WO2006056427A1 - Novel 4-arylamino pyridone derivatives as mek inhibitors for the treatment of hyperproliferative disorders - Google Patents

Novel 4-arylamino pyridone derivatives as mek inhibitors for the treatment of hyperproliferative disorders Download PDF

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WO2006056427A1
WO2006056427A1 PCT/EP2005/012546 EP2005012546W WO2006056427A1 WO 2006056427 A1 WO2006056427 A1 WO 2006056427A1 EP 2005012546 W EP2005012546 W EP 2005012546W WO 2006056427 A1 WO2006056427 A1 WO 2006056427A1
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alkyl
fluoro
heteroaryl
substituted
aryl
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PCT/EP2005/012546
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Ulrich Abel
Holger Deppe
Achim Feurer
Ulrich GRÄDLER
Andreas Goutopoulos
Matthias Schwarz
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Laboratoires Serono S.A.
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Priority to AU2005308956A priority Critical patent/AU2005308956A1/en
Priority to EP05820863A priority patent/EP1838675A1/en
Priority to US11/667,886 priority patent/US20070293544A1/en
Priority to CA002587178A priority patent/CA2587178A1/en
Priority to JP2007541838A priority patent/JP2008520615A/en
Publication of WO2006056427A1 publication Critical patent/WO2006056427A1/en
Priority to IL183105A priority patent/IL183105A0/en
Priority to NO20073259A priority patent/NO20073259L/en

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Definitions

  • the invention relates to a series of substituted 4-arylamino pyridone derivatives that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.
  • the Ras/Raf/MEK/ERK pathway is a central signal transduction pathway, which transmits signals from multiple cell surface receptors to transcription factors in the nucleus which regulate gene expression.
  • This pathway is frequently referred to as the MAP kinase pathway as MAPK stands for mitogen-activated protein kinase indicating that this pathway can be stimulated by mitogens, cytokines and growth factors (Steelman et al., Leukemia 2004, 18, 189-218).
  • this pathway can transmit signals, which result in the prevention or induction of apoptosis or cell cycle progression.
  • the Ras/Raf/MEK/ERK pathway has been shown to play important roles in cell proliferation and the prevention of apoptosis.
  • Ras Aberrant activation of this pathway is commonly observed in malignantly transformed cells. Amplification of ras proto-oncogenes and activating mutations that lead to the expression of constitutively active Ras proteins are observed in approximately 30% of all human cancers (Stirewalt et al., Blood 2001, 97, 3589-95). Mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers as well as many other types of cancers (Kohl et al., Science 1993, 260, 1834-1837). The effects of Ras on proliferation and tumorigenesis have been documented in immortal cell lines (McCubrey et al., lnt J Oncol 1995, 7, 295-310).
  • Ras/Raf/MEK/ERK signaling pathway can exert proliferative or antiproliferative effects through downstream transcription factor targets including NF- ⁇ B, CREB, Ets-1, AP-1 and c-Myc. ERKs can directly phosphorylate Ets-1 , AP-1 and c-Myc, which lead to their activation.
  • ERKs can phosphorylate and activate a downstream kinase target RSK 1 which then phosphorylates and activates transcription factors, such as CREB. These transcription factors induce the expression of genes important for cell cycle progression, for example, Cdks, cyclins, growth factors, and apoptosis prevention, for example, antiapoptotic Bcl-2 and cytokines. Overall, treatment of cells with growth factors leads to the activation of ERKs which results in proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res, 1998, 74, 49-139).
  • MEK proteins are the primary downstream targets of Raf.
  • the MEK family of genes consists of five genes: MEK1 , MEK2, MEK3, MEK4 and MEK5. This family of dual- specificity kinases has both serine/threonine and tyrosine kinase activity.
  • the structure of MEK consists of an amino-terminal negative regulatory domain and a carboxy-terminal MAP kinase-binding domain, which is necessary for binding and activation of ERKs. Deletion of the regulatory MEK1 domain results in constitutive MEK1 and ERK activation (Steelman et a!., Leukemia 2004, 18, 189-218).
  • MEK1 is a 393-amino-acid protein with a molecular weight of 44 kDa (Crews et al., Science 1992, 258, 478-80). MEK1 is modestly expressed in embryonic development and is elevated in adult tissue with the highest levels detected in brain tissue. MEK1 requires phosphorylation of S218 and S222 for activation, and substitution of these residues with D or glutamic acid (E) led to an increase in activity and foci formation in NIH3T3 cells (Huang et al., MoI Biol Cell, 1995, 6, 237-45).
  • MEK1 constitutive activity of MEK1 in primary cell culture promotes senescence and induces p53 and p16 INMa , and the opposite was observed in immortalized cells or cells lacking either p53 or p16 INK4a (Lin et al., Genes Dev, 1998 , 12, 3008-3019).
  • Constitutive activity of MEK1 inhibits NF- KB transcription by negatively regulating p38 MAPK activity (Carter et al., J Biol Chem 2000, 275, 27858-64).
  • the main physiological substrates of MEK are the members of the ERK (extracellular signal-regulated kinase) or MAPK (mitogen activated protein kinase) family of genes. Aberrant expression of MEK1 has been detected in many different types of cancer, and mutated forms of MEK1 will transform fibroblast, hematopoietic and other cell types.
  • MEK1 Constitutive activation of MEK1 results in cellular transformation. It therefore represents a likely target for pharmacological intervention in proliferative and inflammatory diseases (Lee et al., Nature 1994, 372, 739-746; Dudley et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7686-7689).
  • MEK inhibitors have been developed that show potential therapeutic benefit in several studies. For example, small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts (Yen, T. et al, Proceedings of the American Association of Cancer Research 2004, 45, Abs 3889 and Lee, P. et al., Proceedings of the American Association of Cancer Research 2004, 45, Abs 3890). MEK inhibitors also entered clinical trials, i.e. ARRY142886 (Wallace, E.
  • PD-184352 was lacking efficacy in clinical phase Il trials. Tumors were much less responsive, as no partial responses and only a few patients with stable disease were observed. As a result, the clinical trials of this molecule were suspended (Mclnnes C IDDB MEETING REPORT 2003). PD-184352 was limited by poor solubility, high metabolic clearance and low bioavailability. This exemplifies the need for novel MEK inhibitors with superior pharmacological properties.
  • the object of the present invention to provide novel MEK inhibitors useful in the treatment of hyperproliferative diseases related to the hyperactivity of MEK as well as diseases modulated by the MEK cascade, such as cancer and inflammation, in mammals with superior pharmacological properties both with respect to their activities as well as their solubility, metabolic clearance and bioavailability characteristics.
  • this invention provides novel, substituted 4-arylamino pyridone derivatives and pharmaceutically acceptable salts, solvates or prodrugs thereof, that are MEK inhibitors and useful in the treatment of the above mentioned diseases.
  • the compounds are defined by Formula (I):
  • Ri, F? 2 , Rg, Rn Ri 2 , Ri3 and Ri 4 are independently selected from hydrogen, halogen, cyano, nitro, azido, -OR 3 , -C(O)R 31 -C(O)OR 3 , -NR 4 C(O)OR 6 , -OC(O)R 3 ,
  • L is selected from C 1 -C 1 0 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 3 -Ci 0 cycloalkyl, C 3 - Gi 0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted; or LR 10 are together hydrogen;
  • R 3 is selected from hydrogen, trifluoromethyl, C 1 -C 10 alkyl, C 2 - 1 0 alkenyl, C 2 -Ci 0 alkynyl, C 3 -Ci 0 cycloalkyl, C 3 -Ci 0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
  • R 4 is selected from hydrogen or Ci-C 6 alkyl whereby alkyl may be substituted or unsubstituted; or R 3 and R 4 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
  • R 5 is selected from hydrogen or CrC 6 alkyl whereby alkyl may be substituted or unsubstituted; or R 4 and R 5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
  • R 6 is selected from trifluoromethyl,Ci-Cio alkyl, C 3 -C 10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted;
  • W is selected from heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4 heteroatoms each of which is unsubstituted or substituted by 1 to 5 substituents ZRi 5 ; or W is -C(O)OR 15 , -C(O)NR 4 R 15 , -C(O)NR 4 OR 15 , -C(O)(C 3 - C 10 cycloalkyl), -C(O)(C 2 -Ci 0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), S(O)jNR 4 R 15 , S(O)jNR 4 OR 15 , -S(O)jNR 4 C(O)R 15 , or
  • R 4 and R 15 are as defined herein or may form together a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom,
  • Z is a bond, NR 16 , O, NRi 6 SO 2 or S,
  • R 15 is independently selected from hydrogen, trifluoromethyl, CrCi 0 alkyl, C 2 -Ci 0 alkenyl, C 2 -Ci 0 alkynyl, C 3 -C 10 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
  • R 16 is selected from hydrogen or C 1 -Ci 0 alkyl, or R 15 and R 16 form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being substituted or unsubstituted; m is 0, 1, 2, 3, 4 or 5 ;and j is 1 or 2.
  • the variants R r Rie, L 1 W and Z are defined as above but with the proviso that the following compounds are excluded:
  • variants RrRi 6 , L, W and Z are defined as above on pages 3 to 5 but with the proviso that the compounds according to the following formula are excluded
  • Q is -O-(CH 2 )kCH 3 , -NH 2 , -NH[(CH 2 )kCH 3 ], or -NH[O(CH 2 ) k CH 3 ], wherein the -NH 2 is optionally substituted with between 1 and 2 methyl, and the -(CH 2 ) k CH 3 moieties of the -O-(CH 2 ) k CH 3 , -NH[(CH 2 )kCH 3 ], and -NH[O(CH 2 ) k CH 3 ] groups are optionally substituted with between 1 and 3 substituents independently selected from hydroxy, amino, alkyl and cycloalkyl;
  • Z is -NH 2 or -NH[(CH 2 )kCH 3 ], wherein the -NH 2 is optionally substituted with between 1 and 2 methyl, and the -(CH 2 ) k CH 3 moiety of the -NH[(CH 2 )kCH 3 ] group is optionally substituted with between 1 and 3 substituents independently selected from hydroxy and amino;
  • R 1 is hydrogen, Ci -6 alkyl, C 2-4 alkenyl Or -(CH 2 )I-SO(CH 2 )I -3 OCH 3 , wherein the Ci -6 alkyl is optionally substituted with between 1 and 2 substituents independently selected from hydroxy, -COOH, and cyano;
  • R 2 is hydrogen, chlorine, fluorine or methyl
  • R 3 is hydrogen, chlorine, fluorine, methyl, or CF 3
  • R 4 is bromine, chlorine, fluorine, iodine, Ci. 6 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, -(CH 2 )-C 3-6 cycloalkyl, cyano, -O-(Ci- 4 alkyl), -S-(Ci -2 alkyl), -SOCH 3 , -SO 2 CH 3 , -SO 2 NR 6 R 7 , -C ⁇ C-(CH 2 ) n NH 2 , -C ⁇ C-(CH 2 ) n NHCH 3 , -C ⁇ C-(CH 2 ) n N(CH 3 ) 2 , -C ⁇ C-CH 2 OCH 3 , -C ⁇ C(CH 2 ) n OH, -C ⁇ C-(CH 2 ) n NH 2 , (Z)-CHCHCH 2 OCH 3 , -(Z)-
  • R 5 is hydrogen, chlorine, fluorine, or methyl
  • R 6 and R 7 are each independently hydrogen, methyl, or ethyl; k is O to 3; m is 1 to 4; n is 1 to 2; p is O to 2; t is O to 1 ; v is 1 to 5; and pharmaceutically acceptable salts, C 1-6 amides and Ci -6 esters thereof.
  • variants RrRi 6 , L, W and Z are defined as above on pages 3 to 5 but with the proviso that the compounds with the following formula including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof are excluded:
  • R 1 , R 2 , R 8 , R 9 and R 10 are independently hydrogen, halogen, cyano, nitro, azido, -
  • R 7 is hydrogen, CrC 10 alkyl, C 2 -Ci 0 alkenyl, C 2 -C 10 alkynyl, C 3 -Ci 0 cycloalkyl, C 3 -C 10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from -NR 11 SO 2 R 14 , -SO 2 NR 11 R 12 , -C(O)R 11 , C(O)OR 11 , -OC(O)R 11 , -NR 11 C(O)OR 14 , -NR 11 C(O)R 12 , -
  • R 3 and R 4 together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein any of said heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 11 SO 2 R 14 , -SO 2 NR 11 R 12 , -C(O)R 11 , C(O)OR 11 , -OC(O)R 11 , -NR 11 C(O)OR 14 , -NR 11 C(O)R 12 , -C(O)NR 11 R 12 , -SR 11 , -S(O)R 14 , -SO 2 R 14 , -NR 11 R 12 , -NR 11 C(O)NR 12 R 13 , -NR 11 (NCN)NR 12 R 13 , -OR 11 , aryl, heteroaryl,
  • R 4 and R 5 together with the atom to which they are attached form a 4 to 10-membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 11 SO 2 R 14 , -SO 2 NR 11 R 12 , -C(O)R 11 ,
  • R 6 is trifluoromethyl, CrCi 0 alkyl, C 3 -Ci 0 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR 11 SO 2 R 14 , -SO 2 NR 11 R 12 , -C(O)R 11 , C(O)OR 11 , -OC(O)R 11 , -NR 11 C(O)OR 14 ,
  • R 14 is lower alkyl, lower alkenyl, aryl and arylalkyl; or any two of R 11 , R 12 , R 13 or R 14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
  • W is heteroaryl, heterocyclyl, -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)NR 4 OR 3 , -C(O)NR 4 SO 2 R 3 , -C(O)(C 3 -C 10 cycloalkyl), -C(O)(CrC 10 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), wherein any of said heteroaryl, heterocyclyl, -C(O)OR 3 , -C(O)NR 3 R 4 , -C(O)NR 4 OR 3 , -C(O)NR 4 SO 2 R 3 , -C(O)(C 3 -C 10 cycloalkyl), -C(O)(C 1 -C 10 alkyl),
  • -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR 3 R 4 , -OR 3 , C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR 3 R 4 and -OR 3 ; m is 0, 1 , 2, 3 , 4 or 5; and j is 1 or 2.
  • the variants have the following meanings:
  • R 1 is as defined above, preferably hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, cyano, nitro, OR 3 or NR 3 R 4 ; more preferably hydrogen, halo or CrC 4 alkyl, still more preferably hydrogen or halo, most preferably hydrogen or F.
  • R 1 is hydrogen.
  • R-i is -S(O) 1 NR 4 C(O)R 3 , -C(O)NR 4 S(O)jR 6 , or S(O) j R 6 .
  • R 2 is as defined above, preferably hydrogen, halo, CrC 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, cyano, nitro, OR 3 or NR 3 R 4 ; more preferably hydrogen, halo or CrC 2 alkyl, still more preferably halo or methyl, most preferably Cl, F or methyl.
  • R 2 is methyl.
  • methyl is preferably further substituted by 1 , 2 or 3 fluorines, preferably 3 fluorines.
  • R 2 is F.
  • R 2 is -S(O)JNR 4 C(O)R 3 , -C(O)NR 4 S(O)jR 6 , or S(O)jR 6 .
  • R 9 is as defined above, preferably hydrogen, halo, Ci-C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, cyano, nitro, OR 3 or NR 3 R 4 ; more preferably hydrogen, halo or CrC 4 alkyl, still more preferably hydrogen, methyl or halo, most preferably hydrogen, methyl, Cl or F. In one embodiment, R 9 is hydrogen.
  • R 9 is -S(O)jNR 4 C(O)R 3 , -C(O)NR 4 S(O)JR 6 , or S(O)jR ⁇ .
  • Rio is as defined above, preferably hydrogen, -OR 3 , -C(O)R 31 -C(O)OR 3 , -NR 4 C(O)OR 6 , -OC(O)R 3 , -NR 4 S(O) 2 R 6 , -S(O) 2 NR 3 R 4 , S(O) 2 R 6 , -NR 4 C(O)R 3 , -C(O)NR 3 R 41 -NR 5 C(O)NR 3 R 4 , -NR 3 R 4 , more preferably hydrogen, -OR 3 , -NR 4 C(O)R 3 , -C(O)NR 3 R 4 , -NR 3 R 4 , still more preferably hydrogen, -OR 3 , -NR 3 R 4 , most preferably hydrogen.
  • R 3 and R 4 are independently CrC 6 alkyl, more preferably CrC 4 alkyl, optionally substituted by 1 or 2 alkyl amino, dialkyl amino, amino, O-alkyl, hydroxy, or R 3 and R 4 form together a cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl.
  • R 10 is -S(O)]N R 4 C(O)R 3 , -C(O)NR 4 S(O)jR 6 , -S(O)j(Ci-C ⁇ alkyl), -S(O)j(CR 4 R 5 ) m -aryl, -O(CR 4 R 5 )m-aryl, -NR 4 (CR 4 R 5 ) m -aryl, -O(CR 4 R 5 ) m - heteroaryl, -NR 4 (CR 4 R 5 ) m -heteroaryl, -O(CR 4 R 5 ) m -heterocyclyl, or -NR 4 (CR 4 R 5 ) m - heterocyclyl, where each aryl, heteroaryl and heterocyclyl is substituted or unsubstituted.
  • L is as defined above, preferably CrC 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -Ci 0 cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, more preferably CrC 5 alkyl, most preferably methylene, ethylene, n-propylene or n-butylene.
  • L is ethylene, n-propylene or n-butylene.
  • all moieties are divalent so that L serves as a linker between the nitrogen atom and Ri 0 .
  • LR 10 are together methyl.
  • LRi 0 are together hydrogen.
  • R 11 is as defined above, preferably hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 - C 4 alkenyl, C 2 -C 4 alkynyl, cyano, nitro, OR 3 or NR 3 R 4 ; more preferably hydrogen, halo or C 1 -C 4 alkyl or O-d-C 4 alkyl, still more preferably hydrogen, methyl, O-methyl or halo, most preferably hydrogen, methyl, Cl, Br or F.
  • R 11 is hydrogen.
  • Rn is methyl.
  • methyl is preferably further substituted by 1 , 2 or 3 fluorines, preferably 3 fluorines.
  • R 11 is -S(O)jNR 4 C(O)R 3 , -C(O)N R 4 S(O)jR 6 , or S(O)jR 6 .
  • R 12 is as defined above, preferably hydrogen, halo, CrC 10 alkyl, C 3 -C 10 cycloalkyl, C 2 - C 10 alkenyl, C 2 -C 10 alkynyl, cyano, nitro, azido; NR 4 SO 2 R 6 ; SO 2 NR 3 R 4 ; SO 2 R 6 ; C(O)NR 3 R 4 ; C(O)OR 3 ; OR 3 , NR 3 R 4 or -S(C 1 -C 2 alkyl) substituted with 1 to 5 F, more preferably hydrogen, halo, nitro, C r C 4 alkyl, 0-C 1 -C 4 alkyl, SCF 3 , SCHF 2 , SCH 2 F, SO 2 NR 3 R 4 Or C(O)NR 3 R 4 , still more preferably hydrogen, F, Cl, Br, I 1 nitro, methyl, ethyl, n-propyl, i-propyl, cycloprop
  • R 12 is hydrogen. In another embodiment, R 12 is methyl, SCF 3 , SCHF 2 , SCH 2 F or O-methyl, wherein methyl or O-methyl is preferably unsubstituted or further substituted by 1, 2 or 3 fluorines, preferably 2 or 3 fluorines.
  • Ri 2 , R 3 and R 4 are independently C 1 -C 6 alkyl, more preferably CrC 4 alkyl, optionally substituted by 1 or 2 alkyl amino, dialkyl amino, amino, O-alkyl, hydroxy, or R 3 and R 4 form together a cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl.
  • R 12 is Br or I.
  • R 12 is -S(O)jN R 4 C(O)R 3 , -C(O)NR 4 S(O)jR 6 , or S(O)jR 6 .
  • R 6 is C 2 -C 10 alkyl.
  • R 13 is as defined above, preferably hydrogen, halo, C 1 -C 4 alkyl, C 3 -C 4 cycloalkyl, C 2 - C 4 alkenyl or C 2 -C 4 alkynyl, more preferably hydrogen, F, Cl or methyl, most preferably hydrogen or F.
  • R 13 is hydrogen.
  • R 13 is -S(O)jNR 4 C(O)R 3 , -C(O)N R 4 S(O)jR 6 , or S(O)jR 6 .
  • R 14 is as defined above, preferably hydrogen, halo, CrC 4 alkyl, C 3 -C 4 cycloalkyl, C 2 - C 4 alkenyl or C 2 -C 4 alkynyl, more preferably hydrogen, F, Cl or methyl, most preferably hydrogen or F. In one embodiment, R 14 is hydrogen.
  • R 14 is -S(O)jNR 4 C(O)R 3 , -C(O)NR 4 S(O)jR 6 , or S(O)]R 6 .
  • at least one of R 1 , R 2 , R 9 , Rn, R12, R13 and R 14 is selected from -S(O)]N R 4 C(O)R 3 , -C(O)NR 4 S(O)jR 6 , and S(O)jR ⁇ .
  • each of R 1 , R 2 , Rg to R 14 and L may be substituted.
  • they can be substituted with 1 to 5, preferably 1 to 3, more preferably 1 or 2 groups independently selected from oxo, halogen, cyano, nitro, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F, SCF 3 , SCHF 2 , SCH 2 F, azido, NR 4 SO 2 R 6 , SO 2 NR 3 R 4 , C(O)R 3 , C(O)OR 3 , OC(O)R 3 , NR 4 C(O)OR 6 , NR 4 C(O)R 3 , C(O)NR 3 R 4 , NR 3 R 4 , NR 5 C(O)NR 3 R 4 , NR 5 C(NCN)NR 3 R 4 , OR 3 , aryl, heteroaryl, arylalkyl, heteroaryl
  • C(O)OR 3 , OC(O)R 3 , OR 3 more preferably oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy or azido, most preferably halogen, cyano, nitro, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F, SCF 3 , SCHF 2 , SCH 2 F, OH, O-methyl, NH 2 or N(methyl) 2 .
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted, this refers to any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl as a group or sub-structure such as in cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl.
  • R 3 is as defined above, preferably hydrogen, trifluoromethyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylalkyl, more preferably hydrogen or C 1 -C 4 alkyl most preferably hydrogen, methyl or ethyl.
  • R 4 is as defined above, preferably hydrogen Or C 1 -C 4 alkyl, more preferably hydrogen, methyl or ethyl.
  • R 3 and R 4 can be taken together with the atom to which they are attached to form a 4 to 7, preferably 5 or 6, membered heteroaryi or heterocyclic ring.
  • R 5 is as defined above, preferably hydrogen or C 1 -C 4 alkyl, more preferably hydrogen, methyl or ethyl.
  • R 4 and R 5 can be taken together with the atom to which they are attached to form a 4 to 7, preferably 5 or 6, membered carbocyclic, heteroaryl or heterocyclic ring.
  • R 6 is as defined above, preferably trifluoromethyl, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkylalkyl, more preferably C 1 -C 4 alkyl, most preferably methyl or ethyl.
  • R 3 , R 4 , Rs, Re or the rings formed by R 3 and R 4 and R 4 and R 5 may be substituted.
  • R 3 is preferably oxo, halogen, nitro, trifluoromethyl, OH, O-methyl, NH 2 or N(methyl) 2 .
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted, this refers to any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl as a group or sub-structure such as in cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl.
  • R' is selected from hydrogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl, preferably hydrogen or C 1 -C4 alkyl, more preferably hydrogen or methyl.
  • R" is selected from hydrogen, Ci-C 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl, preferably hydrogen or CrC 4 alkyl, more preferably hydrogen or methyl.
  • R" 1 is selected from hydrogen, CrC 4 alkyl, C 2 -C 4 alkenyl, aryl and arylalkyl, preferably hydrogen or C 1 -C4 alkyl, more preferably hydrogen or methyl.
  • R 11 " is selected from CrC 4 alkyl, C1-C 4 alkenyl, aryl and arylalkyl, preferably C 1 -C 4 alkyl, more preferably methyl.
  • any two of R', R", R 1 " or R”" can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano; nitro, CF 3 , CHF 2 , CH 2 F, OCF 3 , OCHF 2 , OCH 2 F 1 azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, preferably halogen, cyano; nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy and azido.
  • W is as defined above, preferably heteroaryl containing 1 , 2 or 3 heteroatoms, or heterocyclyl containing 1, 2, or 3 heteroatoms, more preferably heteroaryl, each of which is unsubstituted or substituted by 1 to 5, preferably 1 to 3, more preferably 1 , substituents ZR 15 , or W is -C(O)ORi 5 , -C(O)NR 4 R 15 , -C(O)NR 4 ORi 5 , -C(O)(C 3 -C 10 cycloalkyl), -C(O)(C 2 -Ci 0 alkyl), -S(O)]NR 4 C(O)Ri 5 , -C(O)NR 4 S(O)jR6, S(O)]NR 4 R 15 or S(O) j NR 4 ORis, more preferably W is heteroaryl containing 1, 2, or 3, specifically 2 or 3 N atoms, C(O)NR 4 ORi 5 or S(O) 2 NR
  • Z and Ri 5 are as defined above, preferably Z is a bond, NRi 6 , NRi 6 SO 2 or O, more preferably NRi 6 , wherein Ri 6 is as defined above, preferably hydrogen or CrC 4 alkyl, more preferably hydrogen.
  • R 15 is preferably selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkenyl, C 4 -C 8 cycloalkylalkyl, each may contain 1 N atom optionally an O atom, where alkyl, alkenyl or cycloalkylalkyl may be further substituted by 1 or 2 of OH, 0-C 1 -C 4 alkyl or NR'R", where R' and R" are independently hydrogen or C 1 -C 4 alkyl where R' and R " may form a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom.
  • R 16 and R 15 may form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl. More preferably R 15 is C 1 - C 4 alkyl or C 1 -C 4 alkenyl optionally substituted with 1 substituent OH, O-Me, NH 2 , N(methyl) 2 or N(ethyl) 2 .
  • Y is O or NR', preferably O.
  • W is preferably -C(O)OR 15 , -C(O)NR 4 R 15 , -C(O)NR 4 OR 15 , S(O)]NR 4 R 15 or S(O)jNR 4 ORi5, more preferably -C(O)NR 4 OR 15 or S(O) 2 NR 4 ORi 5 .
  • R 15 is preferably as defined below.
  • W is -S(O)]NR 4 C(O)R 15 , whereby R 4 and Ri 5 are as defined herein or may form together a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom,
  • Z is as defined above, preferably a bond, NRi 6 , NR 16 SO 2 or O, more preferably NR 16 . in another embodiment, Z is S.
  • Ri 5 is as defined above, preferably hydrogen, Ci-C 4 alkyl, Ci-C 4 alkenyl, C 4 -C 6 cycloalkylalkyl, more preferably C r C 4 alkyl or CrC 4 alkenyl, yet more preferably Ci-C 4 alkyl.
  • Alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heteroaryl or heterocyclyl may be further substituted with 1 to 5, preferably 1 , 2 or 3, more preferably 1 or 2, substituents selected from OR 3 or NR 1 R" wherein R 3 is selected from hydrogen, CrC 4 alkyl or Ci- C 4 alkenyl, C 4 -C 6 cycloalkylalkyl, more preferably hydrogen, methyl or ethyl, and where R 1 and R" are independently hydrogen or d-C 4 alkyl, or R ' and R " may form a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom, more preferably R' and R" are independently hydrogen, methyl or ethyl, still more preferably both R' and R" are methyl. Yet more preferably, Ri 5 may be substituted by 1 or 2 of OH, 0-Ci-C 4 alkyl or NR 1 R".
  • R 15 is C 1 -C 4 alkyl or C1-C 4 alkenyl optionally substituted with 1 substituent OH, O-Me, NH 2 , N(methyl) 2 or N(ethyl) 2 .
  • alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl when it is described that alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted, this refers to any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl as a group or sub-structure such as in cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl.
  • Ri 6 and R 15 may form together a 4 to 10, preferably 5 to 6, membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl.
  • m is as defined above, preferably 0, 1 , 2 or 3, more preferably 0, 1 or 2, most preferably 1.
  • j is as defined above, preferably 2.
  • any of the preferred definitions for each variant can be combined with the preferred definition of the other variants.
  • Aryl is an aromatic mono- or polycyclic moiety with preferably 6 to 20 carbon atoms which is preferably selected from phenyl, biphenyl, naphthyl, tetrahydronaphthyl, fluorenyl, indenyl or phenanthrenyl, more preferably phenyl or naphthyl.
  • Heteroaryl is an aromatic moiety having 6 to 20 carbon atoms with at least one ring containing a heteroatom selected from O, N and/or S, or heteroaryl is an aromatic ring containing at least one heteroatom selected from O, N and/or S and 1 to 6 carbon atoms.
  • heteroaryl contains 1 to 4, more preferably 1 , 2 or 3 heteroatoms selected from O and/or N and is preferably selected from pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl,
  • heteroaryl examples include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, isoxazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl.
  • Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryi, heteroaryl, and hydroxy.
  • Heterocyclyl is a saturated or unsaturated ring containing at least one heteroatom selected from O, N and/or S and 1 to 6 carbon atoms.
  • heterocyclyl contains 1 to 4, more preferably 1 , 2 or 3 heteroatoms selected from O and/or N and is preferably selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,
  • Alkyl is a saturated hydrocarbon moiety, namely straight chain or branched alkyl having 1 to 10, preferably 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl or heptyl.
  • Cycloalkyl is an alkyl ring having 3 to 10, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
  • Alkenyl is an unsaturated hydrocarbon moiety with one or more double bonds, preferably one double bond, namely straight chain or branched alkenyl having 1 to 10, preferably 2 to 8 carbon atoms, more preferably 2 to 4 atoms, such as vinyl, allyl, methallyl, buten-2-yl, buten-3-yl, penten-2-yl, penten-3-yl, penten-4-yl, 3-methyl-but-3- enyl, 2-methyl-but-3-enyl, 1-methyl-but-3-enyl, hexenyl or heptenyl.
  • Alkynyl is an unsaturated hydrocarbon moiety with one or more triple bonds, preferably one triple bond, namely straight chain or branched alkynyl having 1 to 10, preferably 2 to 8 carbon atoms, more preferably 2 to 4 atoms, such as ethynyl, propynyl, butyn-2-yl, butyn-3-yl, pentyn-2-yl, pentyn-3-yl, pentyn-4-yl, 2-methyl-but-3- ynyl, 1-methyl-but-3-ynyl, hexynyl or heptynyl.
  • Halo or halogen is a halogen atom preferably selected from F 1 Cl 1 Br and I 1 preferably F 1 Cl and Br.
  • cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl it is contemplated that cycloalkyl, aryl, heteroaryl and heterocyclyl are bonded via an alkylene moiety.
  • This alkylene moiety may be a straight chain or branched chain group.
  • Said alkylene moiety preferably has 1 to 6 carbon atoms.
  • Examples thereof include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, iso- propylene, sec.-butylene, tert.-butylene, 1,1 -dimethyl propylene, 1,2-dimethyl propylene, 2,2-dimethyl propylene, 1,1 -dimethyl butylene, 1,2-dimethyl butylene, 1,3- dimethyl butylene, 2,2-dimethyl butylene, 2,3-dimethyl butylene, 3,3-dimethyl butylene, 1 -ethyl butylene, 2-ethyl butylene, 3-ethyl butylene, 1-n-propyl propylene, 2- n-propyl propylene, 1-iso-propyl propylene, 2-iso-propyl propylene, 1 -methyl pentylene, 2-methyl pentylene, 3-methyl pentylene and 4-methyl pentylene. More
  • the compounds of the present invention can be in the form of a prodrug compound.
  • Prodrug compound means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically.
  • prodrug examples include compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated.
  • these compounds can be produced from compounds of the present invention according to well-known methods.
  • prodrug examples include compounds, wherein the carboxylate in a compound of the present invention is for example converted into an alkyl-, aryl-, choline-, amino, acyloxymethylester, linolenoyl-ester. Metabolites of compounds of the present invention are also within the scope of the present invention.
  • isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials.
  • the compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the of the present invention which contain acidic groups can be present on these groups and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts.
  • salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids.
  • acids examples include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art.
  • the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions).
  • inner salts or betaines can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts.
  • the present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
  • the present invention provides pharmaceutical compositions comprising a compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier.
  • “Pharmaceutical composition” means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like one or more additional compounds of the present invention, or a prodrug compound or other MEK inhibitors.
  • said compounds and pharmaceutical composition are for the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer.
  • said pharmaceutical composition is for the treatment of a noncancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g. benign prostatic hypertrophy (BPH)).
  • benign hyperplasia of the skin e.g., psoriasis
  • restenosis e.g. benign prostatic hypertrophy (BPH)
  • the invention also relates to a compound or pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephtitis and diabetes induced renal disease) or pain in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • the invention also relates to a compound or pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • the invention also relates to a compound or pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier.
  • said compound or pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, excema, and sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, excema, and sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, heman
  • the invention also relates to of the use for treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • said use relates to the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer.
  • said use relates to the treatment of a non ⁇ cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g. benign prostatic hypertrophy (BPH)).
  • a non ⁇ cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g. benign prostatic hypertrophy (BPH)).
  • the invention also relates to a use for the treatment of a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and anti-androgens.
  • an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and anti-androgens.
  • the invention also relates to a use of treating pancreatitis or kidney disease or pain in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a use of preventing blastocyte implantation in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • the invention also relates to a use of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
  • said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
  • a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma,
  • Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands
  • This invention also relates to a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth.
  • chemotherapeutics are presently known in the art.
  • the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.
  • This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a hyperproliferative disorder which method comprises administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amounts of the compound, salt, solvate, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal.
  • Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.
  • the administration of the compound of the invention in this combination therapy can be determined as described herein.
  • this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt or solvate or prodrug thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation.
  • the amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein.
  • the invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a prodrug thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
  • the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • oral liquid preparations such as, for example, suspensions, elixirs and solutions
  • carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparation
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasal ⁇ as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
  • Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of the present invention are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • LiHMDS Lithium hexamethyldisilazide
  • the compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present invention claimed herein can be readily prepared.
  • the compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention.
  • the examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds.
  • the instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described above.
  • the amine-free bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of the liberated amine-free base into an organic solvent, followed by evaporation.
  • a suitable base such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide
  • the amine-free base, isolated in this manner can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent, followed by addition of the appropriate acid and subsequent evaporation, precipitation or crystallization.
  • diethyl 1,3-acetonedicarboxylate is heated with triethyl orthoformate and acetic anhydride and subsequently treated with ammonia as shown in scheme 2.
  • the resulting product is converted into ethyl 4,6- dichloronicotinate (1) by heating with phosphoryl chloride.
  • This procedure has been previously described in the literature (DenHertog , Reel Trav Chim Pays-Bas 1946, 65, 129-140).
  • Compound 1 is then reacted with an appropriately substituted aniline in an inert solvent, preferable THF, by addition of a base, preferably but not limited to
  • Scheme 3 illustrates the preparation of compounds of the present invention where W is heterocyclic.
  • 4-anilino pyridone compound 3 is reacted with BOC- hydrazine, DIPEA and a coupling reagent as PyBOP, for example.
  • the product is then deprotected with hydrochloric acid at elevated temperatures to give acylhydrazide 5.
  • hydrazide 5 can be reacted with an appropriately substituted isocyanate to yield compound 6.
  • Cyclization to 7 is achieved by addition of triphenyl phosphine, CCI 4 and a base such as triethylamine or DIPEA in an inert solvent like DCM.
  • Suitable anilines, alkyliodides, O-alkyl hydroxylamines, and isocyanates are commercially available from Sigma-AIdrich Chemie GmbH, Kunststoff, Germany or from Acros Organics, Belgium or from Fisher Scientific GmbH, 58239 Schense, Germany or can be routinely prepared by procedures described in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5th Edition; John Wiley & Sons.
  • O-[(4S)2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethyl]-hydroxylamine and O-[(4R)2,2-dimethyl- [1,3]dioxolan-4-ylmethyl]-hydroxylamine are prepared according to a procedure described in WO02/06213 A2.
  • Analytical LC/MS was performed using Reprosil-Pur ODS3, 5 ⁇ M, 1 x 60 mm columns at a flow rate of 250 ⁇ l/min, sample loop 2.5 ⁇ l; retention times are given in minutes.
  • Methods are: (I) runs on a LC10Advp-Pump (Shimadzu) with SPD-M 10Avp UV/Vis diode array detector and QP2010 MS-detector in ESI+ modus with UV-detection at 214, 254 and 275 nm with a gradient of 15-95% acetonitrile (B) in water (A) (0.1% formic acid), 5 min.
  • Ethyl 4,6-dichloronicotinate (1) is synthesised according to a literature procedure (DenHertog, Reel Trav Chim Pays-Bas 1946, 65, 129-140): Diethyl acetone dicarboxylate (1Og, 49mmol, purchased from Sigma-Aldrich) is treated with triethylorthoformiate (7g) and acetic anhydride (1Og) at 130 0 C for 1h and the volatiles are removed in vacuo. The mixture is cooled to O 0 C and cone. Ammonia (14ml) is added slowly.
  • Ethyl 4,6-dichloronicotinate (1) (2.Og, 9.1mmol) and 4-bromo-2-methylaniline (1.7g, 9.1 mmol) are dissolved in dry THF (20ml) under argon and the mixture is cooled to -78°C.
  • a solution of LiHMDS (1.0M in THF, 32ml) is slowly added and the reaction mixture is allowed to warm to ambient temperature. After 18h the reaction is quenched by adding dilute hydrochloric acid (1.0M, 20.0ml) and the mixture is extracted with DCM (3x 60ml).
  • Step C 4-(4-Bromo-2-methyl-phenylamino)-6-chloro-nicotinic acid ethyl ester (2a) (250mg, 0.68mmol) and iodomethane (337 ⁇ l, 5.4mmol) are dissolved in dry DCE (8ml) under argon and the mixture is heated at 140° C for 100 min with microwave irradiation and the volatiles are removed in vacuo. LiOH (101mg, 4.2mmol) is added and the mixture is heated for 10 min at 140° C with microwave irradiation.
  • N-allyl-2-( ⁇ 4-[(4-bromo-2-methylphenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3- yl ⁇ carbonyl)hydrazinecarboxamide (0.472mmol, 205) mg is dissolved in dry DCM (10ml) and CCI 4 (1.89mmol,183 ⁇ l), triethylamine (0.71mmol, 99 ⁇ l) and PPh 3 (0.73mmol,192mg) are added and the solution is heated for 20 min at 100° C with microwave irradiation. The volatiles are removed in vacuo and the product is purified by preparat/ve HPLC to give pure 7a.
  • Ethyl 4,6-dichloronicotinate (1) (3.2g, 14.5mmol) and 4-iodo-2-methylaniline (3.Og, 13.6mmol) are dissolved in dry THF (15ml) under argon and the mixture is cooled to - 78 0 C.
  • a solution of LiHMDS (1.0M in THF, 48ml) is slowly added and the reaction mixture is allowed to warm to ambient temperature. After 18h the reaction is quenched by adding dilute hydrochloric acid (1.0M, 30.0ml) and the mixture is extracted with DCM (3x 80ml).
  • Ester 2b (350mg, 0.84mmol) and iodomethane (1.5ml) are dissolved in dry DCE (8ml) under argon and the mixture is heated at 140° C for 1.5h with microwave irradiation and the volatiles are removed in vacuo. LiOH (81 mg, 3.36mmol) is added and the mixture is heated for 15min at 140 0 C with microwave irradiation. The volatiles are evaporated under reduced pressure 1 N HCI is added (10ml) and extraxted with DCM.
  • the activity of the compounds of the present invitation may be determined by the following procedure: Inhibition of human MEK1 kinase activity was monitored with a homogenous, fluorescence based assay.
  • the assay uses time resolved fluorescence resonance energy transfer to probe for phosphorylation of ERK1 by MEK1.
  • the assay is carried out in low volume 96 well microtiterplates. In a total volume of 15 ⁇ l, compounds are incubated with 10OnM MEK1 , 15 ⁇ M ATP, 30OnM ERK2 employing a buffer containing 2OmM TRIS/HCI, 10 mM MgCI2, 100 ⁇ M NaVO4, 1 mM DTT, and 0.005% Tween 20 (pH 7.4).
  • Assay 2 Tumor cell proliferation assays (ATP Lite)
  • Murine colon C26, human melanoma A375 and human melanoma Mel5 cells were plated in 96 well Corning white plates (1500 cells/well for C26, and 2000 cells/well for A375, and MiaPaCa-2) and cultured overnight at 37 0 C in 5% CO2. Inhibitors were serially diluted in 100 % DMSO and subsequently added to cells to reach a final concentration of 0.25% DMSO. The cells were incubated for 4 days in the presence of test compounds in cell growth media (DMEM with 10% fetal bovine serum, 2mM glutamine for C26, and MiaPaCa-2, and RPMI with 10% fetal bovine serum, 2mM glutamine for A375).
  • DMEM fetal bovine serum
  • 2mM glutamine for C26 and MiaPaCa-2
  • RPMI 10% fetal bovine serum, 2mM glutamine for A375
  • HBM, RLM and MLM Compounds were tested on their stability in human, rat and mouse liver microsomal preparations (HLM, RLM and MLM respectively). At a final concentration of 3 ⁇ M, compounds were incubated at 37 0 C with 0.5 mg/ml human, rat or mouse liver microsomes in a buffer containing 50 mM phosphate, pH 7.4 and 2 mM NADPH. Pooled human liver microsomes or pooled male rat liver microsomes (Sprague Dawley) were obtained from NatuTec (Frankfurt, Germany). Incubations without NADPH served as negative controls.

Abstract

The invention provides novel, substituted 4-arylamino pyridone compounds (formula (I)), pharmaceutically acceptable salts, solvates and prodrug compounds thereof, wherein W, R 1, R2, R9, R 10, R 11, R 12, R 13, R 14 and L are as defined in the specification. Such compounds are MEK inhibitors and useful in the treatment of hyperproliferative diseases, such as cancer, restenosis and inflammation. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.

Description

NOVEL 4-ARYLAMINO PYRIDONE DERIVATIVES AS MEK INHIBITORS FOR THE TREATMENT OF HYPERPROLIFERATIVE DISORDERS
Field of the invention
The invention relates to a series of substituted 4-arylamino pyridone derivatives that are useful in the treatment of hyperproliferative diseases, such as cancer and inflammation, in mammals. Also disclosed is the use of such compounds in the treatment of hyperproliferative diseases in mammals, especially humans, and pharmaceutical compositions containing such compounds.
Summary of the related art
The Ras/Raf/MEK/ERK pathway is a central signal transduction pathway, which transmits signals from multiple cell surface receptors to transcription factors in the nucleus which regulate gene expression. This pathway is frequently referred to as the MAP kinase pathway as MAPK stands for mitogen-activated protein kinase indicating that this pathway can be stimulated by mitogens, cytokines and growth factors (Steelman et al., Leukemia 2004, 18, 189-218). Depending upon the stimulus and cell type, this pathway can transmit signals, which result in the prevention or induction of apoptosis or cell cycle progression. The Ras/Raf/MEK/ERK pathway has been shown to play important roles in cell proliferation and the prevention of apoptosis. Aberrant activation of this pathway is commonly observed in malignantly transformed cells. Amplification of ras proto-oncogenes and activating mutations that lead to the expression of constitutively active Ras proteins are observed in approximately 30% of all human cancers (Stirewalt et al., Blood 2001, 97, 3589-95). Mutated, oncogenic forms of Ras are found in 50% of colon and >90% pancreatic cancers as well as many other types of cancers (Kohl et al., Science 1993, 260, 1834-1837). The effects of Ras on proliferation and tumorigenesis have been documented in immortal cell lines (McCubrey et al., lnt J Oncol 1995, 7, 295-310). όRaf mutations have been identified in more than 60% of malignant melanoma (Davies, H et al., Nature 2002, 417, 949- 954). Given the high level of mutations that have been detected at Ras, this pathway has always been considered a key target for therapeutic intervention (Chang et al., Leukemia 2003, -/7,1263-93). The Ras/Raf/MEK/ERK signaling pathway can exert proliferative or antiproliferative effects through downstream transcription factor targets including NF-κB, CREB, Ets-1, AP-1 and c-Myc. ERKs can directly phosphorylate Ets-1 , AP-1 and c-Myc, which lead to their activation. Alternatively, ERKs can phosphorylate and activate a downstream kinase target RSK1 which then phosphorylates and activates transcription factors, such as CREB. These transcription factors induce the expression of genes important for cell cycle progression, for example, Cdks, cyclins, growth factors, and apoptosis prevention, for example, antiapoptotic Bcl-2 and cytokines. Overall, treatment of cells with growth factors leads to the activation of ERKs which results in proliferation and, in some cases, differentiation (Lewis et al., Adv. Cancer Res, 1998, 74, 49-139).
MEK proteins are the primary downstream targets of Raf. The MEK family of genes consists of five genes: MEK1 , MEK2, MEK3, MEK4 and MEK5. This family of dual- specificity kinases has both serine/threonine and tyrosine kinase activity. The structure of MEK consists of an amino-terminal negative regulatory domain and a carboxy-terminal MAP kinase-binding domain, which is necessary for binding and activation of ERKs. Deletion of the regulatory MEK1 domain results in constitutive MEK1 and ERK activation (Steelman et a!., Leukemia 2004, 18, 189-218).
MEK1 is a 393-amino-acid protein with a molecular weight of 44 kDa (Crews et al., Science 1992, 258, 478-80). MEK1 is modestly expressed in embryonic development and is elevated in adult tissue with the highest levels detected in brain tissue. MEK1 requires phosphorylation of S218 and S222 for activation, and substitution of these residues with D or glutamic acid (E) led to an increase in activity and foci formation in NIH3T3 cells (Huang et al., MoI Biol Cell, 1995, 6, 237-45). Constitutive activity of MEK1 in primary cell culture promotes senescence and induces p53 and p16INMa, and the opposite was observed in immortalized cells or cells lacking either p53 or p16INK4a (Lin et al., Genes Dev, 1998 , 12, 3008-3019). Constitutive activity of MEK1 inhibits NF- KB transcription by negatively regulating p38MAPK activity (Carter et al., J Biol Chem 2000, 275, 27858-64). The main physiological substrates of MEK are the members of the ERK (extracellular signal-regulated kinase) or MAPK (mitogen activated protein kinase) family of genes. Aberrant expression of MEK1 has been detected in many different types of cancer, and mutated forms of MEK1 will transform fibroblast, hematopoietic and other cell types.
Constitutive activation of MEK1 results in cellular transformation. It therefore represents a likely target for pharmacological intervention in proliferative and inflammatory diseases (Lee et al., Nature 1994, 372, 739-746; Dudley et al., Proc. Natl. Acad. Sci. U.S.A. 1995, 92, 7686-7689).
Useful inhibitors of MEK have been developed that show potential therapeutic benefit in several studies. For example, small molecule MEK inhibitors have been shown to inhibit human tumor growth in nude mouse xenografts (Yen, T. et al, Proceedings of the American Association of Cancer Research 2004, 45, Abs 3889 and Lee, P. et al., Proceedings of the American Association of Cancer Research 2004, 45, Abs 3890). MEK inhibitors also entered clinical trials, i.e. ARRY142886 (Wallace, E. et al, Proceedings of the American Association of Cancer Research 2004, 45, Abs 3891 ), PD-0325901 (Swanton C, Johnston S /DDS MEETING REPORT 2O0Z, February 13- 1) and PD-184352 (Waterhouse et al., Proceedings of the American Society for Clinical Oncology 2003, 22, Abs 816).
Compounds suitable as MEK inhibitors are also disclosed in US 5,525,625; WO 98/43960; WO 99/01421 ; WO 99/01426; WO 00/41505; WO 00/42002; WO 00/42003; WO 00/41994; WO 00/42022; WO 00/42029; WO 00/68201; WO 01/68619; WO 02/06213; WO03/035626; A2; WO 03/077855; WO03/077914; WO2004/005284; WO2004/056789.
However, PD-184352 was lacking efficacy in clinical phase Il trials. Tumors were much less responsive, as no partial responses and only a few patients with stable disease were observed. As a result, the clinical trials of this molecule were suspended (Mclnnes C IDDB MEETING REPORT 2003). PD-184352 was limited by poor solubility, high metabolic clearance and low bioavailability. This exemplifies the need for novel MEK inhibitors with superior pharmacological properties.
Description of the invention
In view of the foregoing it is the object of the present invention to provide novel MEK inhibitors useful in the treatment of hyperproliferative diseases related to the hyperactivity of MEK as well as diseases modulated by the MEK cascade, such as cancer and inflammation, in mammals with superior pharmacological properties both with respect to their activities as well as their solubility, metabolic clearance and bioavailability characteristics.
As a result, this invention provides novel, substituted 4-arylamino pyridone derivatives and pharmaceutically acceptable salts, solvates or prodrugs thereof, that are MEK inhibitors and useful in the treatment of the above mentioned diseases. The compounds are defined by Formula (I):
Formula (I)
Figure imgf000005_0001
a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein:
Ri, F?2, Rg, Rn Ri2, Ri3 and Ri4 are independently selected from hydrogen, halogen, cyano, nitro, azido, -OR3, -C(O)R31-C(O)OR3, -NR4C(O)OR6, -OC(O)R3,
-NR4S(O)jR6 , -S(O)jNR3R4, -S(O)jNR4C(O)R3, -C(O)NR4S(O)jR6, S(O)jRβ, -NR4C(O)R3, -C(O)NR3R41-NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4 and d- Cio alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-Ci0 cycloaikyi, C3-Ci0 cycloalkylalkyl, -S(O)j(Ci-Cβ alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m- aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl, -NR4(CR4R5)m-heterocyclyl, and -S(CrC2 alkyl) substituted with 1 to 5 F, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted; R10 is selected from hydrogen, -OR3, -C(O)R31-C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O)jR6 , -S(O)jNR3R4, -S(O)jNR4C(O)R3, -C(O)NR4S(O)jR6, S(O)1R6, -NR4C(O)R3, -C(O)NR3R41-NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4 ; -S(O)1(C1-C6 alkyl), -S(O)j(CR4R5)m-aryl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl, -NR4(CR4R5)m-heterocyclyl, and -S(CrC2 alkyl) substituted with 1 to 5 F, where each, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
L is selected from C1-C10 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-Ci0 cycloalkyl, C3- Gi 0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted; or LR10 are together hydrogen;
R3 is selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C2-10 alkenyl, C2-Ci0 alkynyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
R4 is selected from hydrogen or Ci-C6 alkyl whereby alkyl may be substituted or unsubstituted; or R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R5 is selected from hydrogen or CrC6 alkyl whereby alkyl may be substituted or unsubstituted; or R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R6 is selected from trifluoromethyl,Ci-Cio alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted;
W is selected from heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1-4 heteroatoms each of which is unsubstituted or substituted by 1 to 5 substituents ZRi5; or W is -C(O)OR15, -C(O)NR4R15, -C(O)NR4OR15, -C(O)(C3- C10 cycloalkyl), -C(O)(C2-Ci0 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), S(O)jNR4R15, S(O)jNR4OR15, -S(O)jNR4C(O)R15, or
-C(O)NR4S(O)jR6, whereby R4 and R15 are as defined herein or may form together a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom,
Z is a bond, NR16, O, NRi6SO2 or S,
R15 is independently selected from hydrogen, trifluoromethyl, CrCi0 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
R16 is selected from hydrogen or C1-Ci0 alkyl, or R15 and R16 form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being substituted or unsubstituted; m is 0, 1, 2, 3, 4 or 5 ;and j is 1 or 2.
In a preferred embodiment, the variants RrRie, L1 W and Z are defined as above but with the proviso that the following compounds are excluded:
4-(4-Bromo-2-fluoro-phenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid amide, 1 -Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-chloro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxyiic acid(2-hydroxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1 ,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-1 , 1 -dimethy l-ethoxy)-amide,
4-(4-Bromo-2-chloro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridme-3- carboxylic acid(2-hydroxy-1 ,1-dimethyl-ethoxy)-amide,
4-(4-Bromo-2-chloro-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-ethoxy)-amide, 4-(4-Bromo-2-methyl-ρhenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid(2-hydroxy-ethoxy)-amide,
4-(2,4-Dichloro-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid ethoxy-amide,
4-(2-Fluoro-4-iodo-phenylamino)-1 ,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethoxy)-amide,
5-(5-Amino-[1 ,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluoro-phenylamino)-3-fluoro-1-methyl- 1H-pyridin-2-one, 4-(2-Fluoro-4-iodo-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid(2,3-dihydroxy-propoxy)-amide, 4-(4-Bromo-2-fluoro-phenylamino)-1,5-dimethyl-6-oxo-1 ,6-dihydro-pyricline-3- carboxylic acid hydroxyamide,
5-Fluoro-4-(2-fluoro-4-methylsulfanyl-phenylamino)-1-methyl-6-oxo-1,6-dihydro- pyridine-3-carboxylic acid ethoxy-amide, 4-(2-Fluoro-4-iodo-phenylamino)-1 ,5-dimethyl-6-oxo-1.δ-dihydro-pyridine-S-carboxylic acid methoxy-amide,
4-(2-Fluoro-4-iodo-phenylamino)-1,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid ethoxy-amide,
5-Fluoro-4-(2-fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid methoxy-amide,
5-Fluoro-4-(2-fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid ethoxy-amide,
5-Fluoro-4-(2-fluoro-4-methylsulfanyl-phenylamino)-1-methyl-6-oxo-1,6-dihydro- pyridine-3-carboxylic acid methoxy-amide, 4-(2-Fluoro-4-methylsulfanyl-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxyiic acid methoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-methoxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-pheny!amino)-5-fluoro-1 -methyl-δ-oxo-i.δ-dihydro-pyridine-S- carboxylic acid (2-methoxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1 ,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid methoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid ethoxy-amide, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1 -methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid methoxy-amide,
5-(5-Amino-[1 ,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluoro-phenylamino)-1 ,3-dimethyl-1 H- pyridin-2-one.
2-(4-Bromo-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid cyclopropylmethoxy-amide, 2-(4-Bromo-2-fluoro-phenylamino)-1-methyl-6-oxo-1 ,6-ciihyclro-pyriciine-3-carboxylic acid (2-hydroxy-ethoxy)-amide,
2-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1 -methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-ethoxy)-amide, 2-(4-Bromo-2-fluoro-phenylamino)-1 -ethyl-6-oxo-1.δ-dihydro-pyridine-S-carboxylic acid (2-hydroxy-ethoxy)-amide,
2-(2-Fluoro-4-methyl-phenylamino)-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethoxy)-amide,
2-(2-Fluoro-4-iodo-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methoxy-amide,
^?/)-4-(2-Fluoro-4-iodo-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2,3-dihydroxy-propoxy)-amide,
CRj-4-(4-Bromo-2-fluoro-phenyiamino)-1-ethy!-5-fluoro-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2~hydroxy-propoxy)-amide, (S>4-(4-Bromσ-2-fluoro-phenylamino)-1 -cyclopropylmethyl-δ-methyl-e-oxo-i ,6- dihydro-pyridine-3-carboxylic acid (2-hydroxy-propoxy)-amide, fS>4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-propoxy)-amide,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-chloro-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-chloro-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid amide,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-chloro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide 1 -Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1 ,6-dihydropyridine-3- carboxylic acid,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3- carboxylic acid amide,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1 ,6-dihydropyridine-3- carboxylic acid cyclopropylmethoxy-amide, 1-Benzyl-4-(4-bromo-2-fIuoro-phenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3- carboxylic acid (2-hydroxyethoxy)-amide,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1 ,6-dihydropyridine-3- carboxylic acid (2-amino-ethoxy)-amide hydrogen chloride, 1 -Benzyl-4-(4-bromo-2-fluoro-phenylamino)-6-oxo-1.β-dihydro-pyridine-S-carboxylic acid amide,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid cyclopropylmethoxy-amide,
1-Benzyl-4-(4-bromo-2-fluoro-phenylamino)-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid (2~hydroxy-ethoxy)-amide,
2-(2-Fluoro-2-methyl-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (2-hydroxyethoxy)-amide,
2-(4-Bromo-2-fluoro-phenylamino)-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid,
2-(4-Bromo-2-fluoro-phenylamino)-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(2,4-Dichloro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid,
4-(2,4-Dichloro-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridme-3-carboxylic acid cyclopropylmethoxy-amide, 4-(2,4-Dichloro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridme-3-carboxylic acid ethoxy-amide,
4-(2-Fluoro-4-methyl-phenylamino)-1,2,5-trimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
4-(2-Fluoro-4-methyl-phenylamino)-1,2,5-trimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxyethoxy)-amide,
4-(2-Fluoro-4-methyl-phenylamino)-1 ,3,8-trimethyl-1H,6H-pyrido[2,3-d]pyridazine-2,5- dione,
4-(2-Fluoro-4-methyl-phenylamino)-1 ,3-dimethyl-6,7-dihydro-1 H-pyrrolo[3,4- b]pyridine-2,5-dione, 4-(2-Fluoro-4-methyl-phenylamino)-1 ,3-dimethyl-7,8-dihydro-1 H,6H-pyrido[2,3- d]pyridazine-2,5-dione, 4-(4-Bromo-2-chloro-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihyclro-pyridine-3- carboxylic acid amide,
4-(4-Bromo-2-chloro-phenylamino)-5-fluoro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid, 4-(4-Bromo-2-chloro-phenylamino)-5-fIuoro-1 -methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-chloro-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid amide,
4-(4-Bromo-2-chloro-phenylamino)-5-fluoro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxyethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino) 1 -cyclopropylmethyl-δ-methyl-δ-oxo-i ,6-dihydro- pyridine-3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-1-(2-cyclopropylethyl)-5-fluoro-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid, 4-(4-Bromo-2-fluoro-phenylamino)-1 -(2-cyclopropylethyl)-5-fluoro-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-(2-cyciopropylethyl)-5-fluoro-6-oxo-1,6- dihydropyridine-3-carboxylic acid (2-hydroxethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1 ,3-dimethyl-5-(1 H-tetrazol-5-yl)-1 H-pyridin-2-one, 4-(4-Bromo-2-fluoro-phenylamino)-1 ,3-dimethyl-5-(5-oxo-4,5-dihydro-[1 ,3,4]oxadiazol- 2-yl)-1 H-pyridin-2-one,
4-(4-Bromo-2-fluoro-phenylamino)-1,3-dimethyl-5-[5-(2-methylaminoethylamino)- [1.S^joxadiazol^-yO-i H-pyridin-2-one,
4-(4-Bromo-2-fluoro-phenylamino)-1,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-1,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid amide, 4-(4-Bromo-2-fluoro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridme-3- carboxylic acid (2-cyanol-ethyl)-amide, 4-(4-Bromo-2-fIuoro-phenylamino)-1-cyclohexylmethyl-5-fluoro-6-oxo-1,6- dihydropyridine-3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclohexylmethyI-5-fluoro-6-oxo-1,6- dihydropyridine-3-carboxylic acid (2-hydroxy-1 , 1 -dimethylethoxy)-amide, 4-(4-Bromo-2-fluoro-phenylamino)-1 -cyclohexylmethyl-δ-fluoro-θ-oxo-i ,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine- 3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1,6-dihydro-pyridine- 3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine- 3-carboxylic acid amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine- 3-carboxylic acid (2-hydroxyethoxy)-amide, 4-(4-Bromo-2-fluoro-phenylamino)-1 -cyclopropyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine- 3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropyimethyl-5-fluoro-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid (2-hydroxy-1 , 1 -dimethylethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropylmethyl-5-fluoro-6-oxo-1,6- dihydropyridine-3-carboxylic acid amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-cyclopropylmethyl-5-methyl-6-oxo-1,6-dihydro- pyridine-3-carboxylic acid amide, 4-(4-Bromo-2-fluoro-phenylamino)-1 -cyclopropylmethyl-δ-methyl-δ-oxo-i ,6-dihydro- pyridine-3-carboxylic acid (2-hydroxy-1,1-dimethylethoxy)-arnide,
4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fluoro-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-1 , 1 -dimethylethoxy)-amide, 4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-methoxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid methoxy-amide, 4-(4-Bromo-2-fluoro-phenylamino)-1 -ethyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid methylamide,
4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fluoro-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxyethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-ethyl-5-fIuoro-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2-hydroxybutoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid, 4-(4-Bromo-2-fluoro-phenylamino)-1 -methyl-6-oxo-1 ,6-dihydro-pyridinθ-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid (2-hydroxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid amide,
4-(4-Brorno-2-fluoro-phenylamino)-3-fluoro-1-methyl-5-(5-methyl-4H-[1I2,4]triazol-3- yl)-1 H-pyridin-2-one,
4-(4-Bromo-2-fluoro-phenylamino)-3-fluoro-5-[5-(2-hydroxyethylamino)- [1 ,3,4]oxadiazol-2-yl)-1 -methyl-1 H-pyridin-2-one, 4-(4-Bromo-2-fluoro-phenylamino)-5-[5-(2-hydroxyethylamino)-[1,3,4]oxadia2ol-2-yl)- 1 ,3-dimethyl-1 H-pyridin-2-one,
4-(4-Bromo-2-fluoro-phenylamino)-5-chloro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-chloro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-ethoxy)-amide, 4-(4-Bromo-2-fluoro-phenylamino)-5-chloro-1-methyl-6-oxo-1 ,6-dihyclro-pyridine-3- carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-5-chloro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid ethoxy-amide, 4-(4-Bromo-2-fluoro-phenylamino)-5-fIuoro-1 -(1 H-imidazol-4-ylmethyl)-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1 -(1 -methyl-1 H-imidazol-4-yimethyi)-6- oxo-1.β-dihydropyridine-S-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1 -(1 -methyl-1 H-imidazol-4-ylmethyl)-6- oxo-1.δ-dihydropyridine-S-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-(2-hydroxyethyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-(2-methoxyethyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1 -(2-methoxyethyl)-6-oxo-1 ,6- dihydropyridine-3-carboxyiic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-(2-morpholin-4-yl-ethyl)-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-(2-morpholin-4-yl-ethyl)-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-(6-methylpyridine-2-ylmethyl)-6-oxo-1,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-(6-methylpyridine-2-ylmethyl)-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid methoxy-amide, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1 -methanesulfonylmethyl-6-oxo-1 ,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-clihyclro-pyridine-3- carboxylic acid tert-butoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethyl-amide, 4-(4-Bromo-2-fIuoro-phenylamino)-5-fluoro-1 -methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid methyl-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-1,1-dimethy!ethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-propoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid hydroxyamide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1,6-dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6- dihydropyridine-3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1,6- dihydropyridine-3-carboxylic acid ethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyrazin-2-ylmethyl-1 ,6- dihydropyridine-3-carboxylic acid propoxy-amide, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1 -pyridazin-3-ylmethyl-1 ,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyridine-2-ylmethyl-1,6- dihydropyridine-3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-5-f!uoro-6-oxo-1-pyridine-2-ylmethyl-1,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyridine-2-ylmethyl-1 ,6- dihydropyridine-3-carboxylic acid (2-hydroxy-1 ,1 -dimethylethoxy)-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyridine-2-ylmethyl-1 ,6- dihydropyridine-3-carboxylic acid (2-hydroxyethoxy)-amide, 4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1 -pyridine-3-ylmethyl-1 ,6- dihydropyridine-3-carboxylic acid,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyridine-3-ylmethyl-1 ,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyridine-3-ylmethyl-1,6- dihydropyridine-3-carboxylic acid propoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyridine-3-ylmethyl-1,6- dihydropyridine-3-carboxylic acid (3-aminopropoxy)-amide hydrogen chloride,
4-(4-Bromo-2-fluoro-phenylamino)-5-fluoro-6-oxo-1-pyrimidin-4-ylmethyl-1 ,6- dihydropyridine-3-carboxylic acid cyclopropylmethoxy-amide, 4-(4-Bromo-2-fluoro-phenylamino)-6-oxo-1-phenyl-1,6-dihydro-pyridazine-3-carboxylic acid cyclopropylmethoxy-amide,
4-(4-Bromo-2-fluoro-phenylamino)-6-oxo-1-phenyl-1,6-dihydro-pyridazine-3-carboxylic acid (2-hydroxyethoxy)-amide,
4-(4-Bromo-2-methyl-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid,
4-(4-Bromo-2-methyl-phenylamino)-1,5-dimethyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2-hydroxy-1 ,1-dimethylethoxy)-amide,
4-(4-Bromo-2-methyl-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide, 4-(4-Bromo-2-methyl-phenylamino)-5-fluoro-1 -methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid ethoxy-amide,
4-(4-Bromo-2-methyl-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
4-(4-Chloro-2-fluoro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid, 4-(4-Chloro-2-fluoro-phenylamino)-1,5-dimethyl-6-oxo-1 ,6-clihydro-pyricline-3- carboxylic acid (2-hydroxyethoxy)-amide,
^-Chloro^-fluoro-phenylaminoJ-i.δ-dimethyl-e-oxo-i .e-dihydro-pyridine-S- carboxylic acid cyclopropylmethoxy-amide, 4-(4-Chloro-2-fluoro-phenylamino)-5-fluoro-1 -methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
4-(4-Chloro-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid ethoxy-amide,
4-(4-Chloro-2-fluoro-phenylamino)-5-fluoro-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid amide,
5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluoro-phenylamino)-3-fluoro-1- pyrazin-2-ylmethyl-1 H-pyridin-2-one,
5-(5-Amino-[1,3,4]oxadiazol-2-yl)-4-(4-bromo-2-fluoro-phenylamino)-3-fluoro-1 ,3- dimethyl-1 H-pyridin-2-one, 5-(5-Amino-[1 ,3,4]oxadiazol-2-yl)-4-(4-bromo-2-methyl-phenylamino)-3-fluoro-1 - methyl-1 H-pyridin-2-one,
5-(5-Amino-[1 ,3,4]oxadiazol-2-yl)-4-(4-chloro-2-fluoro-phenylamino)-3-fluoro-1-methyl- 1 H-pyridin-2-one,
5-(5-Amino-[1,3,4]thiadiazol-2-yl)-4-(4-bromo-2-fluoro-phenylamino)-3-fluoro-1-methyl- 1 H-pyridin-2-one,
5-(5-Amino-4H-[1,3,4]triazol-3-yl)-4-(4-bromo-2-fluoro-phenylamino)-3-fluoro-1-methyl- 1 H-pyridin-2-one,
5-[5-(2-Amino-ethylamino)-[1 ,3,4]oxadiazol-2-yl]-4-(4-bromo-2-fluoro-phenylamino)- 1 ,3-dimethyl-1 H-pyridin-2-one, 5-[5-(2-Amino-ethylamino)-[1,3,4]oxadiazol-2-yl]-4-(4-bromo-2-fluoro-phenylamino)-3- fluoro-1 -methyl-1 H-pyridin-2-one hydrogen chloride,
5-Bromo-2-(4-bromo-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (2-hydroxyethoxy)-amide,
5-Bromo-2-(4-bromo-2-fluoro-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridiπe-3- carboxylic acid, 5-Fluoro-4-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1,6-clihydro-pyridine-3- carboxylic acid cyclopropylmethoxy-amide,
5-Fluoro-4-(2-fluoro-4-methylphenylamino)-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3- carboxylic acid ethoxy-amide
N-[4-(4-Bromo-2-fIuoro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carbonylJ-C-phenyl-methanesulfonamide,
N-[4-(4-Bromo-2-fIuoro-phenylamino)-1 ,5-dimethyl-6-oxo-1 ,6-dihydro-pyridine-3- carbonyl]-methanesulfonamide.
In a further preferred embodiment, the variants RrRi6, L, W and Z are defined as above on pages 3 to 5 but with the proviso that the compounds according to the following formula are excluded
Figure imgf000018_0001
wherein W is
Figure imgf000018_0002
Q is -O-(CH2)kCH3, -NH2, -NH[(CH2)kCH3], or -NH[O(CH2)kCH3], wherein the -NH2 is optionally substituted with between 1 and 2 methyl, and the -(CH2)kCH3 moieties of the -O-(CH2)kCH3, -NH[(CH2)kCH3], and -NH[O(CH2)kCH3] groups are optionally substituted with between 1 and 3 substituents independently selected from hydroxy, amino, alkyl and cycloalkyl;
Z is -NH2 or -NH[(CH2)kCH3], wherein the -NH2 is optionally substituted with between 1 and 2 methyl, and the -(CH2)kCH3 moiety of the -NH[(CH2)kCH3] group is optionally substituted with between 1 and 3 substituents independently selected from hydroxy and amino;
R1 is hydrogen, Ci-6 alkyl, C2-4 alkenyl Or -(CH2)I-SO(CH2)I-3OCH3, wherein the Ci-6 alkyl is optionally substituted with between 1 and 2 substituents independently selected from hydroxy, -COOH, and cyano;
R2 is hydrogen, chlorine, fluorine or methyl;
R3 is hydrogen, chlorine, fluorine, methyl, or CF3
R4 is bromine, chlorine, fluorine, iodine, Ci.6 alkyl, C2-4 alkenyl, C2-4 alkynyl, C3-6 cycloalkyl, -(CH2)-C3-6 cycloalkyl, cyano, -O-(Ci-4 alkyl), -S-(Ci-2 alkyl), -SOCH3, -SO2CH3, -SO2NR6R7, -C≡C-(CH2)nNH2, -C≡C-(CH2)nNHCH3, -C≡C-(CH2)nN(CH3)2, -C^C-CH2OCH3, -C≡C(CH2)nOH, -C≡C-(CH2)nNH2, (Z)-CHCHCH2OCH3, -(Z)-CHCH- (CH2)nNHCH3, (Z)-CHCH-(CH2)nN(CH3)2l -(CH2)PCO2R6, C(O)C1-3 alkyl, C(O)NHCH3, -(CH2)mNH2l -(CH2)mNHCH3, -(CH2)mN(CH3)2, -(CH2)mOR8, -(CH2)PCF3, -C≡CCF3, -CH=CHCF3, -CH2CHCF2, -CH=CF2, -(CF2)VCF3, -CH2(CF2)nCF3, -(CH2)tCF(CF3)2, -CH(CFs)2, -CF2CF(CFs)2, or -C(CF3)3, wherein the C1-6 alkyl and C2-6 alkynyl are optionally substituted with between 1 and 3 substituents independently selected from hydroxy and alkyl;
R5 is hydrogen, chlorine, fluorine, or methyl;
R6 and R7 are each independently hydrogen, methyl, or ethyl; k is O to 3; m is 1 to 4; n is 1 to 2; p is O to 2; t is O to 1 ; v is 1 to 5; and pharmaceutically acceptable salts, C1-6 amides and Ci-6 esters thereof.
In a still further preferred embodiment, the variants RrRi6, L, W and Z are defined as above on pages 3 to 5 but with the proviso that the compounds with the following formula including resolved enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof are excluded:
Figure imgf000020_0001
where X is CR10; Y is NH;
R1, R2, R8, R9 and R10 are independently hydrogen, halogen, cyano, nitro, azido, -
SR11,
-OR3, -C(O)R3, -C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4SO2R6, -SO2NR3R4,
-NR4C(O)R3, -C(O)NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4, C1-Ci0 alkyl, C2-CiO alkenyl, C2-Ci0 alkynyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, -S(O)j(CrC6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR5(CR4R5)m-aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl or - NR4(CR4R5)m-heterocyclyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR4SO2R6, -SO2NR3R4, -C(O)R3, -C(O)OR3, -OC(O)R3, -NR4C(O)OR6, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, -NR5C(O)NR3R4, -NR5C(NCN)R3R4, -OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl,
R7 is hydrogen, CrC10 alkyl, C2-Ci0 alkenyl, C2-C10 alkynyl, C3-Ci0 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, or heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from -NR11SO2R14, -SO2NR11R12, -C(O)R11, C(O)OR11, -OC(O)R11, -NR11C(O)OR14, -NR11C(O)R12, -0/O)NR11R12, -SR11, -S(O)R14, -SO2R14, -NR11R12, -NR11C(O)NR12R13, -NR11C(NCN)NR12R13, -OR11, R3 is hydrogen, trifluoromethyl, C1-C10 alkyl, C2-C10 alkenyl, C2-Ci0 alkynyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, wherein any of said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR11SO2R14, -SO2NR11R12, -C(O)R11, -C(O)OR11, -OC(O)R11, -NR11C(O)OR14, -NR11C(O)R12, -C(O)NR11R12, -SR11, -S(O)R14, -SO2R14, -NR11R12, -NR11C(O)NR12R13, -NR11C(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, or
R3 and R4 together with the atom to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein any of said heteroaryl or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR11SO2R14, -SO2NR11R12, -C(O)R11, C(O)OR11, -OC(O)R11, -NR11C(O)OR14, -NR11C(O)R12, -C(O)NR11R12, -SR11, -S(O)R14, -SO2R14, -NR11R12, -NR11C(O)NR12R13, -NR11(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R4 and R5 independently are hydrogen or CrC6 alkyl, or
R4 and R5 together with the atom to which they are attached form a 4 to 10-membered carbocyclic, heteroaryl or heterocyclic ring, wherein said alkyl or any of said carbocyclic, heteroaryl and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR11SO2R14, -SO2NR11R12, -C(O)R11,
C(O)OR11, -OC(O)R11, -NR11C(O)OR14, -NR11C(O)R12, -C(O)NR11R12, -SR11, -S(O)R14, -SO2R14, -NR11R12, -NR11C(O)NR12R13, -NR11(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroaryl-alkyl, heterocyclyl, and heterocyclylalkyl;
R6 is trifluoromethyl, CrCi0 alkyl, C3-Ci0 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl or heterocyclylalkyl, wherein any of said alkyl, cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl portions are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not substituted on an aryl or heteroaryl), halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, -NR11SO2R14, -SO2NR11R12, -C(O)R11, C(O)OR11, -OC(O)R11, -NR11C(O)OR14, -NR11C(O)R12, -C(O)NR11R12, -SR11, -S(O)R14, -SO2R14, -NR11R12, -NR11C(O)NR12R13, -NR11(NCN)NR12R13, -OR11, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl; R11, R12 and R13 independently are hydrogen, lower alkyl, lower alkenyl, aryl and arylalkyl, and
R14 is lower alkyl, lower alkenyl, aryl and arylalkyl; or any two of R11, R12, R13 or R14 together with the atom to which they are attached form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, wherein any of said alkyl, alkenyl, aryl, arylalkyl carbocyclic rings, heteroaryl rings or heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;
W is heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)NR4SO2R3, -C(O)(C3-C10 cycloalkyl), -C(O)(CrC10 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl), wherein any of said heteroaryl, heterocyclyl, -C(O)OR3, -C(O)NR3R4, -C(O)NR4OR3, -C(O)NR4SO2R3, -C(O)(C3-C10 cycloalkyl), -C(O)(C1-C10 alkyl),
-C(O)(aryl), -C(O)(heteroaryl), -C(O)(heterocyclyl) are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, azido, -NR3R4, -OR3, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cycloalkyl and heterocycloalkyl, wherein any of said C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, cycloalkyl and heterocycloalkyl are optionally substituted with 1 or more groups independently selected from -NR3R4 and -OR3; m is 0, 1 , 2, 3 , 4 or 5; and j is 1 or 2.
In more preferred embodiments, the variants have the following meanings:
R1 is as defined above, preferably hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, nitro, OR3 or NR3R4; more preferably hydrogen, halo or CrC4 alkyl, still more preferably hydrogen or halo, most preferably hydrogen or F. In one embodiment, R1 is hydrogen.
In a further embodiment, R-i is -S(O)1NR4C(O)R3, -C(O)NR4S(O)jR6, or S(O)jR6. R2 is as defined above, preferably hydrogen, halo, CrC4 alkyl, C3-C4 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, nitro, OR3 or NR3R4; more preferably hydrogen, halo or CrC2 alkyl, still more preferably halo or methyl, most preferably Cl, F or methyl. In one embodiment, R2 is methyl. In another embodiment, methyl is preferably further substituted by 1 , 2 or 3 fluorines, preferably 3 fluorines. Most preferably, R2 is F.
In still another embodiment, R2 is -S(O)JNR4C(O)R3, -C(O)NR4S(O)jR6, or S(O)jR6.
R9 is as defined above, preferably hydrogen, halo, Ci-C4 alkyl, C3-C4 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, nitro, OR3 or NR3R4; more preferably hydrogen, halo or CrC4 alkyl, still more preferably hydrogen, methyl or halo, most preferably hydrogen, methyl, Cl or F. In one embodiment, R9 is hydrogen.
In another embodiment, R9 is -S(O)jNR4C(O)R3, -C(O)NR4S(O)JR6, or S(O)jRβ.
Rio is as defined above, preferably hydrogen, -OR3, -C(O)R31-C(O)OR3, -NR4C(O)OR6, -OC(O)R3, -NR4S(O)2R6, -S(O)2NR3R4, S(O)2R6, -NR4C(O)R3, -C(O)NR3R41-NR5C(O)NR3R4, -NR3R4, more preferably hydrogen, -OR3, -NR4C(O)R3, -C(O)NR3R4, -NR3R4, still more preferably hydrogen, -OR3, -NR3R4, most preferably hydrogen. In preferred embodiments R3 and R4 are independently CrC6 alkyl, more preferably CrC4 alkyl, optionally substituted by 1 or 2 alkyl amino, dialkyl amino, amino, O-alkyl, hydroxy, or R3 and R4 form together a cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl.
In a further embodiment, R10 is -S(O)]N R4C(O)R3, -C(O)NR4S(O)jR6, -S(O)j(Ci-Cβ alkyl), -S(O)j(CR4R5)m-aryl, -O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, -O(CR4R5)m- heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl, or -NR4(CR4R5)m- heterocyclyl, where each aryl, heteroaryl and heterocyclyl is substituted or unsubstituted.
L is as defined above, preferably CrC6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, C3-Ci0 cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, more preferably CrC5 alkyl, most preferably methylene, ethylene, n-propylene or n-butylene. In one embodiment, L is ethylene, n-propylene or n-butylene. In the definition of L all moieties are divalent so that L serves as a linker between the nitrogen atom and Ri0.
In one preferred embodiment, LR10 are together methyl.
In another preferred embodiment, LRi0 are together hydrogen. R11 is as defined above, preferably hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C2- C4 alkenyl, C2-C4 alkynyl, cyano, nitro, OR3 or NR3R4; more preferably hydrogen, halo or C1-C4 alkyl or O-d-C4 alkyl, still more preferably hydrogen, methyl, O-methyl or halo, most preferably hydrogen, methyl, Cl, Br or F. In one embodiment, R11 is hydrogen. In another embodiment, Rn is methyl. In yet another embodiment, methyl is preferably further substituted by 1 , 2 or 3 fluorines, preferably 3 fluorines.
In still another embodiment, R11 is -S(O)jNR4C(O)R3, -C(O)N R4S(O)jR6, or S(O)jR6.
R12 is as defined above, preferably hydrogen, halo, CrC10 alkyl, C3-C10 cycloalkyl, C2- C10 alkenyl, C2-C10 alkynyl, cyano, nitro, azido; NR4SO2R6; SO2NR3R4; SO2R6; C(O)NR3R4; C(O)OR3; OR3, NR3R4 or -S(C1-C2 alkyl) substituted with 1 to 5 F, more preferably hydrogen, halo, nitro, CrC4 alkyl, 0-C1-C4 alkyl, SCF3, SCHF2, SCH2F, SO2NR3R4 Or C(O)NR3R4, still more preferably hydrogen, F, Cl, Br, I1 nitro, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, O-methyl, SCF3, SCHF2, SCH2F, SO2NR3R4 or C(O)NR3R4, most preferably hydrogen I1 Cl, Br, SCF3, SCHF2, SCH2F, methyl or O-methyl. In one embodiment R12 is hydrogen. In another embodiment, R12 is methyl, SCF3, SCHF2, SCH2F or O-methyl, wherein methyl or O-methyl is preferably unsubstituted or further substituted by 1, 2 or 3 fluorines, preferably 2 or 3 fluorines. In preferred embodiments of Ri2, R3 and R4 are independently C1-C6 alkyl, more preferably CrC4 alkyl, optionally substituted by 1 or 2 alkyl amino, dialkyl amino, amino, O-alkyl, hydroxy, or R3 and R4 form together a cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl. Most preferably, R12 is Br or I.
In still another embodiment, R12 is -S(O)jN R4C(O)R3, -C(O)NR4S(O)jR6, or S(O)jR6. Within this embodiment it is preferred that R6 is C2-C10 alkyl. R13 is as defined above, preferably hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C2- C4 alkenyl or C2-C4 alkynyl, more preferably hydrogen, F, Cl or methyl, most preferably hydrogen or F. In one embodiment, R13 is hydrogen.
In another embodiment, R13 is -S(O)jNR4C(O)R3, -C(O)N R4S(O)jR6, or S(O)jR6.
R14 is as defined above, preferably hydrogen, halo, CrC4 alkyl, C3-C4 cycloalkyl, C2- C4 alkenyl or C2-C4 alkynyl, more preferably hydrogen, F, Cl or methyl, most preferably hydrogen or F. In one embodiment, R14 is hydrogen.
In a further embodiment, R14 is -S(O)jNR4C(O)R3, -C(O)NR4S(O)jR6, or S(O)]R6. In a particular preferred embodiment, at least one of R1, R2, R9, Rn, R12, R13 and R14 is selected from -S(O)]N R4C(O)R3, -C(O)NR4S(O)jR6, and S(O)jRβ.
As set forth above, the variants of each of R1, R2, Rg to R14 and L may be substituted. In this case they can be substituted with 1 to 5, preferably 1 to 3, more preferably 1 or 2 groups independently selected from oxo, halogen, cyano, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, SCF3, SCHF2, SCH2F, azido, NR4SO2R6, SO2NR3R4, C(O)R3, C(O)OR3, OC(O)R3, NR4C(O)OR6, NR4C(O)R3, C(O)NR3R4, NR3R4, NR5C(O)NR3R4, NR5C(NCN)NR3R4, OR3, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, preferably oxo, halogen, cyano, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, SCF3, SCHF2, SCH2F, azido, NR4SO2R6, SO2NR3R4, C(O)R3,
C(O)OR3, OC(O)R3, OR3, more preferably oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy or azido, most preferably halogen, cyano, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, SCF3, SCHF2, SCH2F, OH, O-methyl, NH2 or N(methyl)2. When it is described that alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted, this refers to any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl as a group or sub-structure such as in cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl.
R3 is as defined above, preferably hydrogen, trifluoromethyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, more preferably hydrogen or C1-C4 alkyl most preferably hydrogen, methyl or ethyl.
R4 is as defined above, preferably hydrogen Or C1-C4 alkyl, more preferably hydrogen, methyl or ethyl.
In one preferred embodiment, R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 7, preferably 5 or 6, membered heteroaryi or heterocyclic ring.
R5 is as defined above, preferably hydrogen or C1-C4 alkyl, more preferably hydrogen, methyl or ethyl.
In one embodiment, R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 7, preferably 5 or 6, membered carbocyclic, heteroaryl or heterocyclic ring.
R6 is as defined above, preferably trifluoromethyl, C1-C4 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C6 cycloalkyl, C3-C6 cycloalkylalkyl, more preferably C1-C4 alkyl, most preferably methyl or ethyl. As set forth above, the variants of each of R3, R4, Rs, Re or the rings formed by R3 and R4 and R4 and R5 may be substituted. In this case they can be substituted with 1 to 5, preferably 1 to 3, more preferably 1 or 2 groups independently selected from oxo, halogen, cyano, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, azido, NR1SO2R"", SO2NR", C(O)R', C(O)OR', OC(O)R', NR1C(O)OR"", NR1C(O)R", C(O)NR1R", SR11", S(O)R"", SO2R', NR'R", NR1C(O)NR11R"', NR1C(NCN)NR11R1", OR1, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, preferably oxo, halogen, cyano, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, azido, NR1SO2R"", SO2NR", C(O)R', C(O)OR1, OC(O)R1, NR1C(O)OR"", NR1C(O)R", C(O)NR1R", SR"", S(O)R"", SO2R1, NR1R", NR1C(O)NR11R1", NR1C(NCN)NR11R'" or OR', more preferably oxo, halogen, cyano, nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F, azido, SR"", S(O)R"", SO2R', NR'R" or OR'. In one embodiment, R3 is preferably oxo, halogen, nitro, trifluoromethyl, OH, O-methyl, NH2 or N(methyl)2. When it is described that alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted, this refers to any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl as a group or sub-structure such as in cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl.
R' is selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl, preferably hydrogen or C1-C4 alkyl, more preferably hydrogen or methyl.
R" is selected from hydrogen, Ci-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl, preferably hydrogen or CrC4 alkyl, more preferably hydrogen or methyl.
R"1 is selected from hydrogen, CrC4 alkyl, C2-C4 alkenyl, aryl and arylalkyl, preferably hydrogen or C1-C4 alkyl, more preferably hydrogen or methyl.
R11" is selected from CrC4 alkyl, C1-C4 alkenyl, aryl and arylalkyl, preferably C1-C4 alkyl, more preferably methyl. Alternatively, any two of R', R", R1" or R"" can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is optionally substituted with one to three groups independently selected from halogen, cyano; nitro, CF3, CHF2, CH2F, OCF3, OCHF2, OCH2F1 azido, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, preferably halogen, cyano; nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy and azido.
W is as defined above, preferably heteroaryl containing 1 , 2 or 3 heteroatoms, or heterocyclyl containing 1, 2, or 3 heteroatoms, more preferably heteroaryl, each of which is unsubstituted or substituted by 1 to 5, preferably 1 to 3, more preferably 1 , substituents ZR15, or W is -C(O)ORi5, -C(O)NR4R15, -C(O)NR4ORi5, -C(O)(C3-C10 cycloalkyl), -C(O)(C2-Ci0 alkyl), -S(O)]NR4C(O)Ri5, -C(O)NR4S(O)jR6, S(O)]NR4R15 or S(O)jNR4ORis, more preferably W is heteroaryl containing 1, 2, or 3, specifically 2 or 3 N atoms, C(O)NR4ORi5 or S(O)2NR4ORi5. R4 and R15 are as defined herein or may form together a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom. When W is heteroaryl, it is preferably
Figure imgf000027_0001
where Z and Ri5 are as defined above, preferably Z is a bond, NRi6, NRi6SO2 or O, more preferably NRi6, wherein Ri6 is as defined above, preferably hydrogen or CrC4 alkyl, more preferably hydrogen. R15 is preferably selected from hydrogen, C1-C4 alkyl, C1-C4 alkenyl, C4-C8 cycloalkylalkyl, each may contain 1 N atom optionally an O atom, where alkyl, alkenyl or cycloalkylalkyl may be further substituted by 1 or 2 of OH, 0-C1-C4 alkyl or NR'R", where R' and R" are independently hydrogen or C1-C4 alkyl where R' and R" may form a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom. Alternatively, R16 and R15 may form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl. More preferably R15 is C1- C4 alkyl or C1-C4 alkenyl optionally substituted with 1 substituent OH, O-Me, NH2, N(methyl)2 or N(ethyl)2.
Y is O or NR', preferably O.
Alternatively, W is preferably -C(O)OR15, -C(O)NR4R15, -C(O)NR4OR15, S(O)]NR4R15 or S(O)jNR4ORi5, more preferably -C(O)NR4OR15 or S(O)2NR4ORi5. In these cases R15 is preferably as defined below.
In yet another embodiment, W is -S(O)]NR4C(O)R15, whereby R4 and Ri5 are as defined herein or may form together a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom,
Z is as defined above, preferably a bond, NRi6, NR16SO2 or O, more preferably NR16. in another embodiment, Z is S. Ri5 is as defined above, preferably hydrogen, Ci-C4 alkyl, Ci-C4 alkenyl, C4-C6 cycloalkylalkyl, more preferably CrC4 alkyl or CrC4 alkenyl, yet more preferably Ci-C4 alkyl. Alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heteroaryl or heterocyclyl may be further substituted with 1 to 5, preferably 1 , 2 or 3, more preferably 1 or 2, substituents selected from OR3 or NR1R" wherein R3 is selected from hydrogen, CrC4 alkyl or Ci- C4 alkenyl, C4-C6 cycloalkylalkyl, more preferably hydrogen, methyl or ethyl, and where R1 and R" are independently hydrogen or d-C4 alkyl, or R' and R" may form a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom, more preferably R' and R" are independently hydrogen, methyl or ethyl, still more preferably both R' and R" are methyl. Yet more preferably, Ri5 may be substituted by 1 or 2 of OH, 0-Ci-C4 alkyl or NR1R".
Most preferably, R15is C1-C4 alkyl or C1-C4 alkenyl optionally substituted with 1 substituent OH, O-Me, NH2, N(methyl)2 or N(ethyl)2.
Regarding Ri5 , when it is described that alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl are substituted, this refers to any alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl as a group or sub-structure such as in cycloalkylalkyl, arylalkyl, heteroarylalkyl, heterocyclylalkyl.
Rie is as defined above, preferably hydrogen or CrC4 alkyl, more preferably hydrogen. Alternatively, Ri6 and R15 may form together a 4 to 10, preferably 5 to 6, membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl. m is as defined above, preferably 0, 1 , 2 or 3, more preferably 0, 1 or 2, most preferably 1. j is as defined above, preferably 2.
In the above, any of the preferred definitions for each variant can be combined with the preferred definition of the other variants.
The combinations as set forth in the claims are particularly preferred.
In the above and the following, the employed terms have independently the meaning as described below:
Aryl is an aromatic mono- or polycyclic moiety with preferably 6 to 20 carbon atoms which is preferably selected from phenyl, biphenyl, naphthyl, tetrahydronaphthyl, fluorenyl, indenyl or phenanthrenyl, more preferably phenyl or naphthyl. Heteroaryl is an aromatic moiety having 6 to 20 carbon atoms with at least one ring containing a heteroatom selected from O, N and/or S, or heteroaryl is an aromatic ring containing at least one heteroatom selected from O, N and/or S and 1 to 6 carbon atoms. Preferably, heteroaryl contains 1 to 4, more preferably 1 , 2 or 3 heteroatoms selected from O and/or N and is preferably selected from pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, triazolyl, thiadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. Spiro moieties are also included within the scope of this definition. Preferred heteroaryl include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, isoxazolyl, oxazolyl, isothiazolyl, oxadiazolyl, triazolyl. Heteroaryl groups are optionally mono-, di-, or trisubstituted with, e.g., halogen, lower alkyl, lower alkoxy, haloalkyl, aryi, heteroaryl, and hydroxy.
Heterocyclyl is a saturated or unsaturated ring containing at least one heteroatom selected from O, N and/or S and 1 to 6 carbon atoms. Preferably, heterocyclyl contains 1 to 4, more preferably 1 , 2 or 3 heteroatoms selected from O and/or N and is preferably selected from pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidino, morpholino, thiomorpholino, thioxanyl, piperazinyl, homopiperazinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1 ,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinylimidazolinyl, imidazolidinyl, azetidin-2-one- 1-yl, pyrrolidin-2-one-1-yl, piperid-2-one-i-yl, azepan-2-one-1-yl, 3- azabicyco[3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 3H- indolyl and quinolizinyl. Spiromoieties are also included within the scope of this definition. Carbocyclyl is a monocyclic or polycyclic ring system of 3 to 20 carbon atoms which may be saturated, unsaturated or aromatic.
Alkyl is a saturated hydrocarbon moiety, namely straight chain or branched alkyl having 1 to 10, preferably 1 to 8 carbon atoms, more preferably 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl or heptyl. Cycloalkyl is an alkyl ring having 3 to 10, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
Alkenyl is an unsaturated hydrocarbon moiety with one or more double bonds, preferably one double bond, namely straight chain or branched alkenyl having 1 to 10, preferably 2 to 8 carbon atoms, more preferably 2 to 4 atoms, such as vinyl, allyl, methallyl, buten-2-yl, buten-3-yl, penten-2-yl, penten-3-yl, penten-4-yl, 3-methyl-but-3- enyl, 2-methyl-but-3-enyl, 1-methyl-but-3-enyl, hexenyl or heptenyl.
Alkynyl is an unsaturated hydrocarbon moiety with one or more triple bonds, preferably one triple bond, namely straight chain or branched alkynyl having 1 to 10, preferably 2 to 8 carbon atoms, more preferably 2 to 4 atoms, such as ethynyl, propynyl, butyn-2-yl, butyn-3-yl, pentyn-2-yl, pentyn-3-yl, pentyn-4-yl, 2-methyl-but-3- ynyl, 1-methyl-but-3-ynyl, hexynyl or heptynyl.
Halo or halogen is a halogen atom preferably selected from F1 Cl1 Br and I1 preferably F1 Cl and Br.
In the definitions cycloalkylalkyl, arylalkyl, heteroarylalkyl and heterocyclylalkyl it is contemplated that cycloalkyl, aryl, heteroaryl and heterocyclyl are bonded via an alkylene moiety. This alkylene moiety may be a straight chain or branched chain group. Said alkylene moiety preferably has 1 to 6 carbon atoms. Examples thereof include methylene, ethylene, n-propylene, n-butylene, n-pentylene, n-hexylene, iso- propylene, sec.-butylene, tert.-butylene, 1,1 -dimethyl propylene, 1,2-dimethyl propylene, 2,2-dimethyl propylene, 1,1 -dimethyl butylene, 1,2-dimethyl butylene, 1,3- dimethyl butylene, 2,2-dimethyl butylene, 2,3-dimethyl butylene, 3,3-dimethyl butylene, 1 -ethyl butylene, 2-ethyl butylene, 3-ethyl butylene, 1-n-propyl propylene, 2- n-propyl propylene, 1-iso-propyl propylene, 2-iso-propyl propylene, 1 -methyl pentylene, 2-methyl pentylene, 3-methyl pentylene and 4-methyl pentylene. More preferably, said alkylene moiety has 1 to 3 carbon atoms, such as methylene, ethylene, n-propylene and iso-propylene. Most preferred is methylene.
Preferred embodiments of the compounds according to present invention are shown in scheme 1.
Figure imgf000031_0001
Scheme 1
The compounds of the present invention can be in the form of a prodrug compound. "Prodrug compound" means a derivative that is converted into a compound according to the present invention by a reaction with an enzyme, gastric acid or the like under a physiological condition in the living body, e.g. by oxidation, reduction, hydrolysis or the like, each of which is carried out enzymatically. Examples of the prodrug are compounds, wherein the amino group in a compound of the present invention is acylated, alkylated or phosphorylated to form, e.g., eicosanoylamino, alanylamino, pivaloyloxymethylamino or wherein the hydroxyl group is acylated, alkylated, phosphorylated or converted into the borate, e.g. acetyloxy, palmitoyloxy, pivaloyloxy, succinyloxy, fumaryloxy, alanyloxy or wherein the carboxyl group is esterified or amidated. These compounds can be produced from compounds of the present invention according to well-known methods. Other examples of the prodrug are compounds, wherein the carboxylate in a compound of the present invention is for example converted into an alkyl-, aryl-, choline-, amino, acyloxymethylester, linolenoyl-ester. Metabolites of compounds of the present invention are also within the scope of the present invention.
Where tautomerism, like e.g. keto-enol tautomerism, of compounds of the present invention or their prodrugs may occur, the individual forms, like e.g. the keto and enol form, are claimed separately and together as mixtures in any ratio. Same applies for stereoisomers, like e.g. enantiomers, cis/trans isomers, conformers and the like.
If desired, isomers can be separated by methods well known in the art, e.g. by liquid chromatography. Same applies for enantiomers by using e.g. chiral stationary phases. Additionally, enantiomers may be isolated by converting them into diastereomers, i.e. coupling with an enantiomerically pure auxiliary compound, subsequent separation of the resulting diastereomers and cleavage of the auxiliary residue. Alternatively, any enantiomer of a compound of the present invention may be obtained from stereoselective synthesis using optically pure starting materials.
The compounds of the present invention can be in the form of a pharmaceutically acceptable salt or a solvate. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids, including inorganic bases or acids and organic bases or acids. In case the compounds of the present invention contain one or more acidic or basic groups, the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts. Thus, the compounds of the of the present invention which contain acidic groups can be present on these groups and can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids. Compounds of the present invention which contain one or more basic groups, i.e. groups which can be protonated, can be present and can be used according to the invention in the form of their addition salts with inorganic or organic acids. Examples for suitable acids include hydrogen chloride, hydrogen bromide, phosphoric acid, sulfuric acid, nitric acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acids, oxalic acid, acetic acid, tartaric acid, lactic acid, salicylic acid, benzoic acid, formic acid, propionic acid, pivalic acid, diethylacetic acid, malonic acid, succinic acid, pimelic acid, fumaric acid, maleic acid, malic acid, sulfaminic acid, phenylpropionic acid, gluconic acid, ascorbic acid, isonicotinic acid, citric acid, adipic acid, and other acids known to the person skilled in the art. If the compounds of the present invention simultaneously contain acidic and basic groups in the molecule, the invention also includes, in addition to the salt forms mentioned, inner salts or betaines (zwitterions). The respective salts can be obtained by customary methods which are known to the person skilled in the art like, for example by contacting these with an organic or inorganic acid or base in a solvent or dispersant, or by anion exchange or cation exchange with other salts. The present invention also includes all salts of the compounds of the present invention which, owing to low physiological compatibility, are not directly suitable for use in pharmaceuticals but which can be used, for example, as intermediates for chemical reactions or for the preparation of pharmaceutically acceptable salts.
Furthermore, the present invention provides pharmaceutical compositions comprising a compound of the present invention, or a prodrug compound thereof, or a pharmaceutically acceptable salt or solvate thereof as active ingredient together with a pharmaceutically acceptable carrier. "Pharmaceutical composition" means one or more active ingredients, and one or more inert ingredients that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients. Accordingly, the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
A pharmaceutical composition of the present invention may additionally comprise one or more other compounds as active ingredients like one or more additional compounds of the present invention, or a prodrug compound or other MEK inhibitors.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well- known in the art of pharmacy.
In one embodiment, said compounds and pharmaceutical composition are for the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer. In another embodiment, said pharmaceutical composition is for the treatment of a noncancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g. benign prostatic hypertrophy (BPH)).
The invention also relates to a compound or pharmaceutical composition for the treatment of pancreatitis or kidney disease (including proliferative glomerulonephtitis and diabetes induced renal disease) or pain in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. The invention also relates to a compound or pharmaceutical composition for the prevention of blastocyte implantation in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. The invention also relates to a compound or pharmaceutical composition for treating a disease related to vasculogenesis or angiogenesis in a mammal which comprises a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, and a pharmaceutically acceptable carrier. In one embodiment, said compound or pharmaceutical composition is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, inflammatory bowel disease, atherosclerosis, skin diseases such as psoriasis, excema, and sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer.
The invention also relates to of the use for treating a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof. In one embodiment, said use relates to the treatment of cancer such as brain, lung, squamous cell, bladder, gastic, pancreatic, breast, head, neck, renal, kidney, ovarian, prostate, colorectal, oesohageal, testicular, gynecological or thyroid cancer. In another embodiment, said use relates to the treatment of a non¬ cancerous hyperproliferative disorder such as benign hyperplasia of the skin (e.g., psoriasis), restenosis, or prostate (e.g. benign prostatic hypertrophy (BPH)). The invention also relates to a use for the treatment of a hyperproliferative disorder in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof, in combination with an anti-tumor agent selected from the group consisting of mitotic inhibitors, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzyme inhibitors, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and anti-androgens.
The invention also relates to a use of treating pancreatitis or kidney disease or pain in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof. The invention also relates to a use of preventing blastocyte implantation in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof.
The invention also relates to a use of treating diseases related to vasculogenesis or angiogenesis in a mammal that comprises administering to said mammal a therapeutically effective amount of a compound of the present invention, or a pharmaceutically acceptable salt, prodrug or hydrate thereof. In one embodiment, said method is for treating a disease selected from the group consisting of tumor angiogenesis, chronic inflammatory disease such as rheumatoid arthritis, atherosclerosis, inflammatory bowel disease, skin diseases such as psoriasis, excema, and scleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer. Patients that can be treated with compounds of the present invention, or pharmaceutically acceptable salts, prodrugs and hydrates of said compounds, according to the methods of this invention include, for example, patients that have been diagnosed as having psoriasis, restenosis, atherosclerosis, BPH, lung cancer, bone cancer, CMML, pancreatic cancer, skin cancer, cancer of the head and neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, colon cancer, breast cancer, testicular, gynecologic tumors (e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina or carcinoma of the vulva), Hodgkin's disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system (e.g., cancer of the thyroid, parathyroid or adrenal glands), sarcomas of soft tissues, cancer of the urethra, cancer of the penis, prostate cancer, chronic or acute leukemia, solid tumors of childhood, lymphocytic lymphomas, cancer of the bladder, cancer of the kidney or ureter (e.g., renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms of the central nervous system (e.g., primary CNS lymphona, spinal axis tumors, brain stem gliomas or pituitary adenomas).
This invention also relates to a compound or pharmaceutical composition for inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the compound, salt, solvate, or prodrug, and of the chemotherapeutic are together effective in inhibiting abnormal cell growth. Many chemotherapeutics are presently known in the art. In one embodiment, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens. This invention further relates to a method for inhibiting abnormal cell growth in a mammal or treating a hyperproliferative disorder which method comprises administering to the mammal an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate or prodrug thereof, in combination with radiation therapy, wherein the amounts of the compound, salt, solvate, or prodrug, is in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein. The administration of the compound of the invention in this combination therapy can be determined as described herein. It is believed that the compounds of the present invention can render abnormal cells more sensitive to treatment with radiation for purposes of killing and/or inhibiting the growth of such cells. Accordingly, this invention further relates to a method for sensitizing abnormal cells in a mammal to treatment with radiation which comprises administering to the mammal an amount of a compound of the present invention or pharmaceutically acceptable salt or solvate or prodrug thereof, which amount is effective is sensitizing abnormal cells to treatment with radiation. The amount of the compound, salt, or solvate in this method can be determined according to the means for ascertaining effective amounts of such compounds described herein. The invention also relates to a method of and to a pharmaceutical composition of inhibiting abnormal cell growth in a mammal which comprises an amount of a compound of the present invention, or a pharmaceutically acceptable salt or solvate thereof, a prodrug thereof, or an isotopically-labeled derivative thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents.
In practical use, the compounds of the present invention can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained. The active compounds can also be administered intranasal^ as, for example, liquid drops or spray.
The tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
Compounds of the present invention may also be administered parenterally. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.
Any suitable route of administration may be employed for providing a mammal, especially a human, with an effective dose of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like. Preferably compounds of the present invention are administered orally.
The effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
When treating or preventing cancer, inflammation or other proliferative diseases for which compounds of the present invention are indicated, generally satisfactory results are obtained when the compounds of the present invention are administered at a daily dosage of from about 0.1 milligram to about 100 milligram per kilogram of animal body weight, preferably given as a single daily dose or in divided doses two to six times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1.0 milligrams to about 1000 milligrams, preferably from about 1 milligram to about 50 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 7 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
Some abbreviations that may appear in this application are as follows.
Abbreviations
Designation b Broad peak
Boc tert. -Buty loxycarbonyl
CD! N,N-Carbonyldiimidazole d Doublet
DCM Dichloromethane dd double doublet
DIPEA N-Ethyldiisopropylamine
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide
EDC hydrochloride
HPLC High pressure liquid chromatography
LiHMDS. Lithium hexamethyldisilazide
NMR Nuclear Magnetic Resonance
PG Protecting group
PyBroP Bromo-tris-pyrrolidino-phosphonium hexafluorophosphate
PyBOP Benzotriazole-1-yl-oxy-trispyrrolidinophosphonium hexafluorophosphate q Quartett rt Retention time s Singlet tert Tertiary-butyl
TFA Trifluoroacetic acid
THF Tetrahydrofurane
TLC Thin Layer Chromatography
The compounds of the present invention can be prepared according to the procedures of the following Schemes and Examples, using appropriate materials and are further exemplified by the following specific examples. Moreover, by utilizing the procedures described herein, in conjunction with ordinary skills in the art, additional compounds of the present invention claimed herein can be readily prepared. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. The examples further illustrate details for the preparation of the compounds of the present invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. The instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described above. The amine-free bases corresponding to the isolated salts can be generated by neutralization with a suitable base, such as aqueous sodium hydrogencarbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, and extraction of the liberated amine-free base into an organic solvent, followed by evaporation. The amine-free base, isolated in this manner, can be further converted into another pharmaceutically acceptable salt by dissolution in an organic solvent, followed by addition of the appropriate acid and subsequent evaporation, precipitation or crystallization.
An illustration of the preparation of compounds of the present invention is shown in schemes 2 and 3. Unless otherwise indicated in the schemes, the variables have the same meaning as described above. The examples presented below are intended to illustrate particular embodiments of the invention.
Figure imgf000041_0001
Scheme 2
Figure imgf000042_0001
Scheme 3
According to a literature procedure diethyl 1,3-acetonedicarboxylate is heated with triethyl orthoformate and acetic anhydride and subsequently treated with ammonia as shown in scheme 2. The resulting product is converted into ethyl 4,6- dichloronicotinate (1) by heating with phosphoryl chloride. This procedure has been previously described in the literature (DenHertog , Reel Trav Chim Pays-Bas 1946, 65, 129-140). Compound 1 is then reacted with an appropriately substituted aniline in an inert solvent, preferable THF, by addition of a base, preferably but not limited to
LiHMDS, to yield ethyl δ-chloro^-arylaminonicotinate 2. Heating with an appropriately substituted alkyl iodide leads to an intermediate pyridinium compound which is directly converted into pyridone carboxylate 3. In the next step compound 3 is coupled with an O-alkyl hydroxalamine using an appropriate coupling reagent including but not limited to PyBOP; PyBroP, EDC or DCC in a suitable organic solvents like for example DMF, THF or DCM to yield hydroxamate 4.
Scheme 3 illustrates the preparation of compounds of the present invention where W is heterocyclic. In step 1, 4-anilino pyridone compound 3 is reacted with BOC- hydrazine, DIPEA and a coupling reagent as PyBOP, for example. The product is then deprotected with hydrochloric acid at elevated temperatures to give acylhydrazide 5. Reaction of 5 with CDI or any suitable carbonate equivalent in a preferred solvent such as DMF or DCM and subsequent reaction with a substitued amine in ethanol gives hydrazine carboxamide 6. Alternatively, hydrazide 5 can be reacted with an appropriately substituted isocyanate to yield compound 6. Cyclization to 7 is achieved by addition of triphenyl phosphine, CCI4 and a base such as triethylamine or DIPEA in an inert solvent like DCM.
Suitable anilines, alkyliodides, O-alkyl hydroxylamines, and isocyanates are commercially available from Sigma-AIdrich Chemie GmbH, Munich, Germany or from Acros Organics, Belgium or from Fisher Scientific GmbH, 58239 Schwerte, Germany or can be routinely prepared by procedures described in "March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", 5th Edition; John Wiley & Sons. O-[(4S)2,2-Dimethyl-[1 ,3]dioxolan-4-ylmethyl]-hydroxylamine and O-[(4R)2,2-dimethyl- [1,3]dioxolan-4-ylmethyl]-hydroxylamine are prepared according to a procedure described in WO02/06213 A2.
Compounds with other variants in the position of W can be prepared by derivatizing the COOH group appropriately as known to the person skilled in the art as described in Theophil Eicher, Siegfried Hauptmann "The Chemistry of Heterocycles; Structures, Reactions, Synthesis and Application", 2nd edition, Wiley-VCH 2003. The introduction of alternative heterocyclic or heteroaryl groups is exemplified e.g. in WO 03/077855 and WO 01/05391.
Unless otherwise noted, all non-aqueous reactions were carried out either under an argon or nitrogen atmosphere with commercial dry solvents. Compounds were purified using flash column chromatography using Merck silica gel 60 (230-400 mesh), or by reverse phase preparative HPLC using a Reprosil-Pur ODS3, 5 μm, 20 x 125 mm column with Shimadzu LC8A-Pump and SPD-10Avp UV/Vis diode array detector. The 1H-NMR spectra were recorded on a Varian VXR-S (300 MHz for 1H-NMR) using d6- dimethylsulfoxide or d4-methanol as solvent; chemical shifts are reported in ppm relative to tetramethylsilane. Analytical LC/MS was performed using Reprosil-Pur ODS3, 5 μM, 1 x 60 mm columns at a flow rate of 250 μl/min, sample loop 2.5μl; retention times are given in minutes. Methods are: (I) runs on a LC10Advp-Pump (Shimadzu) with SPD-M 10Avp UV/Vis diode array detector and QP2010 MS-detector in ESI+ modus with UV-detection at 214, 254 and 275 nm with a gradient of 15-95% acetonitrile (B) in water (A) (0.1% formic acid), 5 min. linear gradient; (II) idem but linear gradient 8min 1-30% B; (III) idem but linear gradient 8min 10-60% B; (IV) idem but linear gradient 8min 15-99% B; (V) idem but linear gradient 10min 5-95% B; (Vl) idem but linear gradient 10min 10-95% B; (VII) idem but linear gradient 5min 10-90% B. Examples
The examples below are intended to further illustrate particular embodiments of the invention and are not intended to limit the scope of the specification in any way.
Example 1
4-(4-Bromo-2-methyl-phenylamino)-1~methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (3a)
Figure imgf000044_0001
Compound 3a is synthesised in a multistep procedure as outlined in scheme 2. Step A
Ethyl 4,6-dichloronicotinate (1) is synthesised according to a literature procedure (DenHertog, Reel Trav Chim Pays-Bas 1946, 65, 129-140): Diethyl acetone dicarboxylate (1Og, 49mmol, purchased from Sigma-Aldrich) is treated with triethylorthoformiate (7g) and acetic anhydride (1Og) at 1300C for 1h and the volatiles are removed in vacuo. The mixture is cooled to O0C and cone. Ammonia (14ml) is added slowly. The precipitate is filtered, washed with 25% hydrochloric acid and recrystallised from hot ethanol to give 5g (27mmol, 56% yield) of ethyl 4,6 dihydroxynicotinate. After treating the intermediate with an excess of POCI3 at 1600C for 1h with microwave irradiation, the mixture is hydrolysed on ice and extracted with ethyl acetate to give crude 1 which is purified by flash chromatography using silica and 0-20% ethyl acetate in cyclohaxane as eluent, yielding 3.3g pure 1 (15mmol, 56% yield).
Step B
Ethyl 4,6-dichloronicotinate (1) (2.Og, 9.1mmol) and 4-bromo-2-methylaniline (1.7g, 9.1 mmol) are dissolved in dry THF (20ml) under argon and the mixture is cooled to -78°C. A solution of LiHMDS (1.0M in THF, 32ml) is slowly added and the reaction mixture is allowed to warm to ambient temperature. After 18h the reaction is quenched by adding dilute hydrochloric acid (1.0M, 20.0ml) and the mixture is extracted with DCM (3x 60ml). The combined organic extracts are concentrated in vacuo and the crude material is purified by flash chromatography using silica gel and a gradient of 0-10% ethylacetate in cyclohexane as eluent to give pure 4-(4-bromo-2-methyl-phenylamino)-6-chloro-nicotinic acid ethyl ester (2a) (900mg, 27% yield).
Step C 4-(4-Bromo-2-methyl-phenylamino)-6-chloro-nicotinic acid ethyl ester (2a) (250mg, 0.68mmol) and iodomethane (337μl, 5.4mmol) are dissolved in dry DCE (8ml) under argon and the mixture is heated at 140° C for 100 min with microwave irradiation and the volatiles are removed in vacuo. LiOH (101mg, 4.2mmol) is added and the mixture is heated for 10 min at 140° C with microwave irradiation. The volatiles are evaporated under reduced pressure and the crude material is purified by flash chromatography using silica gel and a gradient of 0-10% MeOH in DCM/formic acid 0.5% as eluent to give 157mg of pure 4-(4-bromo-2-methyl-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid (3a)
LC-MS method (V) rt 5.06 min; m/z 337, 339 [M+H]+, Br pattern. 1 H-NMR (300 MHz, DMSO-d6) δ = 2.2 (s, 3H), 3.35 (s, 3H), 5.45 (s, 1H), 7.20-7.26 (d, 1H), 7.35-7.42 (d, 1 H), 7.48 (s, 1 H), 8.15 (s, 1H).
Example 2
4-(4~Bromo-2-methylψhenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3- carboxylic acid hydroxyamide (4a)
Figure imgf000045_0001
4-(4-Bromo-2-methyl-phenylamino)-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid (3a) (50mg, 0.15mmol) is dissolved in 2.5ml dry DMF and DIPEA (0.59mmol, 103μl), PyBOP (0.222mmol, 116mg) and hydroxylamine hydrochloride (0.37mmol, 26mg) is added. The mixture is stirred for 16h at 50° C and for 48h at ambient temperature. The volatiles are removed in vacuo and the crude material is purified by preparative HPLC to give 14.2mg of 4a.
LC-MS method (V): rt 5.06 min; m/z 352, 354 [M+H]+, Br pattern. 1H-NMR (300 MHz, MeOH-d4) δ = 2.15 (s, 3H), 3.38 (s, 3H), 5.40 (s, 1H), 7.07-7.12 (d, 1H), 7.28-7.33 (d, 1H), 7.40 (s, 1H), 7.86 (b, 1H).
Example 3
4-[(4-Bromθ'2-methylphenyl)amino]-N-{[(2S)-2,3-dihydroxypropyl]oxy}-1-methyl-6- oxo-1, 6-dihydropyridine-3-carboxamide (4b)
Figure imgf000046_0001
4-(4-Bromo-2-methyl-phenylamino)-1-methyl-6-oxo-1 ,6-dihydro-pyridine-3-carboxylic acid (3a) (0.30mmol, 100mg) is dissolved in dry DMF (5ml) followed by the addition of DIPEA (1.2mmol, 153μl), PyBOP (0.45mmol, 231 mg) and O-[(4S)2,2-dimethyl-[1 ,3]dioxolan-4- ylmethyl]-hydroxylamine (0.45mmol, 65.5mg). The mixture is stirred for 16h at 60° C and the volatiles are removed in vacuo. The crude material is redissolved in MeOH (12ml) and H2O (1.4ml), Dowex50X8 (95mg) is added and the mixture is heated for 10 min at 120° C with microwave irradiation. After filtration the volatiles are removed in vacuo and the product is purified by preparat/ve HPLC to give 9.7mg of pure product 4b.
LC-MS method (Vl): rt 2.62min m/z 426, 428 [M+H]+, Br pattern.
1H-NMR (300 MHz, MeOH-d4) δ = 2.15 (s, 3H), 3.39 (s, 3H), 3.50-3.54 (m, 2H), 3.79-3.90 (m, 2H), 3.96-4.01 (m, 1H), 5.38 (s, 1H), 7.07-7.11 (d, 1H), 7.29-7.33 (dd, 1H), 7.41 (s, 1 H), 7.95 (s, 1H).
Example 4
S-(5-AUylamino-[1,3A]oxadiazol'2-yl)-4-(4-bromo-2-methyl-phenylamino)-1-methyl- 1H"pyridin-2-one (Ta)
Figure imgf000047_0001
Compound 7a is synthesised in a multistep procedure as outlined in scheme 3.
Step A
4-(4-Bromo-2-methyl-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3a) (245mg, 0.73mmol) is dissolved in 7ml dry DMF followed by the addition of DIPEA (391 μl, 2.2mmol), PyBOP (0.95mmol, 492mg) and N-t-butoxycarbonylhydrazide
(1.45mmol, 192mg) and the mixture is stirred for 4h at 60° C. DMF is removed in vacuo and the crude material is dissolved in ethylacetate, washed with saturated bicarbonate solution (3x), H2O (1x) and brine (1x) and dried (Na2SO4). The volatiles are removed in vacuo and the product is purified by flash chromatography using silica gel and a gradient of 0-50% ethylacetate in cyclohexane to give an Λ/-Boc-protected intermediate (213 mg, 65% yield). This Intermediate is dissolved in THF (4ml) and a solution of HCI in dioxane (1M) is added (3ml). The reaction mixture is stirred for 3.5h at ambient temperature, the volatiles are removed in vacuo. The crude product is redissolved in dry THF (2ml), DIPEA (0.94mmol, 169μl) is added followed by allylisocyanate (0.52mmol, 46μl). The solution is stirred at ambient temperature for 2h and the volatiles are removed in vacuo to give crude 6a, which is used without purification in step B.
N-allyl-2-({4-[(4-bromo-2-methylphenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3- yl}carbonyl)hydrazinecarboxamide (6a):
LC-MS method (VII): rt 2.65min m/z 351, 353 [M+H]+, Br pattern.
Step B
N-allyl-2-({4-[(4-bromo-2-methylphenyl)amino]-1-methyl-6-oxo-1,6-dihydropyridin-3- yl}carbonyl)hydrazinecarboxamide (6a) (0.472mmol, 205) mg is dissolved in dry DCM (10ml) and CCI4 (1.89mmol,183μl), triethylamine (0.71mmol, 99μl) and PPh3 (0.73mmol,192mg) are added and the solution is heated for 20 min at 100° C with microwave irradiation. The volatiles are removed in vacuo and the product is purified by preparat/ve HPLC to give pure 7a. LC-MS method (III): rt 7.8min m/z 416, 418 [M+H]+, Br pattern.
1H-NMR (400 MHz, DMSOd6) δ = 2.21 (s, 3H), 3.42 (s, 3H), 3.90 (t, J = 5.6Hz, 2H); 5.15 (d, J = 11.6Hz, 1 H), 5.27 (d, J = 17.2Hz, 1 H), 5.32 (S1 1H), 5.88-5.98 (m, 1 H)1 7.28 (d, J = 8.6Hz), 7.47 (dd, J = 2.0Hz, J = 8.1Hz, 1 H), 7.60 (d, J = 2.0 Hz), 8.03 (t, J = 6.1 Hz, 1H), 8.15 (s, 1H), 9.03 (s, 1H).
Example 5
^fl-lodo^-methyl-phenylaminoJ-i-methyl-β-oxo-i.β-dihydro-pyridine-S-carboxylic acid (3b)
Figure imgf000048_0001
Ethyl 4,6-dichloronicotinate (1) (3.2g, 14.5mmol) and 4-iodo-2-methylaniline (3.Og, 13.6mmol) are dissolved in dry THF (15ml) under argon and the mixture is cooled to - 780C. A solution of LiHMDS (1.0M in THF, 48ml) is slowly added and the reaction mixture is allowed to warm to ambient temperature. After 18h the reaction is quenched by adding dilute hydrochloric acid (1.0M, 30.0ml) and the mixture is extracted with DCM (3x 80ml). The combined organic extracts are concentrated in vacuo and the crude material is purified by flash chromatography using silica gel and a gradient of 0-20% ethylacetate in cyclohexane as eluent to give pure 4-(4-iodo-2-methyl-phenylamino)-6-chloro-nicotinic acid ethyl ester (2b) (1.2g, 20% yield).
Ester 2b (350mg, 0.84mmol) and iodomethane (1.5ml) are dissolved in dry DCE (8ml) under argon and the mixture is heated at 140° C for 1.5h with microwave irradiation and the volatiles are removed in vacuo. LiOH (81 mg, 3.36mmol) is added and the mixture is heated for 15min at 1400C with microwave irradiation. The volatiles are evaporated under reduced pressure 1 N HCI is added (10ml) and extraxted with DCM. The organic phase is dried over Na2SO4 and evaporated and the crude material is purified by preparative RP 18- HPLC to give pure 4-(4-iodo-2-methyl-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine- 3-carboxylic acid (3b) (44mg, O.Hmmol, 14%yield). LC-MS method (III) rt 7.07 min; m/z 385 [M+H]+.
1H-NMR (400 MHz, DMSO-d6) δ = 2.16 (s, 3H)1 3.38 (s, 3H), 5.24 (s, 1 H), 7.11 (d, J = 8.1 Hz, 1 H), 7.59 (d, J = 8.6Hz, 1 H), 7.71 (s, 1 H), 8.47 (s, 1H), 9.6 (b, 1 H).
Example 6
4-[(4-lodo-2-methylphenyl)amino]'N-{[(2S)-2,3-dihydroxypropyl]oxy}-1-methyl-6- oxo-1, 6-dihydropyridine-3-carboxamide (4c)
Figure imgf000049_0001
4-(4-lodo-2-methyl-phenylamino)-1-methyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid (3b) (0.467mmol, 180mg) is dissolved in dry DMF (2ml) followed by the addition of DIPEA (0.70mmol, 121μl), PyBOP (0.70mmol, 365mg) and O-[(4S)2,2-dimethyl-[1,3]dioxolan-4- ylmethyl]-hydroxylamine (0.935mmol, 129mg). The mixture is stirred for 16h at 60° C, aqueous phosphate buffer (pH7, 15ml) is added and extracted with DCM. The combined organic phases are washed with brine, dried (Na2SO4) end evaporated. The crude material is purified by flash chromatography using silica and a 0-10% gradient of methanol in DCM to yield 85mg (35% yield) of acetonide-protected 4c. Methanol (2ml), water (0.2ml) and Dowex50X8 (20mg) is added and the mixture is heated for 10 min at 120° C with microwave irradiation. After filtration the volatiles are removed in vacuo and the product is purified by preparat/ve HPLC to give 26mg of pure product 4c. LC-MS method (III): rt 5.45min, m/z 474 [M+H]+.
1H-NMR (400 MHz, DMSO-d6) δ = 2.16 (s, 3H), 3.17 (d, J = 5.5Hz, 3H), 3.38-3.41 (m, 1H), 3.71-3.81 (m, 2H), 3.95 (dd, J = 3.5Hz, J = 9.6 Hz, 1H), 4.10 (dd, J = 5.0 Hz, J = 10.6 Hz, 1H), 4.63 (b, 1H), 4.88 (b, 1H), 5.31 (s, 1H), 7.09 (d, J = 8.1 Hz1 1 H); 7:58 (d, J = 8.6Hz, 1H)1 7.70 (S, 1 H), 8.10 (s, 1H), 9.21 (b's, 1H).
Assay
The activity of the compounds of the present invitation may be determined by the following procedure: Inhibition of human MEK1 kinase activity was monitored with a homogenous, fluorescence based assay. The assay uses time resolved fluorescence resonance energy transfer to probe for phosphorylation of ERK1 by MEK1. The assay is carried out in low volume 96 well microtiterplates. In a total volume of 15 μl, compounds are incubated with 10OnM MEK1 , 15 μM ATP, 30OnM ERK2 employing a buffer containing 2OmM TRIS/HCI, 10 mM MgCI2, 100 μM NaVO4, 1 mM DTT, and 0.005% Tween 20 (pH 7.4). After two hours, 5 nM Europium-anti-PY20 (Perkin Elmer) and 5OnM Anti-GST-Allophycocyanin (CisBio) in buffer containing 5OmM EDTA and 0,05% BSA are added and the reaction incubated for one hour in the dark. Time-resolved fluorescence is measured using a LJL- Analyst (Molecular Devices) with an excitation wavelength of 340 nm and an emission wavelength of 665 nm. The final concentration of DMSO is 2 %. To assess the inhibitory potential of the compounds, IC50-values were determined.
In this assay compounds of the invention exhibited IC50s within certain ranges. The following compounds exemplify such activity with "+" meaning 1 μM < IC50 < 10μM and "++" IC50 ≤ 1μM
Figure imgf000050_0001
Assay 2: Tumor cell proliferation assays (ATP Lite)
Murine colon C26, human melanoma A375 and human melanoma Mel5 cells were plated in 96 well Corning white plates (1500 cells/well for C26, and 2000 cells/well for A375, and MiaPaCa-2) and cultured overnight at 370C in 5% CO2. Inhibitors were serially diluted in 100 % DMSO and subsequently added to cells to reach a final concentration of 0.25% DMSO. The cells were incubated for 4 days in the presence of test compounds in cell growth media (DMEM with 10% fetal bovine serum, 2mM glutamine for C26, and MiaPaCa-2, and RPMI with 10% fetal bovine serum, 2mM glutamine for A375). Cell proliferation was quantitated using the ATP lite cell proliferation kit (Packard). Inhibition of cell proliferation is shown in Table 2. Columns 2-4 show the concentration of compounds required to induce 50% cell death (IC50 in μM) of human endometriotic cells. With "+" meaning 100μM < IC50 < 10μM and "++" IC50 < 1μM and "n.d." means not determined.
Assay 3: Microsomal stability assay
Compounds were tested on their stability in human, rat and mouse liver microsomal preparations (HLM, RLM and MLM respectively). At a final concentration of 3 μM, compounds were incubated at 370C with 0.5 mg/ml human, rat or mouse liver microsomes in a buffer containing 50 mM phosphate, pH 7.4 and 2 mM NADPH. Pooled human liver microsomes or pooled male rat liver microsomes (Sprague Dawley) were obtained from NatuTec (Frankfurt, Germany). Incubations without NADPH served as negative controls. Reactions were stopped after 0, 15, 30, 45 or 60 min by the addition of acetonitrile and microsomes were pelleted by centrifugation (10 min at 6200 x g). Supematants were analyzed by HPLC regarding the concentration of mother compound. Finally, the half-life of compounds in the regarding microsomal preparation was calculated. Results are shown in Table 2. Wherein "+" means ti/2 of 1- 30 min, "++" means ti/2 of 31-120 min and "+++" means ti/2 of >120 min.
Table 2: Results of inhibition of tumor cell proliferation and microsomal stability
Figure imgf000051_0001

Claims

Claims
1. A compound of formula (I)1
Figure imgf000052_0001
Formula (I)
a pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein:
Ri. R2, Rg, R11 R12, Ri3 and R14 are independently selected from hydrogen, halogen, cyano, nitro, azido, -OR3, -C(O)R31-C(O)OR3, -NR4C(O)OR6, -OC(O)R3, - NR4S(O)]R6 , -S(O)jNR3R4, -S(O)jNR4C(O)R3, -C(O)NR4S(O)jR6, S(O)1R6,-
NR4C(O)R3, -C(O)NR3R41-NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4 and C1- C10 alkyl, C2-C10 alkenyl, C2-Ci0 alkynyl, C3-Ci0 cycloalkyl, C3-Ci0 cycloalkylalkyl, -S(O)1(C1-C6 alkyl), -S(O)j(CR4R5)m-aryl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -O(CR4R5)m-aryl, -NR4(CR4R5)m- aryl, -O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl,
-NR4(CR4Rs)m-heterocyclyl, and -S(C1-C2 alkyl) substituted with 1 to 5 F, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
R10 is selected from hydrogen, -OR3, -C(O)R31-C(O)OR3, -NR4C(O)OR6, -OC(O)R3, - NR4S(O)jR6 , -S(O)jNR3R4, -S(O)jNR4C(O)R3, -C(O)N R4S(O)]R6, S(O)1R6,-
NR4C(O)R3, -C(O)NR3R41-NR5C(O)NR3R4, -NR5C(NCN)NR3R4, -NR3R4 ; - S(O)j(CrCβ alkyl),
Figure imgf000052_0002
-O(CR4R5)m-aryl, -NR4(CR4R5)m-aryl, - O(CR4R5)m-heteroaryl, -NR4(CR4R5)m-heteroaryl, -O(CR4R5)m-heterocyclyl, - NR4(CR4R5)m-heterocyclyl, and -S(CrC2 alkyl) substituted with 1 to 5 F, where each, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
L is selected from CrC10 alkyl, C2-Ci0 alkenyl, C2-Ci0 alkynyl, C3-Ci0 cycloalkyl, C3- C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is unsubstituted or substituted; or LR10 are together hydrogen;
R3 is selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C2-10 alkenyl, C2-Ci0 alkynyl, C3-C10 cycloalkyl, C3-Ci0 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
R4 is selected from hydrogen or d-C6 alkyl whereby alkyl may be substituted or unsubstituted; or
R3 and R4 can be taken together with the atom to which they are attached to form a 4 to 10 membered heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R5 is selected from hydrogen or CrC6 alkyl whereby alkyl may be substituted or unsubstituted; or
R4 and R5 can be taken together with the atom to which they are attached to form a 4 to 10 membered carbocyclic, heteroaryl or heterocyclic ring, each of which is substituted or unsubstituted;
R6 is selected from trifluoromethyl,CrC10 alkyl, C3-C10 cycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyciylalkyl, where each alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituted or unsubstituted;
W is selected from heteroaryl containing 1-4 heteroatoms or heterocyclyl containing 1- 4 heteroatoms each of which is unsubstituted or substituted by 1 to 5 substituents ZRi5; or W is -C(O)ORi5, -C(O)NR4Ri5, -C(O)NR4OR15, -C(O)(C3- C10 cycloalkyl), -C(O)(C2-C10 alkyl), -C(O)(aryl), -C(O)(heteroaryl), -
C(O)(heterocyclyl), S(O)jNR4R15, S(O)jNR4OR15, -S(O)JNR4C(O)R15, or - C(O)NR4S(O)jR6, whereby R4 and R15 are as defined herein or may form together a 3 to 7 membered ring with 1 or 2 N atoms and optionally an O atom,
Z is a bond, NR16, O, NR16SO2 or S, R15 is independently selected from hydrogen, trifluoromethyl, C1-C10 alkyl, C2-C10 alkenyl, C2-C10 alkynyl, C3-C10 cycloalkyl, C3-C10 cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
R16 is selected from hydrogen or C1-C10 alkyl, or R15 and R16 form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being substituted or unsubstituted; m is 0, 1 , 2, 3, 4 or 5 ;and j is 1 or 2.
2. The compound of Formula (I) according to claim 1 wherein
R1, R2, Rg, R11 are selected independently from hydrogen, halo, C1-C4 alkyl, C3-C4 cycloalkyl, C2-C4 alkenyl, C2-C4 alkynyl, cyano, nitro, OR3 or NR3R4 where each alkyl, alkenyl, alkynyl, cycloalkyl is optionally substituted with one to five halogens; R10 is selected from hydrogen, -OR3, -NR4C(O)R3, -C(O)NR3R4, -NR3R4; L is selected from C1-C5 alkyl, or LR10 are together hydrogen;
R12 is selected independently from hydrogen, halo, C1-C10 alkyl, C3-C10 cycloalkyl, C2-
C10 alkenyl, C2-Ci0 alkynyl, cyano, nitro, azido; NR4SO2R6; SO2NR3R4; SO2R6; C(O)NR3R4;-S(O)jNR4C(O)R3, -C(O)NR4S(O)jR6, OR3, NR3R4 or -S(C1-C2 alkyl) substituted with 1 to 5 F, where each alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl and heterocyclyl is substituted or unsubstituted;
Ri3 and Ri4 are selected independently from H, F, Cl and C1-C4 alkyl, C3-C4 cycloalkyl,
C2-C4 alkenyl, C2-C4 alkynyl where each alkyl, alkenyl, cycloalkyl, alkynyl is optionally further substituted with one to five halogens;
W is selected from heteroaryl containing 1-4 heteroatoms, heterocyclyl containing 1-4 heteroatoms each of which is unsubstituted or substituted by 1 to 3 substituents ZR15, or W is -C(O)OR15, -C(O)NR4R15, -C(O)NR4OR15, -C(O)(C3-Ci0 cycloalkyl), -C(O)(C2-Ci0 alkyl), -S(O)jNR4C(O)R15, -C(O)NR4S(O)jR6, S(O)jN, NR4R15 or
Figure imgf000054_0001
Z is selected from NR16, NRi6SO2 or O; Ri5 is selected from hydrogen, CrC4 alkyl, d-C4 alkenyl, C4-C6 cycloalkylalkyl, where alkyl or alkenyl may be further substituted by 1 or 2 of OH, 0-C1-C4 alkyl or NR'R";
R16 is selected from hydrogen or C1-C4 alkyl; R' and R" are each independently selected from hydrogen, C1-C4 alkyl, C2-C4 alkenyl, aryl and arylalkyl.
3. The compound of Formula (I) according to claim 1 or 2 wherein
R1 is selected independently from H and F;
R2 is selected independently from F, Cl, Me, where the methyl group is optionally substituted with one to three fluorines;
R9 is selected independently from H, F, Cl; R10 is selected from hydrogen, -OR3, -NR3R4; L is selected from ethylene, n-propylene or n-butylene; or LR10 are together methyl;
Rn is selected independently from H, F, Cl, Br, Me, OMe, where the methyl groups are optionally substituted with one to three fluorines;
R12 is selected independently from H, F, Cl, Br, I, nitro, methyl, ethyl, n-propyl, i-propyl, cyclopropyl, SCF3, SCHF2, SCH2F, SO2NR3R4 or C(O)NR3R4 or OMe, where the methyl groups are optionally substituted with one to three fluorines, wherein R3 and R4 are independently C1-C6 alkyl, optionally substituted by 1 or 2 alkyl amino or O-alkyl, or R3 and R4 form together a cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino or O-alkyl;
R13 is selected independently from H and F; R14 is selected independently from H and F; W is selected from -C(O)NR4OR15 or SO2NR4OR15; or W is
Figure imgf000056_0001
wherein
R15 is Ci-C4 alkyl or CrC4 aikenyl optionally substituted with 1 to 3 substituents OH, 0-Me1 NH2, N(methyl)2 or N(ethyl)2;
R16 is hydrogen or C1-C4 alkyl, or Ri6 and R15 form together a 4 to 10 membered cyclic ring with 1 or 2 N atoms and optionally an O atom, said ring being optionally substituted by 1 or 2 alkyl amino, amino, hydroxy or O-alkyl. Y is O, S or NR'.
4. The compound of Formula (I) according to any of claims 1 to 3 wherein
W is selected from -C(O)NR4ORi5 or SO2NR4ORi5, orW is
Figure imgf000056_0002
wherein
R4 is hydrogen;
Z is NH, R15 is selected from CrC4 alkyl or CrC4 aikenyl that may be further substituted by 1 or 2 of OH, 0-CrC4 alkyl or NR1R",
R' and R" are independently hydrogen, methyl or ethyl; and Y is O.
5. The compound of Formula (I) according to any of claims 1 to 4 wherein LRi0 are together methyl.
6. The compound of any of claims 1 to 5 for use as a medicament.
7. Use of the compound according to any of claims 1 to 5, for the preparation of a medicament for the treatment of hyperproliferative diseases or disorders mediated by aberrant proliferation, including cancer.
8. Use of the compound of any of claims 1 to 5 for the preparation of a medicament for the treatment of hyperproliferative diseases related to the hyperactivity of MEK as well as diseases modulated by the MEK cascade in mammals.
9. Use according to claim 8 for the treatment of diseases selected from the group consisting of cancer, inflammation, pancreatitis or kidney disease, pain, benign hyperplasia of the skin, restenosis, prostate, diseases related to vasculogenesis or angiogenesis, tumor angiogenesis, skin diseases selected from psoriasis, eczema, and sclerodema, diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma and Kaposi's sarcoma.
10. Use according to claim 8 or 9 for the treatment of cancer or inflammation.
11. Use according to any of claims 8 to 10 for the treatment of cancer selected from the group consisting of ovarian, breast, lung, pancreatic, prostate, colon and epidermoid cancer; or inflammation selected from the group consisting of rheumatoid arthritis, inflammatory bowel disease, atherosclerosis.
12. A pharmaceutical composition which comprises a compound of any of claims 1 to 5 and a pharmaceutically acceptable carrier.
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