WO2007076460A2

WO2007076460A2 - Substituted thiazole ureas useful as inhibitors of protein kinases

Info

Publication number: WO2007076460A2
Application number: PCT/US2006/062524
Authority: WO
Inventors: Mark R. Herbert; Hengyuan Lang; Timothy C. Gahman; Stewart A. Noble; Robert L. Davis
Original assignee: Kalypsys, Inc.
Priority date: 2005-12-23
Filing date: 2006-12-21
Publication date: 2007-07-05
Also published as: WO2007076460A3

Abstract

The present invention relates to compounds and methods useful as inhibitors of protein kinases, including B-Raf and several receptor tyrosine and cytoplasmic tyrosine kinases. The present invention is directed to new substituted pyrimidinyloxy urea compounds of Formula (I) and compositions and their application as pharmaceuticals for the treatment of disease. Methods of modulating of protein kinase activity in a human or animal subject are also provided for the treatment diseases such as cancers.

Description

NOVEL SUBSTITUTED THIAZOLE UREAS USEFUL AS INHIBITORS OF PROTEIN

KINASES

This application claims the benefit of priority of United States provisional application No. 60/753,488, filed December 23, 2005 and United States provisional application No. 60/851,504, filed October 13, 2006, the disclosures of which are hereby incorporated by reference as if written herein in their entireties.

FIELD OF THE INVENTION The present invention is directed to new thiazole urea compounds and compositions and their application as pharmaceuticals for the treatment of disease. Methods of modulating of protein kinase activity in a human or animal subject are also provided for the treatment diseases such as cancer.

BACKGROUND OF THE INVENTION Protein kinases catalyze the reversible phosphorylation of serine, threonine, and tyrosine residues of many proteins in mammalian cells. The regulatory control of numerous cell functions depends in part on this post-translational modification to directly or indirectly control enzymatic activities or protein-protein interactions. For instance, growth and increase in mass, cell division, and cell survival (i.e., control of apoptosis) all depend on reversible protein phosphorylation. Dysregulation of phosphorylation is causative of or significantly contributes to a range of human diseases and accompanying pathologies. This dysregulation often takes the form of physiologically excessive protein kinase function that shifts the balance of phosphorylation toward increased serine-, threonine-, and tyrosine-phosphate in cells, resulting in hyperstimulation of key regulatory pathways (Bennasroune, A. et al., Crit Rev Oncol Hematol., 50:23-38, 2004; Fabbro, D. and Garcia-Echeverria, C, Curr Opin Drug Discov Devel., 5:701-712, 2002; Sebolt-Leopold, J. S. and Herrera R., Nat Rev Cancer, 4:937-947,

2004). The successful development of protein kinase inhibitors as therapeutincs in the past decade has served to validate kinases in general for future pharmaceutical research (Beeram, M. et al., J Clin Oncol., 23:6771-6790, 2005; Blackhall, F. H. et al., Expert Opin Pharmacother., 6:995-1002, 2005; O'Dwyer, M. E. et al., Cancer Invest, 21:429-438, 2003; Sakamoto, K. M., Curr Opin Investig Drugs, 5:1329- 1339, 2004).

Although highly selective allosteric kinase inhibitors are particularly desirable, the most straightforward development of small molecule kinase inhibitors has focused on the ATP binding site in the catalytic domain, with much research on reversible or irreversible ATP-competitive inhibitors (Garcia-Echeverria, C. et al., Med Res Rev., 20:28-57, 2000). Despite the sequence similarities and structural homologies that divide the protein kinase superfamily, or kinome, into various families, the requirements of ATP binding and phosphotransferase activity largely result in ATP-competitive kinase inhibitors that have selectivity profiles across the kinome, rather than exquisite selectivity for only one or a few kinase targets (Fabian, M. A. et al., Nat Biotechnol., 23:329-336, 2005; Knight, Z. A. and Shokat, K. M., Chem Biol., 12:621-637, 2005). Some additional selectivity can be derived from small molecule interaction in another hydrophobic pocket close to but not overlapping the ATP binding site. This additional pocket is formed in those kinases where the activation loop is in the so-called "out" conformation and the kinase is in an inactive or low specific activity state. Compounds that bind in the ATP pocket and interact with this second pocket can stabilize the inactive conformation of the kinase (Okram, B. et al., Chem Biol., 13:779-786, 2006). Nevertheless, successful pharmaceutical development relies on selectivity profiles compatible with the desired therapeutic index.

With particular respect to disease, especially cancer, it is recognized that dysregulation of members of multiple kinase families can exist concurrently and contribute to pathology. In oncology applications, even the most selective of the clinically useful kinase inhibitors have a multi-kinase profile that has facilitated their successful application in tumor types with different kinase dysregulation patterns (e.g., the use of imatinib in chronic myeloid leukemia [AbI kinase] and in gastrointestinal stromal tumors [C-Kit kinase], O'Dwyer, M. E. and Druker, B. J., Lancet Oncol., 1:207-211, 2000; Steinert, D. M. et al., Expert Opin Pharmacother., 6:105-113, 2005). Our efforts have focused on the discovery of small molecule protein kinase inhibitors with selectivity profiles encompassing key kinases or kinase families described below. Particular attention is focused, but not limited to, the Raf family of serine-threonine kinases (STKs), and particular receptor tyrosine kinases (RTKs) and cytoplasmic tyrosine kinases (CTKs) implicated in both tumor cell biology and tumor blood vessel biology. i

The Raf genes code for highly conserved STKs that are essential components of the Ras/Mitogen-Activated Protein Kinase (MAPK) signaling cascade (Beeram, M. et al., J Clin Oncol., 23 :6771-6790, 2005). This pathway is best known for its control of a complex response to external cellular stimuli which are commonly mediated by polypeptide growth factors or other small biologically active molecules that bind and activate cell surface receptors. Raf kinases have three distinct isoforms, Raf-1 (C-Raf), A-Raf, and B-Raf, distinguished by their ability to interact with Ras, their ability to activate the MAPK pathway, and their tissue distribution and sub-cellular localization (Kolch, W.,

Biochem. J., 351: 289-305, 2000; Pritchard, C. A. et. al., MoI. Cell. Biol., 15:6430-6442, 1995; Weber, C. K. et. al., Oncogene, 19:169-176, 2000).

In this pathway, ligand dependent or independent activation of specific RTKs results in activation of Ras family GTPases. Raf kinases are recruited to the inner plasma membrane by active Ras and subsequently activated themselves by phosphorylation. Raf kinases then phosphorylate and activate two isoforms of Mitogen- Activated Protein Kinase Kinase (MAPKK, called Mekl and Mek2), that are dual specificity threonine/tyrosine kinases. Both Mek isoforms phosphorylate and activate Mitogen Activated Protein Kinases 1 and 2 (MAPK, also called Extracellular Signal-Regulated Kinase 1 and 2 or Erkl and Erk2). The MAPKs phosphorylate, in particular, various nuclear transcription factors that control gene expression in response to RTK signaling (Cobb, M. H. et al., Semin Cancer Biol., 5:261- 268, 1994; Davis, R. J., MoI Reprod Dev., 42:459-467, 1995). Raf kinases are considered to be the primary Ras effectors involved in the proliferation of animal cells, and regulate many other cellular functions such as differentiation, oncogenic transformation and apoptosis (Avruch J. et al., Trends Biochem. Sci., 19:279-283, 1994; Wellbrock, C. et al., Nat Rev MoI Cell Biol., 5:875-885, 2004).

The Ras/Raf/Mek/Erk pathway is hyperactivated in about 30% of all tumors, and much higher percentages in select tumor types such as pancreatic and colon cancer (Bos, J. L., Cancer Res., 49:4682- 4689, 1989; Hoshino, R. et. al., Oncogene, 18:813-822, 1999). Recent studies have shown that activating mutations in the kinase domain of B-Raf occur in about 67% of melanomas, 12% of colorectal carcinomas and 14% of ovarian carcinomas, as well as smaller percentages in other tumor types (Brose, M. S. et. al., Cancer Res., 62:6997-7000, 2002; Davies, H. et. al., Nature, 417:949-954, 2002; Yuen, S. T. et. al., Cancer Res., 62:6451-6455, 2002). These activating mutations mostly increase basal B-Raf kinase activity in cells, and uniformly increase basal levels of Erk kinase activity in cells (Wan, P. T. C. et al., Cell, 116:855-867, 2004). Greater than 80% of the B-Raf mutations in melanomas occur at a single residue, valine 600 (previously numbered 599 in some publications because of a sequence discrepancy at the amino terminus), which is substituted with a glutamic acid. Additional studies have shown that B-Raf mutation in skin nevi is a critical step in the initiation of melanocytic neoplasia (Pollock, P. M. ct. al., Nature Genetics, 25:1-2, 2002). More recent studies using RNA interference to suppress expression of B-Raf (V600E mutant) in human melanoma cells have demonstrated inhibition of proliferation and induction of apoptosis (Karasarides, M. et al., Oncogene, 23:6292-6298, 2004; Sharma, A. et al., Cancer Res., 65:2412-2421, 2005) . These results have underscored the attractiveness of B-Raf as a target in tumor cells that bear B-Raf mutations, especially melanoma. RTKs are another group of kinases implicated in cancer and other diseases, through excessive expression of cognate ligands, excessive expression of wild-type RTKs (e.g., through gene amplification), or expression of mutant RTKs that are generally ligand-independent and have constitutively activated catalytic domains (Zwick, E. et al., Trends MoI Med., 8:17-23, 2000). Especially important among the receptor tyrosine kinases implicated in cancer are those that directly mediate signaling that promotes neo-angiogenesis, or new blood vessel formation. Neo-angiogenesis is particularly critical to tumor growth and metastasis as early tumors outgrow their surrounding tissue blood supply (Folkman, J. Curr MoI Med., 3:643-651, 2003). Several other receptor tyrosine kinase activities are directly implicated in controlling lymphatic vessel growth and development, or lymphangiogenesis, which is implicated in tumor metastasis (Cao, Y., Nat Rev Cancer, 5:735-743, 2005).

Specific receptor tyrosine kinases that control and promote neo-angiogenesis are the vascular endothelial growth factor A (VEGF-A) receptors (VEGFRl, or FIt-I and VEGFR-2 (KDR) or FIk-I), platelet-derived growth factor (PDGF) receptors alpha and beta (PDGFRα and PDGFRβ), and fibroblast growth factor (FGF) receptors (FGFR1-4), while the VEGF-C receptor (VEGFR-3 or Flt-4) controls lymphangiogenesis. Interestingly, these same RTKs can be expressed by tumor cells themselves, providing proliferation and survival signals (Wey, J. S., Clin Adv Hematol Oncol., 3:37-45, 2005). In addition, there are several other RTKs and CTKs directly implicated in cancer (AbI, C-Kit, C-Met, Flt3, Ret) that are desirable targets for the profile of multi-kinase small molecule inhibitors. Critical signal transduction events for these receptor tyrosine kinases, especially VEGFR-2 and FGFRl, are mediated through Ras activation of Raf kinases. Raf kinase signaling can inhibit apoptosis, thereby promoting cell survival, and this function has been demonstrated particularly in endothelial cells, with implications for targeting tumor neo-angiogenesis (Alavi, A. et al., Science, 301:94-96, 2003). Therefore, small molecule kinase inhibitors whose selectivity profile includes some or all of the RTKs and CTKs referenced above, and Raf kinases, are expected to have improved utility in the direct inhibition of tumor cell proliferation and survival and the inhibition of tumor-promoting neo- angiogenesis.

SUMMARY OF THE INVENTION

Novel compounds and pharmaceutical compositions that inhibit select disease-relevant serine- threonine kinase (STK), receptor tyrosine kinase (RTK), cytoplasmic tyrosine kinase (CTK) activity have been found, together with methods of synthesizing and using the compounds including methods for the treatment of protein kinase-mediated diseases in a patient by administering the compounds.

The present invention discloses a class of compounds, useful in treating protein kinase- mediated disorders and conditions, defined by structural Formula I:

wherein:

A and C are each independently selected from the group consisting of aryl and heteroaryl, either of which may be optionally substituted;

X¹ is selected from the group consisting of C(R²)(R³), N(R²), O and S(O)_n; n is 0,1 or 2; S, T, U, V and W are each independently selected from the group consisting of C(R⁴)(R⁵),

S(O)_1n, O and N(R⁶); m is 0,1 or 2;

B is selected from the group consisting of-N(R⁷)C(O)N(R⁷)- and -N(R⁷)C(O)N(R⁷)CH₂-;

R¹ is selected from the group consisting of amido, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, which may be optionally substituted;

R² and R³ are each independently selected from the group consisting of lower alkyl and hydrogen;

R⁴ and R⁵ are each independently selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylene, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylcarbonyl, arylsulfonyl, cyanoalkenyl, cycloalkyl, haloalkyl, haloalkoxy, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycloalkyl, hydrogen, hydioxyalkyl and null, any of which may be optionally substituted;

R⁶ is selected from the group consisting of alkenyl, alkoxyalkyl, alkyl, alkynyl, C-amido, aminoalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, cyanoalkenyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydrogen, hydroxyalkyl and null, any of which may be optionally substituted; and

R⁷ is selected from the group consisting of lower alkyl, cycloalkyl and heterocycloalkyl, any of which may be optionally substituted, with the proviso that when X¹ is -NH-, A and C are phenyl then R¹ cannot be pyridine or phenyl.

Compounds according to the present invention possess useful protein kinase modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which protein kinase plays an active role. Thus, in broad aspect, the present invention also provides pharmaceutical compositions comprising one or more compounds of the present invention together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. In certain embodiments, the present invention provides methods for modulating protein kinase. In other embodiments, the present invention provides methods for treating a protein kinase- mediated disorder in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention. The present invention also contemplates the use of compounds disclosed herein for use in the manufacture of a medicament for the treatment of a disease or condition ameliorated by the modulation of protein kinase.

DETAILED DESCRIPTION OF THE INVENTION

In certain embodiments, the compounds of the present invention have structural Formulas II, in or IV:

wherein:

X¹ is selected from the group consisting of C(R²)(R³), N(R²), O and S(O)_n; n is 0,1 or 2;

B is selected from the group consisting of -N(R⁷)C(O)N(R⁷)- and -N(R⁷)C(O)N(R⁷)CH₂-; R¹ is selected from the group consisting of amido, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, any of which may be optionally substituted;

T is selected from the group consisting of C(R⁴)(R⁵), S(O)_n,, O and N(R⁶); m is 0,1 or 2; R² and R³ are each independently selected from the group consisting of lower alkyl and hydrogen;

R⁴ and R⁵ are each independently selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylene, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylcarbonyl, arylsulfonyl, cyanoalkenyl, cycloalkyl, haloalkyl, haloalkoxy, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycloalkyl, hydrogen, hydroxyalkyl and null, any of which may be optionally substituted;

R⁷ is selected from the group consisting of lower alkyl, cycloalkyl and heterocycloalkyl, any of which may be optionally substituted.

The invention further provides for compounds of Formula III:

wherein:

X¹ is selected from the group consisting Of-CH₂-, -NH-, O and S;

B is selected from the group consisting of-N(R⁷)C(O)N(R⁷)- and-N(R⁷)C(O)N(R⁷)CH₂-; R¹ is selected from the group consisting of optionally substituted amido and

I, J, K, L and M are each independently selected from the group consisting of C(R⁸)(R⁹), S(O)i, O and N(R¹⁰);

Hs 0,1 or 2; R⁷ is selected from the group consisting of lower alkyl, cycloalkyl and heterocycloalkyl, any of which may be optionally substituted;

R⁸ and R⁹ are each independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, alkynyl, amido, amidoalkyl, amino, aminoalkyl, aminoalkylamino, aryl, arylalkenyl, arylalkyl, arylalkynyl, cyano, cyanoalkyl, cyanoalkenyl, cycloalkyl, ester, esteralkyl, halo, haloalkyl, haloalkoxy, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkyltMo, hydrogen, hydroxy, hydroxy alkyl, nitro and null, any of which may be optionally substituted; and

R¹⁰ is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylene, alkynyl, amidoalkyl, aryl, arylalkoxy, arylalkyl, arylalkenyl, arylalkynyl, arylcarbonyl, arylsulfonyl, cyanoalkenyl, cyanoalkyl, cycloallcyl, ester, esteralkyl, haloalkyl, haloalkoxy, haloalkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylsulfonyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylthio, hydrogen, hydroxy alkyl and null, any of which may be optionally substituted. The invention further provides for compounds of Formula IV:

wherein:

A and C are each independently selected from the group consisting of aryl and heteroaryl, either of which may be optionally substituted; B is selected from the group consisting Of-N(H)C(O)N(H)- and -N(H)C(O)N(H)CH₂-;

R¹ is selected from the group consisting of

Q is selected from the group consisting of S(O)_P> O and N(R¹⁰); p is 0,1 or 2; and R¹⁰ is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylene, alkynyl, amidoalkyl, aryl, arylalkoxy, arylalkyl, arylalkenyl, arylalkynyl, arylcarbonyl, arylsulfonyl, cyanoalkenyl, cyanoalkyl, cycloalkyl, ester, esteralkyl, haloalkyl, haloalkoxy, haloalkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylsulfonyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylthio, hydrogen, hydroxyalkyl and null, any of which may be optionally substituted.

The invention provides for compounds of Formulas LTV for use in the inhibition of protein kinases for the treatment of disease.

The invention provides for compounds of Formulas LTV administered in combination with another therapeutic agent. The invention provides for compounds of Formulas LTV for use as a medicament.

The invention provides for compounds of Formulas LTV for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of protein kinase. The invention provides for a pharmaceutical composition comprising a compound of any of Formulas I-IV together with a pharmaceutically acceptable carrier, useful for the treatment or prevention of a protein kinase-mediated disease.

The invention provides for a method of inhibition of protein kinase comprising contacting a protein kinase with a compound of any of Formulas I-IV.

The invention provides for a method of treatment of a protein kinase -mediated disease comprising the administration of a therapeutically effective amount of a compound of any of Formulas I- IV to a patient in need thereof, wherein said disease is selected from the group consisting of cancers, hematological and non-hematologic malignancies, autoimmune diseases, hematopoiesis, malignancies of the skin, psoriasis, dry eye and glaucoma.

As used herein, the terms below have the meanings indicated.

The term "acyl," as used herein, alone or in combination, refers to a carbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl, heterocycle, or any other moiety were the atom attached to the carbonyl is carbon. An "acetyl" group refers to a -C(O)CH₃ group. An "alkylcarbonyl" or "alkanoyl" group refers to an alkyl group attached to the parent molecular moiety through a carbonyl group. Examples of such groups include methylcarbonyl and ethylcarbonyl. Examples of acyl groups include formyl, alkanoyl and aroyl.

The term "alkenyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain hydrocarbon radical having one or more double bonds and containing from 2 to 20, preferably 2 to 6, carbon atoms. Alkenylene refers to a carbon-carbon double bond system attached at two or more positions such as ethenylene [(-CH=CH-),(-C::C-)]. Examples of suitable alkenyl radicals include ethenyl, propenyl, 2-methylpropenyl, 1,4-butadienyl and the like.

The term "alkoxy," as used herein, alone or in combination, refers to an alkyl ether radical, wherein the term alkyl is as defined below. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

The term "alkyl," as used herein, alone or in combination, refers to a straight-chain or branched-chain alkyl radical containing from 1 to and including 20, preferably 1 to 10, and more preferably 1 to 6, carbon atoms. Alkyl groups may be optionally substituted as defined herein. Examples of alkyl radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl, noyl and the like. The term "alkylene," as used herein, alone or in combination, refers to a saturated aliphatic group derived from a straight or branched chain saturated hydrocarbon attached at two or more positions, such as methylene (-CH₂-).

The term "alkylamino," as used herein, alone or in combination, refers to an alkyl group attached to the parent molecular moiety through an amino group. Suitable alkylamino groups may be mono- or dialkylated, forming groups such as, for example, N-methylamino, N-ethylamino, N,N- dimethylamino, N,N-ethylmethylamino and the like. The term "alkylidene," as used herein, alone or in combination, refers to an alkenyl group in which one carbon atom of the carbon-carbon double bond belongs to the moiety to which the alkenyl group is attached.

The term "alkylthio," as used herein, alone or in combination, refers to an alkyl thioether (R-S-) radical wherein the term alkyl is as defined above and wherein the sulfur may be singly or doubly oxidized. Examples of suitable alkyl thioether radicals include methylthio, ethylthio, n- propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term "alkynyl," as used herein, alone or in combination, refers to a straight-chain or branched chain hydrocarbon radical having one or more triple bonds and containing from 2 to 20, preferably from 2 to 6, more preferably from 2 to 4, carbon atoms. "Alkynylene" refers to a carbon- carbon triple bond attached at two positions such as ethynylene (-C:::C-, -C≡C-). Examples of alkynyl radicals include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, 3- methylbutyn-1-yl, hexyn-2-yl, and the like. The terms "amido" and "carbamoyl,"as used herein, alone or in combination, refer to an amino group as described below attached to the parent molecular moiety through a carbonyl group, or vice versa. The term "C-amido" as used herein, alone or in combination, refers to a -C(=O)-NR₂ group with R as defined herein. The term "N-amido" as used herein, alone or in combination, refers to a RC(=O)NH- group, with R as defined herein. The term "acylamino" as used herein, alone or in combination, embraces an acyl group attached to the parent moiety through an amino group. An example of an "acylamino" group is acetylamino (CH₃C(O)NH-).

The term "amino," as used herein, alone or in combination, refers to — NRR , wherein R and R are independently selected from the group consisting of hydrogen, alkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, and heterocycloalkyl, any of which may themselves be optionally substituted. The term "aryl," as used herein, alone or in combination, means a carbocyclic aromatic system containing one, two or three rings wherein such rings may be attached together in a pendent manner or may be fused. The term "aryl" embraces aromatic radicals such as benzyl, phenyl, naphthyl, anthracenyl, phenanthryl, indanyl, indenyl, annulenyl, azulenyl, tetrahydronaphthyl, and biphenyl.

The term "arylalkenyl" or "aralkenyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkenyl group.

The term "arylalkoxy" or "aralkoxy," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkoxy group.

The term "arylalkyl" or "aralkyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkyl group. The term "arylalkynyl" or "aralkynyl," as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an alkynyl group.

The term "arylalkanoyl" or "aralkanoyl" or "aroyl,"as used herein, alone or in combination, refers to an acyl radical derived from an aryl-substituted alkanecarboxylic acid such as benzoyl, napthoyl, phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl, (2-naphthyl)acetyl, A- chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to an aryl group attached to the parent molecular moiety through an oxy. The terms "benzo" and "benz," as used herein, alone or in combination, refer to the divalent radical CeH₄= derived from benzene. Examples include benzothiophene and benzimidazole.

The term "carbamate," as used herein, alone or in combination, refers to an ester of carbamic acid (-NHCQO-) which may be attached to the parent molecular moiety from either the nitrogen or acid end, and which may be optionally substituted as defined herein. The term "O-carbamyl" as used herein, alone or in combination, refers to a -OC(O)NRR', group-with R and R' as defined herein.

The term "N-carbamyl" as used herein, alone or in combination, refers to a ROC(O)NR'- group, with R and R' as defined herein.

The term "carbonyl," as used herein, when alone includes formyl [-C(O)H] and in combination is a -C(O)- group.

The term "carboxy," as used herein, refers to -C(O)OH or the corresponding "carboxylate" anion, such as is in a carboxylic acid salt. An "O-carboxy" group refers to a RC(O)O- group, where R is as defined herein. A "C-carboxy" group refers to a -C(O)OR groups where R is as defined herein.

The term "cyano," as used herein, alone or in combination, refers to -CN. The term "cycloalkyl," as used herein, alone or in combination, refers to a saturated or partially saturated monocyclic, bicyclic or tricyclic alkyl radical wherein each cyclic moiety contains from 3 to 12, preferably five to seven, carbon atom ring members and which may optionally be a benzo fused ring system which is optionally substituted as defined herein. Examples of such cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, octahydronaphthyl, 2,3-dihydro-lH- indenyl, adamantyl and the like. "Bicyclic" and "tricyclic" as used herein are intended to include both fused ring systems, such as decahydonapthalene, octahydronapthalene as well as the multicyclic (multicentered) saturated or partially unsaturated type. The latter type of isomer is exemplified in general by, bicyclo[l,l,l]pentane, camphor, adamantane, and bicyclo[3,2,l]octane.

The term "ester," as used herein, alone or in combination, refers to a carboxy group bridging two moieties linked at carbon atoms.

The term "ether," as used herein, alone or in combination, refers to an oxy group bridging two moieties linked at carbon atoms.

The term "halo," or "halogen," as used herein, alone or in combination, refers to fluorine, chlorine, bromine, or iodine. The term "haloalkoxy," as used herein, alone or in combination, refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.

The term "haloalkyl," as used herein, alone or in combination, refers to an alkyl radical having the meaning as defined above wherein one or more hydrogens are replaced with a halogen. Specifically embraced are monohaloalkyl, dihaloalkyl and polyhaloalkyl radicals. A monohaloalkyl radical, for one example, may have an iodo, bromo, chloro or fluoro atom within the radical. Dihalo and polyhaloalkyl radicals may have two or more of the same halo atoms or a combination of different halo radicals. Examples of haloalkyl radicals include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, pentafluoroethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl and dichloropropyl. "Haloalkylene" refers to a haloalkyl group attached at two or more positions. Examples include fluoromethylene (-CFH-), difluoromethylene (-CF₂ -), chloromethylene (-CHC1-) and the like.

The term "heteroalkyl," as used herein, alone or in combination, refers to a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, fully saturated or containing from 1 to 3 degrees of unsaturation, consisting of the stated number of carbon atoms and from one to three heteroatoms selected from the group consisting of O, N, and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N and S may be placed at any interior position of the heteroalkyl group. Up to two heteroatoms may be consecutive, such as, for example, -CH₂-NH-OCH₃.

The term "heteroaryl," as used herein, alone or in combination, refers to 3 to 7 membered, preferably 5 to 7 membered, unsaturated heteromonocyclic rings, or fused polycyclic rings in which at least one of the fused rings is unsaturated, wherein at least one atom is selected from the group consisting of O, S, and N. The term also embraces fused polycyclic groups wherein heterocyclic radicals are fused with aryl radicals, wherein heteroaryl radicals are fused with other heteroaryl radicals, or wherein heteroaryl radicals are fused with cycloalkyl radicals. Examples of heteroaryl groups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl, isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl, benzotriazolyl, benzodioxolyl, benzopyranyl, benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl, tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl, thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplary tricyclic heterocyclic groupsinclude carbazolyl, benzidolyl, phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyl and the like. The terms "heterocycloalkyl" and, interchangeably, "heterocycle," as used herein, alone or in combination, each refer to a saturated, partially unsaturated, or fully unsaturated monocyclic, bicyclic, or tricyclic heterocyclic radical containing at least one, preferably 1 to 4, and more preferably 1 to 2 heteroatoms as ring members, wherein each said heteroatom may be independently selected from the group consisting of nitrogen, oxygen, and sulfur, and wherein there are preferably 3 to 8 ring members in each ring, more preferably 3 to 7 ring members in each ring, and most preferably 5 to 6 ring members in each ring. "Heterocycloalkyl" and "heterocycle" are intended to include sulfones, sulfoxides, N-oxides of tertiary nitrogen ring members, and carbocyclic fused and benzo fused ring systems; additionally, both terms also include systems where a heterocycle ring is fused to an aryl group, as defined herein, or an additional heterocycle group. Heterocycle groups of the invention are exemplified by aziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl, dihydroisoquinolinyl, dmydrocinnolinyl, dihydrobenzodioxinyl, dihydro[l,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl, dihy- dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl, isoindolinyl, morpholinyl, piperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl, thiomorpholinyl, and the like. The heterocycle groups may be optionally substituted unless specifically prohibited.

The term "hydrazinyl" as used herein, alone or in combination, refers to two amino groups joined by a single bond, i.e., -N-N-.

The term "hydroxy," as used herein, alone or in combination, refers to -OH. The term "hydroxyalkyl," as used herein, alone or in combination, refers to a hydroxy group attached to the parent molecular moiety through an alkyl group.

The term "imino," as used herein, alone or in combination, refers to =N-.

The term "iminohydroxy," as used herein, alone or in combination, refers to =N(0H) and =N-O-. The phrase "in the main chain" refers to the longest contiguous or adjacent chain of carbon atoms starting at the point of attachment of a group to the compounds of this invention.

The term "isocyanato" refers to a -NCO group.

The term "isothiocyanato" refers to a -NCS group.

The phrase "linear chain of atoms" refers to the longest straight chain of atoms independently selected from carbon, nitrogen, oxygen and sulfur.

The term "lower," as used herein, alone or in combination, means containing from 1 to and including 6 carbon atoms.

The term "mercaptyl" as used herein, alone or in combination, refers to an RS- group, where R is as defined herein. The term "nitro," as used herein, alone or in combination, refers to -NO₂.

The terms "oxy" or "oxa," as used herein, alone or in combination, refer to -O-.

The term "oxo," as used herein, alone or in combination, refers to =O.

The term "perhaloalkoxy" refers to an alkoxy group where all of the hydrogen atoms are replaced by halogen atoms. The term "perhaloalkyl" as used herein, alone or in combination, refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

The terms "sulfonate," "sulfonic acid," and "sulfonic," as used herein, alone or in combination, refer the -SO₃H group and its anion as the sulfonic acid is used in salt formation.

The term "sulfanyl," as used herein, alone or in combination, refers to -S-. The term "sulfmyl," as used herein, alone or in combination, refers to -S(O)-.

The term "sulfonyl," as used herein, alone or in combination, refers to -S(O)2-.

The term "N-sulfonamido" refers to a RS(=O)₂NR'- group with R and R' as defined herein.

The term "S-sulfonamido" refers to a -S(^O)₂NRR', group, with R and R' as defined herein. The terms "thia" and "thio," as used herein, alone or in combination, refer to a -S- group or an ether wherein the oxygen is replaced with sulfur. The oxidized derivatives of the thio group, namely sulfϊnyl and sulfonyl, are included in the definition of thia and thio.

The term "thiol," as used herein, alone or in combination, refers to an -SH group. The term "thiocarbonyl," as used herein, when alone includes thioformyl -C(S)H and in combination is a -C(S)- group.

The term "N-thiocarbamyl" refers to an ROC(S)]SIR'- group, with R and R'as defined herein. The term "O-thiocarbamyl" refers to a -OC(S)NRR', group with R and R'as defined herein. The term "thiocyanato" refers to a -CNS group. The term "trihalomethanesulfonamido" refers to a X₃CS(O)₂NR- group with X is a halogen and

R as defined herein.

The term "trihalomethanesulfonyl" refers to a X₃CS(O)₂- group where X is a halogen. The term "trihalomethoxy" refers to a X₃CO- group where X is a halogen. The term "trisubstituted silyl," as used herein, alone or in combination, refers to a silicone group substituted at its three free valences with groups as listed herein under the definition of substituted amino. Examples include trimethysilyl, tert-butyldimethylsilyl, triphenylsilyl and the like.

Any definition herein may be used in combination with any other definition to describe a composite structural group. By convention, the trailing element of any such definition is that which attaches to the parent moiety. For example, the composite group alkylamido would represent an alkyl group attached to the parent molecule through an amido group, and the term alkoxyalkyl would represent an alkoxy group attached to the parent molecule through an alkyl group.

When a group is defined to be "null," what is meant is that said group is absent. The term "optionally substituted" means the anteceding group may be substituted or unsubstituted. When substituted, the substituents of an "optionally substituted" group may include, without limitation, one or more substituents independently selected from the following groups or a particular designated set of groups, alone or in combination: lower alkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl, lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lower haloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl, phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, lower acyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester, lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, lower alkylamino, arylamino, amido, nitro, thiol, lower alkylthio, arylthio, lower alkylsulfinyl, lower alkylsulfonyl, arylsulfϊnyl, arylsulfonyl, arylthio, sulfonate, sulfonic acid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H, pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Two substituents may be joined together to form a fused five-, six-, or seven-menbered carbocyclic or heterocyclic ring consisting of zero to three heteroatoms, for example forming methylenedioxy or ethylenedioxy. An optionally substituted group may be unsubstituted (e.g., -CH₂CH₃), fully substituted (e.g., -CF₂CF₃), monosubstituted (e.g., -CH₂CH₂F) or substituted at a level anywhere in-between fully substituted and monosubstituted (e.g., -CH₂CF₃). Where substituents are recited without qualification as to substitution, both substituted and unsubstituted forms are encompassed. Where a substituent is qualified as "substituted," the substituted form is specifically intended. Additionally, different sets of optional substituents to a particuar moiety may be defined as needed; in these cases, the optional substitution will be as defined, often immediately following the phrase, "optionally substituted with." The term R or the term R', appearing by itself and without a number designation, unless otherwise defined, refers to a moiety selected from the group consisting of hydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl and heterocycloalkyl, any of which may be optionally substituted. Such R and R' groups should be understood to be optionally substituted as defined herein. Whether an R group has a number designation or not, every R group, including R, R' and Rⁿ where n=(l, 2, 3, ...n), every substituent, and every term should be understood to be independent of every other in terms of selection from a group. Should any variable, substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more than one time in a formula or generic structure, its definition at each occurrence is independent of the definition at every other occurrence. Those of skill in the art will further recognize that certain groups may be attached to a parent molecule or may occupy a position in a chain of elements from either end as written. Thus, by way of example only, an unsymmctrical group such as -C(O)N(R)- may be attached to the parent moiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds of the present invention. These centers are designated by the symbols "R" or "S," depending on the configuration of substituents around the chiral carbon atom. It should be understood that the invention encompasses all stereochemical isomeric forms, including diastereomeric, enantiomeric, and epimeric forms,as well as d-isomers and 1 -isomers, and mixtures thereof. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, direct separation of enantiomers on chiral chromatographic columns, or any other appropriate method known in the art. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art. Additionally, the compounds of the present invention may exist as geometric isomers. The present invention includes all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof. Additionally, compounds may exist as tautomers; all tautomeric isomers are provided by this invention. Additionally, the compounds of the present invention can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

The term "bond" refers to a covalent linkage between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. A bond may be single, double, or triple unless otherwise specified. A dashed line between two atoms in a drawing of a molecule indicates that an additional bond may be present or absent at that position. The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the conditions or disorders described herein.

Protein kinase inhibitor is used herein to refer to a compound that exhibits an IC₅₀ with respect to protein kinase activity of no more than about 100 μM and more typically not more than about 50 μM, as measured in the protein kinase In vitro B-Raf/Mekl composite kinase assay and In vitro VEGFR2 and PDGFRβ kinase assay described generally hereinbelow. IC₅₀ is that concentration of inhibitor that reduces the activity of an enzyme (e.g., B-Raf) to half-maximal level. Representative compounds of the present invention have been discovered to exhibit inhibition activity against protein kinase. Compounds of the present invention preferably exhibit an IC₅₀ with respect to protein kinase of no more than about 10 μM, more preferably, no more than about 5 μM, even more preferably not more than about 1 μM, and most preferably, not more than about 200 nM, as measured in the protein kinase assay described herein.

The phrase "therapeutically effective" is intended to qualify the amount of active ingredients used in the treatment of a disease or disorder. This amount will achieve the goal of reducing or eliminating the said disease or disorder. The term "therapeutically acceptable" refers to those compounds (or salts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitable for use in contact with the tissues of patients without undue toxicity, irritation, and allergic response, are commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.

As used herein, reference to "treatment" of a patient is intended to include prophylaxis. The term "patient" means all mammals including humans. Examples of patients include humans, cows, dogs, cats, goats, sheep, pigs, and rabbits. Preferably, the patient is a human.

The term "prodrug" refers to a compound that is made more active in vivo. Certain compounds of the present invention may also exist as prodrugs, as described in Hydrolysis in Drug and Prodrug Metabolism : Chemistry, Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M. Wiley- VHCA, Zurich, Switzerland 2003). Prodrugs of the compounds described herein are structurally modified forms of the compound that readily undergo chemical changes under physiological conditions to provide the compound. Additionally, prodrugs can be converted to the compound by chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to a compound when placed in a transdermal patch reservoir with a suitable enzyme or chemical reagent. Prodrugs are often useful because, in some situations, they may be easier to administer than the compound, or parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. A wide variety of prodrug derivatives are known in the art, such as those that rely on hydrolytic cleavage or oxidative activation of the prodrug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the "prodrug"), but then is metabolically hydrolyzed to the carboxylic acid, the active entity. Additional examples include peptidyl derivatives of a compound. The compounds of the present invention can exist as therapeutically acceptable salts. The present invention includes compounds listed above in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Basic addition salts may also be formed and be pharmaceutically acceptable. For a more complete discussion of the preparation and selection of salts, refer to Pharmaceutical Salts: Properties, Selection, and Use (Stahl, P. Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term "therapeutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds of the present invention which are water or oil-soluble or dispersible and therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds or separately by reacting the appropriate compound in the form of the free base with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, L- ascorbate, aspartate, benzoate, benzenesulfonate (besylate), bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate, formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride, hydrobromide, hydroiodide, 2- hydroxyethansulfonate (isethionate), lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, phosphonate, picrate, pivalate, propionate, pyroglutamate, succinate, sulfonate, tartrate, L-tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate, para- toluenesulfonate (p-tosylate), and undecanoate. Also, basic groups in the compounds of the present invention can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and steryl chlorides, bromides, and iodides; and ben∑yl and phenethyl bromides. Examples of acids which can be employed to form therapeutically acceptable addition salts include inorganic acids such as hydrochloric, bydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, and citric. Salts can also be formed by coordination of the compounds with an alkali metal or alkaline earth ion. Hence, the present invention contemplates sodium, potassium, magnesium, and calcium salts of the compounds of the compounds of the present invention and the like.

Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine. The cations of therapeutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium, tetramethylammoniurη, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamirte, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, ΛζN-diben∑ylphenethylamine, 1-ephenamine, and N,IΨ- dibenzylethylenediamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.

A salt of a compound can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.

While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical formulation. Accordingly, the subject invention provides a pharmaceutical formulation comprising a compound or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and cxcipicnts may be used as suitable and as understood in the art; e.g., in Remington's Pharmaceutical Sciences. The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of the subject invention or a pharmaceutically acceptable salt, ester, prodrug or solvate thereof ("active ingredient") with the carrier which constitutes one or more accessory ingredients. In general, me formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

Formulations for parenteral administration include aqueous and non-aqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides.

Compounds of the present invention may be administered topically, that is by non-systemic administration. This includes the application of a compound of the present invention externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid or semi-liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose. The active ingredient may comprise, for topical administration, from 0.001% to 10% w/w, for instance from 1% to 2% by weight of the formulation. It may however comprise as much as 10% w/w but preferably will comprise less than 5% w/w, more preferably from 0.1% to 1% w/w of the formulation. For administration by inhalation the compounds according to the invention are conveniently delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, the compounds according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator. Preferred unit dosage formulations are those containing an effective dose, as herein below recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.

The compounds of the invention may be administered orally or via injection at a dose of from 0.1 to 500 mg/kg per day. The dose range for adult humans is generally from 5 mg to 2 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.

Further, the compounds of the invention may be administered on a daily basis or on a schedule containing days where dosing does not take place. In certain embodiments, dosing may take place every other day. In other embodiments, dosing may take place for five consecutive days of a week, then be followed by two non-dosing days. The choice of dosing schedule will depend on many factors, including, for example, the formulation chosen, route of administration, and concurrent pharmacotherapies, and may vary on a patient-to-patient basis. It is considered within the capacity of one skilled in the art to select a schedule that will maximize the therapeutic benefit and minimize any potential side effects in a patient.

The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.

The compounds of the subject invention can be administered in various modes, e.g. orally, topically, or by injection. The precise amount of compound administered to a patient will be the responsibility of the attendant physician. The specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diets, time of administration, route of administration, rate of excretion, drug combination, the precise disorder being treated, and the severity of the indication or condition being treated. Also, the route of administration may vary depending on the condition and its severity. In certain instances, it may be appropriate to administer at least one of the compounds described herein (or a pharmaceutically acceptable salt, ester, or prodrug thereof) in combination with another therapeutic agent. By way of example only, if one of the side effects experienced by a patient upon receiving one of the compounds herein is hypertension, then it may be appropriate to administer an antihypertensive agent in combination with the initial therapeutic agent. Or, by way of example only, the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (i.e., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced). Or, by way of example only, the benefit of experienced by a patient may be increased by administering one of the compounds described herein with another therapeutic agent (which also includes a therapeutic regimen) that also has therapeutic benefit. By way of example only, in a treatment for cancer involving administration of one of the compounds described herein, increased therapeutic benefit may result by also providing the patient with another therapeutic agent for cancer. In any case, regardless of the disease, disorder or condition being treated, the overall benefit experienced by the patient may simply be additive of the two therapeutic agents or the patient may experience a synergistic benefit. Specific, non-limiting examples of possible combination therapies include use of the compounds of the invention with:

For the treatment of oncologic diseases and cancers, compounds according to the present invention may be administered with an agent selected from the group comprising: aromatase inhibitors, antiestrogen, anti-androgen, or a gonadorelin agonists, topoisomerase land 2 inhibitors, microtubule active agents, alkylating agents, antineoplastic, antimetabolite, dacarbazine (DTIC), or platinum containing compound, lipid or protein kinase targeting agents, protein or lipid phosphatase targeting agents, anti-angiogentic agents, agents that induce cell differentiation, bradykinin 1 receptor and angiotensin II antagonists, cyclooxygenase inhibitors, heparanase inhibitors, lymphokines or cytokine inhibitors, bisphosphanates, rapamycin derivatives, anti-apoptotic pathway inhibitors, apoptotic pathway agonists, PPAR agonists, inhibitors of Ras isoforms, telomerase inhibitors, protease inhibitors, metalloproteinase inhibitors, aminopeptidase inhibitors.

For the treatment of oncologic diseases and solid tumors, compounds according to the present invention may be administered with an agent selected from the group comprising: dacarbazine (DTIC), alkylating agents (eg, melphalan) anthracyclines (eg. doxorubicin), corticosteroids (eg. dexamethasome), Akt inhibitor (eg. Perifosine), aromatase inhibitors, antiestrogen, anti-androgen, or a gonadorelin agonists, topoisomerase land 2 inhibitors, microtubule active agents, alkylating agents (eg. cyclophophamide, temozolomide), antineoplastic antimetabolite, or platinum containing compounds, MITC, nitrosoureas, taxancs, lipid or protein kinase targeting agents, protein or lipid phosphatase targeting agents, anti-angiogentic agents, IMiDs (eg. thalidomide, lenalidomide), protease inhibitors (eg. bortezomib, NPI0052), IGF-I inhibitors, CD40 antibody, Smac mimetics (eg. telomestatin), FGF3 modulator (eg. CHIR258), mTOR inhibitor (Rad 001), HDAC inhibitors (eg. SAHA, Tubacin), IKK inhibitors, P38MAPK inhibitors, HSP90 inhibitor (eg 17-AAG), and other mutlikinase inhibitors (eg. sorafenib).

In any case, the multiple therapeutic agents (at least one of which is a compound of the present invention) may be administered in any order or even simultaneously. If simultaneously, the multiple therapeutic agents may be provided in a single, unified form, or in multiple forms (by way of example only, either as a single pill or as two separate pills). One of the therapeutic agents may be given in multiple doses, or both may be given as multiple doses. If not simultaneous, the timing between the multiple doses may be any duration of time ranging from a few minutes to four weeks.

Thus, in another aspect, the present invention provides methods for treating protein kinase- mediated disorders in a human or animal subject in need of such treatment comprising administering to said subject an amount of a compound of the present invention effective to reduce or prevent said disorder in the subject in combination with at least one additional agent for the treatment of said disorder that is known in the art. In a related aspect, the present invention provides therapeutic compositions comprising at least one compound of the present invention in combination with one or more additional agents for the treatment of protein kinase-mediated disorders.

Diseases or disorders in which B-Raf kinase plays a role, include, without limitation: oncologic, hematologic, immunologic, dermatologic and ophthalmologic diseases.

Autoimmune diseases which may be prevented or treated include, without limitation: osteoarthritis, spondyloarthropathies, systemic lupus nephritis, rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, Crohn's disease, multiple sclerosis, diabetes, glomerulonephritis, systemic lupus erythematosus, scleroderma, chronic thyroiditis, Grave's disease, hemolytic anemia, autoimmune gastritis, autoimmune neutropenia, thrombocytopenia, chronic active hepatitis, myasttienia gravis, atopic dermatitis, graft vs. host disease, or psoriasis. The invention further extends to the particular autoimmune disease rheumatoid arthritis. Hematopoiesis diseases which may be treated or prevented include, myelodysplastic disorders

(MDS), and myeloproliferative disorders (polycythemia vera, myelofibrosis and essential thrombocythemia), sickle cell anemia.

Dermatologic diseases which may be treated or prevented include, without limitation, melanoma, basel cell carcinoma, squamous cell carcinoma, and other non-epithelial skin cancer as well as psoriasis and persistent itch, and other diseases related to skin and skin structure, may be treated or prevented with p38 inhibitors of this invention.

Ophthalmologic dieases which may be treated or prevented include, without limitation, dry eye (including Sjogren's syndrome), macular degeneration, closed and wide angle glaucoma, inflammation, and pain of the eye. Hematological and non-hcmatological malignancies which may be treated or prevented include but are not limited to multiple myeloma, acute and chronic leukemias including Acute Lymphocytic Leukemia (ALL), Chronic Lymphocytic Leukemia (CLL), and Chronic Myelogenous Leukemia(CLL), lymphomas, including Hodgkin's lymphoma and non-Hodgkiα's lymphoma (low, intermediate, and high grade), malignancies of the brain, head and neck, breast, lung, reproductive tract, upper digestive tract, pancreas, liver, renal, bladder, prostate and colorectal.

Besides being useful for human treatment, the compounds and formulations of the present invention are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs, and cats. AU references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.

GENERAL SYNTHETIC METHODS FOR PREPARING COMPOUNDS The following scheme can be used to practice the present invention.

Scheme I

V^N

Example 1 can be synthesized using the general synthetic procedures set forth in Scheme I.

The invention is further illustrated by the following example. EXAMPLE 1 l-(3-(3-(lH-Imidazol-l-yl)-l,2,4-thiadiazoI-5-yloxy)phenyl)-3-(4-chloro-3- (trifluoromethyl)phenyl)urea

Ci₃C-S-Ci -

Step 1:

Preparation of example Ia: S-ChIoro-[l,2,4]thiadiazol-3-ylamine.

A solution of NaOH (43 g, 1.08 mmol) and water (43 mL) was added dropwise to a mixture tricHoromethanesulfonyl chloride (20.0 g, 107 mmol), guanidine hydrochloride (10.2 g, 107 mmol) and DCM (200 mL) while maintaining an internal temperature of -10 ⁰C to -20 ⁰C. The reaction was stirred at -10 ⁰C for 3 h prior to warming to room temperature and stirring for 12 h. The resulting suspension was filtered through celite and the filtrate was transferred to a separatory funnel. The phases were separated and the aqueous layer was back extracted with DCM (100 mL). The combined organic layers were concentrated and the product was purified by flash chromatography (0-10% MeOH/DCM) to give 2.15 g (4%) of 5-chloro-[l,2,4]thiadiazol-3-ylarnine (Ia). [M+H]⁺ 136.46. Step 2:

Preparation of example Ib: 5-ChIoiO-3-imidazoI-l-yI-[l,2,4]thiadiazoIe.

A mixture of 5-chloro-[l,2,4]thiadiazol-3-ylamine (1.00 g, 7.40 mmol), glyoxal 40% wt (5.35 g, 92.0 mmol) and ethanol (100 mL) were heated to 80°C for 4 hours. Ammonium chloride (1.97 g, 37.0 mmol), formaldehyde (2.97 g, 37.0 mmol) and phosphoric acid (2.97 g, 30.0 mmol) were added and the reaction mixture was stirred at 80⁰C for 14 hours. The mixture was cooled to room temperature and concentrated under vacuum. Water (50 mL) was added and the solution was washed with ethyl acetate (2 x 50 mL). The aqueous layer was brought to pH 8 with IM NaOH and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were concentrated under vacuum to give 200 mg (20%) of 5- chloro-3-imidazol-l-yl-[l,2,4]thiadiazole (lb). [M+H]⁺ 187.59.

Step 3:

Preparation of example Ic: [3-(3-Imidazol-l-yI-[l,2,4]thiadiazol-5-yIoxy)-phenyl]-carbamic acid tert-butyl ester. Sodium /-butoxidc (230 mg, 2.39 mmol) was added to a solution of tø^-butyl A- hydroxyphenylcarbamate (500 mg, 2.39 mmol) in DMSO (8.00 mL) at room temperature under nitrogen. The reaction mixture was stirred for 1 h prior to the addition of 5-chloro-3-imidazol-l-yl- [l,2,4]thiadiazole (447 mg, 2.39 mmol). The resulting solution was stirred at room temperature for 1 h. Water (20 mL) and ethyl acetate (100 mL) were added and the phases were separated. The aqueous phase was back extracted with ethyl acetate (2 x 100 mL) and the combined organic layers were concentrated under vacuum. The product was purified using column chromatography (1:1 to 9:1 ethyl acetate/hexanes) to give 310 mg of [3-(3-imidazol-l-yl-[l,2,4]thiadiazol-5-yloxy)-phenyl]-carbamic acid tert-butyl ester (Ic) as a white solid. [M+H]⁺ 360.11.

Step 4:

Preparation of example Id: 3-(3-ImidazoI-l-yl-[l,2,4]thiadiazol-5-yloxy)-phenyIamine.

A mixture of [3-(3-imidazol-l-yl-[l,2,4]thiadiazol-5-yloxy)-phenyl]-carbamic acid tert-butyl ester (310 mg, 0.863 mmol), DCM (1 mL) and 2,2,2-trifluoroacetic acid (1 mL) was stirred at room temperature for 1 h under nitrogen. The solution was concentrated under vacuum prior to the addition of H₂O (50 mL). The pH was adjusted to 7-8 with NaHCO₃ (5 mL of a saturated aqueous solution) and the resulting precipitate was collected by vacuum filtration to give 229 mg of 3-(3-imidazol-l-yl-[l,2,4]thiadiazol-5- yloxy)-phenylamine (Id) as a white solid. [M+H]⁺ 260.17.

Step 5: Preparation of example 1: l-(4-Chloro-3-trifluoromethyI-phenyl)-3-[3-(3-imidazol-l-yI- [l,2,4]thiadiazol-5-yIoxy)-phenyl]-urea.

A mixture of 3-(3-imidazol-l-yl-[l,2,4]thiadiazol-5-yloxy)-phenylamine (221 mg, 852 μmol), 4-chloro- 3-trifluoromethylphenylisocyanate (189 mg, 852 μmol) and DCM (4 mL) was stirred at room temperature for 1 h under nitrogen. The resulting precipitate was collected by vacuum filtration to give 220 mg of l-(4-chloro-3-trifluoromethyl-phenyl)-3-[3-(3-imidazol-l-yl-[l,2,4]tMadiazol-5-yloxy)- phenyl]-urea (1) as a white solid. [M+H]⁺ 480.64; ¹H NMR (400MHz, DMSO) δ 9.31 (s, IH), 9.26 (s, IH), 8.37 (d, IH), 8.09 (d, IH), 7.82 (t, IH), 7.79 (t, IH), 7.66-7.58 (m, 2H), 7.49 (t, IH), 7.42 (dd, IH), 7.21 (dd, IH), 7.13 (m, IH).

The following compounds can generally be made using the methods described above. It is expected that these compounds when made will have activity similar to those that have been made in the examples above. The following compounds are represented herein using the Simplified Molecular Input Line Entry System, or SMILES. SMILES is a modern chemical notation system, developed by David Weininger and Daylight Chemical Information Systems, Inc., that is built into all major commercial chemical structure drawing software packages. Software is not needed to interpret SMILES text strings, and an explanation of how to translate SMILES into structures can be found in Weininger, D., J. Chem. Inf. Comput. ScL 1988, 28, 31-36. All IUPAC names and SMILES strings herein were generated using CambridgcSoft's ChcmDraw 10.0.

O=C(NC1=CC=C(C1)C(C(F)(F)F)=C1)NC(C=C2)=CC=C2OC3=CC(C4=NN=CO4)=NS3

O=C(NC1=CC=C(F)C=C1)NC(C=C2)=CC=C2OC3=CC(C4=NC=CO4)=NS3

O=C(NC1=C(F)C(F)=CC(F)=C1F)NC(C=C2)=CC=C2OC3=CC(C4=NOC=N4)=NS3 O=C(NC1=CC=CC(N(C)C)=C1)NC(C=C2)=CC=C2OC3=CC(C4=NC=NO4)=NS3 O=C(NC1=CC=CC=N1)NC(C=C2)=CC=C2OC3=CC(C4=COC=N4)=NS3 O=C(NC1=CC=NC=C1)NC(C=C2)=CC=C2OC3=CC(C4=CC=NO4)=NS3 O=C(NC1=CC=NC=N1)NC(C=C2)=CC=C2OC3=CC(C4=CN=CO4)=NS3 O=C(NC1=CC=CC=C1)NC(N=C2)=NC=C2OC3=CC(C4=NOC=C4)=NS3 O=C(NCl=CC=C(Br)C=Cl)NC(C=C2)=NN=C2OC3=CC(N4N=CN=C4)=NS3 O=C(NC1-CC=C(OC)C=C1)NC(N=C2)=CN=C2OC3=CC(N4C=CN=C4)=NS3 O=C(NC1=CC=CC(S(C)(=O)=O)=C1)NC(C=N2)=CN=C2OC3=CC(C4=NOC=N4)=NS3 O=C(NC1=CC=C(C1)C=C1C1)NC(C=C2)=CC=C2OC3=CC(C4=NN=CS4)=NS3 O=C(NC1=CC=C(C1)C(C(F)(F)F)=C1)NC(C=C2)=€C=C2OC3=NC(C4=NN=CO4)=NS3 O=C(NC1=CC=C(F)C=C1)NC(C=C2)=CC=C2OC3=NC(C4=NC=CO4)=NS3

O=C(NC1=C(F)C(F)=CC(F)=C1F)NC(C=C2)=CC=C2OC3=NC(C4=NOC=N4)=NS3 O=C(NC1=CC=CC(N(C)C)=C1)NC(C=C2)=CC=C2OC3=NC(C4=NC=NO4)=NS3 O=C(NC1=CC=CC=N1)NC(C=C2)=CC=C2OC3=NC(C4=COC=N4)=NS3 O=C(NC1=CC=NC=C1)NC(C=C2)=CC=C2OC3=NC(C4=CC=NO4)=NS3 O=C(NC1=CC=NC=N1)NC(C=C2)=CC=C2OC3=NC(C4=CN=CO4)=NS3 O=C(NC1=CC=CC=C1)NC(N=C2)=NC=C2OC3=NC(C4=NOC=C4)=NS3 O=C(NCl=CC=C(Br)C=Cl)NC(C=C2)=NN=C2OC3=NC(N4N=CN=C4)=NS3 O=C(NC1=CC=C(OC)C=C1)NC(N=C2)=CN=C2OC3=NC(N4C=CN=C4)=NS3 O=C(NC1=CC=CC(S(C)(=O)=O)=C1)NC(C=N2)=CN=C2OC3=NC(C4=NOC=N4)=NS3 O=C(NC1=CC=C(C1)C=C1C1)NC(C=C2)=CC=C2OC3=NC(C4=NN=CS4)=NS3 O=C(NC1=CC=C(C1)C(C(F)(F)F)=C1)NC(C=C2)=CC=C2OC3=CC(C4=NN=CO4)=NN3C O=C(NC1=CC=C(F)C=C1)NC(C=C2)=CC=C2OC3=CC(C4=NC=CO4)=NN3C O=C(NC1=C(F)C(F)=CC(F)=C1F)NC(C=€2)=CC=C2OC3=CC(C4=NOC=N4)=]W3C O=C(NC1=CC=CC(N(C)C)=C1)NC(C=C2)=CC=C2OC3=CC(C4=NC=NO4)=]S1N3C O=C(NC1=CC=CC=N1)NC(C=C2)=CC=C2OC3=CC(C4=COC=N4)=TSIN3C O=C(NC1=CC=NC=C1)NC(C=C2)=CC=C2OC3=CC(C4=CC=NO4)=NN3C 0=C(NC1=CC=NC=N1)NC(C=C2)=COC20C3=CC(C4=CN=C04)=NN3C O=C(NC I=CC=CC=C 1)NC(N=C2)=NC=C2OC3=CC(C4=NOC=C4)=NN3C

O=C(NCl=CC=C(Br)C=Cl)NC(C=C2)=NN=C2OC3=CC(N4N=CN=C4)=lSlN3C O=C(NC1=CC=CC(S(C)(=O)=O)=C1)NC(C=N2)=CN=C2OC3=CC(C4=NOC=N4)=NN3C O=C(NC1=CC=C(OC)C=C1)NC(N=C2)=CN=C2OC3=CC(N4C=CN=C4)=NN3C O=C(NC1=CC=C(C1)C=C1C1)NC(C=C2)=CC=C2OC3=CC(C4=NN=CS4)=NN3C

The activity of the compound in Examples 1 as a protein kinase modulator is illustrated in the following assay(s). The other compounds listed above, which have not yet been made and/or tested, are predicted to have activity in these assay(s) as well.

Biological Activity Assay

In vitro B-RafyMekl composite kinase assay

2.5μl of B-Raf kinase buffer (2OmM MOPS [pH 7.2], 25mM sodium glycerophosphate, 2mM EGTA [pH 8.0], ImM sodium orihovanadate, ImM dithiothieitol, 1OmM MgCl₂, 0.03% Brij-35, 0.3mg/ml bovine serum albumin) containing Ing of recombinant, N-terminal GST-tagged human B-Raf protein kinase (Δl-415, Upstate Inc., cat. #14-530) is dispensed to wells of a 1536 multi-well white solid plate. 60nl of IOOX concentration of test compound in DMSO is dispensed to the well by passive pin transfer and incubated for 15 minutes at room temperature (approx. 22⁰C). 2.5μl of B-Raf kinase buffer containing 12.5ng of recombinant N-terminal GST-tagged, C-terminal His6-tagged human Mekl (inactive, Upstate Inc., cat. #14-420) and 2μM ATP is then dispensed and the kinase reaction allowed to incubate at 3O⁰C for 2 hours. The assay plates are sealed and maintained in a humidified environment. After 2 hours, 2.5 μl of PKLight protein kinase assay reagent (Cambrex, cat. #LT07-501) is dispensed. After an additional 5 minute incubation at room temperature, luminescence activity is measured on a a Molecular Devices Analyst multi-mode plate reader or other suitable plate reader. Kinase inhibition results in less ATP depletion, and therefore increased luminescence signal. Negative control activity is measured with DMSO lacking any test compound. The positive control is [N-(3-trifluoromethyl-4- chlorophenyl)-N'-(4-(2-methylcarbamoyl-pyridin-4-yl)oxyplienyl)urea], aka Bay 43-9006. Efficacy is measured as a percentage of positive control activity. In vitro VEGFR2 and PDGFRβ kinase assays

2.5μl of ADP Quest assay buffer (DiscoverX Inc., cat. #90-0071) containing 20ng VEGFR2 kinase (Invitrogen Inc, cat. # PV3660) or 25ng PDGFRβ kinase (Invitrogen Inc., cat. # P3082) is dispensed to wells of a 1536 multi-well, black solid plate. 60nl of IOOX concentration of test compound in DMSO is dispensed to the well by passive pin transfer and incubated for 10 minutes at room temperature (approx. 22⁰C). 2.5μl of ADP Quest assay buffer containing 0.25μg of poly GlurTyr (4: 1) substrate peptide (Upstate Inc., cat. # 12-440) and 60μM ATP is then dispensed and the kinase reaction allowed to incubate at 3O⁰C for 2 hours. The assay plates are sealed and maintained in a humidified environment. After the 2 hour incubation, 2μl of ADP Quest assay reagent A, followed by 2μl of assay reagent B, is added. After an additional 30 minute incubation at room temperature, fluorescence intensity is measured on a Molecular Devices Aquest multi-mode plate reader or other suitable plate reader (fluorescence excitation filter: 530/25 [Peak(nm)/FWHM passband(nm)]; dichroic beamsplitter: 561nm longpass; fluorescence emission filter: 580/10 [Peak(nm)/FWHM passband(nm)]. The assay measures the conversion of a non-fluoresecent molecule to fluorescent resorufin, which correlates with kinase activity. Negative control activity is measured with DMSO lacking any test compound. The positive control is [N-(3-trifluoromethyl-4-chlorophenyl)-N'-(4-(2-methylcarbamoyl-pyridin-4-yl)oxyphenyl)urea], aka Bay 43-9006. Efficacy is measured as a percentage of positive control activity. IC₅₀ data were obtained for the compounds provided herein. Data for example 1 is shown in

Table 1 below.

From the foregoing description, one skilled in the art can easily ascertain the essential characteristics of this invention, and without departing from the spirit and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

Claims

CLAIMSWhat is claimed is:

1. A compound of structural Formula I

or a salt, ester, or prodrug thereof, wherein:

S(O)_m, O and N(R⁶); m is 0,1 or 2;

B is selected from the group consisting of-N(R⁷)C(O)N(R⁷)- and -N(R⁷)C(O)N(R⁷)CH₂-; R¹ is selected from the group consisting of amido, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, any of which may be optionally substituted;

2. A compound of structural Formula II:

or a salt, ester, or prodrug thereof, wherein:

X¹ is selected from the group consisting of C(R²)(R³), N(R²), O and S(O)_n; n is 0,1 or 2; A and C are each independently selected from the group consisting of aryl and heteroaryl, any of which may be optionally substituted;

B is selected from the group consisting of -N(R⁷)C(O)N(R⁷)- and -N(R⁷)C(O)N(R⁷)CH₂-; R¹ is selected from the group consisting of amido, aryl, heteroaryl, heterocycloalkyl and cycloalkyl, which may be optionally substituted;

T is selected from the group consisting of C(R⁴)(R⁵), S(O)_n,, O and N(R^e); m is 0,1 or 2;

R² and R³ are each independently selected from the group consisting of lower alkyl and hydrogen; R⁴ and R⁵ are each independently selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylene, alkynyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylcarbonyl, arylsulfonyl, cyanoalkenyl, cycloalkyl, haloalkyl, haloalkoxy, haloalkylcarbonyl, heteroaryl, heteroarylalkyl, heteroarylsulfonyl, heterocycloalkyl, hydrogen, hydroxyalkyl and null, any of which may be optionally substituted; R⁶ is selected from the group consisting of alkenyl, alkoxyalkyl, alkyl, alkynyl, C-amido, aminoalkyl, aryl, arylalkenyl, arylalkyl, arylalkynyl, cyanoalkenyl, cycloalkyl, haloalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, hydrogen, hydroxyalkyl and null, any of which may be optionally substituted; and

3. The compound as recited in Claim 2, wherein the compound has Formula IH:

or a salt, ester, or prod

rug thereof, wherein:

X¹ is selected from the group consisting Of-CH₂-, -NH-, O and S; R¹ is selected from the group consisting of optionally substituted amido and

I, J, K, L and M are each independently selected from the group consisting of C(R^S)(R⁹), S(O)₁, O and N(R¹⁰);

1 is 0,1 or 2; R^s and R⁹ are each independently selected from the group consisting of alkenyl, alkoxy, alkoxyalkyl, alkyl, alkynyl, amido, amidoalkyl, amino, aminoalkyl, aminoalkylamino, aryl, arylalkenyl, arylalkyl, arylalkynyl, cyano, cyanoalkyl, cyanoalkenyl, cycloalkyl, ester, esteralkyl, halo, haloalkyl, haloalkoxy, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylthio, hydrogen, hydroxy, hydroxyalkyl, nitro and null, any of which may be optionally substituted; and

R¹⁰ is selected from the group consisting of alkenyl, alkoxyalkyl, alkoxycarbonyl, alkyl, alkylamino, alkylene, alkynyl, amidoalkyl, aryl, arylalkoxy, arylalkyl, arylalkenyl, arylalkynyl, arylcarbonyl, arylsulfonyl, cyanoalkenyl, cyanoalkyl, cycloalkyl, ester, esteralkyl, haloalkyl, haloalkoxy, haloaljkylcarbonyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylsulfonyl, heterocycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl, heterocycloalkylalkoxy, heterocycloalkylalkylthio, hydrogen, hydroxyalkyl and null, any of which may be optionally substituted.

4. The compound as recited in Claim 3, wherein the compound has Formula IV:

or a salt, ester, or p

rodrug thereof, wherein:

B is selected from the group consisting Of-N(H)C(O)N(H)- and -N(H)C(O)N(H)CH₂-; R¹ is selected from the group consisting of

Q is selected from the group consisting of S(O)_P, O and N(R¹⁰); and p is 0,1 or 2.

5. A compound of Example 1.

6. A compound as recited in Claim 1 for use as a medicament.

7. A compound as recited in Claim 1 for use in the manufacture of a medicament for the prevention or treatment of a disease or condition ameliorated by the inhibition of protein kinases.

8. A pharmaceutical composition comprising a compound as recited in Claim 1 together with a pharmaceutically acceptable carrier.

9. The pharmaceutical composition as recited in Claim 8, useful for the treatment or prevention of protein kinase-mediated disease.

10. A method of inhibition of protein kinases comprising contacting said protein kinases with a compound as recited in Claim 1.

11. A method of treatment of a protein kinase-mediated disease comprising the administration of a therapeutically effective amount of a compound as recited in Claim 1 to a patient in need thereof.

12. The method as recited in Claim 11 wherein said disease is selected from the group consisting of cancers, hematological and non-hematologic malignancies, autoimmune diseases, hematopoiesis, malignancies of the skin, psoriasis, dry eye, and glaucoma.

13. A method of treatment of a B-Raf-mediated disease comprising the administration of: a. a therapeutically effective amount of a compound as recited in Claim 1 ; and b. another therapeutic agent.

14. The method as recited in Claim 13 wherein said disease is selected from the group consisting of cancers, hematological and non-hematologic malignancies, autoimmune diseases, hematopoiesis, malignancies of the skin, psoriasis, dry eye, and glaucoma.