidini1) -4-methyl-N-1 - (3- (trifluoromethyl) feni1) -1,3-benzenedicarboxamide; N-1 - (2-cyclopentylethyl) -4-methyl-N-3--5-pyrimidini1-1, 3-benzenedicarboxamide; 4-methyl-N-3-5-pyrimidinyl-N-1 - (4- (trifluoromethyl) feni1) -1,3-benzenedicarboxyamide; 4-methyl-N-1 - (4- (methyloxy) -3- (trifluoromethyl) feni1) -N-3--5-pyrimidini1-1,3-benzenedicarboxamide; N-3 - (2-amino-5-pyrimidini1) -N-1 - (2-cyclopentylethyl) -4-nnetyl-1,3-benzenedicarboxamide; N-3 - (2- (acetylamino) -5-pyrimidiniI) -N-1 - (2-cyclopentylethyl) -4-methyl-1,3-benzenedicarboxamide; 4-Chloro-N-3--5-pyrimidinyl-N-1 - (3- (trifluoromethyl) feniI) -1,3-benzenedicarboxyamide.

7.

Pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound according to any one of claims 1-6.

25 30

8. Compound according to any one of claims 1-6, for use in the treatment of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveitis, acute leukemia honey or oh: mica, destruction of pancreatic f3 cells, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type 1 diabetes , type II diabetes, bone resorption diseases, graft versus host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia-reperfusion injury, atherosclerosis, head trauma, multiple sclerosis, cerebral malaria, septicemia, septicemic shock, syndrome of toxic shock, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenoviru Yes, herpes viruses, herpes zoster infection or a combination thereof in a subject.

35

9. Composed according to any of claims 1-6, for use in the treatment of fibrotic disease, mastocytosis, the presence of one or more mast cell tumors, severe asthma, rheumatoid arthritis, scleroderma, multiple sclerosis and chronic allergic rhinitis.

1 0.

Compound according to any of claims 1-6, for use in the treatment of idiopathic pulmonary fibrosis.

40 45

eleven . Use of the compound according to any of claims 1-6, for the preparation of a medicament for the treatment of rheumatoid arthritis, Paget's disease, osteoporosis, multiple myeloma, uveltis, acute or chronic myelogenous leukemia, destruction of pancreatic cells 13, osteoarthritis, rheumatoid spondylitis, gouty arthritis, inflammatory bowel disease, adult respiratory distress syndrome (ARDS), psoriasis, Crohn's disease, allergic rhinitis, ulcerative colitis, anaphylaxis, contact dermatitis, asthma, muscle degeneration, cachexia, Reiter's syndrome, type I diabetes, type II diabetes, bone resorption diseases, graft versus host reaction, Alzheimer's disease, stroke, myocardial infarction, ischemia-reperfusion injury, atherosclerosis, head trauma,

Multiple sclerosis, cerebral malaria, septicemia, septic shock, toxic shock syndrome, fever, myalgias due to HIV-1, HIV-2, HIV-3, cytomegalovirus (CMV), influenza, adenovirus, herpes viruses, Herpes zoster infection or a combination thereof in a subject. 12. Use of the compound according to any of claims 1-6, for the preparation of a medicament 5 for the treatment of fibrotic disease, mastocytosis, the presence of one or more tumors of mast cells, severe asthma, rheumatoid arthritis, scleroderma, multiple sclerosis and chronic rhinitis associated with allergy. 13. Use of the compound according to any of claims 1-6, for the preparation of a medicament for the treatment of idiopathic pulmonary fibrosis. 14. Method of preparation of a compound according to claim 1, the method comprising the step of react a compound 51 R1 R2 N 0 A2 4 A3 51  A2, A3, 4 wherein Al, kk., R 1 and R2 are tat as defined in claim 1 and L1 is NH2, C001-12 C (0) CI, SO2CI, OC (0) 0H or OC (0) CI, with a compound having a general formula L2-R3, in which L ' 15 is NH2, COON, C (0) CI, SO2CI, OC (0) 0H or OC (0) CI, to prepare a compound according to the claim one.