ES2368305T3 - 8-ANILINOIMIDAZOPIRIDINAS AND ITS USE AS ANTICANCERIGINAL AND / OR ANTI-INFLAMMATORY AGENTS. - Google Patents

Abstract

Compound of formula I: ** Formula ** and salts thereof, where: Z1 is CR1; R1 is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA or NRARA; R1 'is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA, or NRARA; wherein each RA is independently H or C1-C3 alkyl; Z2 is CR2; Z3 is CR3; R2 and R3 are independently selected from H, halo, CN, CF3, -OCF3, -NO2, - (CR14R15) nC (= Y ') R11, - (CR14R15) nC (= Y') OR11, - (CR14R15) nC (= Y ') NR11R12, - (CR14R15) nNR11R12, - (CR14R15) nOR11, - (CR14R15) nSR11, - (CR14R15) nNR12C (= Y') R11, - (CR14R15) nNR12C (= Y ') OR11, - (CR14R15) nNR13C (= Y ') NR11R12, - (CR14R15) nNR12SO2R11, - (CR14R15) nOC (= Y') R11, - (CR14R15) nOC (= Y ') OR11, - (CR14R15) nOC (= Y' ) NR11R12, - (CR14R15) nOS (O) 2 (OR11), - (CR14R15) nOP (= Y ') (OR11) (OR12), - (CR14R15) nOP (OR11) (OR12), - (CR14R15) nS (O) R11, - (CR14R15) nS (O) 2R11, - (CR14R15) n S (O) 2NR11R12, - (CR14R15) nS (O) (OR11), - (CR14R15) nS (O) 2 (OR11) , - (CR14R15) n SC (= Y ') R11, - (CR14R15) nSC (= Y') OR11, - (CR14R15) nSC (= Y ') NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2 alkynyl -C8, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R4 is H, C1-C6 alkyl or C3-C4 carbocyclyl; Y is W-C (O) - or W '; W is R5 is H or C1-C12 alkyl; X1 is selected from R11 'and -OR11'; when X1 is R11 ', X1 is optionally taken together with R5 and the nitrogen atom to which they are attached to form a saturated or unsaturated 4-7 membered ring having 0-2 additional heteroatoms selected from O, S and N, where each ring is optionally substituted with one or more groups selected from halo, CN, CF3, -OCF3, -NO2, oxo, - (CR19R20) nC (= Y ') R16, - (CR19R20) n C (= Y') OR16 , - (CR19R20) nC (= Y ') NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) n-SR16, - (CR19R20) n NR16C (= Y') R17, - (CR19R20) n NR16C (= Y ') OR17, - (CR19R20) n NR18C (= Y') NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y ') R16, - (CR19R20) nOC (= Y') OR16, - (CR19R20) nOC (= Y ') NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y') (OR16) (OR17), - (CR19R20) nOP ( OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - (CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - ( CR19R20) n S (O) 2 (OR16), - (CR19R20) n SC (= Y ') R16, - (CR19R20) n SC (= Y') OR16, - (CR19R20) n SC (= Y ') NR16R17 , and R21; each R11 'is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R11, R12 and R13 are independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, or R11 and R12 together with the nitrogen to which they are attached form a saturated ring, unsaturated or aromatic 3-8 members having 0-2 heteroatoms selected from O, S and N, where said ring is optionally substituted with one or more groups selected from halo, CN, CF3, -OCF3, -NO2, C1- alkyl C6, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl ) 2, -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl ) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl) , -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-C6 alkyl), - NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1 alkyl -C6) 2, -N (C1-C6 alkyl) C (O) NH (al C1-C6 chyl), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-alkyl) C6) 2, -NHC (O) O (C1-C6 alkyl), 5 and -N (C1-C6 alkyl) C (O) O (C1-C6 alkyl); R14 and R15 are independently selected from H, C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl; W 'is X2 is O, S, or NR9; R7 is selected from H, halo, CN, CF3, -OCF3, -NO2, - (CR14R15) nC (= Y ') R11, - (CR14R15) nC (= Y') OR11, - (CR14R15) nC (= Y ') NR11R12, - (CR14R15) nNR11R12, - (CR14R15) nOR11, - (CR14R15) nSR11, - (CR14R15) nNR12C (= Y') R11, - (CR14R15) nNR12C (= Y ') OR11, - (CR14R15) nNR13C (= Y ') NR11R12, - (CR14R15) nNR12SO2R11, - (CR14R15) nOC (= Y') R11, - (CR14R15) nOC (= Y ') OR11, - (CR14R15) nOC (= Y') NR11R12, - (CR14R15) nOS (O) 2 (OR11), - (CR14R11) nOP (= Y ') (OR11) (OR12), - (CR14R15) nOP (OR11) (OR12), - (CR14R15) nS (O) R11, - (CR14R15) nS (O) 2R11, - (CR14R15) n S (O) 2NR11R12, - (CR14R15) nS (O) (OR11), - (CR14R15) nS (O) 2 (OR11), - ( CR14R15) n SC (= Y ') R11, - (CR14R15) nSC (= Y') OR11, - (CR14R15) nSC (= Y ') NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R8 is selected from C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl; R9 is selected from H, - (CR14R15) nC (= Y ') R11, - (CR14R15) nC (= Y') OR11, - (CR14R15) nC (= Y ') NR11R12, - (CR14R15) qNR11R12, - ( CR14R15) qOR11, - (CR14R15) qSR11, - (CR14R15) qNR12C (= Y ') R11, - (CR14R15) qNR12C (= Y') OR11, - (CR14R15) qNR13C (= Y ') NR11R12, - (CR14R15) qNR12SO2R11, - (CR14R15) qOC (= Y ') R11, - (CR14R15) qOC (= Y') OR11, - (CR14R15) qOC (= Y ') NR11R12, - (CR14R15) qOS (O) 2 (OR11) , - (CR14R15) qOP (= Y ') (OR11) (OR12), - (CR14R15) qOP (OR11) (OR12), - (CR14R15) nS (O) R11, - (CR14R15) nS (O) 2R11, - (CR14R15) n S (O) 2NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R10 is H, C1-C6 alkyl or C3-C4 carbocyclyl; X4 is R6 is H, halo, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heteroaryl, heterocyclyl, -OCF3, -NO2 -Si (C1-C6 alkyl) 3, - (CR19R20) nNR16R17, - (CR19R20) nOR16, or - (CR19R20) n-SR16; R6 'is H, halo, C1-C6 alkyl, carbocyclyl, CF3, -OCF3, -NO2, -Si (C1-C6 alkyl) 3, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) n- SR16, C2-C8 alkenyl, C2-C8 alkynyl, heterocyclyl, aryl, or heteroaryl15 or; p is 0, 1, 2 or 3; n is 0, 1, 2 or 3; q is 2 or 3; wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R1, R2, R3, R4, R5, R6, R6 ', R7, R8, R9, R10, R11, R11', R12, R13 , R14, R15 and RA is independently optionally substituted with one or more groups independently selected from halo, CN, CF3, -OCF3, -NO2 oxo, -Si (C1-C6 alkyl) 3, - (CR19R20) nC (= Y ' ) R16, - (CR19R20) n C (= Y ') OR16, - (CR19R20) nC (= Y') NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) nSR16, - (CR19R20) nNR16C (= Y ') R17, - (CR19R20) nNR16C (= Y') OR17, - (CR19R20) nNR18C (= Y ') NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y') R16, - (CR19R20) nOC (= Y ') OR16, - (CR19R20) nOC (-Y') NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y ') (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - (CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) nS (O) 2 (OR16), - (CR19R20) nSC (= Y ') R16, - (CR19R20) nSC (= Y') OR16, - (CR19R20) n SC (= Y ') NR16R17, and R21; each R16, R17 and R18 is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl It is optionally substituted with one or more groups selected from halo, CN, -OCF3, CF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl) , -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2 , -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC ( O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (alkyl C1-C6) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-alkyl) C6), -NHC (O) NH (C1-C6 alkyl), NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) NH (C1-C6 alkyl), - N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-C6 alkyl), and -N (C1-C6 alkyl) C (O) O (C1-C6 alkyl); or R16 and R17 together with the nitrogen to which they are attached form a saturated, unsaturated or aromatic 3-8 membered ring having 0-2 heteroatoms selected from O, S and N, where said ring is optionally substituted with one or more groups selected from halo, CN, -OCF3, CF3, -NO2 C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1 alkyl -C6), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (alkyl C1-C6), -C (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC ( O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) NH (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-C6 alkyl ), and -N (alkyl C1-C6) C (O) O (C1-C6 alkyl); R19 and R20 are independently selected from H, C1-C12 alkyl, - (CH2) n-aryl, - (CH2) n-carbocyclyl, - (CH2) n-heterocyclyl, and - (CH2) n-heteroaryl; R21 is C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each member of R21 is optionally substituted with one or more groups selected from halo, oxo, CN, - OCF3, CF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), - C (O) N (C1-C6 alkyl, N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) NH (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl ) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-C6 alkyl), and -N (C1- alkyl) C6) C (O) O (C1-C6 alkyl); each Y 'is independently O, NR22, or S; and R22 is H or C1-C12 alkyl.

Description

8-Anilinoimidazopyridines and their use as anti-cancer and / or anti-inflammatory agents

[0001] FIELD OF THE INVENTION

[0002] The present invention relates to imidazopyridines with anticancer activity and more specifically to imidazopyridines that inhibit the activity of MEK kinase. The present invention also relates to methods of using the compounds for in vitro, in situ and in vivo diagnosis or treatment of mammalian cells, or associated pathological conditions.

[0003] BACKGROUND OF THE INVENTION

[0004] In the quest to understand how Ras transmits extracellular growth signals, the mechanism of MAP (mitogen activated protein) kinase (MAPK) has emerged as the main route between membrane-bound Ras and the nucleus. The MAPK mechanism comprises a cascade of phosphorylations involving three key kinases, specifically Raf, MEK (MAP kinase) and ERK (MAP kinase). Active GTP-bound Ras results in the activation and indirect phosphorylation of Raf kinase. Next, Raf phosphorylates MEK1 and 2 in two serine residues (S218 and S222 for MEK1 and S222 and S226 for MEK2) (Ahn et al., Methods in Enzymology 2001, 332, 417-431). Activated MEK then phosphorylates only its known substrates, MAP kinases, ERK1 and

2. The phosphorylation of ERK by MEK takes place in Y204 and T202 for ERK1 and Y185 and T183 for ERK2 (Ahn et al., Methods in Enzymology 200I, 332, 41,7-431). Phosphorylated ERK dimerizes and then translocates to the nucleus where it accumulates (Khokhlatchev et al., Cell 1998, 93, 605-615). In the nucleus, ERK is involved in several important cellular functions, including, but not limited to, nuclear transport, signal transduction, DNA repair, nucleosome assembly and translocation, and mRNA processing and translation (Ahn et al., Molecular Cell 2000, 6, 1343-1354). In general, the treatment of cells with growth factors leads to the activation of ERK1 and 2 which leads to proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res. 1998, 74, 49 -139).

[0005] There is important evidence that genetic mutations and / or overexpression of protein kinases in the MAP kinase mechanism lead to uncontrolled cell proliferation and, ultimately, to tumor formation, in proliferative diseases. For example, some cancers contain mutations that result in continuous activation of this mechanism due to the continuous production of growth factors. Other mutations can lead to defects in the deactivation of the Ras complex bound to activated GTP, again leading to the activation of the MAP kinase mechanism. Mutated oncogenic forms of Ras are found in 50% of colon cancers and in more than 90% of pancreatic cancers, as well as many other types of cancers (Kohl et al., Science 1993, 260, 1834-1837 ). Recently, bRaf mutations have been identified in more than 60% of malignant melanomas (Davies, H. et al., Nature 2002, 417, 949-954). These bRaf mutations give rise to a constitutively active MAP kinase cascade. Studies of samples of tumors and primary cell lines have shown a constitutive MAP kinase mechanism or its over-activation in cancers of the pancreas, colon, lung, ovary, and kidney. (Hoshino, R. et al., Oncogene 1999, 18, 813-822).

[0006] MEK has emerged as an attractive therapeutic target in the cascade mechanism of MAP kinase. MEK, downstream of Ras and Raf in the cascade, is highly specific for phosphorylation of MAP kinase; in fact, the only known substrates for MEK phosphorylation are MAP kinase, ERK and 2. It has been observed in several studies that MEK inhibition has potential therapeutic advantages. For example, it has been observed that small molecule MEK inhibitors inhibit the growth of human tumors in xenografts of nude mice, (Sebolt-Leopold et al., Nature-Medicine 1999, 5 (7), 810-816); Trachet et al., AACR Apr. 6-10, 2002, Poster # 5426; Tecle, H. IBC 2.sup.nd International Conference of Protein Kinases, Sep. 9-10, 2002), block static allodynia in animals (WO 01/05390 published January 25, 2001) and inhibit cell growth of myeloid water leukemia (Milella et al., J Clin. Invest 2001, 108 (6), 851-859).

[0007] Several small molecule MEK inhibitors have also been described in, for example, WO02 / 06213, WO 03/077855 and WO03 / 077914. There is still a need for new MEK inhibitors as effective and safe therapeutic agents to treat a set of proliferative disease states, such as conditions related to MEK hyperactivity, as well as diseases modulated by the MEK cascade.

[0008] SUMMARY DESCRIPTION OF THE INVENTION

[0009] The present invention generally relates to imidazopyridines of formula I (and / or solvates, hydrates and / or salts thereof) with anti-cancer and / or anti-inflammatory activity, and more specifically with MEK kinase inhibitory activity. Certain hyperproliferative and inflammatory disorders are characterized by the modulation of MEK kinase function, for example, by mutations or protein overexpression. Accordingly, the compounds of the invention and compositions thereof are useful in the treatment of hyperproliferative disorders, such as cancer and / or inflammatory diseases, such as rheumatoid arthritis.

and you leave them, in which: Z1 is CR1 R1 is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA or NRARA; R1 ’is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA, or NRARA; wherein each RA is independently H or C1-C3 alkyl; Z2 is CR2 Z3 is CR3; R2 and R3 are independently selected from H, halo, CN, CF3, -OCF3, -NO2, - (CR14R15) nC (= Y ’) R11, - (CR14R15) nC (= Y ’) OR11, - (CR14R15) nC (= Y’) NR11R12, - (CR14R15) nNR11R12, - (CR14R15) nOR11, - (CR14R15) nSR11, - (CR14R15) nNR12C (= Y ’) R11, - (CR14R15) nNR12C (= Y’) OR11 - (CR14R15) nNR13C (= Y ’) NR11R12, - (CR14R15) nNR12SO2R11, - (CR14R15) nOC (= Y ’) R11, - (CR14R15) nOC (= Y’) OR11, - (CR14R15) nOC (= Y ’) NR11R12, - (CR14R15) nOS (O) 2 (OR11), - (CR14R15) nOP (= Y ') (OR11) (OR12), - (CR14R15) nOP (OR11) (OR12), - (CR14R15) nS (OR11), - (CR14R15) nS (O) 2R11, - ( CR14R15) n S (O) 2NR11R12, - (CR14R15) nS (O) (OR11), - (CR14R15) nS (O) 2 (OR11), - (CR14R15) n SC (= Y ') R11, - (CR14R15) nSC ( = Y ') OR11, - (CR14R15) nSC (-Y ’) NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R4 is H, C1-C6 alkyl or C3-C4 carbocyclyl; Y is W-C (O) -o W ’; W is

R5 is H or C1-C12 alkyl; X1 is selected between R11 ’and -OR111’; when X1 is R11 ’, X1 is optionally taken together with R5 and the atom of nitrogen to which they bind to form a saturated or unsaturated 4-7-membered ring that has 0-2 heteroatoms additional selected from O, S and N, where each ring is optionally substituted with one or more groups selected from halo, CN, CF3, -OCF3, -NO2, oxo, - (CR19R20) nC (= Y ’) R16, - (CR19R20) n C (= Y’) OR16, - (CR19R20) nC (= Y ’) NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R2O) n-SR16, - (CR19R20) n NR16C (= Y’) R17, - (CR19R20) n NR16C (= Y ’) OR17, - (CR19R20) n NR18C (= Y’) NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y ’) R16, - (CR19R20) nOC (= Y ') OR16, - (CR19R20) nOC (= Y') NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y ') (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOS (O) 2 (OR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) n S (O) 2 (OR16), - (CR19R20) n SC (= Y ') R16, - (CR19R20) n SC (= Y') OR16, - (CR19R20) n SC (= Y ’) NR16R17, and R21; each R11 'is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R11, R12 and R13 are independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl,

or R11 and R12 together with the nitrogen to which they are attached form a saturated, unsaturated or aromatic 3-8 membered ring that has 0-2 heteroatoms selected from O, S and N, where each ring is optionally

substituted with one or more groups selected from halo, CN, CF3, -OCF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6l alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), - CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl ) C (O) (Rent C1-C6), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl )2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C ( O) NH (Alkyl C1-C6), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl )2, -NHC (O) O (C1-C6 alkyl), and -N (C1-C6 alkyl) C (O) O (C1-C6 alkyl); R14 and R15 are independently selected from H, C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl; W ’is

is

each X2 is independently O, S, or NR9; each R7 is independently selected from H, halo, CN, CF3, -OCF3, -NO2, - (CR14R15) nC (= Y ') R11- (CR14R15) nC (= Y') OR11, - (CR14R15) nC (= Y ') NR11R12, - (CR14R15) nNR11R12, - (CR14R15) nOR11, - (CR14R15) nSR11, - (CR14R15) nNR12C (= Y') R11, - (CR14R15) nNR12C (= Y ') OR11, - (CR14R15 ) nNR13C (= Y ') NR11R12, - (CR14R15) nNR12SO2R11, - (CR14R15) nOC (= Y') R11, - (CR14R15) nOC (= Y ') OR11, - (CR14R15) nOC (= Y') NR11R12 , - (CR14R15) nOS (O) 2 (OR11), - (CR14R15) nOP (= Y ') OR11) (OR12), - (CR14R15) nOP (OR11) OR12), - (CR14R15) nS (= Y' ) R11- (CR14R15) nS (O) 2R11, - (CR14R15) nC (O) 2NR11R12, - (CR14R15) nOS (O) (OR11), - (CR14R15) nS (O) 2 (OR11), - (CR14R15 ) n SC (= Y ') R11, - (CR14R15) nSC (= Y') OR11, - (CR14R15) nOS (O) 2 (OR11), C1-C12 alkyl,

C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; each R8 is independently selected from C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl, R9 is selected from H, - (CR14R15) nC (Y ’) R11, - (CR14R15) nC (Y’ OR11, - (CR14R15) nC (Y ’) NR11R12, - (CR14R15) qNR11R12, - (CR14R15) qNR11, - (CR14R15) qNR11, - (CR14R15) qNR12C (= Y ’) R11, - (CR14R15) qNR12C (= Y’) OR11, - (CR14R15) qNR13C (= Y ’) NR11R12, - (CR 14R15) qNR 12SO2R11, - (CR14R15) qOC (= Y’) OR11, - (CR14R15) qOC (= Y ’) OR11, - (CR 14R15) qOC (= Y ’) NR11R12, - (CR14R15) qOS (O) 2 (OR11), - (CR14R15) qOP (= Y’) (OR12), - (CR14R15) qOP (OR11) (OR11), - (CR14R15) nS (O) R11, - (CR14R15) nS (O) 2R11), - (CR14R15) n - (CO) 2NR11R12, C1-C12 alkyl, C2-C8 alkenyl, alkynyl C2-C8, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R10 is H, C1-C6 alkyl or C3-C4 carbocyclyl; X4 is

R6 is H, halo, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heteroaryl, heterocyclyl, -OCF3, -NO2, -Si (C1-C6 alkyl) 3, - (CR19R20) nNR16R17, - (CR19R20) nOR16, or - (CR19R20) nSR16; R6 ’is H, halo, C1-C6 alkyl, carbocyclyl, CF3, -OCF3, -NO2, -Si (C1-C6 alkyl) 3, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) nSR16, C2-C8 alkenyl, C2-C8 alkynyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2 or 3; n is 0,1,2 or 3; q is 2 or 3; wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R1, R2, R3, R4, R5, R6, R6 ’, R7 R8, R9, R10, R11, R11’, R12 R13, R14, R15 and RA is independently optionally substituted with one or more groups independently selected from halo, CN, CF3, -OCF3, -NO2, oxo, -Si (C1-C6 alkyl) 3, - (CR19R20) nC (= Y ’) R16, - (CR19R2) n C (= Y’) OR16, - (CR19R20) nC (= Y ’) NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) nSR16, - (CR19R20) nNR16C (= Y ’) R17, - (CR19R20) nNR16C (= Y’) OR17, - (CR19R20) nNR18C (= Y ’) NR16R17, - (CR19R20) nNR17CO2R16, - (CR19R20) nOC (= Y ’) R16, - (CR19R20) nOC (= Y’) OR16, - (CR19R20) nOC (= Y ’) NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y ') (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - (CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) n S (O) 2 (OR16), - (CR19R20) nSC (= Y ’) R16, - (CR19R20) nSC (= Y’) OR16, (CR19R20) n SC (= Y ’) NR16R17, and R21; each R16, R17 and R18 is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl it is optionally substituted with one or more groups selected from halo, CN, -OCF3, CF3, -NO2, alkyl C1-C6, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -N (alkyl C1-C6) C (O) (alkyl C1-C6), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2 , -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C ( O) NH (alkyl C1-C6), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl )2, -NHC (O) O (C1-C6 alkyl), and -N (C1-C6 alkyl) C (O) O (C1-C6 alkyl);

or R16 and R17 together with the nitrogen to which they are attached form a saturated, unsaturated or aromatic 3-8 membered ring having 0-2 heteroatoms selected from O, S and N, where each ring is optionally substituted with one or more groups selected from halo, CN, -OCF3, CF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (alkyl C1-C6), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH ( C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl) , -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) NH (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-alkyl C6), and -N (alkyl or C1-C6) C (O) O (C1-C6 alkyl);

R19

and R20 are independently selected from H, C1-C12 alkyl, - (CH2) n-aryl, - (CH2) n-carbocyclyl, - (CH2) n-heterocyclyl, and - (CH2) n-heteroaryl; R21 is C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each R21 member is optionally substituted with one or more groups selected from halo, oxo, CN, - OCF3, CF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), - C (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1- alkyl C6), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl) , -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) NH (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) N (alkyl C1-C6) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-C6 alkyl), and -N ( C1-C6 alkyl) C (O) O (C1-C6 alkyl); each Y ’is independently O, NR22, or S; and R22 is H or C1-C12 alkyl.

[0010] The present invention includes a composition (for example, a pharmaceutical composition) comprising a compound of formula I (and / or solvates, hydrates and / or salts thereof) and a carrier (a pharmaceutically acceptable carrier). The present invention also includes a composition (for example, a pharmaceutical composition) comprising a compound of formula I (and / or solvates, hydrates and / or salts thereof) and a carrier (a pharmaceutically acceptable carrier), which further comprises a second chemotherapeutic agent and / or a second anti-inflammatory agent. The present compositions are useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (eg, human). The present compositions are also useful for the treatment of inflammatory diseases in a mammal (eg, human).

[0011] The present invention describes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (eg, human) comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or solvates and salts thereof) or a composition thereof, alone or in combination with a second chemotherapeutic agent.

[0012] The present invention describes a method of treating an inflammatory disease in a mammal (eg, human) comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or solvates and salts thereof) or a composition thereof, alone or in combination with a second anti-inflammatory agent.

[0013] The present invention describes a method of utilizing the present compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms, or associated pathological conditions.

[0014] DETAILED DESCRIPTION OF EXAMPLE EMBODIMENTS

[0015] Reference will now be made in detail to certain embodiments of the present invention, examples of which are illustrated in the accompanying structures and formulas. Although the invention will be described in conjunction with the listed embodiments, it will be understood that they are not intended to limit the invention to these embodiments. Instead, the present invention is intended to cover all alternatives, modifications and equivalents that may be included within the scope of the present invention as defined in the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described in the present invention, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described. In the event that one or more of the incorporated documents, patents and similar materials differ or contradict the present application, including, but not limited to, the defined terms using terms, techniques described or similar, this application has preference.

[0016] DEFINITIONS

[0017] The term " alkyl " as used in the present invention it refers to a saturated straight or straight chain monovalent hydrocarbon radical of one to twelve carbon atoms. Examples of alkyl groups include, but are not limited to, methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH (CH3) 2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH (CH3) 2 ), 2-butyl (s-Bu, s-butyl, -CH (CH3) CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH3) 3), 1-pentyl ( n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH (CH3) CH2CH2CH3), 3-pentyl (-CH (CH2CH3) 2), 2-methyl-2-butyl (-C (CH3) 2CH2CH3), 3- methyl-2-butyl (-CH (CH3) CH (CH3) 2), 3-methyl-1-butyl (-CH2CH2CH (CH3) 2), 2-methyl-1-butyl (-CH2CH (CH3) CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH (CH3) CH2CH2CH2CH3), 3-hexyl (-CH (CH2CH3) (CH2CH2CH3)), 2-methyl-2-pentyl (-C (CH3) 2CH2CH2CH3), 3-methyl-2-pentyl (-CH (CH3) CH (CH3) CH2CH3), 4-methyl-2-pentyl (-CH (CH3) CH2CH (CH3) 2), 3-methyl-3-pentyl (-C (CH3) (CH2CH3) 2), 2-methyl-3-pentyl (-CH (CH2CH3) CH (CH3) 2), 2,3-dimethyl-2-butyl (-C (CH3) 2CH (CH3) 2) , 3,3-dimethyl-2-butyl (-CH (CH3) C (CH3) 3, 1-heptyl, 1-octyl, and the like.

[0018] The term "alkenyl" refers to a monovalent straight or branched chain hydrocarbon radical of two to twelve carbon atoms with at least one point of establishment, ie a sp2 carbon-carbon double bond, where the alkenyl radical includes radicals having "cis" orientations and "trans", or alternatively, "E" and "Z" orientations. Examples include, but are not limited to, ethylene or vinyl (-CH = CH2), allyl (-CH2CH = CH2), and the like.

[0019] The term "alkynyl" a linear or branched monovalent hydrocarbon radical of two to twelve carbon atoms with at least one installation site, that is, a carbon-carbon triple bond sp. Examples include, but are not limited to, ethynyl (-C≡CH), propynyl (propargyl, -CH2C≡CH), and the like.

[0020] The terms "carbocycle", "carbocyclyl", "carbocyclic ring" and "cycloalkyl" refer to a saturated or partially unsaturated monovalent non-aromatic ring having 3 to 12 carbon atoms as a monocyclic ring or 7 to 12 carbon atoms as a bicyclic ring. Bicyclic carbocycles having 7 to 12 carbon atoms can be arranged, for example, as a bicycle system [4,5], [5,5], [5,6] or [6,6], and carbocycles bicyclics having 9 or 10 ring atoms can be arranged as a bicyclo system [5,6] or [6,6],

or as bridge systems, such as bicyclo [2.2.1] heptane, bicyclo [2.2.2] octane and bicyclo [3.2.2] nonane. Examples of monocyclic carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1 -enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, and the like.

[0021] "Arilo" means a monovalent aromatic hydrocarbon radical of 6-18 carbon atoms derived by removing a hydrogen atom from a single carbon atom from a parental aromatic ring system. Some aryl groups are represented in the example structures as "Ar". Aryl includes bicyclic radicals comprising an aromatic ring fused to a saturated, partially unsaturated ring, or an aromatic heterocyclic or carbocyclic ring. Typical aryl groups include, but are not limited to, radicals derived from benzene (phenyl), substituted benzenes, naphthalene, anthracene, indenyl, indanyl, 1,2-dihydronaphthalene, 1,2,3,4-tetrahydronaphthyl, and the like.

[0022] The terms "heterocycle", "heterocyclyl" and "heterocyclic ring" are used interchangeably in the present invention and refer to a saturated or partially unsaturated carbocyclic radical (ie, having one or more double and / or triple bonds in the ring) of 3 to 18 atoms in the ring, in which at least one atom in the ring is a heteroatom selected from nitrogen, oxygen and sulfur, the rest of the atoms being in the C ring, where one or more atoms in the ring Ring is independently optionally substituted with one or more substituents described below. A heterocycle can be a monocycle that has 3 to 7 ring members (2 to 6 carbon atoms and 1 to heteroatoms selected from N, O, P, and S) or a bike that has 7 to 10 members in the ring. ring (4 to 9 carbon atoms and 1 to 6 heteroatoms selected from N, O, P, and S), for example: a two-cycle system [4,5], [5,5], [5,6], or [6.6]. Heterocycles are described in Paquette, Leo A .; " Principles of Modern Heterocyclic Chemistry " (W.A. Benjamin, New York, 1968), particularly chapters 1, 3, 4, 6, 7, and 9; " The Chemistry of Heterocyclic Compounds, A series of Monographs " (John Wiley & Sons, New York, 1950 to the present), in particular volumes 13, 14, 16, 19, and 28; and J. Am. Chem. Soc. (1960) 82: 5566. "Heterocyclyl" It also includes radicals, where heterocycle radicals are fused with a saturated, partially unsaturated ring, or an aromatic heterocyclic or carbocyclic ring. Examples of heterocyclic rings include but are not limited to, pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, tiomorpholinilo, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolylimide, 3-pyrazinylimidazoylimidazole, 3-pyrazinylimidazole, imidazolidylimidazole, 3-pyridylidenezoicide; 3.1.0] hexanyl, 3-azabicyclo [4.1.0] heptanyl, and azabicyclo [2.2.2] hexanyl. Spiro groups are also included in the scope of this definition. Examples of a heterocyclic group where the ring atoms substituted with oxo (= O) groups are pyrimidinonyl and 1,1-dioxo-thiomorpholinyl.

[0023] The term "heteroaryl" refers to a monovalent aromatic radical of 5 or 6 membered rings and includes fused ring systems (at least one of which is aromatic) of 5-18 atoms, which contains one or more heteroatoms independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups are pyridinyl (including, for example, 2-hydroxypyridinyl), imidazolyl, imidazopyridinyl, pyrimidinyl (including, for example, 4-hydroxypyrimidinyl), pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl.

[0024] The heterocycle or heteroaryl groups may be attached to carbon or nitrogen when this is possible. By way of non-limiting example, carbon-bound heterocycles or heteroaryls are attached at the 2, 3, 4, 5, or 6 position of a pyridine, the 3, 4, 5, or 6 position of a pyridazine, the 2 position , 4, 5, or 6 of a pyrimidine, position 2, 3, 5, or 6 of a pyrazine, position 2, 3, 4, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole or tetrahydropyrrole, position 2, 4, or 5 of an oxazole, imidazole or thiazole, position 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole, position 2 or 3 of an aziridine, position 2, 3, or 4 of an azetidine, position 2, 3, 4, 5, 6, 7, or 8 of a quinoline or position 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline.

[0025] By way of non-limiting example, the nitrogen-linked heterocycles or heteroaryls are attached at the 1-position of an aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3 -imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1H-indazole, position 2 of an isoindole, or isoindoline, position 4 of a morpholine, and position 9 of a carbazole, or β-carboline.

[0026] The term " halo " (halogen) refers to F, Cl, Br or I. Heteroatoms present in the heteroaryl or heterocyclyl include oxidized forms, such as N + → O-, S (O) and S (O) 2.

[0027] The terms "treat" and "treatment" refer to both therapeutic treatment and prophylactic or preventive measures, where the objective is to prevent or slow down (decrease) an unwanted physiological change or disorder, such as the development or expansion of the Cancer. For the purposes of the invention, the beneficial or desired clinical results include, but are not limited to, the relief of symptoms, the decrease in the extent of the disease, the stabilized state (i.e., without worsening) of a disease, the delay or slowing of the progression of a disease, the improvement or palliation of the state of a disease, and remission (either partial or total), whether detectable or undetectable. "Treatment" can also mean prolonged survival compared to expected survival if you do not receive treatment. Those in need of treatment include those who already have the condition or disorder, as well as those prone to present the condition or disorder in which the condition or disorder should be prevented.

[0028] The phrase "therapeutically effective amount" means an amount of a compound of the present invention that (i) treats or prevents the particular disease, condition or disorder, (ii) attenuates, improves or eliminates one or more of the symptoms of the particular disease, condition or disorder, or (iii) prevents or delays the occurrence of one or more of the symptoms of the particular disease, condition or disorder described in the present invention. In the case of cancer, the therapeutically effective amount of the drug can reduce the number of cancer cells; reduce tumor size; inhibit (ie, slow down to some extent and preferably stop) the infiltration of cancer cells in the peripheral organs; inhibit (that is, slow to some extent and preferably stop) tumor metastasis; inhibit, to some extent, the growth of tumors; and / or relieve to some extent one or more of the symptoms associated with cancer. As long as the drug can prevent growth and / or eliminate existing cancer cells, it can be cytostatic and / or cytotoxic. For cancer therapy, efficacy can be measured, for example, by assessing the time to disease progression (TTP) and / or determining the response speed (RR).

[0029] The terms "abnormal cell growth" and "hyperproliferative disorder" are used interchangeably in this application. "Abnormal cell growth," as used in the present invention, unless otherwise indicated, refers to cell growth that is independent of normal regulatory mechanisms (eg, loss of contact inhibition). This includes, for example, the abnormal growth of: (1) tumor cells (tumors) that proliferate by expression of a mutated tyrosine kinase or overexpression of a receptor tyrosine kinase; (2) benign and malignant cells of other proliferative diseases in which aberrant tyrosine kinase activation takes place; (3) any tumor that proliferates by receptor tyrosine kinase; (4) any tumor that proliferates by activating aberrant serine / threonine kinase; and (5) benign and malignant cells of other proliferative diseases in which the activation of aberrant serine / threonine kinase.

[0030] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that are usually characterized by unregulated cell growth. A "tumor" comprises one or more cancer cells. Examples of cancer include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia or lymphoid tumors. More particular examples of such cancers include, squamous cell cancer (eg, epithelial squamous cell cancer), lung cancer, including small cell lung cancer, non-small cell lung cancer ("NSCLC"), adenocarcinoma of the lung and squamous cell carcinoma of the lung, peritoneal cancer hepatocellular cancer, gastric stomach cancer, including gastrointestinal cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hematoma, breast cancer, colon cancer, cancer rectal, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney or kidney cancer, prostate cancer, vulvar cancer, thyroid cancer, liver carcinoma, anal carcinoma, penile carcinoma, acute leukemia, as well as cancer Head / brain and neck.

[0031] A "chemotherapeutic agent" is a compound useful in the treatment of cancer. Examples of chemotherapeutic agents include Erlotinib (TARCEVA®, Genentech / OSI Pharm.), Bortezomib (VELCADE®, Millennium Pharm.), Fulvestrant (FASLODEX®, AstraZeneca), Sutent (SU11248, Pfizer), Letrozole (FEMARA®, Novart®) Imatinib mesiolate (GLEEVEC®, Novartis), PTK787 / ZK 222584 (Novartis), Oxaliplatin (Eloxatin®, Sanofi), 5-FU (5-fluorouracil), Leucovorin, Rapamycin (Sirolimus, RAPAMUNE®, Wyeth), Lapatinib (TYB) TY ®, GSK572016, Glaxo Smith Klina), Lonafamib (SCH 66336), Sorafenib (BAY43-9006, Bayer Labs), and Gefitinib (IRESSA®, AstraZeneca), AG1478, AG1571 (SU 5271; Sugen), alkylating agents, such as thiotepa and CYTOXAN® cyclophosphamide; alkyl sulfonate, such as busulfan, improsulfan and piposulfan; aziridines, such as benzodopa, carbocuone, meturedopa, and uredopa; ethyleneimines and methylamelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylene ethiophosphoramide and trimethylomelamine; acetogenins (especially, bulatacin and bulatacinone); a camptothecin (including, the synthetic analogue topotecan); biostatin; calistatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin and bizelesin); cryptophycin (particularly cryptophycin 1 and cryptophycin 8); dolastatin; duocarmycin (including, synthetic analogs, KW-2189 and CB1-TM1); eleutherobin; pancratistatin; a sarcodictiin; spongistatin; nitrogen mustards, such as chlorambucil, chlornafazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine hydrochloride, melphalan, novembiquina, phenesterine, prednimustine, trophophamide, uracil mustard; nitrosureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine; antibiotics, such as enedin antibiotics (for example, calicheamycin, especially gamma 1I calicheamycin and omegaI1 calicheamycin (Angew Chem. Intl. Ed. Engl. (1994) 33: 183-186); dynemycin, including dynemycin A; bisphosphonates, such such as clodronate; a speramycin; as well as neocarzinostatin chromophore and enedin antibiotic chromophores of related chromoproteins), clarcinomysins, actinomycin, autramycin, azaserine, bleomycins, cactinomycin, carabicin, carminomycin, carzinophilin, cromomycinin, dactinicin, dactinicin, dactinicin, dactinicin, dactinicin, dactinicin, dactinicin, dactinicin, dactinicin, dactinicin, dactinicin, 6 -5-oxo-L-norleucine, ADRIAMYCIN® (doxorubicin), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin, mitomycins such as mitomycin C, mycophenolic acid, nogalamicin, olivomycins, peplomycin, porphyromycin, puromycin, chelamycin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites, such as methotrexate and 5-fluorouracil (5-FU); folic acid analogs, such as denopterin, methotrexate, pteropterin, trimetrexate; Purine analogs, such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine; pyrimidine analogs, such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens, such as calusterone, dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-adrenals, such as aminoglutethimide, mitotane, trilostane; folic acid filler, such as frolinic acid; aceglatone; aldophosphamide glycoside; aminoevulinic acid; eniluracil; amsacrine; bestrabucilo; bisantrene; edatraxate; defofamine; demecolcina; diazicuone; elfornithine; elliptinium acetate; an epothilone; ethtoglucid; gallium nitrate; hydroxyurea; lentinano; lonidainin; maitansinoids, such as maitansin and ansamitocins; mitoguazone; mitoxantrone; mopidanmol; nitraerin; pentostatin; fenamet; pyrarubicin; losoxantrone; podophyllinic acid; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, OR); razoxane; rhizoxin; sizofirano; spirogermanium; tenuazonic acid; triazicuone; 2,2 ', 2 "-trichlorotriethylamine; trichothecenes (especially T-2 toxin, verracurin A, roridine A and anguidine); urethane; vindesine; dacarbazine; manomustine; mitobronitol; mitolactol; pipobroman; gacitosina; arabinoside (" Ara-C ");cyclophosphamide;thiotepa; taxoids, for example, TAXOL® (paclitaxel; Bristol-Myers Squibb Oncology, Princeton, NJ), ABRAXANE ™ (no cremophor), albumin-modified paclitaxel formulations (American Pharmaceutical Partners, Schaumberg, Illinois), and TAXOTERE® ( doxetaxel; Rhône-Poulenc Rorer, Antony, France); chlorambucil; GEMZAR® (gemcitabine); 6-thioguanine; mercaptopurine; methotrexate; platinum analogs, such as cisplatin and carboplatin; vinblastine; etoposide (VP-16); ifosfamide; mitoxantrone; vincristine; NAVELBINA® (Vinorelbine); novantrone; teniposide; edatrexate; daunomycin; aminopterin; Capecitabine (XELODA®); ibandronate; CPT-11; topoisomerase inhibitor RFS 2000; difluoromethylornitine (DMFO); retinoids, such as retinoic acid; and pharmaceutically acceptable salts and derivatives of any of the foregoing.

[0032] Also included in the definition of "therapeutic agent" are: (i) anti-hormonal agents that act to regulate or inhibit the action of the hormone in tumors, such as antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX®; tamoxifen citrate), raloxifene, droloxifene, 4-hydroxytyamoxyphene, trioxyphene, keoxifen, LY117018, onapristone, and FARESTON® (toremifine citrate); (ii) aromatase inhibitors that inhibit the enzyme aromatase, which regulate the production of estrogen in the adrenal glands, such as, for example, 4 (5) -imidazoles, aminoglutethimide, MEGASE® (megestrol acetate), AROMASIN® (exemestane ; Pfizer), formestanie, fadrozol, RIVISOR ® (vorozole), FEMARA® (letrozole; Novartis), and ARIMIDEX® (anastrozole; AstraZeneca); (iii) antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; as well as troxacitabine (a 1,3-dioxolane analog of the cytosine nucleoside); (iv) protein kinase inhibitors; (v) lipid kinase inhibitors; (vi) antisense oligonucleotides, particularly those that inhibit gene expression in signaling mechanisms involved in aberrant cell proliferation, such as, for example, PKC-alpha, Ralf and H-Ras; (vii) ribozymes, such as inhibitors of VEGF expression (eg, ANGIOZYME®) and inhibitors of HER2 expression; (viii) vaccines, such as gene therapy vaccines, for example, ALLOVECTIN®, LEUVECTIN®, and VAXID®; PROLEUKIN® rIL-2; a topoisomerase 1 inhibitor, such as LURTOTECAN®; ABARELIX® rmRH; (ix) antiangiogenic agents, such as bevacizumab (AVASTIN®, Genentech); and (x) pharmaceutically acceptable salts, acids and derivatives of any of the foregoing. Other antiangiogenic agents include MMP-2 inhibitors (matrix metalloproteinase 2), MMP-9 inhibitors (matrix metalloproteinase 9), COX-II inhibitors (cyclooxygenase II), and VEGF tyrosine kinase receptor inhibitors. Examples of such useful metalloproteinase matrix inhibitors that can be used in combination with the present compounds / compositions (such as any of the title compounds of examples 5-14) are described in WO 96/33172, WO 96/27583, EP 818442, EP 1004578, WO 98/07697, WO 98/03516, WO 98/34918, WO 98/34915, WO 98/33768, WO 98/30566, EP 606,046, EP 931,788, WO 90/05719, WO 99/52910 , WO 99/52889, WO 99/29667, WO 99/07675, EP 945864, US Pat. No. 5,863,949, U.S. Pat. No. 5,861,510, and EP 780,386, all of them are incorporated by reference in their entirety in the present invention. Examples of VEGF receptor tyrosine kinase inhibitors include 4- (4-bromo-2-fluoroanilino) -6-methoxy-7- (1-methylpiperidin-4-ylomethoxy) quinazoline (ZD6474; Example 2 in WO 01 / 32651), 4- (4-fluoro-2-methylindole-5-yloxy) -6-methoxy-7- (3-pyrrolidin-1-ylopropoxy) -quinazoline (AZD2171; Example 240 in WO 00/47212), vatalanib ( PTK787; WO 98/35985) and SU11248 (sunitinib; WO 01/60814), and compounds, such as those described in PCT Publications Nos. WO 97/22596, WO 97/30035, WO 97/32856, and WO 98/13354 ).

[0033] Other examples of chemotherapeutic agents that can be used in combination with the present compounds (such as any of the title compounds of Examples 5-14) include inhibitors of PI3K (phosphoinositido-3 kinase), such as those described in Yaguchi et al (2006) Jour of the Nat. Cancer Inst. 98 (8): 545-556; US 7173029; US 7037915; US 6608056; US 6608053; US 6838457; US 6770641; US 6653320; US 6403588; WO 2006/046031; WO 2006/046035; WO 2006/046040; WO 2007/042806; WO 2007/042810; WO 2004/017950; US 2004/092561; WO 2004/007491; WO 2004/006916; WO 2003/037886; US 2003/149074; WO 2003/035618; WO 2003/034997; US 2003/158212; EP 1417976; US 2004/053946; JP 2001247477; JP 08175990; JP 08176070; US 6703414; and WO 97/15658, all of them are incorporated by reference in their entirety in the present invention. Specific examples of such PI3K inhibitors include SF-1126 (PI3K inhibitor, Semafore Pharmaceuticals), BEZ-235 (PI3K inhibitor, Novartis), XL-147 (PI3K inhibitor, Exelixis, Inc.) and GDC-0941 (inhibitor from PI3K, Genentech, Inc.).

[0034] The term "inflammatory diseases" as used in this application includes, but is not limited to, rheumatoid arthritis, atherosclerosis, congestive heart failure, inflammatory bowel disease (including, but not limited to, Crohn's disease and ulcerative colitis ), chronic obstructive pulmonary disease in the lung, fibrotic disease in the liver and kidney, Cohn's disease, lupus, dermal diseases, such as psoriasis, eczema and scleroderma, osteoarthritis, multiple sclerosis, asthma, diseases and disorders related to diabetic complications , organ fibrotic organ failure, such as lung, liver, kidney and inflammatory complications of the cardiovascular system, such as acute coronary syndrome.

[0035] An "anti-inflammatory agent" is a compound useful in the treatment of inflammation. Examples of anti-inflammatory agents include injectable protein therapeutic agents, such as Enbrel®, Remicade®, Humira® and Kinaret®. Other examples of anti-inflammatory agents include non-steroidal anti-inflammatory agents (NDICHOs), such as ibuprofen or aspirin (which reduce swelling and relieve pain); anti-rheumatic drugs that modify the disease (DMARDs), such as methotrexate; 5-aminosalicylates (sulfasalazine and sulfate free agenes); corticosteroids; immunomodulators, such as 6-mercaptoputin ("6-MP"), azathioprine ("AZA"), cyclosporins, and biological response modifiers, such as Remicade. RTM. (infliximab) and Enbrel.RTM. (etanercept); fibroblast growth factors; platelet derived growth factors; Enzyme blockers, such as Arava.RTM. (leflunomide); and / or a cartilage protective agent, such as hyaluronic acid, glucosamine, and chondroitin

[0036] The term "prodrug", as used in this application, refers to a precursor form or derivative of a compound of the formula (I) that is capable of being activated or converted enzymatically or hydrolytically into the parental form. more active See, for example, Wilman, "Prodrugs in Cancer Chemotherapy" Biochemical Society Transactions, 14, pp. 375-382, 615th Meeting Belfast (1986) and Stella et al., "Prodrugs: A Chemical Approach to Targeted Drug Delivery," Directed Drug Delivery, Borchardt et al., (Ed.), Pp. 247-267, Humana Press (1985). Prodrugs include, but are not limited to, prodrugs containing ester, prodrugs containing phosphate, prodrugs containing thiophosphate, prodrugs containing sulfate, prodrugs containing peptides, prodrugs containing amino acids D, glycosylated prodrugs, prodrugs containing β-lactam, prodrugs containing optionally substituted phenoxyacetamide, prodrugs containing optionally substituted phenylacetamide, 5-fluorocytosine and other 5-fluoridine prodrugs that can be converted into the most active cytotoxic free drug. Examples of cytotoxic drugs that can be derived in a prodrug form for use in this invention include, but are not limited to, compounds of the invention and chemotherapeutic agents, such as those described above.

[0037] A "metabolite" is a product produced through the metabolism in the body of a specified compound or salt thereof. The metabolites of a compound can be identified using routine techniques known in the art and their activities can be determined using tests, such as those described in the present invention. Such products may result, for example, from the oxidation hydroxylation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzymatic division, and the like, of the compound administered. Accordingly, the present invention describes metabolites of compounds of the invention, including compounds produced by a process comprising contacting a compound of the present invention with a mammal for a period sufficient to produce a metabolic product thereof.

[0038] A "liposome" is a small vesicle composed of several types of lipids, phospholipids and / or surfactants that is useful for the administration of a drug (such as the MEK inhibitors described in the present invention and, optionally, an agent chemotherapeutic) to a mammal. The components of the liposome are normally arranged in the form of a bilayer, similar to the lipid arrangement of the biological membranes.

[0039] The term "prospectus" is used to refer to instructions normally included in commercial packages of therapeutic products that contain information on indications, use, dosage, administration, contraindications and / or notices regarding the use of such products. therapeutic

[0040] The term "chiral" refers to molecules that have the property of non-superposition of the corresponding mirror image, while the term "aquiral" refers to molecules that are superimposable in their respective mirror image.

[0041] The term "stereoisomer" refers to compounds that have an identical chemical constitution and connectivity, but different orientations of their atoms in space that cannot be interconverted by rotating on single bonds.

[0042] "Diastereomer" refers to a stereoisomer with two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, for example, melting points, boiling points, spectral properties and reactivities. Mixtures of diastereomers can be separated under high resolution analytical procedures, such as crystallization, electrophoresis and chromatography.

[0043] "Enantiomers" they refer to two stereosiomers of a compound that are not mirror image superimposed on each other.

[0044] The stereochemical definitions and conventions generally used in the present invention follow the document S. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., " Stereochemistry of Organic Compounds ", John Wiley & Sons, Inc., New York, 1994. The compounds of the present invention may contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. It is intended that all stereosiomeric forms of the compounds of the present invention, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof, such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, that is, they have the ability to rotate the plane of polarized light in the plane. When describing an optically active compound, the prefixes D and L, or R and S, are used to indicate the absolute configuration of the molecules on their chiral center or centers. The prefixes d and l or (+) and (-) are used to indicate the sign of rotation of the polarized light in the plane by the compound, meaning (-) or l that the compound is levorotatory. A compound with a prefix (+) or d is dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror image to each other. A specific stereoisomer can also be referred to as an enantiomer and a mixture of said isomers is often referred to as an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which can take place when there has been no stereoselection or stereospecificity in a chemical reaction or process. The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0045] The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible through a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions through the migration of a proton, such as keto-enol and imine-enamine isomerizations. Valencia tautomers include interconversions by reorganizing some bond electrons.

[0046] The phrase "pharmaceutically acceptable salt", as used in the present invention, refers to pharmaceutically acceptable organic or inorganic salts of a compound of the present invention. Examples of salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate , ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, sucrate, formate, benzoate, glutamate, methanesulfonate “mesyloate”, ethanesufonate, benzenesulfonate, p-toluenesulfonate, pamoate (ie 1,1'-methylene-bis - (2-hydroxy-3-naphthoate)) salts, alkali metal salts (for example, sodium and potassium), alkaline earth metal salts (for example, magnesium), and ammonium salts. A pharmaceutically acceptable salt may involve the inclusion of another molecule, such as an acetate ion, a succinate ion or another counterion. The counterion can be an organic or inorganic group that stabilizes the charge in the parent compound. In addition, a pharmaceutically acceptable salt may have more than one atom charged in its structure. In cases where multiple charged atoms are part of the pharmaceutically acceptable salt they may have multiple counterions. Therefore, a pharmaceutically acceptable salt may have one or more charged atoms and / or one or more counterions.

[0047] If the compound of the invention is a base, the desired pharmaceutically acceptable salt can be prepared by any suitable method available in the art, for example, treatment of the free base with an inorganic acid, such as hydrochloric acid, acid. hydrobromic, sulfuric acid, nitric acid, methane sulphonic acid, phosphoric acid, and the like, or with an organic acid, such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid , glycolic acid, salicylic acid, a pyranosidyl acid, such as glucuronic acid or galacturonic acid, an alpha hydroxy acid, such as citric acid or tartaric acid, an amino acid, such as aspartic acid or glutamic acid, an aromatic acid, such as benzoic acid or cinnamic acid, a sulfonic acid, such as p-toluenesulfonic acid or ethanesulfonic acid, or the like.

[0048] If the compound of the present invention is an acid, the desired pharmaceutically acceptable salt can be prepared by any suitable method, for example, treatment of the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), an alkali metal hydroxide or alkaline earth metal hydroxide, or the like. Illustrative examples of suitable salts include, but are not limited to, organic salts derived from amino acids, such as glycine and arginine, ammonia, primary, secondary and tertiary amines, and cyclic amines, such as piperidine, morpholine and piperazine, and inorganic salts. derived from sodium, calcium, potassium, magnesium, manganese, iron, copper, zinc, aluminum and lithium.

[0049] The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible with the ingredients comprising a formulation, and / or the mammal treated therewith.

[0050] A "solvato" refers to an association or complex of one or more solvent molecules and a compound of the invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term " hydrate " refers to the complex in which the solvent molecule is water.

[0051] The term "protecting group" refers to a substituent that is commonly used to block or protect a particular function, while reacting other functional groups in the compound. For example, an "amine protecting group" it is a substituent attached to an amino group that blocks or protects the amine functionality in the compound. Suitable amine protecting groups include acetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ) and 9-fluorenylmethylene oxycarbonyl (Fmoc). Similarly, a "hydroxyl protecting group" refers to a substituent of a hydroxyl group that blocks or protects the hydroxyl function. Suitable protecting groups include acetyl and triakylsilyl. A "carboxyl protecting group" refers to a substituent of the carboxyl group that blocks or protects the carboxyl function. Typical carboxyl protecting groups include phenylsulfonylethyl, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxymethyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfenyl) ethyl, 2- (diphenylphosphino) -ethyl , nitroethyl, and the like. For an overview of protective groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991.

[0052] The terms "compounds of the present invention", "compounds of the invention" "compounds of formula I", "imidazopyridines" and "imidazopyridines of formula I" unless otherwise indicated, include compounds / imidazopyridines of formula I and stereoisomers, geometric isomers, tautomers, solvates and salts (eg, pharmaceutically acceptable salts) thereof.

[0053] The present invention provides imidazopyridines of formula I as described above useful as kinase inhibitors, particularly useful as MEK kinase inhibitors. In one embodiment of the present invention, when Z1 is N, then R11 ’is not aryl; and all other variables defined in formula I.

[0054] In one embodiment of the present invention, the compounds are of formula I-a and all other variables are as defined in formula I, or as defined in the embodiment described above.

[0055] In one embodiment of the present invention, R2 is H, halo, CF3, or C1-C3 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0056] In another embodiment of the present invention, R2 is H, methyl, CF3, F, or Cl; and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0057] In another embodiment of the present invention, R2 is H, F or Cl; and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0058] In one embodiment of the present invention, R3 is H, halo, CF3, or C1-C3 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0059] In another embodiment of the present invention, R3 is H, methyl, CF3, F, or Cl; and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0060] In another embodiment of the present invention, R3 is H, F or Cl; and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0061] In one embodiment of the present invention, R1 'is H or C1-C3 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments. In another embodiment, R1 ’is H, and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0062] In another embodiment of the present invention, R1 is H or C1-C3 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above. In another embodiment, R1 is H, and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above. In another embodiment, R1 is methyl, and all other variables are as defined in formula I or I-a, or as defined in any of the embodiments described above.

[0063] In one embodiment of the present invention, R4 is H or C1-C6 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0064] In another embodiment of the present invention, R4 is H or methyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments. In another embodiment of the present invention, R4 is H; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0065] In one embodiment of the present invention, R5 is H or C1-C6 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0066] In another embodiment of the present invention, R5 is H or methyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0067] In another embodiment of the present invention, R5 is H; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0068] In another embodiment of the present invention, R5 is methyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0069] In one embodiment of the present invention, X1 is OR11 ’; and all other variables are as defined in formula I or Ia; or as defined in any of the previous embodiments.

[0070] In another embodiment of the present invention, X1 is OR11 ', where R11' is H or C1-C12 alkyl (eg, C1-C6 alkyl) substituted with one or more groups independently selected from halo, CN, CF3, -OCF3, -NO2, oxo, - (CR19R20) n C (= Y ') R16, - (CR19R20) nC (= Y') OR16, - (CR19R20) nC (= Y ') NR16R17, - (CR19R20) nNR16R17 , - (CR19R20) nOR16, - (CR19R20) nSR16, - (CR19R20) nNR16C (= Y ') R17, - (CR19R20) n NR16C (= Y') OR17, - (CR19R20) nNR18C (= Y ') NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y ') R16, - (CR19R20) nOC (= Y') OR16, - (CR19R20) nOC (= Y ') NR16R17, - (CR19R20) nOS (O) 2R16, - (CR19R20) nOP (= Y ') (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16 , - (CR19R20) n S (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) nS (O) 2 (OR16), - (CR19R20) n SC (= Y ') R16, - (CR19R2O) nSC (= Y ') OR16, - (CR19R20) nSC (= Y') NR16R17, and R21; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0071] In another embodiment of the present invention, X1 is OR11 ', where R11' is heterocyclyl (for example, 4-6 membered heterocyclyl) optionally substituted with one or more groups independently selected from halo, CN, CF3, -OCF3 , -NO2, oxo, - (CR19R20) nC (= Y ') R16, - (CR19R20) nC (= Y') OR16, - (CR19R20) nC (= Y ') NR16R17, - (CR19R20) nNR16R17, - ( CR19R20) nOR16, - (CR19R20) nSR16, - (CR19R20) nNR16C (= Y ') R17, - (CR19R20) nNR16C (= Y') OR17, - (CR19R20) nNR18C (= Y ') NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y ') R16, - (CR19R20) nOC (= Y') OR16, - (CR19R20) nOC (= Y ') NR16R17, - (CR19R20) nOS (O) 2 (OR16) , - (CR19R20) nOP (= Y ') OR16 (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - ( CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) n S (O) 2 (OR16), - (CR19R20) nSC (= Y ') R16, - (CR19R20) nSC (= Y ') OR16, - (CR19R20) n SC (= Y') NR16R17, and R21; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0072] In another embodiment of the present invention, X1 is OR11 ', where R11' is a 4 to 6-membered heterocyclic having a ring nitrogen atom, wherein said heterocyclyl is optionally substituted with one or more independently selected groups between halo, CN, CF3, -OCF3, -NO2, oxo, - (CR19R20) nC (= Y ') R16, - (CR19R20) n C (= Y') OR16, - (CR19R20) nC (= Y ') NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) nSR16, - (CR19R20) nNR16C (= Y ') R17, - (CR19R20) nNR16C (= Y') OR17, - (CR19R20) n NR18C (= Y ') NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y') R16, - (CR19R20) nOC (= Y ') OR16, - (CR19R20) nOC (= Y') NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y ') (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16 , - (CR19R20) nS (O) 2R16, - (CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) n S (O) 2 (OR16), - (CR19R20 ) nSC (= Y ') R16, - (CR19R20) nSC (= Y') OR16, - (CR19R20) n SC (= Y ') NR16R17, and R21; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0073] In another embodiment of the present invention, X1 is: and all other variables are as defined in formula I or I-a, or as defined in any of the above embodiments.

[0074] In another embodiment of the present invention, X1 is

and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0075] In another embodiment of the present invention, X1 is

and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0076] In one embodiment of the present invention, X1 is R11 ’; and all other variables are as they have been defined in formula I or Ia, or as defined in any of the previous embodiments.

[0077] In another embodiment of the present invention, X1 is R11 ’, where R11’ is H or C1-C12 alkyl (eg, alkyl C1-C6) substituted with one or more groups independently selected from halo, CN, CF3, -OCF3, -NO2, oxo, -If (C1-C6 alkyl) 3, - (CR19R20) n C (= Y ') R16, - (CR19R21) nC (= Y') OR16, - (CR19R20) nC (= Y ') NR16R17, - (CR19R20 ) nNR16R17, - (CR19R20) nOR16, - (CR19R20) nSR16, - (CR19R20) nNR16C (= Y ’) R17, - (CR19R20) n NR16C (= Y’) OR17, - (CR19R20) nNR18C (= Y ’) NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y’) R16, - (CR19R20) nOC (= Y ’) OR16, - (CR19R20) nOC (= Y ’) NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y’) (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - (CR19R20) n S (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) nS (O) 2 (OR16), - (CR19R20) n SC (= Y ’) R16, - (CR19R20) nSC (= Y’) OR16, - (CR19R20) nSC (= Y ’) NR16R17, and R21; and all the other variables are as defined in formula I or Ia, or as defined in any of the previous embodiments.

[0078] In another embodiment of the present invention, X1 is

and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0080] In another embodiment of the present invention, X1 is

and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0081] In another embodiment of the present invention, R5 is methyl and X1 is and all other variables are as defined in formula I or I-a, or as defined in any of the above embodiments.

[0082] In one embodiment of the present invention, X1 is R11 'and X1 is taken together with R5 and the nitrogen atom to which they are attached to form a 4-5 membered saturated cyclic ring having 0-2 additional heteroatoms selected between OS and N, wherein said cyclic ring is optionally substituted with one or more groups selected from halo, CN, CF3, -OCF3, -NO2, oxo, - (CR19R20) nC (= Y ') R16, - (CR19R20) n C (= Y ') OR16, - (CR19R20) nC (= Y') NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) n-SR16, - (CR19R20) nNR16C (= Y ') R17, - (CR19R20) n NR16C (= Y ') OR17, - (CR19R20) n NR18C (= Y') NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y ') R16, - (CR19R20) nOC (= Y ') OR16, - (CR19R20) nOC (= Y') NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y ') (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17, - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - (CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O) ( OR16), - (CR19R20) n S (O) 2 (OR16), - (CR19R20) n SC (= Y ') R16, - (CR19R20) n SC (= Y') OR16, - (CR19R20) n SC ( = Y ') NR16R17 , and R21; and all other variables are as defined in formula I or I-a, or as defined in any of the above embodiments.

[0083] In another embodiment of the present invention, W is:

and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0084] In one embodiment of the present invention, W is -OR11 "where R11" is H or C1-C12 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0085] In another embodiment of the present invention, W is -OR11 "where R11" is H; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0086] In another embodiment of the present invention, W is -OR11 "where R11" is C1-C6 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0087] In one embodiment of the present invention, W ’is -NHSO2R8; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0088] In one embodiment of the present invention, R6 is halo, C2-C8 alkynyl, carbocyclyl, or -SR16; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0089] In another embodiment of the present invention, R6 is halo, C2-C3 alkynyl, C3 carbocyclyl, or -SR16 where R16 is C2-C2 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0090] In one embodiment of the present invention, R6 'is H, halo, or C1-C3 alkyl; and all other variables are as defined in formula I or I-a, or as defined in any of the previous embodiments.

[0091] In one embodiment of the present invention, p is 1 or 2; and all other variables are as defined in formula I or Ia, or as defined in any of the previous embodiments.

[0092] In one embodiment of the present invention, X4 is 10 and all other variables are as defined in formula 1 or I-a, or as defined in any of the above embodiments.

[0093] In another embodiment of the present invention, X4 is and all other variables are as defined in formula I or I-a, or as defined in any of the above embodiments.

[0094] Another embodiment of the present invention includes compounds described in Examples 5-15 and the following compounds:

[0095] Preparation of compounds of formula I

[0096] The imidazopyridines of formula I are prepared according to the procedures described below in the schemes and examples or by methods known in the art. For example, the compounds of formula (I), where Y = W-C (O) - can be prepared according to Scheme 1.

Scheme 1

[0097] Isonicotinic acids of general structure (II) can be obtained commercially or prepared using methods described in the literature. The acids (II) can be converted into esters of formula (III) by reaction with a chlorinating agent, such as oxalyl chloride, in the presence of a catalyst, such as DMF, in a solvent, such as DCM, followed by treatment with an alkyl alcohol, such as methanol. Alternatively, acids (II) can be reacted in an alkyl alcohol in the presence of an acid, such as sulfuric acid, to provide esterified formula (III).

[0098] 2-Cyanopyridines (IV) can be prepared from 2-halo pyridines (III) by reaction with an inorganic cyanide, such as zinc cyanide, in the presence of a transition metal catalyst, such as Zn, tetrakis (triphenylphosphine) palladium (0) or tris- (dibenzylidenacetone) dipaladium (0) / 1,1'-bis (diphenylphosphino) ferrocene, in a solvent, such as DMF, at a temperature from 50 ° C to reflux temperature , or under microwave radiation at a temperature between 70 ° C to 200 ° C.

[0099] Cyano pyridines (IV) can be reduced to produce 2-aminomethyl pyridines (V), A = CH2, by reacting on hydrogen at a pressure between 1 to 5 atmospheres, in the presence of a catalyst, such as palladium on carbon, in a solvent, such as methanol, acetic acid or formic acid, with or without added strong acid, such as concentrated hydrochloric acid. Alternatively, cyanopyridines (IV) can be converted to 2-aminomethyl pyridines by reaction with an inorganic metal hydride, such as sodium borohydride, in the presence of a metal salt, such as cobalt chloride, in a solvent, such as methanol, at a temperature from 0 ° C to room temperature. Alternatively, the compounds of formula (V), A = NH, can be prepared from the compounds of formula (III) by reaction with hydrazine hydrate, in the presence of a solvent, such as ethanol, at a temperature of 0 ° C to reflux.

[0100] The compounds of formula (VI) may be prepared from the compounds (V) by reaction with an anhydride, such as acetic anhydride, or mixed anhydrides, such as formic-acetic anhydride, in a solvent, such as tetrahydrofuran, at a temperature of 0 ° C until reflux.

[0101] The compounds of formula (VII) can be prepared from compounds (VI) by reaction with a chlorinating agent, such as phosphorus oxychloride, in a solvent such as toluene, at a temperature of 25 ° C to reflux . Alternatively, the compounds of formula (VII) can be prepared from compounds of formula (VI) by reaction with an acid, such as formic acid, pure or in a solvent such as dioxane, at a temperature of 50 ° C to Reflux.

[0102] Compounds of formula (VIII) may be prepared from compounds of formula (VII) by reaction with an aniline (incorporating the appropriate R1 substituents), in the presence of a base such as lithium bis (trimethylsilyl) amide , in a solvent such as THF, at a temperature of -78 ° C to room temperature. Alternatively, the compounds of formula (VIII) can be prepared from the compounds of formula (VII) by reaction with an aniline ((incorporating the appropriate R1 substituents), in the presence of a catalyst, such as tris (dibenzylidenacetone) dipaladium (0), a base such as potassium phosphate, a ligand, such as 2-dicyclohexylphosphino-2 ', 6' - (diisopropoxy) biphenyl, in a suitable solvent, such as toluene, at a temperature of ambient temperatures up to reflux temperature of the solvent, or under microwave radiation at a temperature of 70 ° C to 150 ° C.

[0103] The compounds of formula (IX) can be obtained from the compounds of formula (VIII) by reaction with a base, such as sodium hydroxide, in a protic solvent, such as ethanol or methanol, at a temperature from room temperature to reflux temperature.

[0104] Compounds of formula (IX) can be reacted with a funkylated hydroxylamine of formula

(XII) (commercially available or prepared) or an amine and a suitable coupling agent, such as O- (7-aza-benzo-triazol-1-yl) -N, N, N ', N'- hexafluoro phosphate tetra-methylouronium, N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride or N, N'-dicyclohexylcarbodiimide in the presence of N-hydroxy-1,2,3-benzotriazole, in the presence of a suitable base, such as diisopropylethylamine or triethylamine in an inert solvent, such as tetrahydrofuran, N, N-dimethylformamide, or dichloromethane at a temperature from about room temperature, until the compounds of formula (X) are obtained. The compounds of formula

(X)

they can be obtained directly from the compounds of formula (VIII) by reaction with an amine

or hydroxylamine DNHR in the presence of a Lewis acid, such as trimethyl aluminum in a solvent, such as DCM, at a temperature from room temperature to reflux temperature. Alternatively, the compounds of formula (X) can be prepared from the compounds of formula (VIII) by treatment with a DNHR functionalized hydroxylamine in the presence of a basem such as lithium bis (trimethylsilyl) amide in a solvent, such as THF, at a temperature of -78 ° C to 25 ° C.

[0105] The compounds of formula (I) where Y = R8SO2NH- can be prepared according to scheme 2. Scheme 2

[0106] The compounds of formula (XVI) can be prepared from the compounds of formula (IX) by treatment with diphenylphosphoryl azide in a solvent, such as toluene, in the presence of a base such as triethylamine. The compounds of formula (XVII) can be prepared from the compounds of formula (XVI) by treatment with a base such as sodium hydride in a solvent such as DMF, followed by

5 reaction with a sulfonyl chloride (appropriately substituted). The compounds of formula (XVIII) can be prepared from the compounds of formula (XVII) by deprotection using a base, such as sodium hydroxide in a solvent such as DMF at a temperature of 50 ° C to 150 ° C.

[0107] Hydroxylamines of formula (XII) can be prepared using methods described in the literature or synthetic route 10 described in scheme 3.

Scheme 3

[0108] Primary or secondary alcohols of general formula (XXXVII) can be prepared using the methods described in the literature. They can be reacted with N-hydroxy phthalimide using a phosphine and a coupling reagent, such as diethyl azodicarboxylate to produce compounds of the general formula (XXXVIII). The compounds of the general formula (XXXVIII) can be deprotected using hydrazine or methyl hydrazine to produce hydroxylamines of the general formula (XII-a).

[0109] The compounds of formula (XII-a) may be further modified by reductive amination with aldehydes or ketones using a reducing agent, such as sodium triacetocyl borohydride, sodium cyanoborohydride, or borane-pyridine in a solvent, such as dichloroethane at room temperature to reflux. In addition, the compounds of formula (XII-a) can be further modified by alkylation with a

Alkyl halide in the presence of a base, such as triethylamine, in a solvent, such as dichloromethane, to produce hydroxylamines of the general formula (XII-b).

[0110] Alternatively, the hydroxylamines of formula (XII-a) can be prepared according to scheme 4.

45 Scheme 4

[0111] The alkyl halides of formula (XL) can be reacted with N-hydroxy phthalimide in the presence of

50 a base, such as potassium carbonate in a solvent such as dimethyl sulfoxide at a temperature of 10 ° C to 50 ° C. Compounds of formula (XLI) can be converted to compounds of formula (XII) using the methods described for the conversion of compounds of formula (XXXVIII) into compounds of formula (XII) in scheme 3.

[0112] Alternatively, the compounds of formula (XII-a) can be prepared according to scheme 5.

Scheme 5

[0113] The compounds of formula (XLII) can be reacted with N-hydroxyphthalimide in the presence of a catalytic amount of a base, such as DIPEA, and a co-catalyst, such as tetrabutyl ammonium bromide in a solvent, such as toluene at a temperature from 50 ° C to reflux. The compounds of formula (XLIII) can be converted into the compounds of formula (XII) using the methods described for the conversion of the compounds of formula (XXXVIII) into the compounds of formula (XII) in Scheme 3.

[0114] The anilines of the general formula (XXXI) used in the cross-coupling reactions described above can be prepared using methods described in the literature or according to Scheme 6.

Scheme 6

[0115] The substituted 1-chloro-4-nitro benzene can be reacted with a metallic RMXn, such as cyclopropyl boronic acid or hexamethyldisilazane, in a solvent such as xylene, using a catalyst, such as tetrakis (triphenylphosphine) palladium, a a temperature from room temperature to reflux to produce the compounds of formula (XXX). The nitro group can be reduced using methods described in the literature, such as a reaction under a hydrogen atmosphere at a pressure of 1 to 5 atmospheres, in the presence of a catalyst, such as palladium on carbon, and in a solvent, such as ethanol or ethyl acetate at room temperature, to produce the compounds of formula (XXXI).

[0116] Alternatively, the anilines of formula (LV) can be prepared according to scheme 7.

Scheme 7

[0117] 4-Bromo or iodine anilines of formula (LIV) can be reacted with at least 2 equivalents of a strong organometallic base, such as n-butyllithium in a solvent, such as THF, at a temperature of -100 ° C to -20 ° C, followed by deactivation of the intermediate of aryl lithium species with an electrophile, such as trimethyl silyl chloride, to produce the compounds of formula (LV).

[0118] It will be understood that when appropriate functional groups exist, the compounds of formula (I) or any intermediate used in their preparation can be derived by one or more standard synthetic methods using substitution, oxidation, reduction or division reactions. Particular substitution strategies include conventional alkylation, arylation, heteroarylation, acylation, sulfonylation, halogenation, nitration, formylation and coupling procedures.

[0119] For example, the bromide or aryl chloride groups can be converted to aryl iodides using a FInkelstein reaction using a iodide source, such as sodium iodide, a catalyst, such as copper iodide and a ligand, such as trans-N, N'-dimethyl-1,2-cyclohexane diamine in a solvent such as 1,4-dioxane and heating the reaction mixture at reflux temperature. Aryl trialkylsilanes can be converted to aryl iodides by treating silanmo with an iodide source, such as iodine monochloride, in a solvent such as dichloromethane with or without a Lewis acid, such as silver tetrafluoroborate at a temperature from -40 ° C to reflux.

[0120] In a further example, the primary amine groups (-NH2) can be rented using a reductive alkylation process using an aldehyde or a ketone and a borohydride, for example, sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent such as a halogenated hydrocarbon, for example 1,2-dichloroethane, or an alcohol, such as ethanol, when necessary, in the presence of an acid, such as acetic acid around room temperature. Secondary amine groups (-NH-) can be similarly rented using an aldehyde.

[0121] In a further example, primary or secondary amine groups can be converted to amide groups (-NHCOR ’or -NRCOR’) by acylation. Acylation can be achieved by reacting with an appropriate acid chloride in the presence of a base, such as triethylamine, in a suitable solvent, such as dichloromethane, or by reacting with an appropriate carboxylic acid in the presence of a suitable coupling agent. , such as HATU (O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylouronium hexafluorophosphate) in a suitable solvent, such as dichloromethane. Similarly, the amine groups can be converted into sulfonamide groups (-NHSO2R 'or -NR "SO2R") by reaction with an appropriate sulfonyl chloride in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane. The primary or secondary amine groups can be converted into urea groups (-NHCONR'R " or -NRCONR'R ") by reaction with an appropriate isocyanate in the presence of a suitable base, such as triethylamine, in a suitable solvent, such as dichloromethane

[0122] An amine (-NH2) can be obtained by reducing a nitro group (-NO2), for example, by catalytic hydrogenation, using for example hydrogen in the presence of a metal catalyst, for example palladium on a support, such as carbon, in a solvent, such as, ethyl acetate or an alcohol for example methanol. Alternatively, the transformation can be carried out by chemical reduction using, for example, a metal, for example tin or iron, in the presence of an acid, such as hydrochloric acid.

[0123] In a further example, amine groups (-CH2NH2) can be obtained by reducing nitriles (-CN), for example by catalytic hydrogenation using for example hydrogen in the presence of a metal catalyst, for example palladium on a support, such as carbon, or Raney nickel, in a solvent, such as an ether, for example a cyclic ether, such as tetrahydrofuran, at a temperature from -78 ° C to the reflux temperature of the solvent.

[0124] In a further example, the amine groups (-NH2) can be obtained from carboxylic acid groups (-CO2H) by conversion into the corresponding acyl azide (-CON3), Curtius restructuring and the resulting isocyanate hydrolysis ( -N = C = O).

[0125] Aldehyde groups (-CHO) can be converted to amine groups (-CH2NR'R ")) by reductive amination using an amine and a borohydride, for example sodium triacetoxyborohydride or sodium cyanoborohydride, in a solvent, such as a halogenated hydrocarbon, for example dichloromethane, or an alcohol, such as ethanol, when necessary, in the presence of an acid, such as acetic acid around room temperature.

[0126] In a further example, the aldehyde groups can be converted to alkenyl groups (-CH = CHR ') by using the Wittig or Wadsworth-Emmons reaction using a suitable phosphorane or phosphonate under standard conditions known to those skilled in the art. The matter.

[0127] Aldehyde groups can be obtained by reducing ester groups (such as -CO2Et) or nitriles (-CN) using diisobutylaluminum hydride in a suitable solvent, such as toluene. Alternatively, aldehyde groups can be obtained by oxidation of alcohol groups using any suitable oxidizing agent known to those skilled in the art.

[0128] Ester groups (-CO2R ') can be converted into the corresponding acid group (-CO2H) by acid or base catalyzed hydrolysis, depending on the nature of R. If R is t-butyl, catalyzed hydrolysis by acid it can be achieved for example by treatment with an organic acid, such as trifluoroacetic acid in an aqueous solvent, or by treatment with an inorganic acid, such as hydrochloric acid in an aqueous solvent.

[0129] The carboxylic acid groups (-CO2H) can be converted to amides (CONHR 'or -CONR'R ") by reaction with an appropriate amine in the presence of a suitable coupling agent, such as HATU, in a suitable solvent , such as dichloromethane.

[0130] In a further example, the carboxylic acids can be elongated on a carbon (ie -CO2H to -CH2CO2H) by conversion to the corresponding acid chloride (-COCl) followed by the synthesis of Arndt-Eistert.

[0131] In a further example, the -OH groups can be generated from the corresponding ester (for example -CO2R '), or aldehyde (-CHO) by reduction, using for example a complex metal hydride, such as lithium hydride and aluminum in diethyl ether or tetrahydrofuran, or sodium borohydride in a solvent, such as methanol. Alternatively, an alcohol can be prepared by reducing the corresponding acid (-CO2H), using for example lithium aluminum hydride in a solvent, such as tetrahydrofuran, or using borane in a solvent, such as tetrahydrofuran.

[0132] The alcohol groups can be converted into leaving groups, such as halogen atoms or sulfonyloxy groups, such as an alkylsulfonyloxy, for example trifluoromethylsulfonyloxy or arylsulfonyloxy, for example a p-toluenesulfonyloxy group using conditions known to those skilled in the art. For example, an alcohol can react with thionyl chloride in a halogenated hydrocarbon (for example dichloromethane) to produce the corresponding chloride. A base (for example triethylamine) can also be used in the reaction.

[0133] In another example, the alcohol, phenol or amide groups can be rented by coupling a phenol or an amide with an alcohol in a solvent, such as tetrahydrofuran in the presence of a phosphine, for example triphenylphosphine and an activator, such as diethyl- , diisopropyl, or dimethylazodicarboxylate. Alternatively, alkylation can be achieved by deprotonation using a suitable base, for example sodium hydride followed by the subsequent addition of an alkylating agent, such as an alkyl halide.

[0134] The aromatic halogen substituents in the compounds can be subjected to a halogen-metal exchange by treatment with a base, for example, a lithium base, such as n-butyl or t-butyl lithium, optionally at low temperature , for example around -78 ° C, in a solvent, such as tetrahydrofuran, and then the reaction with an electrophile is deactivated to introduce a desired substituent. Thus, for example, a formyl group can be introduced using N, N-dimethylformamide as an electrophile. The halogen aromatic substituents may alternatively be subjected to metal-catalyzed reactions (for example, palladium or copper) to introduce, for example, acid, ester, cyano, amide, aryl, heteroaryl, alkenyl, alkynyl, thio-or amino substituents. Suitable procedures that can be used include those described by Heck, Suzuki, Stille, Buchwald or Hartwig.

[0135] Aromatic halogen substituents may also undergo a nucleophilic shift after reaction with an appropriate nucleophile, such as an amine or an alcohol. Advantageously, said reaction can be carried out at elevated temperature in the presence of microwave radiation.

[0136] The compounds of the present invention are analyzed for their ability to inhibit the activity and activation of MEK (primary assays) and for their biological effects on growing cells (secondary assays) as described below. Compounds of the present invention having an IC50 of less than 5 µM (more preferably less than 0.1 µM, most preferably less than 0.01 µM) in the MEK activity assay of Example 1, an IC50 of less than 5 µM (more preferably less than 1 µM, even more preferably less than 0.1 µM, most preferably less than 0.01 µM) in the MEK activation test of Example 2, EC50 less than 10 µM (more preferably less than 1 µM, even more preferably less than 0.5 µM, most preferably less than 0.1 µM) in the cell proliferation assay of Example 3, and / or EC50 less than 10 µM (more preferably less than 1 µM, even more preferably less than 0.5 µM, most preferably less than 0.1 µM) in the ERK phosphorylation test of example 4, they are useful as MEK inhibitors.

[0137] The present invention includes a composition (for example, a pharmaceutical composition) comprising a compound of formula I (and / or solvates and / or salts thereof) and a carrier (a pharmaceutically acceptable carrier). The present invention also includes a composition (for example, a pharmaceutical composition) comprising a compound of formula I (and / or solvates and / or salts thereof) and a carrier (a pharmaceutically acceptable carrier), further comprising a second agent chemotherapeutic and / or a second anti-inflammatory agent, such as those described in the present invention. The present compositions are useful for inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (eg, human). The present compositions are also useful for treating inflammatory diseases in a mammal (eg, human).

[0138] The present compounds and compositions are also useful for treating an autoimmune disease, a bone-destroying disorder, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (eg, human). Examples of such diseases / disorders include, but are not limited to, diabetes and diabetic complications, diabetic retinopathy, premature retinopathy, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, rhinitis and atopic dermatitis, kidney disease and kidney failure. , polycystic kidney disease, congestive heart failure, neurofibromatosis, organ transplant rejection, cachexia, stroke, septic shock, heart failure, organ transplant rejection, Alzheimer's disease, chronic pain

or neuropathic, and viral infections, such as HIV, hepatitis (B) virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Chronic pain, for the purposes of the present invention, includes, but is not limited to, idiopathic pain and pain associated with chronic alcoholism, vitamin deficiency, uremia, hypothyroidism, inflammation, arthritis, and pain after operations. Neuropathic pain is associated with numerous conditions that include, but are not limited to, inflammation, pain after operations, phantom limb pain, butt pain, gout, trigeminal neuralgia, acute herpetic or postherpetic pain, causalgia, diabetic neuropathy, avulsion of the plexus, neuroma, vasculitis, viral infection, crush injury, constriction injury, tissue injury, limb amputation, arthritis pain and nerve injury between the peripheral nervous system and the central nervous system.

[0139] The present compounds and compositions are also useful for treating pancreatitis or kidney disease (including proliferative glomerulonephritis and diabetes-induced kidney disease) in a mammal (eg, human).

[0140] The present compounds and compositions are also useful for the prevention of blast implantation in a mammal (eg, human).

[0141] The present invention includes a compound of formula I for use in a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (eg, human). Also included in the present invention is a compound of formula I for use in a method of treating an inflammatory disease in a mammal (eg, human).

[0142] The present invention describes a method of inhibiting abnormal cell growth or treating a hyperproliferative disorder in a mammal (eg, human) comprising administering to said mammal a therapeutically effective amount of a compound of Formula I (and / or solvates and / or salts thereof) or a composition thereof, in combination with a second chemotherapeutic agent, such as those described in the present invention. The present invention also describes a method of treating an inflammatory disease in a mammal (eg, human) comprising administering to said mammal a therapeutically effective amount of a compound of formula I (and / or solvates and / or salts thereof) or a composition thereof, in combination with a second anti-inflammatory agent, such as those described in the present invention.

[0143] The present invention describes a method of treating an autoimmune disease, bone-destroying disorder, proliferative disorders, infectious disease, viral disease, fibrotic disease or neurodegenerative disease in a mammal (eg, human) comprising administering said mammal a therapeutically effective amount of a compound of Formula I (and / or solvates and / or salts thereof) or a composition thereof, and optionally further comprising a second chemotherapeutic agent. Examples of such diseases / disorders include, but are not limited to, diabetes and diabetes complications, diabetic retinopathy, prematurity retinopathy, age-related macular degeneration, hemangioma, idiopathic pulmonary fibrosis, fibrosis, rhinitis and atopic dermatitis, kidney disease and insufficiency. renal, polycystic kidney disease, congestive heart failure, neurofibromatosis, organ transplant rejection, cachexia, stroke, septic shock, heart failure, organ transplant rejection, Alzheimer's disease, chronic or neuropathic pain and viral infections, such as HIV, hepatitis (B) virus (HBV), human papillomavirus (HPV), cytomegalovirus (CMV) and Epstein-Barr virus (EBV).

[0144] The present invention describes a method of treating pancreatitis or renal disease (including proliferative glomerulonephritis and renal disease induced by diabetes) in a mammal (eg, human) comprising administering to said mammal a therapeutically effective amount of a compound of Formula I (and / or solvates and salts thereof) or a composition thereof, and optionally further comprising a second therapeutic agent.

[0145] The present invention describes a method of preventing blast implantation in a mammal (eg, human) comprising administering to said mammal a therapeutically effective amount of a compound of Formula I (and / or solvates and salts thereof) ) or a composition thereof, and optionally further comprising a second therapeutic agent.

[0146] The present invention describes a method of using the present compounds for in vitro, in situ, and in vivo diagnosis or treatment of mammalian cells, organisms or associated pathological conditions.

[0147] It is also believed that the compounds of the present invention can make the abnormal cells more sensitive to radiation treatment in order to eliminate and / or inhibit the growth of said cells. Accordingly, the present invention further describes a method of sensitizing abnormal cells in a mammal (eg, human) for radiation treatment comprising administering to said mammal a therapeutically effective amount of a compound of Formula I (and / or solvates and salts thereof) or a composition thereof, the amount of which is effective in sensitizing abnormal cells to radiation treatment.

[0148] The admission of the compounds of the present invention (hereinafter "the compound or active compounds" can be carried out by any method that allows the release of the compounds to the site of action. These methods include oral routes, intraduodenal routes , parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion), topical, by inhalation and rectal administration.

[0149] The amount of active compound administered will depend on the subject being treated, the severity of the disorder

or condition, the speed of administration, the disposition of the compound and the criteria of the doctor. However, an effective dose in the range of about 0.001 to about 100 mg per kg of body weight per day, preferably about 1 to about 35 mg / kg / day, in individual or divided doses. For a 70 kg human, this would represent approximately 0.05 to 7 g / day, preferably approximately 0.05 to approximately 2.5 g / day. In some cases, dosage levels below the lower limit of the aforementioned range may be more than adequate, while in other cases even larger doses may be used without causing any harmful side effects, provided that such larger doses are divided first in various small doses for administration throughout the day.

[0150] The active compound may be applied as a single therapy or in combination with one or more chemotherapeutic or anti-inflammatory agents, for example those described in the present invention. Said joint treatment can be achieved by simultaneous, sequential or separate dosing of the individual components of the treatment.

[0151] The pharmaceutical composition may be, for example, in a form suitable for oral administration as a tablet, capsule, tablet, powder, prolonged release formulations, solution, suspension, for parenteral injection as sterile solution, suspension or emulsion, for topical administration as an ointment or cream or for rectal administration as a suppository. The pharmaceutical composition may be in unit dosage forms suitable for individual administration of exact doses. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient and a compound according to the present invention as active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0152] Exemplary parenteral admission forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms, if desired, can be buffered appropriately.

[0153] Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions, if desired, may contain additional ingredients, such as flavorings, binders, excipients and the like. Thus, for oral administration, tablets containing various excipients, such as citric acid, can be used together with various disintegrants, such as starch, alginic acid and certain complex silicates and with binding agents, such as sucrose, gelatin and acacia. Additionally, lubricating agents, such as magnesium stearate, sodium lauryl sulfate and talc are often useful for obtaining tablets. Solid compositions of a similar type can also be used in soft and hard filled gelatin capsules. Therefore, preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring or coloring materials and, if desired, emulsifying agents or suspending agents, together with diluents, such such as water, ethanol, propylene glycol, glycerin or combinations thereof.

[0154] The methods of preparing various pharmaceutical compositions with a specific amount of active compound are known or will be apparent to those skilled in the art. For example, see Remington’s Pharmaceutical Sciences, Mack Publishing Company, Ester, Pa., 15.sup.th Edition (1975).

EXAMPLES

Abbreviations

[0155]

nBu Li n-Butyl lithium CDCl3 deuterated chloroform CD3OD Deuterated methanol DCM Dichloromethane DIPEA Diisopropylethylamine DMF Dimethylformamide DMSO Dimethylsulfoxide Dppf 1,1'-Bis (diphenylphosphino) ferrocene EDCI 1-ethyl-3-ethylamine T-3-ethylamine T-3-ethylamine O- (7-Azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium HCl hydrochloric acid Hyflo® diatomaceous earth HOBt 1-Hydroxybenzotriazole IMS Industrial methylated alcohol K3PO4 Triassic potassium phosphate LHMDS bis (trimethyl trimethyl LHMDS bis) lithium amide MeOH Methanol NaOH Sodium hydroxide Pd (PPh3) 4 Tetrakis (triphenylphosphine) palladium (0) Pd2dba3 Tris- (dibenzylidenacetone) dipaladium (0) Si-PPC Cartridge for flash chromatography “prepackaged silica: Isolute® SPE, Biotage SNAP ® or ISCO Redisep® SCX-2 Isolute ® silica based sorbent with a chemically bonded THF Tetrahydrofuran chemically bonded acid functional group

[0156] General experimental conditions

[0157] 1H NMR spectra were recorded at room temperature using a Varian Unity Inova spectrometer (400MHz) with a 5mm triple resonance probe. Chemical shifts are expressed in ppm relative to tetramethylsilane. The following abbreviations have been used: br = broad signal, s = singlet, d = doublet, dd = double doublet, t = triplet, q = quartet, m = multiplet.

[0158] Experiments with High Liquid Chromatography - Mass Spectrometry (LCMS) to determine retention times (RT) and associated mass ions were performed using one of the following methods.

[0159] Method. A: The experiments were performed on a Waters Micromass ZQ quadrupole mass spectrometer attached to a Hewlett Packard HP1100 LC system with a diode device detector. This system uses a Higgins Clipeus 5 micron C18 100 x 3.0mm column and a flow rate of 1 ml / minute. The initial solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetronitrile containing 0.1% formic acid (solvent B) for the first minute followed by a gradient of up to 5% solvent A and 95% solvent B for the next 14 minutes. The final solvent system was kept constant for another 5 minutes.

[0160] Method B: The experiments were performed on a Waters Platform LC quadrupole mass spectrometer attached to a Hewlett Packard HP1100 LC system with a diode device detector and 100 autosamplers in position using a Phenomenex Luna C 18 column (2 ) 30 x 4.6mm and a flow rate of 2 ml / min. The solvent system was 95% water containing 0.1% formic acid (solvent A) and 5% acetronitrile containing 0.1% formic acid (solvent B) for the first 0.5 min followed by a gradient of up to 5% solvent A and 95% solvent B for the next 4 minutes. The final solvent system was kept constant for an additional 0.5 minutes.

[0161] Experiments with microonates were carried out using a Personal Chemistry Emrys Initiator ™ or Optimizer ™, which uses an individual mode resonator and dynamic field adjustment, producing both reproducibility and control. A temperature of 40-250 ° C can be achieved and pressures of up to 20 bar can be achieved.

[0162] EXAMPLE 1: MEK test (MEK activity test)

[0163] Constitutively activated human mutant MEK1 expressed in insect cells is used as a source of enzymatic activity at a final concentration in the 15 nM kinase assay.

[0164] The assay is carried out for 30 minutes in the presence of 50 µM ATP using recombinant GST-ERK1 produced in E. Coli as a substrate. Phosphorylation of the substrate is detected and quantified using HTRF reagents supplied by Cisbio. These consist of an allophycocyanin-conjugated anti-GST antibody (XL665) and an anti-phosphorus ERK antibody (ThR202 / TyR204) conjugated to europium cryptate. These are used at a final concentration of 4 µg / ml and 0.84 µg / ml, respectively. The anti-phospho antibody recognizes duplicate phosphorylated ERK1 in ThR202 and TyR204. When both antibodies are bound to ERK1 (that is, when the substrate is phosphorylated), the transfer of energy from the cryptate to the allophycocyanin takes place after excitation at 340 nm, resulting in a fluorescence emission that is proportional to the amount of phosphorylated substrate produced. Fluorescence is detected using a multiwell fluorimeter.

[0165] The compounds are diluted in DMSO before addition to the assay buffer and the final concentration of DMSO in the assay is 1%.

[0166] IC50 is defined as the concentration at which a given compound achieves 50% control inhibition. The IC50 values are calculated using the XLfit software package (version 2.0.5).

[0167] The compounds of examples 5-14 showed an IC50 of less than 1 µM in the assay described in the example

one.

[0168] EXAMPLE 2 bRaf test (MEK activation test)

[0169] Constitutively activated mutant bRaf expressed in insect cells is used as a source of enzymatic activity

[0170] The assay is carried out for 30 minutes in the presence of 200 µM ATP using recombinant GST-MEK1 produced in E. Coli as a substrate. Phosphorylation of the substrate is detected and quantified using HTRF and reagents supplied by Cisbio. These consist of an allophycocyanin-conjugated anti-GST antibody (XL665) and an anti-phospho MEK (Ser217 / Ser221) antibody conjugated to europium crypto. The anti-phospho antibody recognizes MEK phosphorylated in duplicate in Ser217 and Ser221 or phosphorylated only in Ser217. When both antibodies are bound to MEK (that is, when the substrate is phosphorylated), the transfer of energy from the cryptate to the allophycocyanin takes place after excitation at 340 nm, resulting in a fluorescence emission that is proportional to the amount of phosphorylated substrate produced. Fluorescence is detected using a multiwell fluorimeter.

[0171] The compounds are diluted in DMSO before addition to the assay buffer and the final concentration of DMSO in the assay is 1%.

[0172] IC50 is defined as the concentration at which a given compound achieves 50% inhibition of control. The IC50 values are calculated using the XLfit software package (version 2.0.5).

[0173] EXAMPLE 3 Cell Proliferation Assay

[0174] The compounds are analyzed in a cell proliferation assay using the following cell lines:

[0175] HCT116 human colorectal carcinoma (ATCC)

[0176] Human malignant melanoma A375 (ATCC) [0177] Both cell lines are maintained in DMEM / F12 (1: 1) medium (Gibco) supplemented with 10% FCS at 37 ° C in a humidified incubator with 5% of CO2

[0178] The cells are seeded in 96-well plates at 2,000 cells / well and after 24 hours they are exposed to different concentrations of compounds in 0.83% DMSO. The cells develop for an additional 72 hours and an equal volume of CellTiter-Glo reagent (Promega) is added to each well. This smooths the cells and generates a luminescent signal proportional to the amount of ATP released (and therefore proportional to the number of cells in the well) that can be detected using a multiwell luminometer.

[0179] EC50 is defined as the concentration at which a given compound achieves 50% inhibition of control. The IC50 values are calculated using the XLfit software package (version 2.0.5).

[0180] In this assay, the compounds of examples 5-11 and 13-14 showed an EC50 of less than 10 µM in both cell lines. The title compound of Example 12 showed an EC50 of less than 0.1 µM in the HCT116 cell line.

[0181] EXAMPLE 4 Assay based on phospho-ERK cells

[0182] The compounds are analyzed in an ELISA based on phospho-ERK cells using the following cell lines:

[0183] HCT116 human colorectal carcinoma (ATCC)

[0184] Human malignant melanoma A375 (ATCC)

[0185] Both cell lines are maintained in a DMEM / F12 (1: 1) medium (Gibco) supplemented with 10% FCS at 37 ° C in a humidified incubator with 5% CO2.

[0186] The cells are seeded in 96-well plates at 2,000 cells / well and after 24 hours they are exposed to different concentrations of compounds in 0.83% DMSO. The cells develop for a further 2 or 24 hours, are fixed with formaldehyde (final 2%) and permeabilized with methanol. After blocking with 3% BSA-TBST, the fixed cells are incubated with a primary antibody (rabbit anti-phosphorus ERK) overnight at 4 ° C. The cells are incubated with propidium iodide (DNA fluorescent dye) and the detection of cellular p-ERK is performed using a secondary anti-rabbit antibody conjugated to the Alexa Fluor 488 fluorescent dye (Molecular probes). Fluorescence is analyzed using Acumen Explorer (TTP Labtech), a laser tracking microplate cytometer and the Alexa Fluor 488 signal is normalized to the PI signal (proportional to the number of cells).

[0187] The EC50 is defined as the concentration at which a given compound achieves a signal midway between the baseline and the maximum response. EC50 values are calculated using the XLfit software package (version 2.0.5).

[0188] In this assay, the compounds of Examples 5-11 and 13-14 showed an EC50 of less than 0.2 µM in both cell lines. The title compound of Example 12 showed an EC50 of less than 0.2 µM in the HCT116 cell line.

[0189] IMIDAZO SYNTHESIS [1,5-a] PIRIDINES

[0190] 8-Chloro-imidazo [1,5-alpyridine-7-carboxylic acid methyl ester

[0191] Stage 1: 2,3-Dichloro-isonicotinic acid

[0192] To a solution of diisopropylamine (7.0 mL, 50 mmol) in anhydrous THF (100 mL) at -25 ° C was added dropwise a solution of 1.6M nBuLi in hexanes (31 mL, 50 mmol) under inert atmosphere. Then, the reaction mixture was cooled to -78 ° C and 2,3-dichloropyridine was added. The reaction mixture was stirred at -78 ° C for 3 hours, then poured onto solid carbon dioxide and aged for 18 hours at room temperature. The mixture was diluted with water (100 mL) and washed with diethyl ether (3 x 40 mL), then cooled to 0 ° C, acidified with concentrated HCl (approximately 5 mL) and extracted with diethyl ether (3 x 50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated to yield the title compound as a white solid (7.7 g, 80%). 1H NMR (d6-DMSO, 400MHz) 8.49 (d, J = 5.0 Hz, 1H), 7.72 (d, J = 5.0 Hz, 1H).

[0193] Stage 2: 2,3-Dichloro-isonicotinic acid methyl ester

[0194] To a suspension of 2,3-dichloro-isonicotinic acid (7.7 g, 40 mmol) in dichloromethane (45 mL) was added DMF (0.1 mL) and oxalyl chloride (17.5 mL, 200 mmol). The reaction mixture was stirred at room temperature for 18 hours and then concentrated under reduced pressure. The resulting residue formed an azeotrope with toluene, then cooled to 0 ° C and dissolved in methanol (135 mL). The mixture was allowed to warm to room temperature and then concentrated under reduced pressure to produce a residue. The residue was dissolved in ethyl acetate and the resulting solution was washed with a saturated sodium hydrogen carbonate solution, water and a saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to yield the title compound as a colorless oil that crystallized at rest (7.9 g, 96%). 1H NMR (CDCl3, 400MHz) 8.38 (d, J = 5.0 Hz, 1H), 7.52 (d, J = 5.0 Hz, 1H), 3.99 (s, 3H).

[0195] Stage 3: 3-Chloro-2-cyano-isonicotinic acid methyl ester

[0196] It was loaded with a microwave vial with 2,3-dichloro-isonicotinic acid methyl ester (7.6 g, 36.9 mmol), zinc cyanide (4.75 g, 40.6 mmol), tetrakis (triphenylphosphine) palladium (1.0 g, 0.9 mmol) and DMF (37 mL), then covered, evacuated and refilled with nitrogen. The reaction solution was subjected to microwave radiation, heating at 190 ° C for 20 minutes, then filtered through a pad of Celite ® which was subsequently washed with ethyl acetate. The resulting mixture was washed with water, followed by a saturated sodium hydrogen carbonate solution, then a saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to column chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in cyclohexane) to yield the title compound as a white solid (3.1 g, 43%). 1H NMR (CDCl3, 400MHz) 8.70 (d, J = 5.0 Hz, 1H), 7.87 (d, J = 5.0 Hz, 1H), 4.01 (s, 3H).

[0197] Stage 4: 3-Chloro-2-formylaminomethyl-isonicotinic acid methyl ester

[0198] A mixture of 3-chloro-2-cyano-isonicotinic acid methyl ester (2.9 g, 14.8 mmol) and 10% palladium on carbon (293 mg) in acetic acid (65 mL) was degassed and it was refilled with hydrogen three times. The reaction mixture was stirred at room temperature under hydrogen atmosphere (1 bar) for 18 hours and then filtered. The filtrate was concentrated under reduced pressure to produce a residue that was dissolved in methanol and loaded into a 50 g Isolute® SCX-2 cartridge, eluted with methanol followed by a 2M solution in methanol. The appropriate fractions were combined and concentrated under reduced pressure to produce a residue. The reissue was dissolved in a mixture of formic acid (40 mL) and acetic anhydride (8 mL), which was stirred at room temperature for 30 minutes. The solvents were removed under reduced pressure to produce a residue that was dissolved in dichloromethane. The resulting solution was washed with a saturated sodium hydrogen carbonate solution, the aqueous phase was separated and extracted twice with dichloromethane. The combined organic extracts were passed through a phase separator and concentrated under reduced pressure to produce a residue that was subjected to column chromatography (Si-PPC, 0% to 10% gradient, methanol in dichloromethane). The title compound was obtained as a white solid (1.5 g, 44%). LCMS (method B): RT = 2.15 min, [M + H] + = 229.

[0199] Stage 5: 8-Chloro-imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester

[0200] A mixture of 3-chloro-2-formylaminomethyl-isonicotinic acid methyl ester (1.5 g, 6.6 mmol) and phosphorus oxychloride (1.3 mL, 14.2 mmol) in toluene was stirred ( 80 mL) at 90 ° C for 15 minutes, then cooled to room temperature and concentrated under reduced pressure. The residue was partitioned between ethyl acetate and a saturated sodium bicarbonate solution. The organic phase was separated and washed with water and a saturated sodium chloride solution, dried (Na2SO4), filtered and concentrated to yield the title compound as a pale yellow solid (1.3 g, 93%). LCMS (method B): RT = 2.38 min, [M + H] + = 211.

[0201] 8- (4-Cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid

[0202] Stage 1: 8- (4-Cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester

[0203] A suspension of 8-chloro-imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (105 mg, 0.50 mmol), 4-cyclopropyl-2-fluoroaniline (101 mg, was degassed 0.60 mmol), Pd2dba3 (18 mg, 0.02 mmol), 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (37 mg, 0.08 mmol) and K3PO4 (148 mg, 0.70 mmol) in toluene (2 mL) and then heated to 100 ° C for 24 hours. Then, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting solution was washed with water and a saturated solution of sodium chloride, then loaded into a 10 g Isolute® SCX-2 cartridge eluted with methanol followed by a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated. The resulting residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 10%, ethyl acetate in dichloromethane) to yield the title compound as a yellow oil (68 mg, 42%). LCMS (method B): RT = 3.45 min, [M + H] + = 326.

[0204] Stage 2: 8- (4-Cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid

[0205] A suspension of 8- (4-cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (0.28 g, 0.86 mmol) was heated and 1M NaOH (1.03 mL, 1.03 mmol) in IMS (5 mL) up to 65 ° C for 5 hours. The reaction mixture was then cooled to room temperature and 1M HCl was added to adjust the pH to 2. The precipitate formed was filtered and dried in a drying gun at 40 ° C for 18 hours to produce the title compound as a cream solid (0.22 g, 81%). LCMS (method B): RT = 2.84 min, [M + H] + = 312.

[0206] EXAMPLE 5: 8- (4-Cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid amide

[0207] To a solution of 8- (4-cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (23 mg, 0.07 mmol) in IMS ( 1.0 mL) a 1.0 M aqueous solution of sodium hydroxide (0.10 mL, 0.10 mmol) was added. The reaction mixture was heated to 65 ° C for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting residue formed an azeotrope with toluene, and then dissolved in DMF (1 mL). Ammonium chloride (7 mg, 0.13 mmol), NN-diisopropylethylamine (47 uL, 0.27 mmol) and HATU (51 mg, 0.13 mmol) were added sequentially before stirring the reaction mixture for 18 hours at room temperature. Then, the reaction mixture was diluted with methanol and loaded into an Isolate® SCX-2 cartridge (5g). The cartridge was then washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to produce a residue. The residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 5%, methanol in dichloromethane) to yield the title compound as a pale yellow solid (5 mg, 23%). LCMS (method A): RT = 6.64 min, [M + H] + = 311. 1H NMR (CD3OD) 8.18 (1H, d, J = 0.88 Hz), 7.64 (1H, dd, J = 7.40, 0.97 Hz), 7.13 (1H, t, J = 8.28 Hz), 6.93-6.86 (3 H, m), 6.35 (1H, s), 1.98-1.90 (1 H, m), 1.05-0.97 (2 H, m ), 0.73-0.68 (2H, m).

[0208] EXAMPLE 6: 8- (4-Cyclopronyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-hydroxyethoxy) -amide

[0209] Step 1: 8- (4-Cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-vinyloxyethoxy) -amide

[0210] To a solution of 8- (4-cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (68 mg, 0.21 mmol) in IMS ( 2.5 mL) a 1.0 M aqueous solution of sodium hydroxide (0.25 mL, 0.25 mmol) was added. The reaction mixture was heated at 65 ° C for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting residue formed an azeotrope with toluene, and was then suspended in THF (4 mL). Then O- (2-Vinyloxy-ethyl) -hydroxylamine (43 mg, 0.42 mmol), NN-diisopropylethylamine (0.14 mL, 0.84 mmol), EDCI (81 mg, 0.42 mmol) were added sequentially ) and HOBt (57 mg, 0.42 mmol), before stirring the reaction mixture for 18 hours at room temperature. Then, the reaction mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride before drying (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 5%, methanol in dichloromethane) to yield the title compound as a pale yellow oil (56 mg, 67%). LCMS

(method B): RT = 3.02 min, [M + H] + = 397.

[0211] Stage 2: pyridine-7-carboxylic

(2-hydroxyethoxy) -amide of the  acid 8- (4-cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a]

[0212]

Be dissolved (2-vinyloxy-ethoxy) -amide of the acid 8- (4-cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a]

pyridine-7-carboxylic acid (56 mg, 0.14 mmol) in methanol and loaded into an Isolute® SCX-2 cartridge (5g). Then, the cartridge was washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to produce a residue. The residue was subjected to flash chromatography (Si-PPC, gradient 0% to 20%, methanol in dichloromethane) to yield the title compound as a pale yellow solid (37 mg, 71%). LCMS (method A): RT = 6.40 min, [M + H] + = 371. 1H NMR (CH3OH-d4): 8.20 (1 H, d, J = 0.71 Hz), 7.67-7.65 (1 H, m), 7.17-7.11 (1 H, m), 6.94-6.87 (2 H, m), 6.73 (1 H, d, J = 7.38 Hz), 6.39 (1 H, s), 400-3.97 (2 H , m), 3.75-3.72 (2 H, m), 1.98-1.89 (1 H, m), 1.04-0.98 (2 H, m), 0.73-0.68 (2 H, m).

[0213] EXAMPLE 7: 8- (2-Fluoro-4-methylsulfanyl-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-hydroxy-ethoxy) -amide

[0214] Stage 1: 8- (2-Fluoro-4-methylsulfanyl-phenylamino) -imidazo [1,5-a], pyridine-7-carboxylic acid methyl ester

[0215] A suspension of 8-chloro-imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (223 mg, 1.06 mmol), 2-fluoro-4-methylsulfanyl-phenylamine (200) was degassed mg, 1.27 mmol), Pd2dba3 (39 mg, 0.04 mmol), 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (79 mg, 0.17 mmol) and K3PO4 (315 mg, 1.48 mmol) in toluene (4 mL) and then heated at 100 ° C for 18 hours. Then, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water followed by a saturated solution of sodium chloride, before loading into a 10 g Isolute® SCX-2 cartridge, which was eluted with methanol, and then a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated in vacuo to yield a residue. The residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 10%, ethyl acetate in dichloromethane) to yield the title compound as a yellow oil (136 mg, 39%). LCMS (method B): RT = 3.26 min, [M + H] + = 332.

[0216] Step 2: 8- (2-Fluoro-4-methylsulfanyl-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-vinyloxyethoxy) -amide

[0217] To a solution of 8- (2-fluoro-4-methylsulfanyl-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (136 mg, 0.41 mmol) in IMS ( 10 mL) a 1.0 M aqueous solution of sodium hydroxide (0.82 mL, 0.82 mmol) was added. The reaction mixture was heated at 65 ° C for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting residue formed an azeotrope with toluene, and was then suspended in THF (10 mL). O- (2-vinyloxy-ethyl) -hydroxylamine (84 mg, 0.82 mmol), NN-diisopropylethylamine (0.28 mL, 1.64 mmol), EDCI (157 mg, 0.82 mmol) were added sequentially. HOBt (111 mg, 0.82 mmol), before stirring the reaction mixture for 18 hours at room temperature. Then, the reaction mixture was diluted with ethyl acetate and washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride, dried (Na2SO4), filtered and concentrated. The resulting residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in dichloromethane) to produce the title compound as a pale yellow oil (160 mg, 97%). LCMS (method B): RT = 2.91 min, [M + H] + = 403.

[0218]

Stage 3: (2-hydroxyethoxy) -amide of the  acid 8- (2-Fluoro-4-methylsulfanyl-phenylamino) -imidazo [1,5-a]

pyridine-7-carboxylic

[0219]

Be dissolved (2-vinyloxy-ethoxy) -amide of the acid 8- (2-Fuoro-4-methylsulfanyl-phenylamino) -imidazo [1,5-a]

pyridine-7-carboxylic acid (160 mg, 0.40 mmol) in methanol and loaded onto an Isolute® SCX-2 cartridge (10g). Then, the cartridge was washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to yield a residue, which was subjected to "flash" chromatography (Si-PPC, 0% to 10% gradient, methanol in dichloromethane) to yield the title compound as a pale yellow solid (77 mg, 51%). LCMS (method A): RT = 5.96 min, [M + H] + = 377. 1 H NMR (DMSO-d6) 11.54 (1 H, s), 10.51 (1 H, s), 8.29 (1 H, d, J = 0.80 Hz), 7.80 (1H, dd, J = 7.37, 0.94 Hz), 7.24-7.16 (2 H, m), 7.06 (1 H, dd, J = 8.38,

2.11 Hz), 6.80-6.74 (1 H, m), 6.39 (1 H, s), 4.70 (1 H, s), 3.86 (2 H, t, J = 4.95 Hz), 3.57 (2 H, t, J = 4.95 Hz), 2.49 (3 H, s).

[0220] EXAMPLE 8: 8- (2-Fluoro-4-iodo-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid 2-hydroxy-ethoxy-amide

[0221] Stage 1: 8- (4-Bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester

[0222] A suspension of 8-chloro-imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (500 mg, 2.38 mmol), 4-bromo-2-fluoroaniline (543 mg,) was degassed 2.86 mmol), Pd2dba3 (110 mg, 0.12 mmol), 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (224 mg, 0.48 mmol) and K3PO4 (710 mg, 3.33 mmol) in toluene (10 mL) and then heated at 100 ° C for 18 hours. Then, the reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with water and a saturated solution of sodium chloride, then loaded into a 10 g Isolute® SCX-2 cartridge eluted with methanol and then a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated in vacuo. The resulting residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 20%, ethyl acetate in DCM) to produce the title compound as a yellow oil (240 mg, 28%). LCMS (method B): RT = 3.40 min, [M + H] + = 364/366.

[0223] Stage 2: 8- (2-Fluoro-4-iodo-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester [0224] Heated at 110 ° C for 26 hours under an atmosphere of argon a mixture of 8- (4-bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (235 mg, 0.65 mmol), iodide of copper (I) (6 mg, 0.03 mmol), sodium iodide (195 mg, 1.3 mmol) and trans-N, N'-dimethyl-1,2-cyclohexane diamine (0.01 mL, 0, 06 mmol) in 1,4-dioxane (1.0 mL). The reaction mixture was cooled to room temperature, diluted with methanol and loaded into an Isolute® SCX-2 cartridge (10 g). Then, the cartridge was washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The eluent was collected and concentrated to produce a residue. The residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 20%, ethyl acetate in dichloromethane) to yield the title compound as a pale yellow solid (182 mg, 67%). LCMS (method B): RT = 3.45 min, [M + H] + = 412.

[0225] Step 3: 8- (2-Fluoro-4-iodo-phenylamino-imidazo [1,5-a] pyridine-7-carboxylic acid (2-vinyloxy-ethoxy) -amide]

[0226] To a solution of 8- (2-fluoro-4-iodo-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (200 mg, 0.49 mmol) in IMS ( 10 mL) a 1.0 M aqueous solution of sodium hydroxide (1.0 mL, 1.0 mmol) was added. The reaction mixture was heated at 65 ° C for 2 hours and then cooled to room temperature and concentrated in vacuo. The resulting residue formed an azeotrope with toluene, and was then suspended in THF (10 mL). O- (2-vinyloxy-ethyl) -hydroxylamine (103 mg, 1.0 mmol), NN-diisopropylethylamine (0.34 mL, 1.96 mmol), EDCI (192 mg, 1.0 mmol) were added sequentially. HOBt (135 mg, 1.0 mmol) before stirring the reaction mixture for 18 hours at room temperature. Then, the reaction mixture was diluted with ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and then a saturated solution of sodium chloride, dried (Na2SO4), filtered and concentrated in vacuo. . The resulting residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in dichloromethane) to yield the title compound as a pale yellow oil (151 mg, 64%). LCMS (method B): RT = 3.05 min, [M + H] + = 483.

[0227] Step 4: 8- (2-Fluoro-4-iodo-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-hydroxy-ethoxy) -amide

[0228] 8- (2-Fluoro-4-iodo-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-vinyloxy-ethoxy) -amide (151 mg, 0.31) mmol) in methanol and loaded into an Isolute® SCX-2 cartridge (10g). Next, the cartridge was washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The appropriate fractions were combined and concentrated to yield a residue that was subjected to "flash" chromatography (Si-PPC, 0% to 10% gradient, methanol in dichloromethane) to yield the title compound as a pale yellow solid (115 mg , 81%). LCMS (method A): RT = 6.36 min, [M + H] + = 457. 1H NMR (CD3OD): 8.27 (1H, d, J =

0.85 Hz), 7.80-7.77 (1H, m), 7.57-7.53 (1H, m), 7.49-7.46 (1H, m), 6.95 (1H, t, J = 8.48 Hz), 6.76 (1 H, d, J = 7.37 Hz), 6.68 (1 H, s), 400-3.94 (2 H, m), 3.75-3.71 (2 H, m).

[0229] EXAMPLE 9: 8- (4-Cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid ((S) -2-hydroxy-propoxy) -amide

[0230] A suspension of 8- (4-cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (0.11 g, 0, was stirred at room temperature for 18 hours 35 mmol), EDCI (0.081g, 0.42 mmol), HOBt (0.057g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and (S) -1-aminoxypropan-2-ol hydrochloride (0.05 g, 0.39 mmol) in DMF (1.5 mL). The reaction mixture was partitioned between DCM (5 mL) and a saturated aqueous solution of NaHCO3 (5 mL). The organic phase was washed with water (5 mL), followed by a saturated solution of sodium chloride (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 60%, ethyl acetate in DCM) to produce a sticky yellow solid, which was subsequently purified by preparative HPLC (Gemini 5 micron C18 250x21 column. 20mm, 0.1% formic acid, acetonitrile / water gradient, 5 to 98%, ramp time of 20 minutes) to produce the title compound as a yellow solid (38 mg, 27%). LCMS (method A): RT = 6.87 min, [M + H] + = 385. 1H NMR (DMSO-d6) 10.54 (1H, s), 8.27 (1 H, s), 7.76 (1H, dd, J = 7.37, 0.93 Hz), 7.14 (1H, t, J = 8.37 Hz), 6.98 (1H, dd, J = 11.87.1.95 Hz), 6.95-6.89 (1H, m), 6.76 (1H, d, J = 7.33 Hz), 6.27 (1H, s), 3.89-3.79 (1H, m), 3.72-3.62 (2H, m), 1.99-1.90 (1H, m), 1.04 (3H, d, J = 6.34 Hz) , 0.99-0.93 (2H, m), 0.76-0.67 (2H, m).

[0231] EXAMPLE 10: 8- (4-Cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-hydroxy-1,1-dimethyl-ethoxy) -amide

[0232] A suspension of 8- (4-cyclopropyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (0.11 g, 0, was stirred at room temperature for 18 hours 35 mmol), EDCI (0.081g, 0.42 mmol), HOBt (0.057g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and 2-aminoxy-2-methylpropan-1-ol hydrochloride (0.055g, 0.39 mmol) in DMF (1.5 mL). The reaction mixture was partitioned between DCM (5 mL) and a saturated aqueous solution of NaHCO3 (5 mL). The organic phase was washed with water (5 mL), followed by a saturated solution of sodium chloride (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 40%, ethyl acetate in DCM) to produce a yellow solid, which was subsequently purified by preparative HPLC (Gemini column 5 microns C18 250x21.20mm , 0.1% formic acid, acetonitrile / water gradient, 5 to 98%, ramp time of 20 minutes) to produce the title compound as a yellow solid (11 mg, 8%). LCMS (method A): RT = 7.57 min, [M + H] + = 399. 1H NMR (DMSO-d6): 10.37 (1H, s), 8.28 (1H, s), 7.79 (1H, dd, J = 7.35, 0.95 Hz), 7.14 (1H, s), 7.02-6.93 (1H, m), 6.91 (1H, d, J = 8.28 Hz), 6.82 (1H, s), 6.27 (1H, s), 1.99-1.90 (1H, m), 1.15 (6H, s), 0.99-0.92 (2H, m), 0.73-0.67 (2H, m).

[0233] EXAMPLE 11: 8- (4-Bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-hydroxyethoxy) -amide

[0234] Step 1: 8- (4-Bromo-2-fluoro-phenylamino) -imidazo [1,5-a] (2-vinyloxy-ethoxy) -amide

pyridine-7-carboxylic

[0235] To a solution of 8- (4-bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (50 mg, 0.14 mmol) in IMS ( 3 mL) a 1.0 M aqueous solution of sodium hydroxide (0.3 mL, 0.3 mmol) was added. The reaction mixture was heated at 65 ° C for 2 hours and then cooled to room temperature and concentrated in vacuo. The resulting residue formed an azeotrope with toluene, and was then suspended in THF (3 mL). Then, O- (2-vinyloxy-ethyl) -hydroxylamine (29 mg, 0.28 mmol), N, N diisopropylethylamine (0.10 mL, 0.56 mmol), EDCI (54 mg, 0,) were added sequentially 28 mmol) and HOBt (38 mg, 0.28 mmol) before stirring the reaction mixture for 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with water, followed by a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride. The organic phase was isolated, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to "flash" chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in dichloromethane) to yield the title compound as a pale yellow oil (40 mg, 65%). LCMS (method B): RT = 2.98 min, [M + H] + = 435/437.

[0236] Step 2: 8- (4-Bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-hydroxy-ethoxy) -amide

[0237] 8- (4-Bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methanol (2-vinyloxy-ethoxy) -amide (40 mg, 0 , 09 mmol) and loaded into an Isolute® SCX-2 cartridge (5 g). Then, the cartridge was washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The appropriate fractions were combined and concentrated to yield a residue that was subjected to "flash" chromatography (Si-PPC, 0% to 20% gradient, methanol in dichloromethane) to yield the title compound as a pale yellow solid (11 mg , 29%). LCMS (method A): RT = 6.06 min, [M + H] + = 409/411. 1 H NMR (CD3OD): 8.27 (1 H, d, J = 0.85 Hz), 7.79 (1 H, dd, J = 7.39, 0.97 Hz), 7.42 (1 H, dd, J = 10.00, 2.19 Hz), 7.31 (1 H, ddd, J = 8.53, 2.20,

1.19 Hz), 7.12 (1 H, t, J = 8.60 Hz), 6.79-6.73 (1H, m), 6.65 (1 H, s), 3.97 (2 H, t, J = 4.69 Hz), 3.73 (2 H, t, J = 4.68 Hz).

[0238] EXAMPLE 12: 8- (4-Bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyrimidine-7-carboxylic acid ((S) -2-hydroxypropoxy) -amide

[0239] To a solution of 8- (4-bromo-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (587 mg, 1.61 mmol) in IMS ( 20 mL) was added to a 1.0 M aqueous solution of sodium hydroxide (1.7 mL, 1.7 mmol). The mixture reaction was heated at 65 ° C for 2 hours and then cooled to room temperature and concentrated in vacuo. The resulting residue formed an azeotrope with toluene, and was then suspended in dioxane (15 mL). Then, EDCI (614 mg, 3.2 mmol) and HOBt (432 mg, 3.2 mmol) were added before stirring the reaction mixture for 30 min at room temperature. (S) -1-aminoxy-propan-2-ol hydrochloride (408 mg, 3.20 mmol) and NN-diisopropylethylamine (1.1 mL, 6.44 mmol) were added sequentially before stirring the reaction mixture during 18 hours at room temperature. Then, the reaction mixture was concentrated under reduced pressure. The resulting residue was taken up in ethyl acetate, then washed with water, followed by a saturated aqueous solution of sodium bicarbonate and a saturated solution of sodium chloride, dried (Na2SO4), filtered and concentrated in vacuo. The resulting residue was subjected to flash chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane). The appropriate fractions were combined and concentrated to yield a residue that was subjected to HPLC (Gemini column 5 microns C18 250x21.20mm, 0.1% formic acid, acetonitrile in water, gradient 5% to 85%, ramp time of 20 minutes) to produce the title compound as a pale yellow solid (180 mg, 26%). LCMS (method A): RT = 6.55 min, [M + H] + = 423/425. 1H NMR (CDCl3): 10.46 (1H, s), 8.75 (1H, s), 7.99 (1H, s), 7.39 (1H, d, J = 7.36 Hz), 7.32 (1H, dd, J = 9.31, 2.15 Hz), 7.28 (1H, d, J = 8.83 Hz), 7.12 (1H, t, J = 8.38 Hz), 6.63 (1H, s), 6.46 (1H, d, J = 7.33 Hz), 4.10-4.01 ( 1H, m), 3.93 (1H, dd, J = 11.43, 2.28 Hz), 3.70 (1H, t, J = 10.42 Hz), 1.14 (3H, d, J = 6.47 Hz).

[0240] EXAMPLE 13: 8- (4-Bromo-2-chloro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-hydroxyethoxy) -amide

[0241] Stage 1: 8- (4-Bromo-2-chloro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester

[0242] A suspension of 8-chloro-imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (300 mg, 1.43 mmol), 4-bromo-2-chloroaniline (354 mg,) was degassed 1.72 mmol), Pd2dba3 (65 mg, 0.07 mmol), 2-dicyclohexylphosphino-2 ', 6'-diisopropoxybiphenyl (131 mg, 0.28 mmol) and K3PO4 (424 mg, 2.00 mmol) in toluene (5 ml) and then heated at 110 ° C for 18 hours. Then, the reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was washed with water and a saturated solution of sodium chloride, then loaded into a 10 g Isolute® SCX-2 cartridge eluted with methanol and then a 2M solution of ammonia in methanol. The appropriate fractions were combined and concentrated in vacuo. The resulting residue was subjected to flash chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in DCM) to produce the title compound as yellow oil (271 mg, 50%). LCMS (method B): RT = 3.65 min, [M + H] + = 381/383.

[0243] Step 2: 8- (4-Bromo-2-chloro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-vinyloxy-ethoxy) -amide [0244] To a solution of 8- (4-bromo-2-chloro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (271 mg, 0.71 mmol) in IMS (10 mL) was added a 1.0 M aqueous solution of sodium hydroxide (0.8 mL, 0.8 mmol). The reaction mixture was heated at 65 ° C for 1 hour and then cooled to room temperature and concentrated in vacuo. The resulting residue formed an azeotrope with toluene, and was then suspended in THF (10 mL). Then, O- (2-vinyloxy-ethyl) -hydroxylamine (89 mg, 0.87 mmol), NN-diisopropylethylamine (0.30 mL, 1.73 mmol), EDCI (166 mg, 0.87) were added sequentially mmol) and HOBt (117 mg, 0.87 mmol) before stirring the reaction mixture for 18 hours at room temperature. The reaction mixture was then diluted with ethyl acetate and washed with water followed by a saturated aqueous solution of sodium bicarbonate and then a saturated solution of sodium chloride. The isolated organic phase was dried (Na2SO4), filtered and concentrated in vacuo to yield the title compound as a pale yellow solid (210 mg, 65%). LCMS (method B): RT = 3.17 min, [M + H] + = 451/453.

[0245] Step 8: 8- (4-Bromo-2-chloro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid 2-hydroxy-ethoxy) -amide

8- (4-Bromo-2-chloro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-vinyloxy-ethoxy) -amide (196 mg, 0.43 mmol) was dissolved in methanol and loaded into an Isolute® SCX-2 cartridge (10g). Then, the cartridge was washed with methanol and the desired product was subsequently eluted using 2M NH3 in MeOH. The appropriate fractions were combined and concentrated to produce a residue that was subjected to "flash" chromatography (Si-PPC, gradient 0% to 10%, methanol in dichloromethane). The appropriate fractions were combined and concentrated to yield a residue that was subjected to HPLC (preparative column C18, 0.1% formic acid, acetonitrile in water, gradient 5% to 98%, ramp time of 20 minutes) to produce the title compound as a pale yellow solid (43 mg, 23%). LCMS (method A): RT = 6.71 min, [M + H] + = 425/427. 1H NMR (DMSO-d6): 11.68 (1H, s), 10.46 (1H, s), 8.35 (1H, d, J = 0.79 Hz), 7.95 (1H, d, J = 7.36 Hz), 7.78 (1H, d, J = 2.27 Hz), 7.42 (1H, dd, J = 8.62, 2.29 Hz), 7.01 (1H, d, J = 8.63 Hz), 6.79 (1H, d, J = 7.35 Hz), 6.56 (1H, s), 4.69 (1H, s), 3.87 (2H, t, J = 4.89 Hz), 3.57 (2H, m).

[0246] EXAMPLE 14: 8- (4-Cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid 2-hydroxyethoxy amide

[0247] Stage 1: 4-cyclobutyl-2-fluoro-nitrobenzene

[0248] A solution of 3-fluoro-4-nitro-phenyl ester of trifluoro-methanesulfonic acid (1.8 g, 6.2 mmol), boronic cyclobutyl acid (0.78 g, 7.5 mmol), was degassed, Pd (dppf) Cl2 (0.40 g, 0.5 mmol), and 2M aqueous cesium (aq) carbonate (5 mL, 9.9 mmol) in toluene (10 ml) with argon for 10 minutes and then heated up to 90 ° C for 2.5 hours. Then, the reaction mixture was cooled to room temperature and filtered through hyflo®. The reaction mixture was partitioned between ethyl acetate (70 mL) and water (70 mL). The organic phase was isolated, then washed with a saturated solution of sodium chloride (50 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting solid was subjected to flash chromatography (Si-PPC, gradient 0% to 30%, DCM in pentane)

to produce the title compound as a yellow liquid (0.504 g, 42%). 1H NMR (DMSO-d6): 8.08 (1H, t, J =

8.3 Hz), 7.44 (1H, d, J = 13.2 Hz), 7.28 (1H, d, J = 8.5 Hz), 3.65 (1H, m), 2.33 (2H, m), 2.13 (2H, m), 1.99 (1H, m),

1.84 (1H, m).

[0249] Stage 2: 4-Cyclobutyl-2-fluoroaniline

[0250] A solution of 4-cyclobutyl-2-fluoro-nitrobenzene (0.5 g, 2.6 mmol) in IMS (5 mL) was degassed with argon for 2 minutes, before adding 10% Pd / C (0 , 05 g), and a hydrogen balloon was fixed. The resulting mixture was stirred for 18 hours at room temperature, before passing a stream of nitrogen, and filtered through hyflo®. The filtrate was concentrated in vacuo to yield the title compound as an orange / red oil (0.31 g, 74%). 1H NMR (CDCl3): 6.84 (1H, d, J = 12.3 Hz), 6.77 (1H, d, J = 8.1 Hz), 6.70 (1H, t, J = 9.1 Hz), 3.58 (2H, wide),

3.42 (1H, m), 2.28 (2H, m), 2.01 (3H, m), 1.82 (1H, m).

[0251] Stage 3: 8- (4-Cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester

[0252] A suspension of 8-chloro-imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (250 mg, 1.2 mmol), 4-cyclobutyl-2- was degassed with argon for 10 minutes fluoroaniline (230 mg, 1.4 mmol), Pd2dba3 (43 mg, 0.047 mmol), 2-dicyclohexylphosphino-2 ', 6'-dimethoxy-1,1'-biphenyl (80 mg, 0.19 mmol) and K3PO4 ( 350 mg, 1.7 mmol) in toluene (5 ml) and then heated at 100 ° C for 18 hours. Then, the reaction mixture was cooled to room temperature and filtered through hyflo®. The filtrate was concentrated in vacuo, and the resulting gum was subjected to "flash" chromatography (Si-PPC, eluting with 5% ethyl acetate in DCM) to yield the title compound as a yellow oil (150 mg, 38% ). 1H NMR (CDCl3): 7.95 (1H, s), 7.73 (1H, d, J = 7.4 Hz), 7.23 (1H, t, J = 8.6 Hz), 7.07 (1H, d, J = 7.3 Hz), 7.01 (2H, m), 6.50 (1H, s), 3.90 (3H, s), 3.59 (1H, m),

2.39 (2H, m), 2.17 (2H, m), 2.06 (1H, m), 1.93 (1H, m).

[0253] Stage 4: 8- (4-Cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid

[0254] A suspension of 8- (4-cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid methyl ester (150 mg, 0.46 mmol) and NaOH was heated 1M (1.5 mL, 1.5

mmol) in IMS (2 mL) at 60 ° C for 2 hours. Then, the reaction mixture was cooled to room temperature, diluted with water and glacial acetic acid was added to adjust the pH to 4. The precipitate was filtered and dried in a drying gun at 40 ° C for 18 hours to produce the title compound as a creamy solid (154 mg, 99%). 1 H NMR (DMSO-d6): 10.53 (1 H, s), 8.34 (1 H, s), 7.74 (1 H, d, J = 7.3 Hz), 7.35 (1H, t, J =

8.3 Hz), 7.24 (1 H, d, J = 11.2 Hz), 7.13 (1H, d, J = 8.1 Hz), 7.01 (1H, d, J = 9.3 Hz), 6.23 (1 H, s), 3.61 (1H, m), 2.38 (2 H, m), 2.14 (2 H, m), 1.99 (1H, m), 1.84 (1H, m).

[0255] Step 5: 8- (4-Cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (2-vinyloxyethoxy) -amide

[0256] A suspension of 8- (4-cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (154 mg, 0.46 mmol) was stirred at room temperature for 18 hours ), EDCI (105 mg, 0.55 mmol), HOBt (74 mg, 0.55 mmol), DIPEA (0.19 mL, 1.14 mmol) and O- (2-vinyloxy-ethyl) -hydroxylamine (52 mg, 0.50 mmol) in THF (2.5 mL). The reaction mixture was partitioned between DCM (20 mL) and a saturated aqueous solution of NaHCO3. The organic phase was isolated, then washed with water (20 mL), followed by a saturated solution of sodium chloride (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting gum was subjected to "flash" chromatography (Si-PPC, gradient 0% to 100%, ethyl acetate in cyclohexane) to produce the title compound as a brown gum (149 mg, 80%). LCMS (method B): RT = 3.49 min, [M + H] + = 411.

[0257] pyridine-

7-carboxylic stage 6: (2-hydroxyethoxy) -amide of the  acid 8- (4-Cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a]

[0258]

 Be  dissolved  in methanol  (2  ml)  the  (2-vinyloxy-ethoxy) -amide  of the  acid

8- (4-Cyclobutyl-2-fluoro-phenylamino) -imidazo [1,5-a] pyridine-7-carboxylic acid (149 mg, 0.36 mmol) and treated with 1 M HCl (1.5 mL). The reaction mixture was stirred at room temperature for 2 hours. The solvents were removed in vacuo and the residue was purified by preparative HPLC (Gemini column 5 microns C18 250x21.20mm, 0.1% formic acid, acetonitrile / water gradient, 5 to 98%, 20 minute ramp time) to produce the title compound as a yellow solid (16 mg, 11%). LCMS (method A): RT = 7.40 min, [M + H] + = 385. 1H NMR (DMSO-d6): 11.59 (1H, s), 10.60 (1H, s), 8.32 (1H, s) , 7.82 (1H, d, J = 7.7 Hz), 7.24 (1H, d, J = 8.5 Hz), 7.15 (1H, d, J = 11.2 Hz), 7.07 (1H, d, J = 8.11 Hz), 6.79 (1H, d, J = 7.3 Hz), 6.33 (1H, s), 4.73 (1H, s), 3.69 (2H, t, J = 4.8 Hz), 3.61 (2H, t, J = 5.0 Hz), 3.57 (1H, d, J = 8.8 Hz), 2.36 (2H, m), 2.12 (2H, m), 1.96 (1H, m), 1.83 (1H, m).

Claims (18)

1. Compound of formula I: and you leave it, where: Z1 is CR1; R1 is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA or NRARA; R1 ’is H, C1-C3 alkyl, halo, CF3, CHF2, CN, ORA, or NRARA; wherein each RA is independently H or C1-C3 alkyl; Z2 is CR2; Z3 is CR3; R2 and R3 are independently selected from H, halo, CN, CF3, -OCF3, -NO2, - (CR14R15) nC (= Y ’) R11,

-

(CR14R15) nC (= Y ') OR11, - (CR14R15) nC (= Y') NR11R12, - (CR14R15) nNR11R12, - (CR14R15) nOR11, - (CR14R15) nSR11, - (CR14R15) nNR12C (= Y ' ) R11, - (CR14R15) nNR12C (= Y ') OR11, - (CR14R15) nNR13C (= Y') NR11R12, - (CR14R15) nNR12SO2R11, - (CR14R15) nOC (= Y ') R11, - (CR14R15) nOC (= Y ') OR11, - (CR14R15) nOC (= Y') NR11R12, - (CR14R15) nOS (O) 2 (OR11), - (CR14R15) nOP (= Y ') (OR11) (OR12), - (CR14R15) nOP (OR11) (OR12), - (CR14R15) nS (O) R11, - (CR14R15) nS (O) 2R11, - (CR14R15) n

30 S (O) 2NR11R12, - (CR14R15) nS (O) (OR11), - (CR14R15) nS (O) 2 (OR11), - (CR14R15) n SC (= Y ') R11, - (CR14R15) nSC (= Y ') OR11, - (CR14R15) nSC (= Y') NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R4 is H, C1-C6 alkyl or C3-C4 carbocyclyl; Y is W-C (O) -o W ’; 35 W is nitrogen to which they bind to form a saturated or unsaturated 4-7-membered ring that has 0-2 heteroatoms 40 additional selected from O, S and N, where each ring is optionally substituted with one or more groups selected from halo, CN, CF3, -OCF3, -NO2, oxo, - (CR19R20) nC (= Y ') R16, - (CR19R20) n C (= Y ') OR16, - (CR19R20) nC (= Y') NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) n-SR16, - (CR19R20) n NR16C (= Y ') R17, - (CR19R20) n NR16C (= Y') OR17, - (CR19R20) n NR18C (= Y ') NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y') R16 , - (CR19R20) nOC (= Y ') OR16, - (CR19R20) nOC (= Y') NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y ') (OR16) ) (OR17), 45 - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - (CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O ) (OR16), - (CR19R20) n S (O) 2 (OR16), - (CR19R20) n SC (= Y ') R16, - (CR19R20) n SC (= Y') OR16, - (CR19R20) n SC (= Y ') NR16R17, and R21; each R11 'is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl; R11, R12 and R13 are independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, or R11 and R12 together with the nitrogen to which they are attached form a saturated, unsaturated or aromatic 3-8 membered ring having 0-2 heteroatoms selected from O, S and N, where said ring is optionally substituted with one or more groups selected from halo, CN, CF3, -OCF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (alkyl C1-C6), -S (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, - CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2 , -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-alkyl) C6) 2, -OC (O) O (C1-C6 alkyl), - NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1- alkyl) C6) C (O) NH (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-C6 alkyl), and -N (C1-C6 alkyl) C (O) O (C1-C6 alkyl); R14 and R15 are independently selected from H, C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl; W ’is is X2 is O, S, or NR9; R7 is selected from H, halo, CN, CF3, -OCF3, -NO2, - (CR14R15) nC (= Y ’) R11, - (CR14R15) nC (= Y’) OR11, - (CR14R15) nC (= Y ’) NR11R12, - (CR14R15) nNR11R12, - (CR14R15) nOR11, - (CR14R15) nSR11, - (CR14R15) nNR12C (= Y’) R11, - (CR14R15) nNR12C (= Y ’) OR11, - (CR14R15) nNR13C (= Y’) NR11R12, - (CR14R15) nNR12SO2R11, - (CR14R15) nOC (= Y ’) R11, - (CR14R15) nOC (= Y ') OR11, - (CR14R15) nOC (= Y') NR11R12, - (CR14R15) nOS (O) 2 (OR11), - (CR14R11) nOP (= Y ') (OR11) (OR12), - (CR14R15) nOP (OR11) (OR12), - (CR14R15) nS (O) R11, - (CR14R15) nS (O) 2R11, - (CR14R15) n S (O) 2NR11R12, - (CR14R15) nS (O) (OR11), - (CR14R15) nS (O) 2 (OR11), - (CR14R15) n SC (= Y ’) R11, - (CR14R15) nSC (= Y’) OR11, - (CR14R15) nSC (= Y ’) NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R8 is selected from C1-C12 alkyl, aryl, carbocyclyl, heterocyclyl, and heteroaryl; R9 is selected from H, - (CR14R15) nC (= Y ’) R11, - (CR14R15) nC (= Y’) OR11, - (CR14R15) nC (= Y ’) NR11R12, - (CR14R15) qNR11R12, - (CR14R15) qOR11, - (CR14R15) qSR11, - (CR14R15) qNR12C (= Y ’) R11, - (CR14R15) qNR12C (= Y’) OR11, - (CR14R15) qNR13C (= Y ’) NR11R12, - (CR14R15) qNR12SO2R11, - (CR14R15) qOC (= Y’) R11, - (CR14R15) qOC (= Y ') OR11, - (CR14R15) qOC (= Y') NR11R12, - (CR14R15) qOS (O) 2 (OR11), - (CR14R15) qOP (= Y ') (OR11) (OR12), - (CR14R15) qOP (OR11) (OR12), - (CR14R15) nS (O) R11, - (CR14R15) nS (O) 2R11, - (CR14R15) n S (O) 2NR11R12, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl; R10 is H, C1-C6 alkyl or C3-C4 carbocyclyl; X4 is R6 is H, halo, C1-C6 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heteroaryl, heterocyclyl, -OCF3, -NO2 -If (C1-C6 alkyl) 3, - (CR19R20) nNR16R17, - (CR19R20) nOR16, or - (CR19R20) n-SR16; R6 ’is H, halo, C1-C6 alkyl, carbocyclyl, CF3, -OCF3, -NO2, -Si (C1-C6 alkyl) 3, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) n-SR16, C2-C8 alkenyl, C2-C8 alkynyl, heterocyclyl, aryl, or heteroaryl; p is 0, 1, 2 or 3; n is 0, 1, 2 or 3; q is 2 or 3; wherein each said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl and heteroaryl of R1, R2, R3, R4, R5, R6, R6 ’, R7, R8, R9, R10, R11, R11’, R12, R13, R14, R15 and RA is independently optionally substituted with one or more groups independently selected from halo, CN, CF3, -OCF3, -NO2 oxo, -Si (C1-C6 alkyl) 3, - (CR19R20) nC (= Y ’) R16, - (CR19R20) n C (= Y’) OR16, - (CR19R20) nC (= Y ’) NR16R17, - (CR19R20) nNR16R17, - (CR19R20) nOR16, - (CR19R20) nSR16, - (CR19R20) nNR16C (= Y ’) R17, - (CR19R20) nNR16C (= Y’) OR17, - (CR19R20) nNR18C (= Y ’) NR16R17, - (CR19R20) nNR17SO2R16, - (CR19R20) nOC (= Y ’) R16, - (CR19R20) nOC (= Y’) OR16, - (CR19R20) nOC (-Y ’) NR16R17, - (CR19R20) nOS (O) 2 (OR16), - (CR19R20) nOP (= Y ') (OR16) (OR17), - (CR19R20) nOP (OR16) (OR17), - (CR19R20) nS (O) R16, - (CR19R20) nS (O) 2R16, - (CR19R20) nS (O) 2NR16R17, - (CR19R20) nS (O) (OR16), - (CR19R20) nS (O) 2 (OR16), - (CR19R20) nSC (= Y ’) R16, - (CR19R20) nSC (= Y’) OR16, - (CR19R20) n SC (= Y ’) NR16R17, and R21; each R16, R17 and R18 is independently H, C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein said alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl is optionally substituted with one or more groups selected from halo, CN, -OCF3, CF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (alkyl C1-C6), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), -C (O) N (C1-C6 alkyl) 2, -N (alkyl C1-C6) C (O) (alkyl C1-C6), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl )2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O ) NH (alkyl C1-C6), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl )2, -NHC (O) O (C1-C6 alkyl), and -N (C1-C6 alkyl) C (O) O (C1-C6 alkyl); or R16 and R17 together with the nitrogen to which they are attached form a saturated, unsaturated or aromatic 3-8 membered ring having 0-2 heteroatoms selected from O, S and N, where said ring is optionally substituted with one or more groups selected from halo, CN, -OCF3, CF3, -NO2 C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1 alkyl -C6), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (alkyl C1-C6), -C (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC ( O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) NH (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-C6 alkyl ), and -N (alkyl C1-C6) C (O) O (C1-C6 alkyl); R19 and R20 are independently selected from H, C1-C12 alkyl, - (CH2) n-aryl, - (CH2) n-carbocyclyl, - (CH2) n-heterocyclyl, and - (CH2) n-heteroaryl; R21 is C1-C12 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, carbocyclyl, heterocyclyl, aryl, or heteroaryl, wherein each member of R21 is optionally substituted with one or more groups selected from halo, oxo, CN, - OCF3, CF3, -NO2, C1-C6 alkyl, -OH, -SH, -O (C1-C6 alkyl), -S (C1-C6 alkyl), -NH2, -NH (C1-C6 alkyl), -N (C1-C6 alkyl) 2, -SO2 (C1-C6 alkyl), -CO2H, -CO2 (C1-C6 alkyl), -C (O) NH2, -C (O) NH (C1-C6 alkyl), - C (O) N (C1-C6 alkyl, N (C1-C6 alkyl) C (O) (C1-C6 alkyl), -NHC (O) (C1-C6 alkyl), -NHSO2 (C1-C6 alkyl), -N (C1-C6 alkyl) SO2 (C1-C6 alkyl), -SO2NH2, -SO2NH (C1-C6 alkyl), -SO2N (C1-C6 alkyl) 2, -OC (O) NH2, -OC (O) NH (C1-C6 alkyl), -OC (O) N (C1-C6 alkyl) 2, -OC (O) O (C1-C6 alkyl), -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -N (C1-C6 alkyl) C (O) NH (C1-C6 alkyl), -N (C1-C6 alkyl) C (O) N (C1-C6 alkyl ) 2, -NHC (O) NH (C1-C6 alkyl), -NHC (O) N (C1-C6 alkyl) 2, -NHC (O) O (C1-C6 alkyl), and -N (C1- alkyl) C6) C (O) O (C1-C6 alkyl); each Y 'is independently and O, NR22, or S; and R22 is H or C1-C12 alkyl.

2.

Compound according to claim 1, wherein R2 is H, methyl, CF3, Cl, F.

3.

Compound according to claim 2, wherein R3 is H, methyl, CF3, Cl, F.

Four.

Compound according to claim 3, wherein R1 is H or methyl.

5.

Compound according to claim 3, wherein R1 ’is H.

6.

Compound according to claim 5, wherein Y is W-C (O), W is X1-N (R5) -, and X1 is selected from:

7.

Compound according to claim 5, wherein Y is W-C (O), W is X1-N (R5) -, and X1 is selected from:

8.

Compound according to claim 6 or 7, wherein X4 is selected from:

9.

Compound according to claim 8, wherein R4 is H or methyl.

10.

Compound according to claim 9, wherein R5 is H or methyl.

eleven.

Pharmaceutical composition comprising a compound according to any of claims 1-10, and a pharmaceutically acceptable carrier.

12.

Pharmaceutical composition according to claim 11, further comprising an additional chemotherapeutic agent.

13.

Pharmaceutical composition according to claim 11, further comprising an additional anti-inflammatory agent.

14.

Pharmaceutical composition according to claim 11 or 12, for use in the inhibition of abnormal cell growth or in the treatment of a hyperproliferative disorder in a mammal.

fifteen.

Pharmaceutical composition according to claim 11 or 13, for use in the treatment of an inflammatory disease in a mammal.

16.

Composition according to claim 14 or 15, wherein said additional agent is administered sequentially

or consecutive.

17.

Use of a composition according to claim 11 or 12 in the manufacture of a medicament for the inhibition of abnormal cell growth or the treatment of a hyperproliferative disorder in a mammal.

18.

Use of a composition according to claim 11 or 13 in the manufacture of a medicament for the treatment of an inflammatory disease in a mammal.