AU2012244331A1 - Heterocyclic compounds and methods of use - Google Patents

Abstract

Heterocyclic compounds derived from benzotriazine, triazines, triazoles and oxadiazoles are disclosed. The methods of synthesis and of use of such heterocyclic compounds are also provided.

Description

P=OI1 11 Regulaon 3.2 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Invention Title: Heterocyclic compounds and methods of use The following statement is a full description of this invention, including the best method of performing it known to us: 1A HETEROCYCLIC COMPOUNDS AND METHODS OF USE CROSS REFERENCE TO RELATED APPLICATIONS [00011 This application claims the benefit of priority under 35 U.S.C. § 119(e) of patent applications U.S. Serial Number 60/604,298 filed August 25, 2004, and 60/696,168 filed July 1, 5 2005, the entire content of which is incorporated herein by reference. FIELD OF THE INVENTION 100021 The present invention relates generally to the use of compounds to treat a variety of disorders, diseases and pathologic conditions and more specifically to the use of various heterocyclic compounds for therapeutic purposes. 10 BACKGROUND [00031 Kinases are a large family of cellular proteins involved in signal transduction of cascades which control cell growth and death, survival, migration, differentiation, gene expression, metabolism, protein synthesis and cell cycle regulation. A common mechanism by which these signals are transmitted is reversible phosphorylation, which induces conformational changes in 15 these enzymes and alters their structure and function. The entire kinase genome discovered so far incorporates over 500 individual proteins and their isoforms. Different branches of this genomic tree have been characterized into groups specific for phosphorylating either serine/threonine residues or tyrosines. Some kinases exhibit dual specificity, capable of substrate phosphorylation of tyrosine as well as serine/threonines. Further differentiation can be made in terms of their 20 location in cells. Transmembrane receptor protein kinases exhibit an extracellular domain, capable of ligand binding. These ligand binding mechanisms trigger activation of the kinase catalytic domain which initiates a cascade of signals that controls intracellular functions. Examples of a receptor protein kinase are growth factors such as EGF, FGF, PDGF and IGF. Nonreceptor protein kinases can be found in many compartments of a cell from inner-cell 25 surface membranes to the cell nucleus. One example of a nonreceptor protein kinase is the mitogen activated protein kinase (MAPK) which regulates a pathway, which is important in cell signaling initiated on the exterior cell surfaces via growth factors, for example, VEGF, or hormones, and extending to the cell nucleus by activating transcription factors. These nuclear factors in turn control gene expression in the regulation of cell cycle progression and ultimately 30 cell proliferation, and differentiation.

2 [00041 The MAPK cell signaling pathway is important for drug targeting as this path impinges on nearly all functional hallmarks of cancer cells such as immortalization, growth factor independent proliferation, insensitivity to growth inhibitory signals, metastasis, blood vessel attraction, evasion of apoptosis, and other functional hallmarks. Inappropriate activation though 5 mutation of this molecule is associated with nearly 30% of all human cancers. In general, the inhibition of disregulated kinases such as Ras, PBK and Raf is an important approach to discover novel treatments for cancer and other diseases. One approach is the discovery of small molecules capable of binding either to the kinase catalytic domain or a regulatory domain in order to modulate the function of protein kinases. Important in this respect is to discover molecules which 10 inhibit a specific signaling path with a high degree of selectivity and a potency within a practical therapeutic window. While significant progress has been made in developing various compounds for the treatment of cancer and inflammatory diseases, there remains a need for specific chemical structures capable of modulating protein kinases, whose disregulated function has been implicated in these diseases. 15 SUMMARY OF THE INVENTION 10004a] Reference to any prior art in the specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other jurisdiction or that this prior art could reasonably be expected to be ascertained, understood and regarded as relevant by a person skilled in the art. 20 [0004b] As used herein, except where the context requires otherwise the term 'comprise' and variations of the term, such as 'comprising', 'comprises' and 'comprised', are not intended to exclude other additives, components, integers or steps. [00051 The present invention provides compounds which affect the MAPK pathway. The compounds of the invention are useful as pharmaceutical compositions, for example where 25 modulation of the MAPK pathway is indicated for the treatment of various human diseases, such as cancer. [00061 According to one embodiment of the invention, compounds having the structure (A) are provided, or an N-oxide, N,N'-dioxide, N,N',N"-trioxide, or a pharmaceutically acceptable salt thereof: 2a R 3 (A) wherein Y can be absent or can be one of the following moieties: 3 H ? H H/ [00071 According to another embodiment of the invention, compounds having the structure (B) are provided, or an N-oxide, N,N'-dioxide, N,N',N"-trioxide, or a pharmaceutically acceptable salt thereof: 2 1 3 3 (B) wherein X can be absent or can be NH, and Y can be absent or can be one of the following moieties: H/ H H [00081 In compounds having structure (B), each of Z 1 , Z 2 and Z 3 can be, independently, N, N=CH, CH, 0, S or N-R 4 , wherein R 4 is hydrogen or lower alkyl, with the further proviso that at least one of Z 1 , Z 2 and Z 3 is not CH. [00091 In compounds having structure (A), the substitutent R, can be an aryl, a substituted aryl, a heterocycle, a heteroaryl, a substituted heterocycle, and a substituted heteroaryl. For example, R, can be one of CG-Cu aryl; C 3

-C

12 heteroaryl having 1-3 heteroatoms such as N, S and 0; substituted C 3

-C

1 o cycloalkyl having 0-3 heteroatoms such as N, S, and 0; substituted

C

6

-C

12 aryl; substituted C 3

-C

12 heteroaryl having 1-3 heteroatoms such as N, S and 0; C-C 24 aralkyl; CrC24 alkylaryl; substituted CrC24 aralkyl; and substituted C-C 24 alkaryl. [00101 In compounds having structure (B), the substitutent R, can be, independently of the substitutent R, present in the structure (A), an unsubstituted or a substituted C 3 -Ci2 heteroaryl having 1-3 heteroatoms such as N, S or 0. The substituent R, that can be present in compounds having structure (B), can include a substituted pyridyl group. The substituents in the substituted pyridyl group can include an amido moiety, an aminoalkyl group (e.g., aminomethyl), or a carboxyl group, or a carboxylate group. The amido moiety attached to the pyridyl group can be in turn also substituted by attaching to the nitrogen in the amido 4 moiety a substitutent selected from an alkyl (e.g., methyl), an alkylaminoalkyl (e.g., diethylamino alkyl), a pyridyl, an alkyl pyrrolidine, an alkyl morpholine, and an alkyl piperazine groups. [0011] Some examples of the substitutent R, that can be present in compounds having either structure (A) or structure (B), can be selected from one of the following moieties: HMe Me 2

H

2 H H H I H j H n nn n Me H n H O, Me 64~ 6 1 6 'NH 2 16 'NH 2

H

2 I&..H2 H 2 N H 2 N N N H2u- H2N! H2 H2 MeS H2 H2W6 Me HMe Me 2

H

2 HMe Me 2

H

2 H H H H,22 2 N HH H n n-r n N H N H N H 6 H 1 N H N H H H2H 2 H2N -H I-I n H Hn

NH

2 HH H n H

H

2 &Rl H Hn H n 6- n & n 6 Me .- Me - H H H H H -Me .- Me H .- H H H H, where n can be an integer selected from a group consisting of 0, 1, 2, and 3. [00121 In compounds having structure (A) or (B), R 2 can be, independently, any one of hydrogen, halogen, C-Cis alkyl (e.g., methyl), -OH, -NO 2 , -CN, CrCis alkoxy (e.g., methoxy), -NHSO 2

R

5 , -SO 2 NHR5, -NHCOR, -NH 2 , -NR R 6 , -S(O)R', -S(O) 2

R

5 , -CO 2 R5, CONRR , and where R 5 and R 6 are independently selected from hydrogen, a C 1

-C

1 2 alkyl and a substituted CI-C 12 alkyl. [00131 In compounds having structure (A), the substituent R 3 can be an aryl, a substituted aryl, a heterocycle, a heteroaryl, a substituted heterocycle, and a substituted heteroaryl. For example, R 3 can be one of C 6

-C

12 aryl; C 3 -C2 heteroaryl having 1-3 heteroatoms such as N, S and 0; substituted C 3 -Cio cycloalkyl having 0-3 heteroatoms such as N, S, and 0; substituted

C

6

-C

12 aryl; substituted C 3 -Ciz heteroaryl having 1-3 heteroatoms such as N, S and 0; C 7

-C

24 aralkyl; C 7

-C

24 alkylaryl; substituted C 7

-C

2 4 aralkyl; and substituted C 7

-C

2 4 alkaryl. [00141 In compounds having structure (B), the substitutent R 3 can be, independently of the substitutent R 3 present in the structure (A), hydrogen, a Cl-Cis alkyl, a substituted CrCis alkyl, a C 1

-C

1 2 cycloalkyl, a substituted CI-C 12 cycloalkyl, a substituted C 3

-C

10 cycloalkyl having 0-3 heteroatoms such as N, S, or 0, an aryl such as a C 6

-C

12 aryl, a substituted aryl such as a substituted C 6

-C

1 2 aryl, a heterocycle, a substituted heterocycle, a heteroaryl such as a C 3

-C,

2 heteroaryl having 1-3 heteroatoms such as N, S or 0, a substituted heteroaryl such as substituted C 3

-C

12 heteroaryl having 1-3 heteroatoms such as N, S or 0, a CrC 2 4 aralkyl, a substituted C 7

-C

24 aralkyl, a C 7

-C

24 alkylaryl, and a substituted C 7

-C

24 alkaryl. Some particular examples of the substituent R 3 than can be used include tert-butyl phenyl, trifluoromethoxyphenyl, methoxyphenyl, dimethylaminophenyl, aminophenyl, trifluoroethoxyphenyl, trifluoromethoxychlorophenyl, trifluoromethoxybromophenyl, trifluoroethoxychlorophenyl, chlorophenyl, dichlorophenyl, trifluoromethyl phenyl, 7 trifluoromethylchlorophenyl, chlorotoluyl, N-phenylacetamide, N,N-alkyl-benzamide, isopropoxyphenyl, alkoxyphenyl, dialkoxyphenyl, or acetylphenyl. {00151 To summarize, some examples of the substitutent R 3 that can be present in compounds having either structure (A) or structure (B), can be selected from one of the following moieties: F3CF3 F3 6 CF 36 ,1 eCF C F 3 Me I r e F 3 MMe2 - I I Mez Me2 F3 F3 F3 8 L e Me 2 r

CF

3

CF

3 qCF, CF CF CF 3 - CF 3 . r e Me 2

F

3

F

3

F

3

F

3

F

3

F

3

F

3 I F 3

'CF

3

F

3

I~F

3

F

3 Z'N Me H HH

F

3 HH I H C , 6;CF 3 H H H H

H

n9 H (H (H (MV HH H (f f n ( n (

H

10 N N N N N N I I (fl (N (II (fl (ft (ft (ft HY N N N N N N N I I I I I I o Q Q y N N N N N N 1 I I I I R )~ R R R )~ R )~ R C Q N N N N N R R R R R N~N H N N N N N N I I I I I R R )~ R R R )~ R H N N N N N N R R )~ R R R )~ R

H

11 [00161 According to another embodiment of the invention, compounds that are derivatives of benzotriazine are provided, the compounds including a benzotriazine moiety having at least a first substituent attached to the benzene ring of benzotriazine and a second substituent attached to the triazine ring of the benzotriazine, where the first substituent includes a substituted pyridyl group, and the second substituent includes a secondary amino group, a substituted aide group, or a substituted sulfonylamino group. [00171 According to yet another embodiment of the invention, compounds including a benzene-derived moiety bridged to a heterocyclic moiety are provided, where the benzene derived moiety includes a molecule of benzene substituted with either a sulfonyl group or a pyridyl group connected to the benzene molecule via an oxygen link, and the heterocyclic moiety includes triazole, oxadiazole, oxazole, pyrazol, imidazole, thiadiazole and triazine. 100181 According to yet another embodiment, articles of manufacture are provided, the articles including packaging material and a pharmaceutical composition contained within the packaging material, wherein the packaging material includes a label which indicates that the pharmaceutical composition can be used for treatment of disorders associated with cancer. The pharmaceutical composition can include at least one compound set forth in Structures (A) and (B) or any combination thereof. 100191 According to another embodiment, a method for treating a disorder including administering to a subject in need thereof an effective amount of a compound, wherein the compound is set forth in Structures (A) and (B) or any combination thereof. [00201 In one aspect, the disorder is cancer, eye disease, inflammation, psoriasis, or a viral infection, for example. More particularly, the cancer is an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer. [00211 According to yet another embodiment, a pharmaceutical composition is provided, at least one compound set forth in structures (A) and (B) or any combination thereof, in a pharmaceutically acceptable carrier.

12 BRIEF DESCRIPTION OF THE DRAWINGS [00221 FIG. 1 shows the results of the Rafl direct assay of invention compounds [00231 FIG. 2 shows the results of XTT cell viability assay of invention compounds DETAILED DESCRIPTION OF THE INVENTION [00241 The present invention is directed to heterocyclic compounds, sr as heterocyclic compounds derived from benzotriazine, triazines, triazoles, oxadiazoles, umazoles and thiadiazole and to use of the heterocyclic compounds for therapeutic purposes. [00251 The following terminology and definitions apply as used in the present application, generally in conformity with the terminology recommended by the International Union of Pure and Applied Chemistry (IUPAC). [0026] The term "heterocyclic," when used to describe an aromatic ring, means that the aromatic ring contains at least one heteroatom. The abbreviation "Het" is sometimes used to signify a heterocyclic structure. [00271 The term "heteroatom" is defined to include any atom other than carbon, for example, N, 0, or S. 100281 The term "aromatic" or "aryl" is defined to include a cyclically conjugated molecular entity with a stability, due to delocalization, significantly greater than that of a hypothetical localized structure, such as the Kekul6 structure. [00291 The term "heterocyclic," when not used to describe an aromatic ring, is defined to include cyclic (i.e., ring-containing) groups other than aromatic groups, the cyclic group being formed by between 3 and about 14 carbon atoms and at least one heteroatom described above. [00301 The term "substituted heterocyclic" is defined to include both aromatic and non aromatic structures to heterocyclic groups further bearing one or more substituents described above. [00311 The term alkyll" is defined to include a monovalent straight or branched chain hydrocarbon group having from one to about 12 carbon atoms, for example, methyl, ethyl, n propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, n-pentyl (also known as n-amyl), n-hexyl, 13 and the like. The abbreviations "Me" and "Et" stand for the methyl and ethyl groups, respectively. 100321 The term "aralkyl" refers to an aryl or heteroaryl group, as defined herein, attached through a CI-C6 alkyl linker. Examples of "aralkyl" include, but are not limited to, benzyl, phenylpropyl, 2-pyridylmethyl, 3-isoxazolylmethyl, 2-imidazolylethyl. [00331 The term "methoxy" is defined as the group -OCH 3 . [00341 The term "halogen" is defined to include an atom of fluorine, chlorine, bromine or iodine. 100351 The term carboxyll" or "carboxyl group" is defined as an acid moiety having the structure -COOH. 100361 The term "amino" or "amino group" is defined to include moieties -NRR', where each of R and R' is hydrogen ("primary amino"), or one of them is an organic radical ("secondary amino"), or each is an organic radical ("tertiary amino"). [00371 The term "aminoalkyl" or "aminoalkyl group" is defined to include moieties -R-N(R'R"), wherein R is an organic radical and each of R' and R" is hydrogen or an organic radical. If at least one of R' and R" is an organic radical, the moiety is defined as "alkylaminoalkyl" or "alkylaminoalkyl group." 100381 The term "sulfonyl" or "sulfonyl group" is defined to include moieties that comprise structure (S), in which R is an organic radical: (S) [00391 The term "sulfonylainino" or "sulfonylamino group" is defined to include moieties that comprise structure (SA), in which R is an organic radical: (Sa) 14 [00401 The term "amide," or "amido," or "amide group," or "amido group" is defined to include moieties containing at least one acyl group >C=O attached to nitrogen. The term "substituted amide" is defined to include moieties containing a structure RNH-CO-, in which R is an organic radical. [00411 The term "phenyl" is defined to include moieties having structure (Ph): 6 (Ph) [00421 The term "toluyl" is defined to include moieties having structure (Tl): (TI) [00431 The term "heteroaryl" is defined to include aromatic rings, where the ring structure is formed by between 3 and about 14 carbon atoms and by at least one heteroatom described above, and the term "substituted heteroaryl" refers to heteroaryl groups further beating one or more substituents described above. [00441 The term "triazine" is defined to include moieties containing the aromatic 6 member heterocycle having three atoms of nitrogen in the ring. Two examples of such heterocycle are shown as the following structures (Tr): or (Tr) [00451 The term "benzotriazine" is defined to include moieties containing a heterocyclic structure in which the triazine ring is fused with the benzene ring, as shown by structure (BTr): 15 {00461 (BTr) 100471 The terms "N-oxide," "N,N'-dioxide," and "N,N',N"-trioxide" are defined to include nitrogen-containing heterocyclic moieties in which at least one nitrogen atom is associated with oxygen to form the structures N-0. The heterocyclic moiety can be any nitrogen-containing heterocycle, for example, benzotriazine, triazine, pyridine, pyrimidine, etc. Where the heterocyclic structure is benzotriazine, for example, some N-oxides or dioxides can be described as the following structures: 100481 The term "pteridine" is defined to include moieties containing a heterocyclic structure having two fused 6-member rings, each ring containing two atoms of nitrogen, as shown by structure (PTr): (PTr) {00491 The term "pyridazine" is defined to include moieties containing the aromatic 6 member heterocycle having two atoms of nitrogen in the ring in ortho position, as shown by the structure (PAz): 0 (PAz) 100501 The term "pyrimidine" is defined to include moieties containing the aromatic 6 member heterocycle having two atoms of nitrogen in the ring in mneta position, as shown by the structure (PRm): 16 (PRm) [0051] The term "thiadiazole" is defined to include moieties containing the aromatic 5 member thiophene-based heterocycle, having two atoms of nitrogen and one atom of sulfur, as shown by the structure (TDa): (TDa) [00521 The tern "pyridyl" is defined to include moieties containing a radical derived from pyridine. One structure of pyridyl is shown as the structure (Py): (Py) [00531 The term "alkyl pyrrolidine" is defined to include moieties containing a radical derived from pyrrolidine (a 5-member saturated heterocycle having one nitrogen atom), where an alkylene group R is attached to the nitrogen atom of the pyrrolidine ring. One structure of alkyl pyrrolidine is shown as the structure (APy): (APy) [00541 The term "alkyl morpholine" is defined to include moieties containing a radical derived from morholine, (a 6-member saturated heterocycle having one nitrogen atom and one oxygen atom), where an alkylene group R is attached to the nitrogen atom of the morpholine ring. One structure of alkyl morpholine is shown as the structure (AMr): 17 (AMr) [00551 The term "alkyl piperazine" is defined to include moieties containing a radical derived from piperazine (a 6-member saturated heterocycle having two nitrogen atoms), where an alcylene group R is attached to one nitrogen atom of the piperazine ring. One structure of alkyl piperazine is shown as the structure (APi): (APi) 100561 The term "isoxazole" is defined to include moieties containing the aromatic 5 member heterocycle, having one atoms of nitrogen and one atom of oxygen, as shown by the structure (ISo): (Iso) [00571 The term "hydrophobic" is defined as a group or structure free of strongly polar groups such as -OH, -COOH,

-NH

2 , -NH-CO-, halogens, or the like. [00581 The term "kinase" is defined to include any enzyme that catalyzes the addition of phosphate groups to a protein residue; for example, seine and threonine kinases catalyze the addition of phosphate groups to seine and threonine residues. 100591 The term "therapeutically effective amount" is defined as the amount of the compound or pharmaceutical composition that will elicit the biological or medical response of a tissue, system, animal or human that is being sought by the researcher, veterinarian, medical doctor or other clinician, e.g., restoration or maintenance of vasculostasis or 18 prevention of the compromise or loss or vasculostasis; reduction of tumor burden; reduction of morbidity and/or mortality. [00601 The term "pharmaceutically acceptable" is defined as a carrier, whether diluent or excipient, that is compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. [00611 The terms "administration of a compound" or "administering a compound" is defined to include an act of providing a compound of the invention or pharmaceutical composition to the subject in need of treatment. [0062] According to embodiments of the present invention, two types of heterocyclic compounds are provided for treatment of various diseases, disorders, and pathologies, including cancer. The heterocyclic compounds of the invention can inhibit the activity of a kinase, such as any kinase in the MAPK signaling pathway. [00631 According to an embodiment of the invention, a first type of compounds is provided for treatment of various diseases, disorders, and pathologies, including cancer. The first type of compounds can include derivatives of benzotriazine. The derivatives of benzotriazine that can be used can comprise the compounds that include a benzotriazine moiety having at least one substituent attached to the benzene ring of benzotriazine and a at least one substituent attached to the triazine ring of the benzotriazine, and an N-oxide, N,N' dioxide, N,N',N"-trioxide, or pharmaceutically acceptable salts thereof. [00641 A substituent attached to the benzene ring of benzotriazine can include a substituted pyridyl group. The substituents in the substituted pyridyl group can include an amido moiety, an aminoalkyl group (e.g., aminomethyl), or a carboxyl group, or a carboxylate group. The amido moiety attached to the pyridyl group can be in turn also substituted by attaching to the nitrogen in the amido moiety a substituent selected from an alkyl (e.g., methyl), an alkylaminoalkyl (e.g., diethylamino alkyl), a pyridyl, an alkyl pyrrolidine, an alkyl morpholine, and an alkyl piperazine groups. [00651 Optionally, the benzene ring of the compounds of the first type can contain a second substituent located in any available position of the ring, for example, methyl, halogen or methoxy. Some particular examples of benzene-ring containing moieties that can be used include tert-butyl phenyl, trifluoromethoxyphenyl, methoxyphenyl, dimethylamino, dimethylaminophenyl, aminophenyl, trifluoroethoxyphenyl, trifluoromethoxychlorophenyl,

O

19 trifluoromethoxybromophenyl, trifluoroethoxychlorophenyl, chlorophenyl, dichlorophenyl, trifluoromethyl phenyl, trifluoromethylchloro phenyl, chlorotoluyl, N-phenylacetamide,

N,N

alkyl-benzamide, isopropoxyphenyl, alkoxyphenyl, dialkoxyphenyl, acetylphenyl. (00661 A substituent attached to the triazine ring of benzotriazine in the compounds of the first type can include a secondary amino group, a substituted amide group, or a substituted sulfonylamino group; each of these groups can further contain a moiety derived from benzene, thiophene, or isoxazole. If the substituent attached to the triazine ring of benzotriazine in the compounds of the first type is a secondary amino group, the moiety derived from benzene, thiophene, or isoxazole can be attached to the nitrogen of the secondary amino group. If the substituent in the triazine ring is a substituted amide group or the substituted sulfonylamino group, the moiety derived from benzene, thiophene, or isoxazole can be attached via the acyl group or the sulfonyl group, respectively. Moieties derived from benzene, thiophene, or isoxazole can further include alkyls, e.g., t-butyl phenyl, chlorophenyl, dichlorophenyl, trifluoromethyl phenyl, trifluoromethylchloro phenyl, and chlorotoluyl. [00671 Compounds of the first type can be described as compounds having the general structure (A), and an N-oxide, NN'-dioxide, N,N',N"-trioxide, or a pharmaceutically acceptable salt thereof The general structure (A) is as follows: R 'bR (A) wherein Y can be absent or can be one of the following moieties: HH (00681 In structure (A), R, can be an aryl, a substituted aryl, a heterocycle, a heteroaryl, a substituted heterocycle, and a substituted heteroaryl, such as C 6

-C

12 aryl; C 3

-C

12 heteroaryl having 1-3 heteroatoms such as N, S and 0; substituted C 3 -CIO cycloalkyl having 0-3 heteroatoms such as N, S, and 0; substituted C 6

-C

12 aryl; substituted C 3 -Ca heteroaryl 20 having 1-3 heteroatoms such as N, S and 0; C7-C24 aralkyl; C7-C24 alkylaryl; substituted C7 C24 aralkyl; and substituted C7-C24 alkaryl. In particular, Ri can be any one of the following moieties: HMe 2 H 2 H I I H I H H WR I R Me H a HH2 H H2 H H Me nn u 6 H 2 N, H 2 W, %H 2

H

2 MeS, H 2

H

2 W Me HMe Me2 H 2 HMe Me 2 - r H H H H H22 ~2 21 H H H HH H&H nn n n 6 H H H H N H2N

H

2

HH

2 H H 2 H Hr( r Hn Ho H H H H n H Hn H n H n 22 Me - Me - H H H H H Me ... Me H H H H H, where n can be an integer selected from a group consisting of 0., 1, 2, and 3. [00691 In structure (A), the substituent R 2 can be any one of hydrogen, halogen, Ci-C 18 alkyl (e.g., methyl), -OH, -NO 2 , -CN, CI-Cs alkoxy (e.g., methoxy), -NHSO 2

R

5 , -SO 2 NHR,

-NHCOR

5 , -NH 2 , -NR , -S(O)R, -S(O) 2 R5, -CO 2

R

5 , -CONRR 6 , and where R 5 and R6 are independently selected from hydrogen, a Ci-C 12 alkyl and a substituted Ci-Cj 2 alkyl. [00701 In structure (A), group R 3 can be an aryl, a substituted aryl, a heterocycle, a heteroaryl, a substituted heterocycle, and a substituted heteroaryl. For example, R 3 can be one of C 6

-C

12 aryl; C 3

-C

12 heteroaryl having 1-3 heteroatoms such as N, S and 0; substituted

C

3

-C

10 cycloalkyl having 0-3 heteroatoms such as N, S, and 0; substituted C 6

-C

12 aryl; substituted C 3

-C

12 heteroaryl having 1-3 heteroatoms such as N, S and 0; C 7

-C

2 4 aralkyl; C

C

2 4 aikylaryl; substituted C 7

-C

24 aralkyl; and substituted CrC24 alkaryl. In particular, the substitutent R 3 can be one of the following: NZN 091 CF3 F 3 6 5 N F3 6 'C1 CF3

OCF

3 k I C1- N N C F 3 Me H I e I CF 3 23 Ir e F 3 6 4Me 2 Me Me Me Me Me IMe 2 OO Mee2

F

3

F

3

F

3 e MeW 2 Br

CF

3

CF

3 C F 3 q CF, qCF,

CF

3 0 CF 3 'N ' 'N 'N F 3 r e Me 2 - ~ I F 3

F

3

F

3

F

3

F

3 F3 F 3

F

3

F

3

F

3

F

3 'IX Me H

-

4H H HH

F

3 F H

HH

2-S H2H Hr H i IN (In (i (in i 25 n n n Hn H H H H ~H H n n n n

NZI

26 R ) n R R R R R R n R R ) nR R )n R R R H n nn n Rn)nn RH 100711 Some general examples of compounds described by the general structure (A). include a compound having the general structure (I), a compound having the general structure (II), a compound having the general structure (III) or a compound having the general structure (IV): R R 3()(I H2 H R2 H 27 R R H W 3 R H R 3 (I)(V) {0 0721 Some non-limiting examples of particular compounds described by the general structure (A) that can be used include compounds having formulae (1)-(33):

F

3 %HeH %HMe H (1) (2) He W He H

F

3 F 3 (3) (4) HiMe H IHMeH . (5) (6) % HMe H _F He F

F

3

F

3 (7) (8) NHMe H F HMe F3

CF

3

CF

3 (9) (10) 28 %HMe HMeH F3 F 3 (11) (12) - OF 3

NCF

3 %HMe HH.e HI (13) (14) %HMe H HI H71 (15) (16) N N N'-N CF 3 %HMe H cHMe

H

(17) (IS) H H %HMe H~ Me (19) (20) (21) (22) %HMe H %HMe H NCF (23) (24) 29 % HMe H HMeH 1 H H (25) (26) MeCF3 M I CF 3 (27) (28) M e CF 3 H CF3 (29) (30) H MCF3 M CF 3 (31) (32) -H

CF

3 (33) 100731 The benzotriazine derivatives described above and illustrated by the general structure (A) can be prepared as shown by Scheme I: H22H2 H Ht, Pd/C ,- H 2 1. AcOH, HCI C'O-C&'H2 HH 2 .30 % NaOH 2 3 H H

R

1 -Hal RH2 t-BuOK, K2CO 3 , DMF 3 Intermediate

A

30 R IT al b.R1, Pd 2 (dba) 3 , BINAP, Cs 2

CO

3 , DMF H R Intermediate A I\1 RR1 t-BuOK, DMF H 3 Scheme I [0074] To prepare the intermediate A, where R, is, for example, 2-pyr'ine carboxamide, H HH % HCH P/ H H 2 2. 30 % NaOH 2 3 kONHMe H H2H t-BOK, K DC F H 3 5 Scheme H [00751 As seen from Scheme II, the synthesis of the intermediate A -requires using 4 chloro-2-pyridinaecarboxamide 4, which can be separately preliminarily synthesized as shown by Scheme III: 31 SOC1 2 MeOll NeNH2 2 JMeOH QNCOOH SOCI COOMeleN e ONHMe 6 7 S Scheme III The benzotriazine derivatives described in the formula (IV) and illustrated by the general structure (A) can be prepared as shown by Scheme IV: NaNO 2 , CuCI, HCI R1 Pd(PPh 3 )Cl,, CO H2 Intermediate A R11. (COCIh2 R r o( 1 H 1.ooH -RrNH2 , 3 IV Scheme IV. [00761 According to an embodiment of the invention, a second type of compounds is provided for treatment of various diseases, disorders, and pathologies, including cancer. The second type of compounds can include a benzene derived moiety bridged to a heterocyclic moiety, or pharmaceutically acceptable salts thereof The bridge between the benzene derived moiety and the heterocyclic moiety can include a single bond or a nitrogen atom. If the heterocyclic moiety contains at least one nitrogen, the second type of compounds can be an N-oxide, or N,N'-dioxide, or N,N',N"-trioxide. 100771 Whether the compound can be an N-oxide, or N,N'-dioxide, or NN',N"-trioxide, depends on the number of nitrogen atoms contained in the heterocyclic moiety. For example, if the heterocyclic moiety has only one nitrogen, the second type of compounds can be an N oxide. If the heterocyclic moiety has two atoms of nitrogen, the second type of compounds can be an N-oxide or N,N'-dioxide. If the heterocyclic moiety has three atoms of nitrogen, the second type of compounds can be any of an N-oxide, an N,N'-dioxide, an N,N',N" trioxide.

32 [00781 The benzene-derived moiety can include a substituent such as a pyridyl group connected to the benzene molecule via an oxygen link, or a sulfonyl group. The pyridyl group connected to the benzene molecule can be further substituted. The substituents in the pyridyl group can include the same moieties as described above for the first type of compounds of the present invention. The sulfonyl group connected to the benzene molecule can be also further substituted. The substituents in the sulfonyl group can include the substituted pyridyl group described above for the first type of compounds of the present invention. [0079] Optionally, the benzene-derived moiety of the compounds of the second type can contain a second substituent, e.g., methyl, halogen or methoxy, which can be located in any position of the benzene ring. Some exemplary benzene-derived moieties that can be included in the second type of compounds can include tert-butyl phenyl, trifluoromethoxyphenyl, methoxyphenyl, dimethylamino, dimethylaminophenyl, aminophenyl, trifluoroethoxyphenyl, trifluoromethoxychlorophenyl, trifluoromethoxybromophenyl, trifluoroethoxychlorophenyl, chlorophenyl, dichlorophenyl, trifluoromethyl pheny. trifluoromethylchloro phenyl, chlorotoluyl, N-phenylacetamide, NN-alkyl-benzamide, isopropoxyphenyl, alkoxyphenyl, dialkoxyphenyl, acetylphenyl. [00801 The compounds of the second type include heterocyclic compounds having the general structure (B), or an N-oxide, or N,N'-dioxide, N,N',N"-trioxide, or a pharmaceutically acceptable salt thereof, and can inhibit the activity of a kinase, such as any kinase in the MAPK signaling pathway. The general structure (B) can be represented as follows: 2 2 R1 03 3, (B) [00811 In structure (B), each of Z 1 , Z 2 and Z 3 can be, independently, N, CH, N=CH, 0, S or N-R 4 , wherein R 4 is hydrogen or lower alkyl, with the further proviso that at least one of

Z

1 , Z 2 and Z 3 is not CH; X can be absent or be NH; Y can be absent or can be one of the following moieties: /H HNJ 33 [00821 Further, in structure (B), the substitutents

R

1 , R 2 , and R 3 can be as follows: [00831 R can be an unsubstituted or a substituted

C

3 -Ci heteroaryl having 1-3 heteroatoms such as N, S or 0; 100841 R 2 can be any one of hydrogen, halogen, C-CIS alkyl (e.g., methyl), -OH, -NO 2 , CN, CI-Cis alkoxy (e.g., methoxy), -NHSO 2

R

5 , -SO 2 NHR, -NHCOR,

-NH

2 , -NRR 6 ,

S(O)R

5 , -S(O) 2

R

5 , -C0 2

R

5 , -CONR 5

R

6 , and where Rs and R are independently selected from hydrogen, a C-CIs alkyl and a substituted

-C

1 2 alkyl; and [00851 R 3 can be hydrogen, a CI-Cis alkyl, a substituted CI-Cn 2 alkyl, a Ci-CI 2 cycloalkyl, a substituted C-Cn 2 cycloalkyl, a substituted C 3 -Cio cycloalkyl having 0-3 heteroatoms such as N, S, or 0, an aryl such as a C 6

-C

2 aryl, a substituted aryl such as a substituted C 6

-C

2 aryl, a heterocycle, a substituted heterocycle, a heteroaryl such as a C 3 -C 12 heteroaryl having 1-3 heteroatoms such as N, S or 0, a substituted heteroaryl such as substituted C 3 -C 12 heteroaryl having 1-3 heteroatoms such as N, S or 0, a C 7

-C

24 aralkyl, a substituted C 7 -C24 aralkyl, a C 7 -C24 alkylaryl, and a substituted C7rC 2 4 alkaryl. 100861 The substituent R, can include a substituted pyridyl or a substituted pyrimidyl group. The substituents in the substituted pyridyl or substituted pyrimidyl group can include an amido moiety, an aminoalkyl group (e.g., aminomethyl), or a carboxyl group, or a carboxylate group. The amido moiety attached to the pyridyl/pyrimidyl group can be in turn also substituted by attaching to the nitrogen in the amido moiety a substitutent selected from an alkyl (e.g., methyl), an alkylaminoalkyl (e.g., diethylamino alkyl), a pyridyl, an alkyl pyrrolidine, an alkyl morpholine, and an alkyl piperazine groups. 10087] Particular, non-limiting examples of R, that can be used in compounds having the structure (B) include any of the following moieties:

H

2 h:S NH 2 6 H 2 k}.H, H 2 N& H 2 SH 2 W H 2 A6rNH 2

!NH

2 MeSX!1 H 2

H

2 N OMe 34a HMe 6 rMe 2 - H 2 ~- HMe - Me 2 - H 2 H H

HNH

2

Y

2 2 N HI; HN H i; H n n rnn N HHH H &?n n -- 6n H IH-H H H H2 N - H 2H H , 't N

H

2

HH

2 H2 p H2&N { ~JJ H H H 2 H H H r n H n H nH nH 3S H n MenH M H H Me Me H H H H H where n can be an integer selected from a group consisting of 0, 1, 2, and 3. 100881 Some particular non-limiting examples of the substituent

R

3 that can be used in compounds having the structure (B) include tert-butyl phenyl, trifluoromethoxyphenyl, methoxyphenyl, dimethylaiinophenyl, aminophenyl, trifluoroethoxyphenyl, trifluoromethoxychlorophenyl, trifluoromethoxybromophenyl, trifluoroethoxychlorophenyl, chlorophenyl, dichlorophenyl, trifluoromethyl phenyl, trifluoromethylchlorophenyl, chlorotoluyl, N-phenylacetamide, N,N-alkyl-benzanide, isopropoxyphenyl, alkoxyphenyl, dialkoxyphenyl, and acetylphenyl. These and yet other moieties that can be used as the substituent

R

3 can be illustrated as follows: CF3 C 3

"FCF

3 I F3 M I IF 3 Me .

cCF 3

M

36 Ir We F 3 'N ("m'Me z Me Me Me Me Me NMe 2 F F I Me 2

F

3

F

3

F

3 Me H, H F3HN HH e Me 2 r NF NF CF, F F F . F CF 3

CF

3 37 re NMe 2

F

3 F FF 3 F F., r

F

3

F

3

F

3

F

3

F

3

F

3 Me H H H H H N N N N N0 38 R n n n ) In R j OH R R )n R R R )n R H R R ) R R R ) H R H R- R )R R% R )~ R where n can be an integer selected from a group consisting of 0, 1, 2, and 3, and R' is hydrogen, a Ci-Cis alkyl, or a substituted Cl-CIS alkyl.

39 100891 Some general examples of compounds described by the general structure (B) include a compound having the general structures (V)-(XXVIII): R 3 RR3 H H H H H H H V III V R, 3 Rea3 RK 3 R_ 33 RH H H ViXl Ix X R R R 3 X XXI XII R HH HH 3 H 3H XIV Xv XVI 'CIIXvIII XIX XX XXT

XXII

40 R , - R R H oH 3 \H 3 XXIII XXIV XXV R R R R H H 3 H 3 XXVI XXVII XXVII 100901 In the case of 1,2,4-triazoles, there exist three tautomeric structures, as shown below: 1 2 1 2 2 I H 4H-1,2,4-triazole IH-1,2,4-triazole 1H-1,2,4-triazole [00911 Which tautomeric structure is prevailing depends on the substituents on the triazole moiety and on the reaction conditions. As known to those having ordinary skill in the art, typically, lIH-1,2,4-triazole is the most common tautomeric form, especially if an amino substituent is attached to the ring. Even though all three tautomeric structures can be present, all the generic structures and all the examples having 1,2,4-triazole moiety are shown herein in one tautomeric form, such as 4H-1,2,4-triazole, for simplicity and for the comparison with its direct analogues, such as examples containing 1,3,4-oxadiazole moiety. Using only 4H tautomeric fonn to draw the structures for the sake of simplicity, does not imply that the compounds of the examples (30)-(74) shown below exist in that particular tautomeric fonn. [00921 Some examples of particular compounds described by the general structure (B) include compounds having formulae (34)-(S3): 41

F

3

CF

3 NHMe C HMe (34) (35) - - ~. CF 3 H F3 QHC HMe (36) (37)

CF

3

H

2

CF

3 (38) (39)

H

2 F CF 3 (40 0\0 N- H H

H

2 H H (40) (41) H2 H H CF 3

H

2 W6 H H F

H

2 (42) (43)

H

2 0, IH

F

3 N'e - HF 3 (4) (44) (5

H?

2 I I

H

2 .- H H H - H F (4G) (47) 42 /2N I I 2 - - H 3 HF, ' (48) (49) -H F3 H F 3 (50) (I - H F3 F %HMeH (52) (53) HN "q IH HHH HI H H (56) (57) F 3 NN f N~N HPA H H Ir HH 14

F

3 F 3 (58) (59) 43 Hz F 3

F

3 (60) (61)

H

2 (62) (63)

H

2

HF

3 HF (64) (65)

H

2

H

2 A -- U H' (66) (67)

F

3 H - H (68) (69)

NH

2 N, -C H H F 3

H

2 H H (70) (71) Me NH 2

H

2 W6 H H F 3 Me - H H F 3 (72) (73) 44a NF F

H

2 U H H F 3 N - H H F 3 (74) (75) - H H F -~ H H CF3 (76) (77) H- H H

F

3

CF

3 (78) (79) H H rMe

F

3 (80) (81) H H H H

F

3 (32) [0093] Appropriately substituted 1,2,4-triazoles of the type (V) described above and illustrated by the general structure (B) can be synthesized using one of several reaction schemes, for example as shown in Schemes V, VI and VII below. The appropriate method can be chosen based on the required substitution, availability of the starting materials and the ease of synthesis.

45

H

2 H ) H) o H3 ,aT4,.IeOR R~ A'H H__ _ _ _ _ _ _ RA~M a

IR

1 -CI 3 3 NZ____________ H H- H HR A H H H A H HKHMNDS, DNvIF, miv Scheme V

R

1 -Hal, KIIMDS, K 2 C0 3 R Hao DNU R N 1-N 11,, EtO H R *R H 2 H ® EQ R

H

2 3___ H + ~.~JSeI AH H Scheme VI 46

R

1 H (COCl) 2 R NaSCN R N R NCS R CS + R 3 H2 EtOI R 3

NH,--NH

2 r N R TN.HR H H TFIF-EtOH . H H Scheme VHI 100941 1,2,4-triazoles of the type (VI) described above, can be made as shown in Scheme VIII or by an alternative route as outlined in Scheme IX. NH,-NH' R N R R N NH 2 H EtOH R R HH H H2 Mel/Meo H H

~KA

2 MeI~ H M- ,k~H G N_______ H H HR a R H H HKHMS, DHF, mw 3 Scheme VIII 47 NaSCN

S

2 R-Hal, KHMDS, K2CO 3 )

H

2 H H2DMF R R NH2 * RE1H H EH R Scheme IX [00951 Appropriately substituted 2-amino-1,3,4-oxadoazoles of type (VIII), can be synthesized using one of several reaction schemes, for example, as shown by Schemes X, XI and XII. H H H2+ RC EtOH H H HKHMDS, 03, DMF R Scheme X 4$8

R

1 -f CHCi, r.t. N NH 2 + Cs EtOLIH HOHC' ~-~ H -0 H I 3 H H ilgO HQ- H I± 3 EtOH Ha H R 3

R

1 -HaI 3 Hl r H' KHMIDS, K 2 C0 3 , DMff R - OHN Scheme XIJ N R 1 -Hal HO KHMDS, K 2 C0 3 , DNEF R NI2Ni i R *; N W NH 2 EtOH H l'O H H H -R H + R~-1i-~j THF-EtOH RlNl<~c H HC,'CI 4 Br-,, Et 3 N 3 H Y' 3 PP11 3 , H 3 CN - OOH Scheme XII 49 [0096] Appropriately substituted 2-amino-1,3,4-oxadiazoles of type (IX), can be synthesized using one of several reaction schemes, for example, as shown by Schemes XIII and XIV. ~aV H R-EbI H KHMS, K 2 C0 3 , DNI RH RH2 R CS CH2

C

I

2 , r.t. R H2 HC MeOH R Scheme X= HO H2 . H CS CH1 2 C1 2 , r. R H leoH, CI RMe NH2-NH 2 R

H

2 RR EtOH -R I-i

H

2 + H CS EtOH H H RH +H O H HI 3 H EtOII H 3 R -H al H 3 KIIMDS, ( 2 C0 3 , DMF H 3 50 Scheme XIV [00971 Appropriately substituted 2-amino-1,3,4-thiadiazoles of type (XI), can be prepared by a method which is outlined in Scheme XV. RI-Hal S R ~ H KHMDS, I 2

CO

3 , DMiF N11 2 -NtH 2 R t -H R H H 2 H2 +'CS THF-EtOH RH H H + H K H H AcOH, microwave R N R H Scheme XV [00981 Appropriately substituted 2-amino-1,3,4-thiadiazoles of type (XII), can be prepared by a method which is outlined in Scheme XVI. R I-F ala KIDS, K 2 C0 3 , DMF RH R1 H2 R1CS CfH 2 C1 2 , r.t.

NR

2

-NH

2 Rr EtOR R& H2 51 H2 CS THF-EtOH , RH H H AcOH, microwave R 3 H0& H 3 Scheme XVI 100991 Appropriately substituted 3-amino-1,2,4-triazines of type. (XXI)(XXV) can be prepared by a method which is outlined in Scheme XVII. H H ( e H2 MCI R3 I H 2

N-NH

2

R

3 H *R3H0fMH 3N H ) e) HOI*HN

H

2 HH R,-HaI t-BuOKor KHMDS or Cs 2

CO

3 or K 2 CO3 HO-fi~r H R c!N I H HH N HH

H

2 %-qLsEt *tIUr If..H IN11 3 /1VtcO" HO NH, HO(Et H_ O WH 2 52 RrIlaI R 3 COCI N t-BuOK or KHMDS or Cs2C0 3 or K2CO 3 XXiV

SH

2 ~

R

3

SO

2 CI R 4 XXV Scheme XVII Appropriately substituted 3-amino-1,2,4-triazines of type (XXVI)-(XXVII), can be prepared by a method which is outlined in Scheme XVIII. H H 0G H ( 3Mel R3

H

2

N--NH

2 R R- J R3aU(C H H R,-CI HO-t-BuOK or C, HO

CSCO_

3 orlU-IMNDS N H H *HBr H H H2 H Et H Et NH 3 /IMCOH H H2 53 RrC1

R

3 COCI ' t-BuOK or K 2 C0 3 R Cs.,C 3 or 1GMDS RNH

H

2

R

3

SO

2 CI 'N ~y3 Scheme XVIII [01001 The compounds and methods of the present invention, either when administered alone or in combination with other agents (e.g., chemotherapeutic agents or protein therapeutic agents described below) are useful in treating a variety of disorders, including, but not limited to, for example, cancer, eye disease, inflammation, psoriasis, and a viral infection. The kinds of cancer that can be treated include, but are not limited to, an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer. [01011 Embodiments of the present invention also provide articles of manufacture that can include a packaging material and a pharmaceutical composition contained within the packaging material. The packaging material can comprise a label which indicates that the pharmaceutical composition can be used for treatment of one or more disorders identified above. {0102] The pharmaceutical composition can include a compound according to the present invention. In addition to a compound of the present invention, the pharmaceutical may also contain other therapeutic agents, and may be formulated, for example, by employing conventional solid or liquid vehicles or diluents, as well as pharmaceutical additives of a type appropriate to the mode of desired administration (for example, excipients, binders, preservatives, stabilizers, flavors, etc.) according to techniques known in the art of pharmaceutical formulation.

54 [0103] Thus, in one embodiment, the invention provides a pharmaceutical composition including a therapeutic agent and a compound of the invention. The compound is present in a concentration effective to treat cancer. [01041 The compounds of the invention may be formulated into therapeutic compositions as natural or salt forms. Pharmaceutically acceptable non-toxic salts include the base addition salts (formed with free carboxyl or other anionic groups) which may be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. Such salts may also be formed as acid addition salts with any free cationic groups and will generally be forced with inorganic acids such as, for example, hydrochloric, sulfuric, or phosphoric acids, or organic acids such as acetic, citric, p toluenesulfonic, methanesulfonic acid, oxalic, tartaric, mandelic, and the like. 101051 Salts of the invention can include amine salts formed by the protonation of an amino group with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like. Salts of the invention can also include amine salts formed by the protonation of an amino group with suitable organic acids, such as p-toluenesulfonic acid, acetic acid, methanesulfonic acid and the like. Additional excipients which are contemplated for use in the practice of the present invention are those available to those of ordinary skill in the art, for example, those found in the United States Pharmacopeia Vol. XXII and National Formulary Vol. XVII, U.S. Pharmacopeia Convention, Inc., Rockville, MD (1989), the relevant contents of which is incorporated herein by reference. In addition, polymorphs of the invention compounds are included in the present invention. [01061 Pharmaceutical compositions of the invention may be administered by any suitable means, for example, orally, such as in the form of tablets, capsules, granules or powders; sublingually; buccally; parenterally, such as by subcutaneous, intravenous, intramuscular, intrathecal, or intracisternal injection or infusion techniques (e.g., as sterile injectable aqueous or non-aqueous solutions or suspensions); nasally such as by inhalation spray; topically, such as in the form of a cream or ointment; or rectally such as :n the form of suppositories; in dosage unit formulations containing non-toxic, pharmaceutically acceptable vehicles or diluents. The present compounds may, for example, be administered in a form suitable for immediate release or extended release. Immediate release or extended release may be achieved by the use of suitable pharmaceutical compositions comprising the present compounds, or, particularly in the case of extended release, by the use of devices such as subcutaneous implants or osmotic pumps. The present compounds may also be administered liposomally. [01071 In addition to primates, such as humans, a variety of other mammals can be treated according to the method of the present invention. For instance, mammals including, but not limited to, cows, sheep, goats, horses, dogs, cats, guinea pigs, rats or other bovine, ovine, equine, canine, feline, rodent or murine species can be treated. However, the method can also be practiced in other species, such as avian species (e.g., chickens). 101081 The pharmaceutical compositions for the administration of the compounds of this embodiment, either alone or in combination with other therapeutic agents, may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy. All methods include bringing the active ingredient into association with the carrier which constitutes one or more accessory ingredients. In general, the pharmaceutical compositions are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation. In the pharmaceutical composition the active object compound is included in an amount sufficient to produce the desired effect upon the process or condition of diseases. The pharmaceutical compositions containing the active ingredient may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. [0109] Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceiyl monostearate 56 or glyceryl distearate may be employed. They may also be coated to form osmotic therapeutic tablets for control release. 101101 Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. [01111 Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydroxy propylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. Also useful as a solubilizer is polyethylene glycol, for example. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin. [01121 Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid. {01131 Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already 57 mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present. [01141 Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. [01151 The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable diluent or solvent or cosolvent or complexing agent or dispersing agent or excipient or combination thereof, for example 1,3-butanediol, polyethylene glycols, polypropylene glycols, ethanol or other alcohols, povidones, various brands of TWEEN surfactant, sodium dodecyl sulfate, sodium deoxycholate, dimethylacetamide, polysorbates, poloxamers, cyclodextrins, lipids, and excipients such as inorganic salts (e.g., sodium chloride), buffering agents (e.g., sodium citrate, sodium phosphate), and sugars (e.g., saccharose and dextrose). Among the acceptable vehicles and solvents that may be employed are water, dextrose solutions, Ringer's solutions and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. {01161 Depending on the condition being treated, these pharmaceutical compositions may be formulated and administered systemically or locally. Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences" (Mack Publishing Co, Easton Pa.). Suitable routes may, for example, include oral or transmucosal administration; as well as parenteral delivery, including intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration. For injection, the pharmaceutical compositions of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline. For tissue or cellular administration, penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art. Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds 58 in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. 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 that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. [01171 The compounds of the present invention may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols. 101181 For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compounds of the present invention are employed. (For purposes of this application, topical application shall include mouthwashes and gargles). [01191 In one embodiment, the invention compounds are administered in combination with an anti-inflanatory agent, antihistamines, chemotherapeutic agent, immunomodulator, therapeutic antibody or a protein kinase inhibitor, e.g., a tyrosine kinase inhibitor, to a subject in need of such treatment While not wanting to be limiting, chemotherapeutic agents include antimetabolites, such as methotrexate, DNA cross-linking agents, such as cisplatin/carboplatin; alkylating agents, such as canbusil; topoisomerase I inhibitors such as dactinomicin; microtubule inhibitors such as taxol (paclitaxol), and the like. Other chemotherapeutic agents include, for example, a vinca alkaloid, mitomycin-type antibiotic, bleomycin-type antibiotic, antifolate, colchicine, demecoline, etoposide, taxane, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, idarubicin, mithoxanthrone, 4-dimethoxy-daunomycin, I 1-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin-14-benzoate, adriamycin-14-octanoate, adriamycin-14-naphthaleneacetate, amsacrine, carmustine, cyclophosphamide, cytarabine, etoposide, lovastatin, melphalan, topetecan, oxalaplatin, chlorambucil, methtrexate, lomustine, thioguanine, asparaginase, vinblastine, vindesine, tamoxifen, or mechlorethamine. While not wanting to be limiting, therapeutic antibodies include antibodies directed against the HER2 protein, such as trastuzumab; antibodies directed against growth factors or growth factor receptors, such as bevacizumab, which targets vascular endothelial growth factor, and OSI-774, which targets 59 epidermal growth factor; antibodies targeting integrin receptors, such as Vitaxin (also known as MEDI-52 2 ), and the like. Classes of anticancer agents suitable for use in compositions and methods of the present invention include, but are not limited to: 1) alkaloids, including, microtubule inhibitors (e.g., Vincristine, Vinblastine, and Vindesine, etc.), microtubule stabilizers (e.g., Paclitaxel [Taxol), and Docetaxel, Taxotere, etc.), and chromatin function inhibitors, including, topoisomerase inhibitors, such as, epipodophyllotoxins (e.g., Etoposide [VP-16), and Teniposide [VM-26), etc.), and agents that target topoisomerase I (e.g., Camptothecin and Isirinotecan [CPT- 11, etc.); 2) covalent DNA-binding agents [alkylating agents], including, nitrogen mustards (e.g., Mechlorethamine, Chlorambucil, Cyclophosphamide, Ifosphamide, and Busulfan [Myleran], etc.), nitrosoureas (e.g., Cannustine, Lonustine, and Semustine, etc.), and other alkylating agents (e.g., Dacarbazine, Hydroxymethylmelamine, Thiotepa, and Mitocycin, etc.); 3) noncovalent DNA-binding agents [antitumor antibiotics], including, nucleic acid inhibitors (e.g., Dactinomycin [Actinomycin D], etc.), anthracyclines (e.g., Daunorubicin [Daunomycin, and Cerubidine], Doxorubicin [Adriamycin], and Idarubicin [Idamycin], etc.), anthracenediones (e.g., anthracycline analogues, such as, [Mitoxantrone], etc.), bleomycins (Blenoxane), etc., and plicamycin (M\ithramycin), etc.; 4) antimetabolites, including, antifolates (e.g., Methotrexate, Folex, and Mexate, etc.), purine antimetabolites (e.g., 6-Mercaptopurine [6-MP, Purinethol], 6-Thioguanine [6-TG}, Azathioprine, Acyclovir, Ganciclovir, Chlorodeoxyadelosine, 2 Chlorodeoxyadenosine [CdA), and 2'-Deoxycoformycin [Pentostatin], etc.), pyrimidine antagonists (e.g., fluoropyrimidines [e.g., 5-fluorouracil (Adrucil), 5-fluorodeoxyuridine (FdUrd) (Floxuridine)] etc.), and cytosine arabinosides (e.g., Cytosar {ara-C] and Fludarabine, etc.); 5) enzymes, including, L-aspaTaginase; 6) hormones, including, glucocorticoids, such as, antiestrogens (e.g., Tamoxifen, etc.), nonsteroidal antiandrogens (e.g., Flutamide, etc.), and aromatase inhibitors (e.g., anastrozole [Arimidex], etc.); 7) platinum compounds (e.g., Cisplatin and Carboplatin, etc.); 8) monoclonal antibodies conjugated with anticancer drugs, toxins, and/or radionuclides, etc.; 9) biological response modifiers (e.g., interferons [e.g., IFN-.alpha., etc.] and interleukins [e.g., IL-2, etc.], etc.); 10) adoptive immunotherapy; 11) hematopoietic growth factors; 12) agents that induce tumor cell differentiation (e.g., all-trans-retinoic acid, etc.); 13) gene therapy techniques; 14) antisense therapy techniques; 15) tumor vaccines; 16) therapies directed against tumor metastases (e.g., Batimistat, etc.); and 17) inhibitors of angiogenesis. 101201 The pharmaceutical composition and method of the present invention may further comprise other therapeutically active compounds as noted herein which are usually applied in 60 the treatment of the above mentioned pathological conditions. Examples of other therapeutic agents include the following: cyclosporins (e.g., cyclosporin A), CTLA4-Ig, antibodies such as ICA.M-3, anti-IL- 2 receptor (Anti-Tac), anti-CD45RB, anti-CD2, anti-CD3 (OKT-3), anti CD4, anti-CD80, anti-CD86, agents blocking the interaction between CD40 and gp39, such as antibodies specific for CD40 and/or gp39 (i.e., CD 154), fusion proteins constructed from CD40 and gp 3 9 (CD40Ig and CD8gp39), inhibitors, such as nuclear translocation inhibitors, of NE-kappa B function, such as deoxyspergualin (DSG), cholesterol biosynthesis inhibitors such as HMG CoA reductase inhibitors (lovastatin and simvastatin), non-steroidal antiinflammatory drugs (NSAIDs) such as ibuprofen and cyclooxygenase inhibitors such as rofecoxib, steroids such as prednisone or dexamethasone, gold compounds, antiproliferative agents such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil, cytotoxic drugs such as azathioprine and cyclophosphamide, TNF-a inhibitors such as tenidap, anti TNF antibodies or soluble TNF receptor, and rapamycin (sirolimus or Rapamune) or derivatives thereof. (01211 Other agents that may be administered in combination with invention compounds include protein therapeutic agents such as cytokines, immunomodulatory agents and antibodies. As used herein the term "cytokine" encompasses chemokines, interleukins, lymphokines, monokines, colony stimulating factors, and receptor associated proteins, and functional fragments thereof. As used herein, the term "functional fragment" refers to a polypeptide or peptide which possesses biological function or activity that is identified through a defined functional assay. (01221 The cytokines include endothelial monocyte activating polypeptide II (EMAP-II), granulocyte-macrophage-CSF (GM-CSF), granulocyte-CSF (G-CSF), macrophage-CSF

(M

CSF), IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-12, and IL-13, interferons, and the like and which is associated with a particular biologic, morphologic, or phenotypic alteration in a cell or cell mechanism. 101231 When other therapeutic agents are employed in combination with the compounds of the present invention they may be used for example in amounts as noted in the Physician Desk Reference (PDR) or as otherwise determined by one having ordinary skill in the art. 101241 In the treatment or prevention of conditions which involve cellular proliferation, an appropriate dosage level can generally be between about 0.01 and about 1000 mg per 1 kg of patient body weight per day which can be administered in single or multiple doses. For 61 example, the dosage level can be between about 0.01 and about 250 mg/kg per day; more narrowly, between about 0.5 and about 100 mg/kg per day. A suitable dosage level can be between about 0.01 and about 250 mg/kg per day, between about 0.05 and about 100 mg/kg per day, or between about 0.1 and about 50 mg/kg per day, or about 1.0 mg/kg per day. For example, within this range the dosage can be between about 0.05 and about 0.5 mg/kg per day, or between about 0.5 and about 5 mg/kg per day, or between about 5 and about 50 mg/kg per day. For oral administration, the compositions can be provided in the form of tablets containing between about 1.0 and about 1,000 mig of the active ingredient, for example, about 1.0, about 5.0, about 10.0, about 15.0, about 20.0, about 25.0, about 50.0, about 75.0, about 100.0, about 150.0, about 200.0, about 250.0, about 300.0, about 400.0, about 500.0, about 600.0, about 750.0, about 800.0, about 900.0, and about 1,000.0 mg of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day, such as once or twice per day. There may be a period of no administration followed by another regimen of administration. 101251 It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy. 101261 Compounds of the present invention can be used, alone or in combination with an effective amount of a therapeutic antibody or chemically attached to a tumor tissue targeting antibody (or therapeutic fragment thereof), a chemotherapeutic or an immunotoxic agent, for treatment of tumors. Illustrative examples of chemotherapeutic agents that can be used for this purpose include doxorubicin, docetaxel, or taxol. It should be further understood that the invention includes combination therapy including a compound of the invention, including but not limited to vasculostatic agents, such as tyrosine, seine or threonine kinase inhibitors, for example, Src-family inhibitors, and any chemotherapeutic agent or therapeutic antibody. 101271 The present invention also provides screening assays using appropriate cells which express any kinases within the MAPK pathway. Such cells include cells from mammals, yeast, Drosophila or E. coli. For example, cells which express the Raf polypeptide or any kinase downstream of Raf such as MEK or ERKI/2 or respond to Raf polypeptide or MAPK 62 pathway polypeptides are contacted with a test compound to observe binding, or stimulation or inhibition of a functional response. The cells which are contacted with the candidate compound are compared with the same cells which are not contacted for Raf polypeptide or MAPK pathway polypeptide activity [01281 This invention contemplates the treatment and/or amelioration of such diseases by administering a MAPK pathway polypeptides inhibiting amount of a compound. Without wishing to be bound by any particular theory of the functioning of the MAPK pathway polypeptides, it is believed that among the useful inhibitors of MAPK pathway polypeptides function are those compounds which inhibit the kinase activity of the MAPK pathway polypeptides. Other sites of inhibition are, of course, possible owing to its position in a signal transduction cascade. Inhibitors of protein-protein interactions between, for example Raf polypeptide or MAPK pathway polypeptides and other factors could lead to the development of pharmaceutical agents for the modulation of Raf polypeptide or KAP pathway polypeptides activity. [01291 Targeting an allosteric site of the protein is a very promising approach for pharmaceutical intervention. Further, the traditional approach of inhibiting various protein kinases includes targeting the ATP binding site. The invention is not meant to be limited by any particular mechanism of inhibition. The assays of the invention may test binding of a candidate compound wherein adherence to the cells bearing the Raf polypeptide or MAPK pathway polypeptides is detected by means of a label directly or indirectly associated with the candidate compound or in an assay involving competition with a labeled competitor. Further, these assays may test whether the candidate compound results in a signal generated by activation of MAPK pathway polypeptides, using detection systems appropriate to the cells bearing the Raf polypeptide or MAPK pathway polypeptides. Inhibitors of activation are generally assayed in the presence of a known agonist and the effect on activation by the agonist by the presence of the candidate compound is observed. Standard methods for conducting such screening assays are well understood in the art and are also illustrated in the examples below (e.g., direct and rafl-MEK1 assays or MAPK pathway cellular assays). 101301 The following examples are provided to further illustrate the advantages and features of the present invention, but are not intended to limit the scope of the invention.

63 Example 1 --General Methods [01311 Example I describes general synthetic procedures that were used to make the compounds described in the subsequent examples. All solvents were used without further purification. Reactions can be usually conducted without an inert gas atmosphere unless specified otherwise. The reported yields are based on unoptimized conditions and single test runs. The yields can be optimized by changing the reaction conditions, such as solvent, use of base or acid, temperature, use of catalyst and the time of the reaction. Microwave reactions were run in EmrysTIM Process vials (2-5 mL) using Initiator module (Biotage/Personal chemistry). All 1 H NMR were run on a 500 MHz Bruker NMR or Bruker Avance 400 MHz NMR. Chemical shifts are reported in delta (S) units, parts per million (ppm) downfield from tetramethylsilane. Coupling constants are reported in hertz (Hz). A Waters LC/MS system is used in identity and purity analysis. This system includes a 2795 separation module, a 996 photodiode array detector and a ZQ2000 mass spectrometer. A Zorbax SB column (150 x 4.6 mm 3.5g, Agilent Technologies) was used for the LC. Column temperature was 40 0 C. Compounds were separated using gradient elution with mobile phases of water (0.05% TFA (A)) and acetonitrile (0.05% TFA (B)). Flow rate was ImL/min. The gradient program used in separation was 0-15 min: 5-60 % B; 15-15.5 min: 60-100 % B; 15.5-17 min: 100 % B. Example 2. Synthesis of 3-amino-benzof I .2,41triazine-7-ol- I-oxide H0O + H2 {01321 7.7 g (0.05 mol) of 4-amino-3-nitrophenol was dissolved in 20 mL of glacial acetic acid and the resulting bright-red solution was heated to approximately 100*C in 500 mL round-bottom flask equipped with a long condenser. To this solution was added a solution of 16.81 g (8.0 equivalent, 0.4 mol) of cyanamide in 20 mL of concentrated hydrochloric acid. In approximately 5-10 min the reaction mixture started to boil vigorously, so the heating was removed and it was stirred without heating until boiling subsided. Then the heating was reapplied and the reaction mixture was refluxed for 48 hrs. Then 150 mL of 30 % NaOH was added and the resulting dark-reddish solution was refluxed for additional 3 hrs. Then it was cooled down to room temperature and dark-red slurry was formed. The red precipitate was filtered, re-dissolved in 200 mL of water and IN HCI was added in portions with stirring until 64 pH reached 5-4. The solution changed color from dark-red into light-yellow and a light yellow fine precipitate was formed. The precipitate was filtered, washed twice with 50 mL of water, twice with 50 rnL of acetonitrile and finally twice with 50 mL of diethyl ether and dried in vacuum to give 4.6 g of a bright-yellow solid. Yield: 51.7 %. 101331 1H NMR (DMSO-d): 8 6.96 (s, 2H), 7.35-7.38 (m, 2H), 7.45-7.47 (m, 1H), 10.36 (s, IH). Example 3. Synthesis of 3-amino-benzof[,2.4]triazine-7-ol H H2 101341 4.6 g (25.82 mmol) of 3-amino-benzo[I,2,4]triazine-7-ol-1-oxide was dissolved in 200 mL of 1:1 mixture of dimethylformamide and methanol. 0.5 g of 10% Pd/C was added to this solution and H2 gas was bubbled through the solution for 3 hours. The progress of the reaction was monitored by TLC, using a 9:1 mixture of dichloromethane/methanol as an eluent and a UV lamp. The starting material is highly fluorescent under UV, while the product is not. When the reaction was complete, the resulting dark solution was filtered through a short pad of silica gel and solvent was removed in vacuum to produce a dirty brown solid. 40 mL of ethyl acetate and 40 mL of methanol were added to the solid and the resulting suspension was heated to reflux for about 10 min. Then the suspension was allowed to cool down to ambient temperature. The solid was collected by filtration, washed with 40 mL of ethyl acetate, 40 mL of diethyl ether and dried in vacuum to yield 3.2 g of the product in a form of a greenish solid. Yield: 76%. 101351 'H NMR (DMSO-d 6 ): 8 7.18 (s, 1 H), 7.36 (d, J= 2.6 Hz, 1 H), 7.40-7.42 (dd, J = 9.1 Hz, J.1 = 2.6 Hz, I H). 7.45-7.46 (d, J= 9.1 Hz, IH). Example 4. Synthesis of 4-chloro-pyridine-2-carboxylic acid methyl ester hydrochloride salt Me HCI 101361 2.4 mL (0.031 mol, 0.16 equivalent) of anhydrous N,N-dimethylformamide was added dropwise to 72 mL (1.23 mol, 5.0 equivalent) of thionyl chloride in a temperature 65 range of 40-50 0 C under argon blanket. The solution was stirred at this temperature for 10 min, then 24.0 g (0.195 mol, 1.0 equivalent) of picolinic acid was added slowly in portions. The reaction mixture was heated at 70-75 0 C with a reflux condenser under argon for 30 hours. Evolution of S02 gas was observed. The reaction mixture changed colors from green to orange, then to purple over 2 hours, then resulted in an orange solution with a yellow precipitate. It was cooled down to ambient temperature and 150 mL of anhydrous toluene was added. The suspension was concentrated to about 50 mL total on rotovap. This process was repeated three times. [01371 The resulting orange suspension was cooled down to - 20"C and 200 mL of methanol was added. The reaction mixture was left to stir at ambient temperature for 18 hours. Then the clear-yellow solution was transferred into a round-bottom flask and solvent was removed in vacuum. The resulting yellow solid was dissolved with heating to 50*C in 50 mL of methanol, upon cooling 300 mL of diethyl ether were added. The solution was left to stand at 0 0 C for 18 hours. The white precipitate that formed was collected by filtration, washed extensively with diethyl ether and dried in vacuum to yield 29.05 g of the product as a white fluffy solid. Yield: 71.5 %. [01381 1H NMR (DMSO-d6): 8 3.88 (s, 3H), 7.81-7.83 (dd, J, = 1.9 Hz, J 2 = 5.4 Hz, 1H), 8.06-8.07 (d, J= 1.9 Hz, 111), 8.68-8.69 (d, J= 5.4 Hz, IH). Example 5. Snthesis of 4-chloro-pyrdine-2-carboxylic acid methyl aide HMe [01391 A suspension of 17.8 g (0.103 mol, I eq) of 4-chloro-pyridine-2-carboxylic acid methyl ester hydrochloride in 15 nL of methanol was cooled to 0*C and slowly treated with a 2.0 M solution of methylamine in tetrahydrofuran at a rate that kept internal temperature below 5*C. The reaction mixture was stirred at 0*C for 2 hours, then slowly allowed to warm up to ambient temperature and stirred for 18 hours. Solvent was removed in vacuum, approx. 200 mL of ethyl acetate was added and the resulting suspension was filtered. The precipitate was washed with 100 mL of ethyl acetate. The combined ethyl acetate solutions were 66 washed three times with 100 mL of brine and dried over sodium sulfate. Solvent was removed in vacuum to yield 14.16 g of the product as orange oil. Yield: 80.5 %. [01401 'H NMR (DMSO-d 6 ): 8 2.81-2.82 (d, J= 4.8 Hz, 3H), 7.73-7.75 (dd, J, = 2.1 Hz, 1 2 = 5.4 Hz, 1H), 8.00-8.01 (d, J= 2.1 Hz, 1H), S.60-8.61 (d, J= 5.4 Hz, 1H), 8.84 (q, J= 4.8 Hz, 1Hf). Example 6. Synthesis of 4-(3-amino-benzo1.2,41triazin-7-yloxy)-pyridine-2-carboxylic acid methylamide

H

2 HMe (0141] 3.2 g (19.73 mmol) of 3-amino-benzo[1,2,4]triazine-7-ol was dissolved in 80 maL of anhydrous dimethylformamide under argon atmosphere. 2.44 g (21.71 mmol, 1.1 equivalent) of solid potassium tert-butoxide was added to the solution. The resulting dark red mixture was heated to about 100'C and stirred at that temperature for 15 min. A solution of 3.7 g (21.71 rnmol, 1.1 equivalent) of 4-chloro-pyridine-2-carboxylic acid methylamide in 10 mL of anhydrous dimethylformamide was added, followed by 3.28 g (23.68 mmol, 1.2 equivalent) of anhydrous K 2 C0 3 . The reaction mixture was heated at 140"C for 30 hrs. The progress of the reaction was monitored by LC/MS. Then it was allowed to cool down to ambient temperature. The resulting dark-brown slurry was poured into 500 mL of water and 100 mL of ethyl acetate. The foRmed precipitate was collected by filtration, washed with 50 mL of water, 50 mL of methanol, 50 mL of diethyl ether and dried in vacuum to produce 3.22 g of the product as a dirty-yellow solid. The filtrate was extracted four times with 100 mL of ethyl acetate. The combined extracts were washed 3 times with 100 mL of water, then with brine and dried over anhydrous sodium sulfate. Solvent was removed in vacuum to yield additional 1.2 g of the product in a form of a yellow solid. Yield: 75% combined. [01421 'H NMR (DMSO-d 6 ): 5 2.78-2.79 (d, J= 4.8 Hz, 3H), 7.25-7.27 (dd, J1 = 2.6 Hz, 12 = 5.6 Hz, I H), 7.50-7.51 (d, J= 2.6 Hz, 1H), 7.66-7.68 (d, J= 9.2 Hz, 1H), 7.71-7.73 (dd, J, = 2.7 Hz, J 2 = 9.2 Hz, 1 H), 7.71 (s, 2H), 8.03-8.05 (d, J = 2.7 Hz, 1H), 8.54-8.55 (d, J= 5.6 Hz, 111), 8.78-8.80 (q, J= 4.8 Hz, 1H).

67 Example . SynthesiSof_4 -(_4-chloro-3-trifluoromethyl-phenylamino)-benzo[1,2,41triazin 7 --y 1 xv-pyidine-2carboxylic acid methylamide trifluoroacetate salt

F

3 HMe

CF

3 COOH {0143] To a vial with 2 rmL of anhydrous dimethylformamide under argon atmosphere were added 15.4 ng (0.0168 mmol, 0.05 equivalent) of tris(dibenzyllideneatone) dipalladium(O), 21.0 mg (0.033 mmol, 0.1 equivalent) of BINAP, 220.0 mg (0.675 mmol, 2.0 equivalent) of anhydrous cesium carbonate, 175.1 mg (0.675 mmol, 2.0 equivalent) of 5 bronio-2-chlorobenzotrifluoride, and 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino benzo[1, 2

,

4 ]triazin-7-yloxy)-pyridine-carboxylic acid methylamide, in that particular order. Argon gas was bubbled through the mixture for 5 min. Then the vial was capped and the reaction mixture was heated to 120"C with stirring under argon atmosphere for 18 hours. At this point LCIMS indicated about 40 % conversion to the product. As pointed out in the previous examples, the longer reaction times result in the formation of the by-product and partial decomposition. So, the reaction mixture was allowed to cool down to ambient temperature, filtered through 0.3 pUm syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1 % of TFA. {01441 ESI-MS: [I+H), 475,477. 'H NMR (DMSO-d6 ): 52.79-2.90 (d, J= 4.8 Hz, 3H), 7.31-7.33 (dd, J, = 2.4 Hz, J 2 = 5.4 Hz, 1H), 7.55-7.55 (d, J= 2.4 Hz, lH), 7.73-7.75 (d, J= S.9 Hz, 1H), 7.89-7.91 (dd, J, = 2.5 Hz, J2 = 9.2 Hz, 1H), 7.94-7.95 (d, J= 9.2 Hz, 1H), S.24 (d, J= 2.5 Hz, 2H), 8.25-8.27 (dd, J, = 2.6 Hz, J 2 = 8.9 Hz, 1H), 8.55 (d, J = 2.6 Hz, 1H), 8.60 (d, J= 5.4 Hz, 1H), 8.81-8.82 (q, J = 4.8 Hz, IH), 11.36 (s, 1H). Examples. Synthesis of 4-[3-(4-chloro-phenylamino)-benzo[1,2,41triazin-7-yloxyl-pyrdine 2-carboxylic acid methylamide trifluoroacetate salt H HMe

CF

3

COOH

68 [01451 To a vial with 2 mL of anhydrous dimethylfonnamide under argon atmosphere were added 15.4 mg (0.0 168 mmol, 0.05 equivalent) of tris(dibenzyllideneatone) dipalladium(0), 21.0 rug (0.033 mmol, 0.1 equivalent) of BINAP, 220.0 mg (0.675 mmol, 2.0 equivalent) of anhydrous cesium carbonate, 161.0 mg (0.675 mmol, 2.0 equivalent) of 1 chloro-4-iodobenzene, and 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino benzo[1,2,4]triazin-7-yloxy)-pyndine-carboxylic acid methylamide, in that particular order. Argon gas was bubbled through the mixture for 5 min. Then the vial was capped and the reaction mixture was heated to 120 0 C with stirring under argon atmosphere for 18 hours. At this point LC/MS indicated about 30 % conversion to the product. As it was observed from previous examples, the longer reaction times result in the formation of the by-product and partial decomposition. The reaction mixture was allowed to cool down to ambient temperature, filtered through. 0.22 .t syringe filter and purified by reverse-phase preperative HPLC using acetonitrile/water mixture with 0.1 % of TFA. (01461 ESI-MS: [M+H]*, 407,409. 'HNMR (DMSO-d,): S 2.79-2.80 (d, J= 4.88 Hz, 311), 7.30-7.32 (dd, J, = 2.6 Hz,]? = 5.6 Hz, 1H), 7.44-7.46 (d, J= 6.8 Hz, 2H), 7.54-7.55 (d, J=2.6 Hz, UH), 7.84-7.87 (dd, JI = 2.6 Hz, 2 = 9.05 Hz, 1H), 7.92-7.94 (d, J=9.05Hz, 11), 8.00-8.01 (d, J= 6.8 Hz, 2H), 8.19-8.20 (d, J=2.6 Hz, 1H), 8.58-8.59 (d, J= 5.6 Hz, 1H), 8.81-8.82 (qJ= 4.88 Hz, IH), 11.08 (s, 1H). Example 9. Synthesis of 4-[3-(3-trifluromethyl-benzenesulfonylamino)-ben-zof1,2.41triazin 7-yloxyl-pyridine-2-carboxylic acid methyl amide trifluoroacetate salt NHMe CF3COOH F [01471 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1,2,4]triazin-7-yloxy) pyridine-carboxylic acid methylamide were dissolved in 2 mL of anhydrous dimethylformamide with heating to about 100 0 C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid tert-BuOK was added to the solution. The resulting dark-red solution was stirred at 100*C for 30 min, then it was allowed to cool down to ambient temperature. 100 mng (0.405 mmol, 1.2 equivalent) of 3-trifluoromethyl-benzenesulfonyl chloride was added to the mixture via a syringe. It was allowed to stir at ambient temperature for 2 hours. The reaction 69 mixture was filtered through 0.22 .L syringe filter and purified by reverse-phase preperative HPLC using acetonitrile/water mixture with 0.1 % of TFA. {01481 ESI-MS: [M+H)*, 505, 506, 507. 'H NMR (DMSO-d6): S 2.78-2.79 (d, J = 4.8 Hz, 311), 7.29-7.31 (dd, J, = 2.6 Hz, J 2 = 5.7 Hz, 1H), 7.56 (d, J= 2.6 Hz, 1H), 7.87-7.90 (t, J= 7.8 Hz, 1H), 7.93-7.94 (d, J= 9.2 Hz, 1H), 7.97-7.99 (dd, J, 2.6 Hz, J = 9.2 Hz, IH), 8.06 8.08 (d, J= 7.8 Hz, IH), 8.21 (d, J= 2.5 Hz, 1H), 8.43-8.46 (m, 211), 8.57-8.58 (d, J= 5.7 Hz, 1H), 8.80-8.81 (q, J= 4.8 Hz, 1H). Example 10. Sythesis of 4-[3-(3-tr-ifluromethl -benzovlanno)-benzo[1,2.41triazin-7 ylox-N-pyridile-2-carboxylic acid methyl amide trifluoroacetate salt H I . HMe

CF

3 COOH

F

3 101491 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1,2,4]triazin- 7 -yloxy) pyridine-carboxylic acid methylamide were dissolved in 2 mL of anhydrous dimethylfonnamide with heating to about 100 C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid tert-BuOK was added to the solution. The resulting dark-red solution was stirred at 100"C for 30 min, then it was allowed to cool down to ambient temperature. 84.5 mg (0.405 mmol, 1.2 equivalent) of 3-trifluoromethyl-benzoyl chloride was added to the mixture via a syringe. It was allowed to stir at ambient temperature for 2 hours. The reaction mixture was filtered through 0.22 p syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1 % of TFA. [01501 ESI-MS: [M+H]*, 469, 470. 'HNMR(DMSO-d6): 2.80-2.81 (d,J= 4.88 Hz, 3H), 7.37-7.39 (dd, J, =2.6 Hz, J 2 =5.7 Hz, 1H), 7.64 (d, J= 2.6 Hz, 1H), 7.81-7.84 (t, J= 7.8 Hz, 1H), 8.03-8.06 (n, 2H), 8.15-8.17 (d,J= 9.2 Hz, 1H), 8.33-8.34 (d,J= 2.6 Hz, 1H), 8.36-8.38 (d, J= 8.0 Hz, 111), 8.45 (s, 111), 8.62-8.63 (d, J= 5.7 Hz, 1H), 8.84-8.85 (q, J 4.88 Hz, 1H), 12.29 (s, 1H).

70 Example 11. Synthesis of 4

-[

4 -(trifluromethoxy-benzoylamino)-benzof

L

2

,

4 1triazin-7.. yloxy]-pyridine-2-carboxylic acid thyl amide trifluoroacetate salt H I HMe

CF

3

CF

3 COOH [01511 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1, 2

,

4 ]triazin-7-yloxy) pyridine-carboxylic acid methylamide were dissolved in 2 mL of anhydrous DMF with heating to about 100 *C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid t-BuOK was added to the solution. The resulting dark-red solution was stirred at 100 *C for 30 min, then it was allowed to cool down to ambient temperature. 64 p.L (91.0 mg, 0.405 mmol, i.2 equivalent) of 4-trifluoromethoxy-benzoyl chloride was added to the mixture via a syringe. It was allowed to stir at ambient temperature for 2 hours. The reaction mixture was filtered through 0.22 syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1 % of TFA as a solvent system. [0152] ESI-MS: [M+H]*, 485, 486. 'H NMR (DMSO-d 6 ): 8 2.80-2.81 (d, J= 4.8 Hz, 3H), 7.37-7.38 (dd, J, =2.6 Hz, J 2 = 5.6 Hz, I8), 7.55-7.57 (d, J= 8.8 Hz, 2H), 7.63-7.64 (d, J= 2.6 Hz, 18), 8.03-8.05 (dd, J,= 2.7 Hz, J1= 9.1 Hz, IH), S.14-8.15 (d, J= 9.1 Hz, 1H), 8.20-8.22 (d, J= 8.8 Hz, 2H), 8.32-8.33 (d, J=2.7 Hz, 1H), 8.83-8.S4 (q, J= 4.8 Hz, 1H), 12.12 (s, IH). Example 12. Synthesis of 4

-[

3 -(trifluromethoxy-benzoylamino)-benizo[ 1,2,4]triazin-7 yloxyl-pvridine-2-carboxylic acid methyl aide trifluoroacetate salt H N HMe

CF

3

CF

3 COOH [0153] 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1, 2

,

4 ]triazin-7-yloKy) pyridine-carboxylic acid methylamide were dissolved in 2 mL of anhydrous DMF with heating to about 100 *C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid t-BuOK was added to the solution. The resulting dark-red solution was stirred at 100 *C for 30 min, then it was allowed to cool down to ambient temperature. 64 p.L (91.0 mg, 0.405 mniol, 1.2 equivalent) of 3-trifluoromethoxy-benzoyl chloride was added to the mixture via a syringe. It was allowed to stir at ambient temperature for 2 hours. The reaction mixture was filtered through 71 0.22 pL syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1 % of TFA as a solvent system. 101541 ESI-MS: [M+H]*, 485, 486. 'H NMR (DMSO-d 6 ): 5 2.80-2.81 (d, J= 4.8 Hz, 3 H), 7.37-7.39 (dd, Ji = 2.5 Hz, .12= 5.6 Hz, IH), 7.63-7.64 (d, J= 2.6 Hz, 1H), 7.67-7.74 (m, 2H), 8.03-8.05 (dd, Ji = 2.8 Hz, J= 9.36 Hz, 1H), 8.05 (in, IH), 8.12-8.14 (in, 1H), 8.14-8.16 (d, j=9.36 Hz, 1H), 8.33 (d, J= 2.8 Hz, 1H), 8.62-8.63 (d, J= 5.7 Hz, 1H), 8.83-8.84 (q, J= 4.8 Hz, 1H), 12.21 (s, 1H). Example 13. Synthesis of 4- 3-(chloro-benzenesulfonylamino)-benzof 1.2,4]triazin-7-vloxyl pyridine-2-carboxylic acid methyl amide trifluoroacetate salt H HMe CFCOOH 101551 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1,2,4]triazin--7-yloxy) pyridine-carboxylic acid methylamide were dissolved in 2 mL of anhydrous DMF with heating to about 100 *C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid t-BuOK was added to the solution. The resulting dark-red solution was stirred at 100 "C for 30 min, then it was allowed to cool down to ambient temperature. 85.8 mg (0.405 mmol, 1.2 equivalent) of 3 chloro-benzene sulfonyl chloride was added to the mixture via a syringe. It was allowed to stir at ambient temperature for 2 hours. The reaction mixture was filtered through 0.22 i syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1 % of TFA. 101561 ESI-MS: [M+H*, 471, 473, 474. 'H NMR (DMSO-d 6 ): S 2.78-2.79 (d, J= 4.9 Hz, 3H), 7.30-7.32 (dd,J; = 2.6 Hz, J2 = 5.6 Hz, IH), 7.57 (d,J= 2.6 Hz, 1H), 7.65-7.68 (t, J= 9.0 Hz, IH), 7.75-7.77 (m, IH), 7.98-7.99 (i, 2H), 8.10-8.12 (d, J= 7.8 Hz, lH), 8.15 (t, J= 1.8 Hz, IH), 8.22 (d, J=2.5 Hz, 1H), 8.57-8.58 (d, J= 5.4 Hz, lH), 8.80-8.83 (q, J=4.9 Hz,

IH).

72 Example 14. Synthesis of 4-[2-(trifluoromethyl-benzenesulfonylamino)-benzo(1.2,4]triazin 7-yloxy]-pyridine-2-carboxylic acid methyl amide trifluoroacetate salt N N F 3 H8 | HMe

CF

3 COOH (01571 100 mg (0.337 mmol, 1.0 equivalent) of 4-(3-amino-benzo[1.2,4]triazin-7-yloxy) pyridine-carboxylic acid methylamide were dissolved in 2 mL of anhydrous DMF with heating to about 100 *C. 45.4 mg (0.405 mmol, 1.2 equivalent) of solid t-BuOK was added to the solution. The resulting dark-red solution was stirred at 100 *C for 30 min, then it was allowed to cool down to ambient temperature. 100 mg (0.405 mmol, 1.2 equivalent) of 2 trifluoromethyl-benzenesulfonyl chloride was added to the mixture via a syringe. It was allowed to stir at ambient temperature for 2 hours. The reaction mixture was filtered through 0.22 [. syringe filter and purified by reverse-phase prep-HPLC using acetonitrile/water mixture with 0.1 % of TFA. [01581 ESI-MS: [M+H]+, 505, 506, 507. 'H NMR (DMSO-d 6 ): 5 2.78-2.79 (d, J=4.8 Hz, 3H), 7.29-7.31 (dd, J, = 2.6 Hz,.12 = 5.7 Hz, 1H), 7.56 (d, J= 2.6 Hz, 1H), 7.87-7.99 (m, 5H), 8.21 (d, J= 2.6 Hz, 1H), S.56-8.58 (d, 1H), 8.59-8.60 (d, J= 8.0 Hz, 1H), S.SO-8.81 (q, J= 4.8 Hz, 111). Example 15. Synthesis of 4-[2-chloro-5-(trifluoromethyl-benzenesulfonylamino) benzo1.2,41triazin-7-yloxy]-pyridine-2-carboxylic acid methyl aide trifluoroacetate salt HI NHMe

CF

3 COOH F 3 {01591 The experimental procedure that was used was the same as described in Example 9. [01601 ESI-MS: [M+H]*, 539, 541, 542. 'H NMR (DMSO-d 6 ): 5 (ppm) 2.78-2.79 (d, J= 4.9 Hz, 3H), 7.27-7.29 (dd, J; = 2.6 Hz, J 2 =5.7 Hz, 1H), 7.55 (d, J= 2.6 Hz, 11), 7.63-7.65 (d, J= 9.1 Hz, 1H), 7.86-7.88 (d, J =8.4 Hz, 1H), 7.91-7.94 (dd, J, = 2.6 Hz, J2 = 9.1 Hz, 1H), 8.04-8.06 (dd, , J;= 2.0 Hz, J= 8.4 Hz, 1H), 8.17-8.18 (d, J= 2.6 Hz, 1H), 8.56-8.57 (d, J= 5.7 Hz, 1H), 8.60-8.61 (d, J= 2.0 Hz, 111), 8.80-8.81 (q, J= 4.9 Hz, 111).

f 73 Example 16. Synthesis of 4-[3-chloro--6-methoxy-benzenesulfonylaminol benzof 12,41triazin-7-yloxyl-pyridine-2-carboxylic acid methyl amide trifluoroacetate salt Me NHMe H

CF

3 COOH [01611 The experimental procedure that was used was the same as described in Example 9. [01621 ESI-MS: [M+H)*, 501, 503, 504. 'H NMR (DMSO-d): 6 (ppm) 2.78-2.79 (d, J= 4.9 Hz, 3H), 3.85 (s, 3H), 7.20-7.22 (d, J= 8.9 Hz, 1H), 7.29-7.31 (dd, J, = 2.6 Hz, J 2 = 5.7 Hz, IH), 7.55 (d, J= 2.6 Hz, 1H), 7.67-7.70 (dd, JI = 2.8 Hz, J2 = 8.9 Hz, 1H), 7.80-7.81 (d, J= 9.2 Hz, 1H), 7.92-7.95 (dd, J1 = 2.8 Hz, 12 = 9.2 Hz, 1H), 8.05-8.06 (d, J= 2.8 Hz, 1H), 8.19-8.20 (d, J= 2.6 Hz, 1H), 8.57-8.58 (d, J= 5.6 Hz, 1H), 8.80-8.81 (q, J= 4.9 Hz, 1H), 13.00 (br.s. 1H). Example 17. Synthesis of 4-f 3-(5-chloro-thiophene-2-sulfonylamino)-benzo1.2,41triazin-7 yloxyl-pvridine-2-carboxylic acid methyl amide trifluoroacetate salt HMe CFCOOH [01631 The experimental procedure that was used was the same as described in Example 9. 101641 ESI-MS: [M+H}*, 477, 479. 'H NMR (DMSO-d 6 ): 6 (ppm) 2.79-2.80 (d, J= 4.8 Hz, 3H), 7.26-7.27 (d, J= 4.1 Hz, 1H), 7.32-7.34 (dd, J, = 2.6 Hz, 1, = 5.6 Hz, 1H), 7.59 (d, J= 2.6 Hz, 1H), 7.88-7.89 (d, J= 4.1 Hz, 1H), 7.99-8.02 (dd, J; = 2.7 Hz, 12 = 9.1 Hz, iH), 8.12-8.14 (d, J= 9.1 Hz, 1H), 8.26 (d, J= 2.7 Hz, 1H), 8.59 (d, J= 5.6 Hz, 11), 8.82-8.83 (q, J= 4.8 Hz, 1H), 13.00 (br.s. 1H).

74 Example 18. Synthesis of4-[2-chloro-3-trifluromethyl-benzoylamino)-benzo 1.

2 ,41triazin-7 yloxyl-pyridine-2-carboxylic acid methyl amide trifluoroacetate salt H HMe

CF

3 COOH F3 101651 The experimental procedure that was used was the same as described in Example 10. 101661 ESI-MS: [M+H], 503, 505, 506. 'H NMR (DMSO-d 6 ): 8 (ppm) 2.80-2.81 (d, J= 4.8 Hz, 3H), 7.36-7.37 (dd, J1 = 2.6 Hz, J 2 = 5.6 Hz, I H), 7.61 (d, J= 2.6 Hz, IH), 7.82-7.83 (d, J= 8.4 Hz, IH), 7.90-7.92(dd,J1 = 2.1 Hz, J 2 = 8.4 Hz, IH), 8.00-8.03 (m, 2H), 8.09 (m, IH), 8.29 (m, 1H), 8.61-8.62 (d, J = 5.6 Hz, 1H), 8.83-8.84 (q, J= 4.8 Hz, 1H), 12.41 (s, 1H). Example 19. Synthesis of 4-f2-chloro-3-trifluromethyl-benzovlamino)-benzof 1,2,41triazin-7 yloxyl-pyridine-2-carboxylic acid methyl aide trifluoroacetate salt H HMe

CF

3 COOH I 101671 The experimental procedure that was used was the same as described in Example 10. 101681 ESI-MS: [M+H]*, 435, 437. 'H NMR (DMSO-d 6 ): 5 (ppm) 2.80-2.81 (d, J = 4.8 Hz, 3H), 7.37-7.39 (dd, Jr = 2.6 Hz, J-2 = 5.6 Hz, 1H), 7.59-7.62 (t, J= 7.8 Hz, 1H), 7.63-7.64 (d, J=2.6 Hz, 1H), 7.72-7.74 (m, IH), 8.03-8.05 (m, 2H), 8.13 (m, IH), 8.15 (d, J= 9.1 Hz, 1H), 8.33 (d, J= 2.6 Hz, 11), 8.62-8.63 (d, J= 5.6 Hz, 1H), 8.83-8.84 (q, J= 4.8 Hz, lH), 12.12 (s, 1H).

75 Example 20. Sythesis of 4-[2,4-dichloro-benzoylamino)-benzo 1,2,4 tiazin-7-yloxyl pyidine-2-carboxylic acid methyl amide trifluoroacetate salt HMe

CF

3 COOH {01691 The experimental procedure that was used was the same as described in Example 10. [01701 ESI-MS: [M+H)*, 469, 471, 472. 'H NIVMR (DMSO-d6): 6 (ppm) 2.80-2.81 (d, J 4.8 Hz, 3H), 7.35-7.37 (dd, Ji = 2.6 Hz, J 2 = 5.6 Hz, 1H), 7.55-7.57 (dd, J; = 1.9 Hz,]'= 8.3 Hz, 1H), 7.61 (d, J= 2.6 Hz, 1H), 7.68-7.69 (d, J= 8.3 Hz, 1H), 7.76-7.77 (d, J= 1.9 Hz, 1H), 8.01 (m, 2H), 8.28-8.29 (m, 1H), 8.61 (d, J = 5.6 Hz, 1H), 8.83-8.84 (q, J= 4.8 Hz, IIH), 12.28 (s, 1H). Example 21. Synthesis of 4-[2-fluoro-3-chloro-5.triflUoroiethyl-benzoylamino) benzo(l, 2

,

4 ltriazin-7-loxy-pydine-2-carboxylic acid methyl amide trifluoroacetate salt H I7 HMe

CF

3 COOH

F

3 [01711 The experimental procedure that was used was the same as described in Example 10. {01721 ESI-MS: [M+H)*, 521, 523, 524. 1 H NMVfR (DMSO-d,): S (ppm) 2.80-2.81 (d, J 4.8 Hz, 3H), 7.36-7.38 (dd, J1 = 2.6 Hz, J2= 5.6 Hz, IH), 7.62 (d, J= 2.6 Hz, 1 H), 8.02-8.05 (dd, J, = 2.6 Hz, J2= 9.2 Hz, 1H), 8.07-8.09 (d, J= 9.2 Hz, IH), 8.14-8.15 (dd, 1H), 8.31 8.32 (d, J= 2.6 Hz, 11), 8.33-8.34 (dd, J, = 2.1 Hz, 1k = 6.4 Hz, 11), 8.62 (d, J= 5.6 Hz, 1H), 8.83-8.84 (q, j= 4

.

8 Hz, 1H), 12.45 (s, 1H).

76 Example 22. Synthesis of 4-[3-(4-chloro-3-trifluoromethyl-benzoylamino) benzofl,2,41triazin-7-yloxyl-pyridine-2-carboxylic acid methyl amide trifluoroacetate salt H| HMe

CF

3 COOH

F

3 [0173] The experimental procedure that was used was the same as described in Example 10. [01741 ESI-MS: [M+H)+, 503, 505, 506. 'H NMR(DMSO-d 6 ): 8 (ppm) 2.80-2.81 (d, J= 4.8 Hz, 3H), 7.37-7.39 (dd, Ji = 2.6 Hz,J = 5.6 Hz, 1H), 7.63-7.64 (d,J= 2.6 Hz, 1H), 7.95 7.97 (d, J= S.4 Hz, IH), 8.04-8.06 (dd, J = 2.7 Hz, J 2 = 9.3 Hz, IH), 8.15-8.17 (d, J= 9.3 Hz, IH), S.33-8.34 (d, J= 2.7 Hz, IH), 8.34-8.36 (dd,J; = 2.1 Hz, J,= 8.4 Hz, IH), S.54 8.56 (d,J= 2.1 Hz, 1H), 8.62-8.63 (d,J= 5.6 Hz, 1H), 8.83-8.84 (q, J= 4.8 Hz, lH), 12.35 (s, 1H). Example 23. Synthesis of 4-[3-(2-chloro-3-trifluoromethyl-benzoylamino) benzol ,2,4]triazin-7-yloxyl-pyridine-2-carboxylic acid methyl aide trifluoroacetate salt H HMe C CFCOOH

F

3 [01751 The experimental procedure that was used was the same as described in Example 10. 101761 ESI-MS: (M+H)*, 503, 505, 506. 'H NMR (DMSO-d 6 ): 8 (ppm) 2.80-2.81 (d, J= 4.8 Hz, 3H), 7.35-7.36 (dd, J, = 2.6 Hz, J 2 = 5.5 Hz, IH), 7.60-7.61 (d, J= 2.6 Hz, 1H), 7.66 7.69 (t, J= 7.8 Hz, 1H), 7.92-7.94 (m, 2H), 7.99-8.02 (m, 2H), 8.29 (d, J= 2.8 Hz, 1H), 8.61 8.62 (d, J= 5.6 Hz, IH), 8.83-8.84 (q, J= 4.8 Hz, 1H), 12.43 (s, IH).

77 Example 24. Synthesis of 4-[3-(3-trifluoromethoxy-benzoylamino)-benzor 1.2,4]triazin-7 yloxy]-pyridine-2-carboxylic acid methyl aide trifluoroacetate salt

CF

3 H HMe

CF

3 COOH (0177} The experimental procedure that was used was the same as described in Example 10. 101781 ESI-MS: [M+H], 485, 486, 487. 'H NMR (DMSO-d 6 ): 5 (ppm) 2.80-2.81 (d, J= 4.8 Hz, 3H), 7.35-7.37 (dd, J, = 2.6 Hz, J2 = 5.6 Hz, 111), 7.48-7.50 (d, J= 8.3 Hz, 1H), 7.53 7.56 (dt, J,= 0.9 Hz, 12 = 7.6 Hz, 1H), 7.62 (d, J= 2.6 Hz, 1H), 7.66-7.68 (dt, Jj= 1.7 Hz, J 2 = 8.0 Hz, IH), 7.78-7.79 (dt, J, = 1.7 Hz, J 2 = 7.6 Hz, 1H), 7.99-8.02 (m, 2H), 8.29 (d, J= 2.6 Hz, 111), 8.61 (d, J= 5.6 Hz, 111), 8.83-8.84 (q, J= 4.8 Hz, 1H), 12.22 (s, 1H). Example 25. Synthesis of 4-{3-f(5-Methyl-isoxazole-3-carbonyl)-aminol benzof 1,2,4]triazin-7-yloxyl-pyridine-2-carboxylic acid methyl amide trifluoroacetate salt H HMe

CF

3 COOH [01791 The experimental procedure that was used was the same as described in Example 10. 'HNIv (DMSO-d6): (ppm) 2.53 (s, 3H), 2.80-2.81 (d,J= 4.8 Hz, 3H), 6.79 (s, 1H), 7.37-7.38 (dd,1; =2.5 Hz, .J2 5.5 Hz, 1H), 7.63-7.64 (d, J= 2.4 Hz, IH), 8.04-8.06 (dd, Ji= 2.5 Hz, J2= 9.2 Hz, IH), 8.15-8.17 (d,J= 9.2 Hz, IH), S.32-8.33 (d, J= 2.5 Hz, 1H), 8.61 S.62 (d,J=5.5 Hz, IH), 8.83-8.84 (q, J= 4.8 Hz, LH), 12.04 (s, lH). Example 26 Testing of Inhibition of Raf Kinase In Vitro 101801 The ability of compounds of general structure (A) of the present invention to inhibit the kinase activity of Rafl was evaluated using two methods: a direct and a Rafl MEKI assay. In the direct assay, kinase reactions were conducted in 96-well plates by 78 combining recombinant human raf1 (29.4 U/well, Upstate, Lake Placid, NY), ATP (3 pM) myelin basic protein substrate (MBP, 1mg/ml, Upstate, Lake Placid, NY), and test agents (at concentrations ranging from about I nM/l to about 10 p.M), in the presence of kinase reaction buffer. The Raf1-MEKI assay utilized 2.9U/well rafi and 0.25 ug/well inactive MvLEK1 (MEK1 inactive, Upstate, Lake Placid, NY) and 3uM ATP. After reacting for 60 minutes at 30 *C, residual ATP was measured using a luciferase-based assay (KinaseGlo, Promega Corp.) as a measure of kinase activity. Data from four wells were then averaged and used to determine IC 50 values for the test compounds (Prism software package, GraphPad Software, San Diego CA). [01811 The test results were as follows: a known Raf inhibitor, compound A, displayed an

IC

50 of 16 nM; a known Raf inhibitor, compound B, displayed an IC 50 of 43 ruM; and an invention compound C, showed an IC 50 of 76 nM. Other invention compounds exemplified in Figure 1, displayed an IC 5 o below 100 pLM. Example 27. Testing of Inhibition of MAPK Pathway in Cellular Assay [01821 Western Blot Early passage primary human umbilical vein endothelial cells (HUVECs) were maintained in EGM-2 containing SingleQuots (Cambrex, East Rutherford, NJ), 10% FBS, 10mM HEPES, and 50 pg/ml gentamicin. Prior to treatment of the cells with inhibitor, the HUVECs were starved for I 8h by replacing serum-containing complete media with serum-free and SingleQuot-free media. The starved cells were pre-treated with inhibitors for 60 min at various concentrations (0-20 jiM). Next the HUVECs were treated with 50 ng/ml VEGF or FGF (Peprotech, Rocky Hill, NJ) for 6 min and the cells were immediately washed with ice-cold PBS. Cells were lysed with ice-cold RIPA buffer containing 100mM Tris pH 7.5, 150 mM NaCl, I mM EDTA, 1% deoxycholate, 1% Triton X-100, 0.1% SDS, 2 mM PMSF, one Complete-Mini protease inhibitor tablet (Roche, Indianapolis, IN; 1 tablet/ 7 ml of lysis buffer) and the phophatase inhibitors NaF (500 mM) and orthovanadate (1 mM). The cells were scraped and lysates transferred and centrifuged at 15,000 g for 10 min. Supernatants were transferred to new tubes and protein concentration was quantitated using the BCA protein reagent (Pierce, Rockford, IL). Cell lysates containing 20 jig of total protein were separated by 10% SDS-PAGE, transferred to nitrocellulose, and blocked in 5% milk in TBST. Anti phospho-ERK Thr 202/Tyr 204 (Cell Signaling, Beverly, MA), anti-phospho-MEK Ser2l7/221 (Cell Signaling), and c-Raf (BD Biosciences Pharmingen, San Diego, CA) used as primary antibodies were detected with 79 horseradish peroxidase-conjugated goat anti-mouse or rabbit secondary antibodies and bands were visualized using the SuperSignal West Pico chemiluminescence reagent system (Pierce) and Kodak X-ray film (Rochester, NY). [01831 Bay 43-9006 (Raf/FGF inhibitor) showed reduction of expression of p--MEK and p-ERK with IC50 between 200 and 300 nM when tested in this assay. U0126 (MEK inhibitor) showed reduction in p-Erk levels with IC 50 between 200 and 300 nM, while p MEK levels were unaffected. The results are shown in Table 1. As can be seen, compounds of the invention showed reduction in p-MEK and p-ERK levels with ICso between 400 nM and 20 p.M. Example 28. Cell Viability Assay 101841 XTT assay: HUVECs were seeded at 10,000 cells/well of a tissue culture treated 96-well plate treated with collagen type I and grown overnight in the complete EGM-2 media as described above. The following morning, the inhibitors were serial diluted with DMSO and added to the cells with a final DMSO concentration of 1%. After 24-48 hours cell viability was measured with an XTT assay (Sigma, St. Louis, MO). The cells were also photographed to compare morphological differences to the XT trends observed. Determination of the IC 50 values was performed with quantitative software (Prism software package, GraphPad Software, San Diego CA). Several inhibitors blocked cell proliferation and induced apoptosis at concentrations below 1 FM and experiments were repeated three times to confirm the observations. The compounds of the invention displayed IC 5 o between 100 nM and 40 uM in this assay (Table 1).

80 Table 1. Test Results for Examples 26, 27 and 28. Structure Examples RAF-MEK assay (blocheical Westerm Blot Inhibition of HUVEC cell assay) prollfirat1on (IC50) .py I0-50 M in R -Me; 77 n a ot active at 5 u &*4"*=""" "' direct assay; 100 % windowv alOIYC3 S .. 0 . F .- , 11.6 ;--20%w dow not active at 5 aM flat -at aolo atS 5 uh flat not active at 5 uM .mer.1ato o.

0 .. ,.uSema.yl'- u, -ioht notvactivet5uM brI5t..4rs ia- ytein34terb ~3V l > s [ ul anot active atuS M1 o~oa.Il±411..b.,tn> ,I.3tO 0>50 I ntadoatS oh!1 asede t~ai.l pyun-4 - 655.M; -70/ i50 uM not active at 5 uM Hase '''*e "" 5"" temr(.u a n-e yiymiek, say u >50M ot active at 5 UM a ~ ~ ~ ~ ~ ~ ~ 1 nAoI;II.01a~ol,0n~.t0O - 3% vid al Sule at S ott , bene 021.:.4>t~tame~esi annad50 uM not ative at 5 AtM fl'lat asd -i at50 t~nafl2.1034,O~ololon.lu.I11 6552 nM; -730% wind-ow 00t active3 at M 0e.l. inds-.LI hirel~tl .anO'I not acilve at15 uM! 81 ~ P.2.lhlY acive at S .. MI ~ :V( partly active at 5 LdNI CF. Example 29. Synthesis of S-methyl N-[4-chloro-3 (trifluoromethyl)phenyllisothiourea hydroiodide H C,,qN SMe z NH 2 CI CF3 101851 4-Chloro-3-trifluoromethyl-phenylthiourea (5.0 g, 19.63 mmol) was dissolved in ca. 80 mL of anhydrous MeOH and methyl iodide (2.93 g, 20.61 mmol) was added via a syringe. The reaction mixture was refluxed for 12 hours. Then it was cooled down to ambient temperature and solvent was removed in vacio to give colorless oil (7.85 g), which was taken to the next step without further purifications. 101861 S-methyl N-[4-trifluoromethoxyphenyl]isothiourea hydroiodide, S-methyl N-[4 hydroxy-phenyl]lisothiourea hydroiodide, S-methyl N-[3-hydroxy-phenyllisothiourea hydroiodide and S-methyl N-[3-(trifluoromethyl)pheniyl]isothiourea hydroiodide-were prepared according to the method of this example. 101871 In the case of 1,2,4-triazoles three tautomeric structures can be present, as shown below: 82 1 21 22 A--- A H 4H-1,2,4-triazole 1H-1,2,4-triazole IH-1,2,4-triazole [01881 Even though all three tautomeric structures can exist, all the generic structures and all the examples having 1,2,4-triazole moiety are shown only in one tautomeric form, such as 4H-1,2,4-triazole for simplicity and for the comparison with its direct analogues, such as examples containing 1,3,4-oxadiazole moiety. The prevailing tautomeric structure depends on the substituents on the triazole moiety and on the reaction conditions. As has been shown in the literature, 1H-1,2,4-triazole is usually the most common tautomeric form, especially if an amino substituent is attached to the ring. Using only 4H-tautomeric form to draw the structures for the sake of simplicity, does not imply that the compounds of the examples that follow necessarily exist in that particular tautomeric form. Using this approach, the IUPAC names for the examples below are provided for 4H-tautomeric form only, however it is understood, that upon the elucidation of the exact tautomeric structure the numbering of the substituents may differ from the one that is provided. Example 30. -Synthesis of 4-[5-(4-chloro-3 -trifluoromethyl-phenvlamino) 1.,2.41triazol-3-yll -phenol 1\ I HO- H H

F

3 101891 4-hydroxybenzoic acid hydrazide (3.0 g, 19.66 mmol) and S-methyl N-[4-chloro 3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.8 g, 19.66 mmol) were suspended in 100 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. Then it was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow oil was re-dissolved in a small amount of ethyl acetate, loaded on a short pad of silica gel and eluted with 5:1 hexane/ethyl acetate, then with 100 % ethyl acetate to collect the product. The product was re-purified by a second silica gel column chromatography, using ISCO system (80 g pre-packed column, 25 min run, 20% to 50 % EtOAc gradient in hexane). Solvent was removed in vacuo to give the title product as a white solid (2.83 g). Yield 40.4 %.

83 [01901 ESI-MS: [M+H]* 355.1, 356.8,. 'H NMR (DMSO-d 6 ): 5 6.89-6.91 (d, J= 8.7 Hz, 2H), 7.53-7.55 (d, J= S.8 Hz, 111), 7.70-7.72 (dd, J; = 8.8 Hz, J 2 = 2.6 Hz, 1H), 7.77-7.79 (d, J= 8.7 Hz, 2H), 8.24-8.25 (d, J= 2.6 Hz, IH), 9.81 (s, 1H), 9.98 (s, 1H), 13.62 (s, 1H). Example 31. Synthesis of 4-{4-[5-(4-chloro-3-trifluoromethyl-phenvlamino)-4H [1,2,4ltriazol- 3 -yll-phenoxy}-pyridine-2-carboxylic acid methylamide trifluoroacetic acid salt %\J::F3 -- H H HMe

CF

3 COOH 101911 ESI-MS: [M+H}*,490, 491. 'H NMR (DMSO-d 6 ): 5 2.78-2.79 (d, J= 4.8 Hz, 3H), 7.24-7.25 (m, 111), 7.40-7.42 (d, J= 8.7 Hz, 2H), 7.48 (s, 1H), 7.56-7.58 (d, J= 8.8 Hz, 1H), 7.79-7.82 (dd, J, = 2.6 Hz, J 2 = 8.8 Hz, 1H), 8.07-8.09 (d, J= 8.7 Hz, 211), 8.24-8.25 (d ,J=2.6 Hz, 1H), 8.55-8.56 (m, 1H), 8.80-8.81 (m, 1H), 9.95 (s, IH). Example 32. Synthesis of(4-chloro-3-trifluoromethyl-phenyl)-{5-f4-(pyridin-3 yloxy)-phenyll-4H- I .2,41triazol-3-yl} -amine trifluoroacetic acid salt -1 I Z-, I I F3 N) - H H F CFCOOH 101921 4 -[5-(4-chloro-3-trifluoronethyl-phenylamino)4H[1,2,4]triazol-3-yl]-phenol (127.8 mg, 0.36 rrmol) was dissolved in 3 mL of anhydrous DMF in a 5 nil microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (144.0 mg 0.72 mmol) was added and the reaction mixture was stirred with heating at 80 *C for 15 min, then 3 bromopyridine (68.3 mg, 0.432 mmol) was added, followed by anhydrous KICO3 (50.0 mg, 0.36 rmmol). Then the vial was capped and microwaved at 250 *C for 30 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (15.1 mg). 101931 ESI-MS: [M+H], 432, 433. 'H NMR (DMSO-d 6 ): 5 7.19-7.21 (d, J= 8.8 Hz, 2H), 7.49-7.51 (dd, J,= 4.5 Hz, J 2 = 8.6 Hz, 1H), 7.53-7.55 (d, J= 8.8 Hz, 1H), 7.58-7.60 84 (in, 1H), 7.74-7.76 (i, 1H), 7.95-7.98(d,J=8.8 Hz,2H), 8.21-8.21 (d,J= 2.6 Hz, IH), 8.44 (m, 1H), 8.48 (m, IH), 9.88 (s, 1H). Example 33. Synthesis of methyl 4-(pyridine-3-yloxy)benzoate 0 [01941 3-hydroxypyridine (6.17 g, 64.87 mmol) was dissolved in 100 mL of anhydrous DMF under argon atmosphere. Solid K 2 C0 3 (8.96 g, 64.87 mmol) was added, followed by neat methyl 4-fluorobenzoate (10.0 g, 64.87 mmol). The reaction mixture was heated at 135 "C for 10 hrs. The absence of the starting material was confirmed by LC/MS. The reaction mixture was cooled down to ambient temperature and poured into ca. 500 mL of H 2 0. The resulting solution was extracted 3 times with ca. 150 mL of EtOAc (during the extraction small volumes of MeOH, Et 2 O and brine were added to facilitate the separation). Combined EtOAc layers were washed twice with sat. NaHCO 3 , twice with brine and dried over anhydrous Na 2

SO

4 . Solvent was removed in vacuo to give dark-red oil, which was purified by silica gel chromatography using 1:1 mixture of EtOAc/Hexane as eluent to give the title product (4.8 g, 32.3 % yield) as yellow solid. 101951 ESI-MS: [M+H], 230, 231. 'H NMR (DMSO-d 6 ): 5 3.83 (s, 3H), 7.09-7.12 (d, J = 8.8 Hz, 2H), 7.48-7.51 (dd, J, = 8.4 Hz, J 2 = 4.9 Hz, 1H), 7.58-7.61 (dq, J, = 8.4 Hz, J 2 = 1.4 Hz, 1H), 7.96-7.99 (d, J= 8.8 Hz, 2H, 8.46-8.47 (in, 2H). Example 34. Synthesis of 4-(pyridine-3-yloxy)benzohydrazide 0 N O NH2 [0196] Methyl 4-(pyridine-3-yloxy)benzoate (4.8 g, 20.94 mmol) was dissolved in ca. 150 mL of EtOH and anhydrous hydrazine (4.08 g , 4.0 mL) was added via a syringe. The resulting yellow solution was refluxed for 24 hrs. Then solvent was removed in vacuo to give the title product (4.8 g, 100 % yield) as yellow viscous oil, which upon standing slowly solidified.

85 101971 ESI-MS: [M+H], 230,231. H NMR (DMSO-d6): 8 4.13 (br s., 2H), 7.06-7.09 (d, J= 8.7 Hz, 2H), 7.45-7.47 (dd, J1 = 8.4 Hz,J2= 4.9 Hz, 1H), 7.51-7.54 (dq, J, = 8.4 Hz, 12= 1.4 Hz, 1H), 7.85-7.88 (d, J= 8.8 Hz, 2H), 8.42-8.43 (in, 211), 9.74 (s, IH). Example 35. Synthesis of (4-chloro-3-trifluoromethyl-Phenyl)- {5-F4-(pyridin-3 yloxy)-phenyll-4H-f l,2,4]triazol-3-yl}-amine C1 N-N l N N CF3 N..H H [01981 4-(pyridine-3-yloxy)benzohydrazide (2.33 g, 10.2 mmol) was dissolved in ca. 70 mL of anhydrous pyridine and S-methyl N-[4-chloro-3-(trifluoromethyl)phenyl] isothiourea hydroiodide (4.04 g, 10.2 mmol) was added. The reaction mixture was refluxed for 18 hrs under Ar. The pyridine was removed in vacuo and the resulting residue was purified by silica gel chromatography using EtOAc as eluent to give the title product (0.56 g) as a white solid. [01991 ESI-MS: [M+H]*, 432, 433. 'H NMR (DMSO-d 6 ): 5 7.20-7.23 (d, J= 8.8 Hz, 2H), 7.46-7.49 (dd, J;= 8.4 Hz, J 2 = 4.5 Hz, 11), 7.54-7.57 (m, 2H), 7.75-7.77 (dd, J, = 8.8 Hz, J2= 2.6 Hz, 1H), 7.97-7.99 (d , J= 8.8 Hz, 2H), 8.23-8.24 (d , J= 2.6 Hz, IH), 8.43 (in, IH), 8.46 (d, J= 2.6 Hz, lH), 9.88 (s, 1H), 13.91 (s, 1H). Example 36. Synthesis of 6- (4-{5-(4-chloro-3-trifluoromethyl-phenylamino)- 4

H

r,2,41triazol-3-yll-phenoxy} -pyrimidine-2.4-diamine

NH

2 N\N N-NC

H

2 N N N CF3 0 ~ H H 102001 4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl}-phenol (1.3 g, 3.66 mmol) was dissolved in 18 mL of anhydrous dioxane in a 10-20 mL microwave vial (Personal Chemistry). Solid Cs 2

CO

3 (1.19 g, 3.66 mmol, 1.0 eq) was added and the reaction mixture was stirred with heating at 80 "C for 10 min, then 4-chloro-2,4-diaininopyrinidine (0.530 g, 3.66 mmol) was added. The vial was capped and nucrowaved at 200 "C for 25 min. Then the reaction mixture was diluted with ca. 10 mL of MeOH, transferred into a round bottom flask and concentrated in vacuo to ca. 20 mL. The resulting reddish solution was loaded on a short pad of silica gel and eluted first with 100 % ethyl acetate to remove the 86 unreacted starting material and then with 20 % MeOH in EtOAc to elute the product. The product was further purified by ISCO system (80 g pre-packed column, 40 min method, 0% to 10 % MeOH gradient in ethyl acetate). Solvent was removed in vacuo to give the title product as an off-white solid (0.785 g). Yield 46.3 %. [0201] ESI-MS: [M+H]*, 463, 464, 465. 'H NMR (DMSO-d 6 ): 8 5.15 (s, I H), 6.03 (s, 2H), 6.31 (s, 2H), 7.25-7.27 (d, J = 8.6 Hz, 21H), 7.55-7.57 (d, J= 8.8 Hz, 11), 7.77-7.78 (m, 1H), 7.96-7.97 (d , J= 8.8 Hz, 21), 8.25-8.26 (d , J= 2.6 Hz, 1H), 9.91 (s, 111), 13.91 (s, IH). Anal. Calcd for (Cj 9

H

1 4

CLF

3 NsO x 0.4 EtOAc): C, 49.68; H, 3.48; N, 22.50, Found: C, 49.61; H, 3.55; N, 22.90. Example 37. Synthesis of 6-{4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H [,2.41triazol-3-vll-phenoxyl-pyrimidine-2,4-diamine methanesulfonic acid salt

NH

2

H

2 N

CF

3 0 - H H McSO 3 H 102021 6-{4-[5-(4-Chloro-3-trifluoromethyl-phenylamino)-4H-1 ,2,4]triazol-3-yl] phenoxy}-pyrimidine-2,4-diamine x 0.4 EtOAc complex (470.0 mg, 0.943 minmol) was dissolved in ca. 50 mL of anhydrous methanol and methasulfonic acid (0.0612 mL, 0.943 mmol, 1.0 eq.) was added. The resulting solution was stirred for 30 min. Solvent was removed in vacuo and the resulting light-yellow foam was dried at 70 *C in high vacuum for 3 hrs to give the title compound as an off-white solid (527.3 mg). Yield 100%. 102031 ESI-MS: [M+H]*, 463, 464. 'H NMR (DMSO-d 6 ): 8 2.36 (s, 3H), 5.40 (s, 1H), 7.39-7.40 (d, J= 8.6 Hz, 2H), 7.57-7.58 (d, J= 8.8 Hz, 111), 7.78 (in, 1 H), 7.80 (br.s., 411), 8.02-8.03 (d , J= 8.8 Hz, 2H), 8.25--8.26 (d ,J= 2.6 Hz, 1H), 9.94 (s, lH), 13.98 (br..s. 1H). Anal. Calcd for (Cj 9

H

1 4 ClF 3

N

8 0 x I CH 3

SO

3 H): C, 42.98; H, 3.25; N, 20.05, Fqund: C, 42.93; H, 3.62; N, 20.12.

87 Example 38. Synthesis of methyl 4-[(2,6-diaminopyrimidin-4-yl)oxylbenzoate 0 o 0&

N

7

H

2 N N NH 2 102041 Methyl 4-hydroxybenzoate (1.52 g, 10.0 mmol) was dissolved in 18 mL of anhydrous dioxane in 10-20 mL microwave vial (Personal Chemistry) and solid Cs2CO3 was added to this solution. The suspension was stirred at ambient temperature for 10 min, then 4 chloro-2,6-diaminopyriidine (1.45 g, 10.0 mmol) was added. The vial was capped and microwaved at 200 *C for 40 min. Then MeOH was added to dissolve the formed suspension to produce a clear amber solution. The solution was transferred into a round-bottom flask and concentrated down to ca. 20 mL. This solution was purified by silica gel chromatography using 100 % ethyl acetate as eluent. The product was additionally re crystallized from ca. 50 mL of 4:1 mixture of EtOAc/MeOH. The product was filtered, washed with 40 mL of EtOAc, 40 mL of anhydrous Et2O and dried in vacuo to give the title product as a white solid (0.812 g). Yield 31.2%. 102051 ESI-MS: [M+H]*, 261.01. 'H NMR (DMSO-d6): 8 3.84 (s, 3H), 5.19 (s, IH), 6.06 (br. s, 2H), 6.37 (br.s, 2H), 7.19-7.21 (d, J= 8.7 Hz. 21), 7.95-7.97 (d, J= 8.7 Hz, 2H). "C NMR (DMSO-d 6 ) 52.1, 78.3, 121.0, 125.3, 130.9, 157.8, 163.2, 165.7, 166.6, 169.2. Example 39. Synthesis of 4-[(2.6-diaminnovrimidin-4-ylloxylbenzohydrazide 0 O NH2 0& H

N

7

H

2 N N NH 2 102061 Methyl 4-((2,6-diaminopyrimidin4-yl)oxy]benzoate (2.74 g, 10.52 mmol) was suspended in ca. 180 niL of anhydrous methanol and anhydrous hydrazine (1.021 g, 1.0 mL, 31.85 mmol, 3.03 eq) was added to this suspension. The reaction mixture was refluxed for 3 hours, then MeOH was very slowly distilled off till the total volume reached ca. 30 mL. This 88 solution was allowed to stand at ambient temperature for 48 hrs. A white precipitate slowly crystallized out. It was collected, washed with 40 mL of EtOAc, 40 niL of anhydrous Et 2 O and dried in vacuo to give the title product as a fine white powder (2.02 g). Yield 73.7 %. [0207] ESI-MS: [M+H], 261.12. 'H NMR (DMSO-d 6 ): S 4.54 (br.s., 2H), 5.13 (s, 1 H), 6.01 (br. s, 2H), 6.30 (br.s, 2H), 7.13-7.14 (d, J= 8.7 Hz, 2H), 7.83-7.84 (d, J 8.7 Hz, 2H), 9.75 (s, 1H). "C NMR (DMSO-d6) 77.9, 120.9, 128.5, 129.3, 155.8, 163.3, 4, 166.6, 169.7. Example 40. Synthesis of 6-{4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H f1.2,4]triazol-3-vil-phenoxyl-pyrimidine-2.4-diamine

NH

2 N N-N CI

H

2 N O N N CF 3 0H H [02081 4-[(2,6-diaminopyrimidin-4-yl)oxy]benzohydrazide (1.48 g, 5.68 mmol) and S methyl N-[4-chloro-3-(trifluoromethyl)phenyl]isothiourea hydroiodide (2.33 g, 5.89 mmol) were suspended in 30 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours under Ar atmosphere. The formed yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting yellow foamy solid was re dissolved in 50 mL of 5:1 EtOAc/MeOH; ca. 15 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was packed into ISCO column and the product was purified using ISCO system (80 g pre-packed column, 50 min run, 0% to 10 % gradient of solvent B in solvent A [Solvent A - 4 mL of MeOH, 4mL of Et 3 N in 4 L of CH 2 C12; Solvent B - 4 mL of Et 3 N in 4 L of MeOH)). Solvent was removed in iacuo to give the title product as a white solid (1.33 g). Yield 50.5 %. 102091 ESI-MS: [M+H]*, 463, 464. 'H NMR (DMSO-d): 8 5.15 (s, 1H), 6.03 (s, 2H), 6.31 (s, 2H), 7.25-7.27 (d, J= 8.6 Hz, 211), 7.55-7.57 (d, J= 8.8 Hz, 1H), 7.77-7.78 (m, 1H), 7.96-7.97 (d , J= 8.8 Hz, 2H), 8.25-8.26 (d , J= 2.6 Hz, 1H), 9.91 (s, 1H), 13.91 (s, 1H). Anal. Calcd for (C 19 H1 4 ClF 3 N8O x 0.4 EtOAc): C, 49.68; H, 3.48; N, 22.50, Found: C, 49.61; H, 3.55; N, 22.90.

89 Example 41. Synthesis of 6-{4-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H [1,2,41triazol-3-ll-phenoxyl-pyridazin-3-ylainle tifluoroacetic acid salt H2 F3 "_ H H

F

3

CF

3 COOH 102101 4 -[5-(4-chloro-3-trifluoromethyl-phenlylamino)-4H[ I ,2,4]triazol-3-yl]-phenol (120.0 mg, 0.338 mmol) was dissolved in 3 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (81.0 mg, 0.406 mrmnol) was added and the reaction mixture was stirred with heating at 80 'C for 15 min, then 3-amino-6 chloro-pyridazine (48.2 mg, 0.372 mmol) was added, followed by anhydrous K 2 C0 3 (46.7 mg, 0.338 mmol). Then the vial was capped and microwaved at 200 *C for 30 min. After reaction was complete, the reaction mixture was diluted with ca. ImL of MeOH, filtered through 0.22 urn syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (18.2 mg). 102111 ESI-MS: [M+H)*, 44S, 449. 'H NMR (DMSO-d6): 5 7.42-7.43 (d, J= S.7 Hz, 2H), 7.54-7.56 (d, J= 9.7 Hz, IH), 7.56-7.58 (d, J= 8.8 Hz, IH), 7.76-7.79 (m, IH), 7.78 7.80 (d, J= 9.7 Hz, 1H), 8.01-8.04 (d , J= 8.8 Hz, 211), 8.25-8.26 (d , J= 2.6 Hz, IH), 8.49 (br.s., 2H), 9.94 (s, 1H). Example 42. Synthesis of 4-{5-(4-trifluoromethoxy-phenvlamino) 411 ,2,4]triazol-3-yll-phenol HO

CF

3 H -0 H H [02121 4-hydroxybenzoic acid hydrazide (0.643 g, 4.23 mmol) and S-methyl N-[4 (trifluoromethoxy)phenyl]isotliourea hydroiodide (1.6 g, 4.23 mmol) were suspended in 10 mL of anhydrous pyridine. The reaction mixture was refluxed for 24 hours, during which time it changed color from yellow into orange-red. Then it was cooled down to ambient temperature and poured with stirring into 150 mnL of ice-water. The formed white solid was collected, washed thoroughly with water and dried in air. The resulting residue was purified 90 by silica gel chromatography using Isco column with 10% to 100 % gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a pinkish solid (575.2 mg). Yield 40.4 %. [ 2131 ESI-MS: [M+H]* 337, 338. 'H NMR (DMSO-d 6 ): S 6.85-6.87 (d, J= 8.0 Hz, 2H), 7.19-7.20 (d, J= 8.0 Hz, 2H), 7.61-7.63 (d, J= 8.7 Hz, 2H), 7.75-7.77 (d , J= 8.7 Hz, 2H), 9.39 (s, IH), 9.92 (s, IH), 13.42 (s, 1IH). Example 43. Synthesis of 4-{4-[5-(4- ifluoromethoxy-phenylamino)-4H [1.2,41triazol-3-yll-phenoxyl -pyridine-2-carboxylic acid methvlamide trifluoroaL -. tic acid salt

CF

3 % P_- H H HM, [02141 4-[5-(4-trifluoromethoxy-phenylamxino)-4H[1, 2 ,4]triazol-3-yl]-phenol (66.4 mg, 0.197 nunol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (39.4 mg, 0.197 mmol) was added and the reaction mixture was stirred with heating at 80 *C for 15 min, then 4-chloro-2 pyridinecarboxamide (33.7 mg, 0.197 mmol) was added, followed by anhydrous K 2

CO

3 (27.3 mg, 0.197 mmol). Then the vial was capped and microwaved at 200 *C for 15 min. Then the reaction mixture was diluted with ca. 1mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (46.6 mg). [02151 ESI-MS: [M+H]* 471, 472. 'H NMR (DMSO-d 6 ): 8 2.78-2.79 (d, J= 4.8 Hz, 3H), 7.23-7.25 (dd, J = 5.6 Hz, J = 2.6 Hz, 1H), 7.25-7.27 (d, J= 8.6 Hz, 2H), 7.38-7.40 (d, J= 8.6 Hz, 2H), 7.47-7.47 (d,J= 2.6 Hz, 1H), 7.66-7.70 (d, J= 8.7 Hz, 2H), 8.08-8.11 (d, J= 8.7 Hz, 2H), 8.55-8.56 (d,J= 5.6 Hz, IH), 8.79-8.82 (t, J= 4.8 Hz, lH), 9.58 (s, lH). Example 44. Synthesis of {5-[4-(pyridin-4-yloxy)-phenvl]-4H-f 1,2,41triazol-3-yll-(4 trifluoromethoxy-phenyl)-amine trifluoroacetic acid salt

CF

3 CH H

CFCOOH

91 102161 4-[5-(4-trifluoromethoxy-phenylamino)-4H[ 1,2,4]triazol-3-yll-phenol (106.0 mg, 0.3 15 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (157.2 ng, 0.788 rmmol) was added and the reaction mixture was stirred with heating at 80 *C for 15 min, then 4-chloropyridine hydrochloride (56.7 mg, 0.378 mmol) was added, followed by anhydrous K 2 C0 3 (44.0 mg, 0.315 mmol). Then the vial was capped and microwaved at 250 "C for 20 min. Then the reaction mixture was diluted with ca. ImL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.0 1% TFA. The product was isolated as a TFA salt (66.5 mg of off-white solid). 102171 ESI-MS: {M+H)*, 415, 416. 'H NMR (DMSO-d6): 8 7.26-7.27 (d, J= 8.7 Hz, 2H), 7.46-7.48 (m, 2H), 7.46-7.48 (d, J= 7.1 Hz, 2H), 7.67-7.70 (d, J= 8.7 Hz, 2H), 8.13 8.16 (d, J= 8.7 Hz, 2H), 8.77-8.78 (d, J= 7.1 Hz, 2H), 9.64 (s, IH). Example 45. Synthesis of 6-{4-f5-(4-trifluoromethoxy-phenylamino)-4H-(1,2,4]triazol-3-yll phenoxy}-pyridazin-3-ylamine trifluoroacetic acid salt

H

2

CF

3 CFCOOH 102181 4 -[5-(4-trifluoromethoxy-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (112.0 mg, 0.33 mrol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (132.8 mg, 0.66 mmol) was added and the reaction mixture was stirred with heating at 80 "C for 15 min, then 3-amino-6 chloropyridazine (47.4 mg, 0.366 mmol) was added, followed by anhydrous K 2 C0 3 (46.0 mg, 0.33 mmol). Then the vial was capped and microwaved at 250 *C for 15 min. Then the reaction mixture was diluted with ca. ImL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (52.1 mg of brown crystalline solid). 102191 ESI-MS: [M+H)*, 431. 'H NMR (DMSO-di): S 7.25-7.26 (d, J= 8.7 Hz, 2H), 7.39-7.41 (d, J= 8.7 Hz, 2H), 7.52-7.54 (d, J= 9.7 Hz, 1H), 7.67-7.68 (d, J= 8.7 Hz, 2H), 7.76-7.78 (d, J= 9.7 Hz, 1H), 8.03-8.06 (d, J= 8.7 Hz, 2H), 9.58 (s, 1H).

92 Example 46. Synthesis of 6-{4-[5-(4-trifluoromethoxy-phenylamino)-4H-f l,2.4ltriazol-3 yll-phenoxyl-pyrimidine-2,4-diamine trifluoroacetic acid salt

H

2

CF

3 H2 - H H CFCOOH [0220] 4-[5-(4-tTrifluoromethoxy-phenylamino)-4H[l,2,4]triazol-3-yl]-phenol (112.0 mg, 0.33 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (132.8 mg, 0.66 mmol) was added and the reaction mixture was stirred with heating at 80 *C for 15 min, then 4-chloro-2,6-diamino pyrimidine (53.0 mg, 0.366 mmol) was added, followed by anhydrous K 2

CO

3 (46.0 mg, 0.33 mmol). Then the vial was capped and microwaved at ' 0 *C for 15 min. Then the reaction mixture was diluted with ca. 1mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (51.1 mg of beige solid). [02211 ESI-MS: [M+H)*, 445, 446. 1H NMR (DMSO-d 6 ): 8 5.36 (s, I H), 7.25-7.27 (br. d, J= 8.0 Hz, 2H), 7.35-7.36 (br. d, J= 8.0 Hz, 2H), 7.67-7.6S (d, J = 8.7 Hz, 2H), 7.67 (br.s., 4H), 8.02-S.04 (d, J= 8.7 Hz, 2H), 9.57 (br. s, 1H). Example47. Synthesis of 4-(5- { [3-(trifluromethyl)phenyllamino} -4H- 1.2.4-triazol-3-vl) phenol N-N HO N N

CF

3 102221 S-methyl N-[3-(trifluoromethyl)phenyl]isothiourea hydroiodide (9.09 g, 25.11 mmol) and 4-hydroxybenzoic acid hydrazide (3.82 g, 25.11 mmol) were suspended in ca. 50 mT anhydrous pyridine under Ar. The mixture was brought to reflux and refluxed under Ar tor 12 hrs. Then the dark-yellow solution was cooled down to ambient temperature and pyridine was removed in vacuo. The resulting reddish-yellow solid was re-dissolved in ca. 50 mL of 4:1 mixture of EtOAc/MeOH, ca. 20 g of silica gel was added and solvent was removed in vacuo. The impregnated silica gel was loaded into 25 g ISCO sample cartridge and the product was purified using ISCO system (solid method, 80 g column, 45 min, 0% to 93 50% EtOAc gradient in hexane). Solvent was removed in vacuo to give the title product as a white solid (3.83 g). Yield 47.6%. [02231 ESI-MS: [M+H]',321.09. 'HNMR (DMSO-d 6 ): S 6.89-6.90 (d,J= 8.6 Hz, 2H), 7.09-7.11 (d, J= 7.3 Hz, IH), 7.42-7.46 (t, J= 7.9 Hz, IH), 7.73-7.74 (d, J= 7.0 Hz, 1H), 7.77-7.79 (d, J= 8.6 Hz, 2H), 8.09 ( s, 1H), 9.65 (s, 1H), 9.97 (br. s., IH). Example 48. Synthesis of 6-f4-(5-f[3-(trifluoromethyl)phenyllaminol--4H [1,2,4triazol-3-yl)-phenoxyl-pyimidine-2,4-diamine

NH

2 N- N N--N HN~K

H

2 N \ N N CF 3 0 ~- H H [02241 4-(5-{[3-(trifluromethyl)phenyl]amino} -4H-1,2,4-triazol-3-yl)phenol (160 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs 2 CO3 (163.0 mg, 0.5 mmol) was added, followed by 4-chloro-2,6, diaminopyrimidine (79.5 mg, 0.55 mmol). The vial was capped and microwaved at 200 *C for 20 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.0 1% of TFA. [02251 The fractions containing the product were collected and partitioned between EtOAc and saturated aqueous NaHCO 3 . Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as an off-white solid (92.2 mg). 102261 ESI-MS: [M+H)*, 429.08. 'H NMR (DMSO-d6): 8 5.15 (s, 1H), 6.02 (s, 2H), 6.30 (s, 2H), 7.12 (m, lH), 7.25-7.27 (d, J= 7.4 Hz, 2H), 7.45-7.47 (in, 1H), 7.75-7.76 (m, 1H1), 7.95-7.97 (d, J= 8.6 Hz, 2H), 8.10 (s, lH), 9.73 (s, 1H), 13.84 (s, IH). Example 49. Synthesis of 5-[4-(pyrimidi-5-yloxy)phenyll-N-[3 (trifluoromethyllphenyll- 4 H-1,2,4-triazol-3-amine N NN N CF 0 ~- H H CF 94 [02271 4-(5- [3-(trifluromethyl)phenyl]armino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs 2

CO

3 (203.4 mg, 0.62 rnmol) was added, followed by 5-bromo pyrimidine (100 mg, 0.62 mmol). Then I mL of anhydrous DMF was added, the vial was capped and microwaved at 250 "C for 30 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension, the solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 nL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions containing the product were collected and partitioned between EtOAc and saturated aqueous NaHCO 3 . Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a light-brown foamy solid (34.7 mg). 102281 ESI-MS: [M+H}f, 399.06. 'H NMR (DMSO-d 6 ): 5 7.12 (i, IH), 7.30-7.32 (d, J= 7.4 Hz, 2H), 7.46 (in, IH), 7.76 (in, 1H), 8.00-8.02 (d, J= 8.6 Hz, 2H), 8.09 (s, IH), 8.73 (s, 2H), 9.06 (s, 1H), 9.73 (s, 1H1), 13.95 (s, 1H). Example 50. Synthesis of 5-[4-(pyridin-3-yloxy)phenyll-N-f3 (triflIuoromethyl)phenyll-4H-[ 1,2.41triazol-3-amine N N -N ON N CF 3 0 ..- 1 H H [02291 4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mrnol) was dissolved in 2 rL of anhydrous DMF in 2-5 mL microwave vial (Personal Chemistry). Solid Cs 2

CO

3 (203.4 mg, 0.62 mmol) was added, followed by 3-bromopyridine (74.0 mg, 0.468 imol). The vial was capped and microwaved at 250 *C for 30 min. Then ca. I mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO 3 . Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a yellow solid (22.4 mg). [02301 ESI-MS: [M+H], 398.11. 'H NMR (DMSO-d 6 ): 6 7.09 (d, J=7.6 Hz, 1H), 7.20 7.22 (d, J= 8.6 Hz, 2H), 7.46-7.48 (m, 2H), 7.52-7.54 (m, 1H), 7.75-7.76 (d, J= 8.2 Hz, 1H), 95 7.99-8.02 (d, J= 8.6 Hz, 2H),8.09 (s, 1H), 8.42-8.43 (d, J= 4.5 Hz, IH), 8.45-8.46 (d, J= 2.6 Hz, 1H), 9.73 (s, 1H), 13.85 (s, IH). Example 51. Synthesis of 4-Methoxy-6-r4-(5- { f3-(trifluoromethyllphenyllamino} 4H-1.2,4-triazol-3-yl)phenoxylpyrimidin-2-amine

NH

2 N N N-N M e O \ N\ N . N CF 3 Me-OH H [02311 4-(5-{[3-(trifluromethyl)phenyllamino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid CS 2 CO3 (101.7 mg, 0.31 mmol) was added, followed by 2-amino-4 chloro-6-methoxypyfimidine (55.0 mg, 0.34 mmol). The vial was capped and microwaved at 200 "C for 15 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.0 1% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO 3 . Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as an off-white solid (55.6 mg). 102321 ESI-MS: [M+H]*, 443.87. 'H NMR (DMSO-d6): S 3.80 (s, 3H), 5.53 (s, 1H), 6.70 (s, 2H), 7.11-7.12 (d, J= 7.4 Hz, 11), 7.30-7.32 (d, J= 8.4 Hz, 2H), 7.44-7.47 (t, J= 7.6 Hz, IH), 7.74-7.76 (d, J= 8.4 Hz, IH), 7.97-7.98 (d, J= 8.4 Hz, 2H), 8.10 (s, 1H), 9.73 (s, 1H), 13.88 (s, 11). Example 52. Synthesis of 6-{4-(5-{f3-(trifluoromethyl)phenllamiino}.-4H r1.2.41triazol-3-yl)-phenoxyl-pyrimidin-4-amine NA N-N

H

2 N O_( N N C F 3 0 .- H H {0233] 4-(5-{[3-(trifluromethyl)phenyl]amino}-4H-1,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal 96 Ch. istry). Solid Cs 2

CO

3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6 chloro-pyrimidine (48.5 mg, 0.37 mmol). The vial was capped and microwaved at 200 "C for 5 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCC.

3 . Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (76.6 mg). [02341 ESI-MS: [M+H)*, 461.0. 'H NMR (DMSO-d 6 ): 5 2.31 (s, 3H), 5.49 (s, I H), 6.93 (s, 2H), 7.14 (m, 1H), 7.33-7.35 (d, J= 7.5 Hz, 2H), 7.45-7.48 (t, J= 7.6 Hz, I H), 7.75 (in, lH), 8.00-8.02 (d, J= 8.6 Hz, 2H), 8.10 (s, IH), 9.75 (s, IH), 13.88 (s, IH). Example 53. Synthesis of 2-(Methylthio)-6-[4-(5- ff3 (trifluoromethyl)phenyllamino} -4H-1,2,4-triazol-3-yl)-phenoxyl-pyrimidin-4-amine SMe N N-N

H

2 N N N N CF 3 0 - H H 102351 4-(5- {[3-(trifluromethyl)phenyl]amino} -4H- I,2,4-triazol-3-yl)phenol (100 mg, 0.31 mmol) was dissolved in 3 mL of anhydrous dioxane in 2-5 mL microwave vial (Personal Chemistry). Solid Cs2CO3 (101.7 mg, 0.31 mmol) was added, followed by 4-amino-6 chloro-2-(methylthio)-pyrimidine (60.3 mg, 0.34 mmol). The vial was capped and microwaved at 200 *C for 10 min. Then ca. 3 mL of MeOH was added to dissolve the formed suspension. The resulting reddish-brown solution was transferred into a round-bottom flask and solvent was removed in vacuo. The residue was re-dissolved in 3 mL of DMF, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetontrile/water system with 0.01% of TFA. The fractions, containing the product, were collected and partitioned between EtOAc and saturated aqueous NaHCO 3 . Ethyl acetate layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title compound as a white solid (39.5 mg).

97 102361 ESI-MS: [M+H]*,461.0. 'HNMR(DMSO-d 6 ): 6 3.80 (s, 3H), 5.53 (s, 1H), 6.70 (s, 2H), 6.30 (s, 2H), (d, J= 8.6 Hz, 2H), Example 54. Synthesis of 4-f5-(4-trifluoromethoxy-phenyl)- 4 H-f1,2.41triazol-3-ylaminol phenol HO N

OCF

3 [02371 4-trifluoromethoxybenzoic acid hydrazide (1.1 g, 5.0 rnmol) and S-methyl N-[4 hydroxy-phenylisothiourea hydroiodide (1.55 g, 5.0 mmol) were suspended in 10 muL of anhydrous pyridine. The reaction mixture was refluxed for 24 hours, during which time it changed color from yellow into orange-red. Then it was cooled down to ambient temperature and poured with stirring into 150 mL of ice-water. The aqueous layer was decanted and the resulting residue was purified by silica gel chromatography using 1:1 mixture of ethyl acetate/hexane. Solvent was removed in vacuo to give the title product as a pinkish-grey solid (684.0 mg). 40.6 % yield. [02381 ESI-MS: [M+H)*, 337, 338. 'H NMR (DMSO-d): 6 7.68-6.71 (d, J= 8.8 Hz, 2H), 7.32-7.35 (d, J= 8.8 Hz, 2H), 7.47-7.49 (d, J= 8.8 Hz, 2H), 8.04-8.07 (d, J= 8.8 Hz, 2H), 9.05 (br. s, 1H). Example 55. Synthesis of 4-{4-f5-(4-trifluoromethoxy-phenyl)-4H-[1,2,4]triazol-3 ylaminol-phenoxy}-pyrdine-2-carboxylic acid methylamide trifluoroacetic acid salt HMe H H / CF, cFcOOH [02391 4-[5-(4-trifluoromethoxy-pheiyl)- 4 H[1,2,4}triazol-3-ylanino)-phenol (134.5 mg, 0.4 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (120.0 mg, 0.6 mmol) was added and the reaction mixture was stirred with heating at 80 0C for 15 min, then 4-chloro-2-pyridine carboxamide (68.2 mg, 0.4 mmol) was added, followed by anhydrous K 2 C0 3 (62.0 mg, 0.44 mimol). Then the vial was capped and microwaved at 150 0C for 30 min. Then the reaction 98 mixture was diluted with ca. ImL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.0 1% TFA. The product was isolated as a TFA salt (31.7 mg of white solid). [0240] ESI-MS: [M+H]*471, 472. 'H NMR (DMSO-d 6 ): S 2.77-2.78 (d, J= 4.8 Hz, 3H), 7.13-7.15 (d, J= 8.3 Hz, 2H), 7.13 (m, IH), 7.40 (br. s, IH), 7.51-7.53 (d, J= 8.3 Hz, 2H), 7.70-7.73 (d, J = 8.8 Hz, 2H), 8.09-8.11 (d, J = 8.8 Hz, 2H), 8.48-8.49 (d, J = 5.3 Hz, lH), 8.77-8.78 (q, J= 4.8 Hz, 1H), 9.56 (s, IH). Example 56. Synthesis of 3-[ 5-( 4 -chloro-3-trifluoromethyl-phenylamino) 4Hf1.2,41triazol-3-vil-ohenol N-N C1 HO 1 )K t I N N

CF

3 rI H [0241] 3-hydroxybenzoic acui hydrazide (2.98 g, 19.58 mmol) and S-methyl N-[4-chloro 3-(trifluoromethyl)phenyl]isothiourea hydroiodide (7.78 g, 19.63mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography on Isco column using 0 => 50 % gradient of ethyl acetate in hexane. Solvent was removed in vacuo to give the title product as a white solid (2.176 g). 31.3 % yield. [0242] ESI-MS: [M+H] 355.1, 356.8,. 'H NMR (DMSO-d 6 ): 8 6.88-6.90 (dq, J; = 7.9 Hz, J 2 0.9 Hz, IH), 7.31-7.34 (t, J= 7.9 Hz, IH), 7.35-7.39 (m, 2H), 7.54-7.56 (d, J= 8.8 Hz, IH), 7.74-7.76 (dd,J, = 8.8 Hz,J 2 = 2.7 Hz, IH), 8.23-8.24 (d, J= 2.7 Hz, 1H), 9.79 (s, 1H), 9.87 (s, 1H), 13.86 (s, 1H).

99 Example_57. Synthesis of 4-{3-5-(4-chloro-3-trifluoromethyl-phenylamino)-4H f1.2,41triazol- 3 -yll-phenoxy}-pyridine-2-carboxylic acid methylamide trifluoroacetic acid salt --- H H HMe

CF

3 COOH [02431 3-[5-(4-chloro-3-tri fluoromethyl-phenylamino)-4H[ I ,2,4]triazol-3-yl)-phenol (100 mg, 0.282 runol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 mmol) was added and the reaction mixture was stirred with heating at 80 *C for 15 min, then 4-chloro-2 pyridine-carboxamide (52.9 mg, 0.31 mmol) was added, followed by anhydrous

K

2 C0 3 (19.5 mg, 0.141 mmol). Then the vial was capped and microwaved at 250 *C for 20 min. Then the reaction mixture was diluted with ca. lmL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (25.0 mg of white solid). {02441 ESI-MS: [M+H)*489,490,491. 'HNMR(DMSO-d6): 52.78-2.79(d,J=4.8 Hz, 3H), 7.25-7.26 (dd, J, = 2.5 Hz, J 2 5.5 Hz, lH), 7.3S (i, 1H), 7.48-7.49 (d, J= 2.5 Hz, I H), 7.55-7.57 (d, J= 8.8 Hz, lH), 7.67-7.70 (t, J= 7.8 Hz, I H), 7.73 (br. s., 1H), 7.78 (br. s., 1 H), 7.91-7.93 (d, J= 7.8 Hz, 1H), 8.20-8.21 (d, J= 2.6 Hz, 1-1), 8.56-8.57 (d, J= 5.5 Hz, 1H), 8.80-8.81 (q, J= 4.8 Hz, 1H), 9.93 (s, 1H). Example 5S. Synthesis of 6-{3-[5-(4-chloro-3-trifluoromethyl-phenv amino)-4H [1,2,41triazol-3-yl-l-Ipenoxy}-pyrimidine-2,4-diamine trifluoroacetic acid salt

H

2 \IF

H

2 - H H F 3

CF

3 COOH [0245] 3-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H{1,2,4)triazol-3-yli-phenol (100 ng, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial. Solid 100 potassium bis(trimrethylsilyl)amide (140.6 mg, 0.705 nmol) was added and the reaction mixture was stirred with heating at 80 *C for 15 min, then 4-chloro-2,6-diamino-pyrimidine (44.8 mg, 0.31 mmol) was added, followed by anhydrous K 2 C0 3 (19.5 ng, 0.141 mmol). Then the vial was capped and microwaved at 250 *C for 20 min. Then the reaction mixture was diluted with ca. ImL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (37.8 mg of beige solid). 102461 ESI-MS: [M+H] 4 464, 465. 'H NMR (DMSO-d 6 ): 5 5.40 (s, lH), 7.33-7.35 (d, J= 7.6 Hz, 1H), 7.57-7.59 (d, J= 8.8 Hz, 1ff), 7.62-7.65 (t, J= 7.8 Hz, IH), 7.73 (br. s., IH), 7.80 (br. in., 1H), 7.88-7.89 (d, J= 7.8 Hz, 1H), 8.21-8.22 (d, J= 2.6 Hz, I H), 9.96 (s, IH). Example 59. Synthesis of (4-chloro-3-trifluoromethvl-phenyl)-{5-3-(pyridin-4 yloxy)-phenyll-4H-[1,2,4ltriazol-3-yl}-amine trifluoroacetic acid salt - H H

F

3

CF

3 COOH [02471 3-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4Hl,2,4]triazol-3-yi]-phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 mmol) was added and the reaction mixture was stirred with heating at 80 "C for 15 min, then 4-chloro-pyridine hydrochloride (46.5 mg, 0.31 mmol) was added, followed by anhydrous K 2 C0 3 (19.5 mg, 0.141 mumol). Then the vial was capped and microwaved at 250 *C for 20 min. Then the reaction mixture was diluted with ca. ImL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (34.6 ig of beige solid). [02481 ESI-MS: [M+H) 432, 433. 'HNMR(DMSO-d6): S7.43-7.45 (br. s. 1H), 7.46 7.47 (d,J= 7.0 Hz, 2H), 7.56-7.58 (d, J= 8.8 Hz, 1H), 7.72-7.75 (t, J=7.8 Hz, 1H), 7.80 (br. s., 1H), 7.81 (br. s, 1H), 7.98-8.00 (d,J= 7.8 Hz, IH), 8.21-8.22 (d, J= 2.6 Hz, 1H8.76 8.78 (d, J= 7.0 Hz, IH), 9.98 (s, 1H).

101 Example 60. Synthesis of 6-f3-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H {1,2,41ttiazol-3-yl-plhenoxyl-pyridazin-3-vlamine trifluoroacetic acid salt

H

2 I H H

F

3

CF

3 COOH [02491 3 -[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H{I,2,4]triazol-3-yl]-phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 nnrnol) was added and the reaction mixture was stirred with heating at 80 'C for 15 min, then 3-amino-6-chloro-pyridazine (40.2 mg, 0.31 numol) was added, followed by anhydrous

K

2 C0 3 (19.5 mg, 0.141 mmol). Then the vial was capped and microwaved at 250 *C for 20 min. Then the reaction mixture was diluted with ca. ImL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (35.5 mg of light-brown solid). [02501 ESI-MS: [M+H) 448,449. 'H NMR (DMSO-d 6 ): 8 7.38-7.39 (br. s. IH), 7.55 7.57 (d, J= 9.6 Hz, 1H), 7.57-7.58 (d, J= 8.6 Hz, 1H), 7.62-7.65 (t, J= 7.8 Hz, 1H), 7.78 (br. s., 1H), 7.80 (br. s, IH), 7.82-7.84 (d, J= 9.6 Hz, IH), 7.86-7.88 (d, J= 7.8 Hz, IH), 8.22-8.23 (d, J= 2.6 Hz, 1H), 8.52 (br.s., 2H), 9.94 (s, 1H). Example 61. Synthesis of 4-(5-{f4-chloro-3-(trifluoromethyl)-phenyllamino}-1.3.4 oxadiazol-2-yl)phenol

F

3 H {02511 Mercury (II) oxide (yellow) (4.55 g, 21.0 mmol) was suspended in 60 mL of anhydrous MeOH under Ar. A bright-orange suspension was formed. To this suspension was added 4-hydroxybenlzoic acid hydrazide (3.20 g, 21.0 mmol) and 4-chloro-3 trifuoromethyl-phenylisothiocyanate (5.0 g, 21.0 mmol). The reaction mixture was refluxed for 2 hours. The solvent was removed in vacuo. The black residue was redissolved in 100 mL of EtOAc and the resulting black suspension was filtered through a short pad of silica gel.

102 The filtrate was mixed with 10 g of dry silica gel and solvent was remove. vacuo. The impregnated silica gel was loaded on silica gel column and the product wz .tparated using a gradient of hexane:ethyl acetate mixture starting from 50:50 ratio and finishing at 0:100. All fractions containing the product were combined; solvent was removed in vacuo to give a grey solid. The solid was heated in 50 mL of 4:1 mixture of EtOAc/MeOH. The formed suspension was cooled down to ambient temperature and filtered to give the title product as a white crystalline solid (4.54 g, 60.7 % yield). 102521 ESI-MS: [M+H]* 356.0. 'H NMR (DMSO-d 6 ): 5 6.92-6.95 (d, J= 8.8 Hz, 2H), 7.69-7.70 (d, J= S.8 Hz, 1H), 7.71-7.73 (d, J= 8.8 Hz, 2H), 7.82-7.84 (dd, J, = 8.8 Hz, J, = 2.6 Hz, 1H), 8.16-8.17 (d, J= 2.6 Hz, 1H), 10.21 (br s., IH), 11.11 (br s., H). Example 62. Synthesis of 6-[4-(5-{[4-Chloro-3-trifluoromethvl-phenyllaminol-1.3,4 oxadiazol-2-yl)-phenoxyl-pyrimidine-2,4-diamine

H

2 / I

H

2 .- H F 3 1.02531 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl]amino}-1,3,4-oxadiazol-2-yl)phenol (1.067 g, 3.0 mmol) was dissolved in ca. 70 mL of anhydrous DMF under argon. Solid potassium bis(trimethylsilyl)amide (0.718 g, 3.6 mmol) was added and the resulting yellow solution was heated at 70 *C for 1.5 hours. Then solid K 2 C0 3 (0.414 g, 3.0 mmol) was added, followed by 2,6-diamino-4-chloropyrimidine (0.520 g, 3.6 mmol). The reaction mixture was left to reflux under argon for 30 hours. Then it was allowed to cool down to ambient temperature and poured into ca. 500 mL of water. The aqueous mixture was extracted 5 times with 100 mL of EtOAc. Combined EtOAc extracts were washed three times with 100 mL of brine, and dried over anhydrous Na 2

SO

4 . Solvent was removed in vacuo to a give a reddish-yellow residue, which was purified by silica gel chromatography using EtOAc as an eluent. Fractions, containing the product, were collected; solvent was removed in vacuo to give the product as a reddish-yellow solid. The solid was re-crystallized from 10 mL of EtOAc, collected, washed thoroughly with diethyl ether and dried in vacuo to give the title compound (0.527 g, 38 % yield) as beige solid. {02541 ESI-MS: [M+H]* 464,465. 'H NMR (DMSO-d 6 ): 8 5.20 (s, 1H), 6.05 (br s., 2H), 6.34 (br.s., 2H), 7.27-7.30 (d, J= 8.7 Hz, 2H), 7.71-7.72 (d, J= 8.8 Hz, 1H), 7.84-7.88 (dd, Jr = 8.8 Hz, J 2 = 2.6 Hz, 1H), 7.89-7.91 (d, J= 8.7 Hz, 2H), 8.18-8.19 (d, J= 2.6 Hz, 1H), 103 11.26 (s, 1H). Anal. Calcd for CiqH 13 ClF 3 N7O 2 : C, 49.20; H, 2.83; N, 21.14, Found: C, 49.08; H, 3.21; N, 20.95. Example 63. Synthesis of 6-f4-(5- {f4-chloro-3-trifluoromethyl-phenllamino} -1.3.4 oxadiazol-2-yl)-phenoxyl-pyrimidine-2,4-diamine trifluoroacetic acid salt

H

2 1

F

3 I H

H

2

CF

3 COOH 102551 4-(5- {[4-chloro-3-(trifluoromethyl)-phenyl] amino} -1 ,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol was dissolved in 2.5 mL of anhydrous DMF in a 5 mL microwave vial. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.703 mmol) was added and the reaction mixture was stirred with heating at 80 *C for 15 min, then 6-chloro-2,4-diamino pyrimidine (81.3 mg, 0.562 mmol) was added, followed by anhydrous

K

2

CO

3 (19.5 mg, 0.141 mmol). Then the vial was capped and microwaved at 200 *C for 15 min. Then the reaction mixture was diluted with ca. I rmL of MeOH, filtered through 0.22 urn syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (75.8 mg of beige solid). 102561 ESI-MS: [M+H]* 464, 465. 'H NMR (DMSO-d 6 ): 5 5.41 (s, 1H), 7.39-7.42 (d, J= 8.7 Hz, 2H), 7.63 (br s., 4H), 7.72-7.74 (d, J= 8.8 Hz, 1H), 7.85-7.87 (dd, J, = 8.8 Hz, 12 = 2.7 Hz, 1H), 7.95-7.97 (d, J= 8.7 Hz, 2H), 8.20 (d, J= 2.7 Hz, IH), 11.29 (s, I H). Example 64. Synthesis of N-{4-chloro-3-(trifluoromethyl)phenyll-5-{4-(pyridin-3 vloxy)phenyll-1.3.4-oxadiazol-2-anine trifluoroacetate salt H

F

3 CFCOOH 102571 4-(5-{[4-chloro-3-(trifluoronethyl)-phenylamno} -1,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol) was dissolved in ca. 2 mL of anhydrous DMF under argon. Solid potassium bis(trimethylsilyl)amide (140.2 mg, 0.702 mmol) was added and the resulting yellow solution was heated at 80*C for 15 min. Then solid K 2 C0 3 (19.4 mg, 0.140 mmol) was added, followed by 3-bromopyridine (89.0 mg, 0.562 mmol). The reaction mixture was 104 microwaved at 250 *C for 10 min. Then it was diluted with 1 mL of MeOH, filtered and purified by preparative reverse-phase chromatography using acetonitrile/water with 0.1 % TFA gradient. The major peak having the mass of the product was collected; solvent was removed in vacuo to give the title product as a brown oil (20.6 mg). {02581 ESI-MS: [M+H)*433.5, 434.3. 'H NMR (DMSO-d,): 5 7.24-7.26 (d, J= 8.8 Hz, 2H), 7.57-7.59 (dd, J; = 8.4 Hz, J2 = 4.7 Hz, IH), 7.68-7.71 (dq, J, = 8.4 Hz, J= 1.4 Hz, 1H), 7.71-7.73 (d, J= 8.8 Hz, "), 7.84-7.86 (dd, J1 = 8.8 Hz, J, = 2.7 Hz, 1H), 7.92-7.94 (d, J= 8.8 Hz, 2H), 8.17-8.18 (d, J= 2.7 Hz, 1H), 8.50 (br d, J= 4.0 Hz, 1H), 8.54 (br s, 111), 1 1.24 (s, IH). Example 65. Synthesis of N-[4-chloro-3-(trifluoromethyl)phenyll-5-[4-(pyridin-4 yloxy)phenyll-1.3,4-oxadiazol-2-amine trifluoroacetate salt

F

3

CF

3 COOH [02591 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl)amino} -1,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol) was dissolved in ca. 2 mL of anhydrous DMF under argon. Solid potassium bis(trimethylsilyl)amide (225 mg, 1.12 mmol) was added and the resulting yellow solution was heated at 80"C for 15 min. Then solid K 2 C0 3 (38.8 mg, 0.281 mmol) was added, followed by 4-chloropyridine hydrochloride (84.3 mg, 0.562 mmol). The reaction mixture was microwaved at 200 *C for 25 min (Initiator, Biotage). Then it was diluted with 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected; solvent was removed in vacuo to give the title product as a white fluffy solid (85.6 mg). 102601 ESI-MS: [M+H] 435.3. 'H NMR (DMSO-d 6 ): 5 7.37-7.38 (d, J=4.8 Hz, 2H), 7.48-7.50 (d, J= 8.8 Hz, 2H), 7.72-7.74 (d, J= 8.8 Hz, 1H1), 7.85-7.88 (dd, J, = 8.8 Hz, J2= 2.7 Hz, 1H), 8.03-8.06 (d, J= 8.8 Hz, 1H), 8.19-8.20 (d, J= 2.7 Hz, IH), 8.74 (br s., 211), 11.31 (s, 1H).

105 Example 66. Synthesis of N-{4-chloro-3-(trifluoromethyl)phenyll-5-{ 4 -(pyrimidin-5 vloxy)phenyll-1,3,4-oxadiazol-2-amine trifluoroacetate salt

F

3 H

CF

3 COOH 102611 4-(5-{[4-chloro-3-(trifluoromethyl)-phenylamino}-1,3,4-oxadiazol-2-yl)phenol (100 mug, 0.281 mmol) was dissolved in ca. 2 mL of anhydrous DMIF under argon. Solid potassium bis(trimethylsilyl)amide (140.2 mg, 0.702 nmol) was added and the resulting yellow solution was heated at 80*C for 15 min. Then solid K 2 C0 3 (19.4 mg, 0.140 mmol) was added, followed by 3-bromopyrimidine (89.4 mg, 0.562 mmol). The reaction mixture was microwaved at 200 "C for 15 min. Then it was diluted with 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected; solvent was removed in vacuo to give the title product as a white fluffy solid (73.0 mg of white crystalline solid). 102621 ESI-MS: [M+H]*434.3,435.3. IHNMR(DMSO-d6): S7.31-7.33 (d,J= 8.8 Hz, 2H), 7.71-7.73 (d,J= 8.8 Hz, 1H), 7.84-7.86 (dd,J;= 8.8 Hz,J = 2.7 Hz, IH), 7.93-7.95 (d, J= 8.8 Hz, 2H), 8.17-8.18 (d, J= 2.7 Hz, 1H), 8.77 (s, 2H), 9.09 (s, 1H), 11.25 (s, 1H). Example 67. Synthesis of 4-f4-(5- f f4-chloro-3-(trifluoromethvl)phenyll amino } - 1,3,4 adiazol-2-yl)phenoxyl-N-methylpydine-2-carcetate salt cFc F3 1H Me CF3COOHI [02631 4-(5-{[4-chloro-3-(trifluoromethyl)-phenyl]amino} -1,3,4-oxadiazol-2-yl)phenol (100 mg, 0.281 mmol) was dissolved in ca. 2 mL of anhydrous DMF under argon. Solid potassium bis(trimethylsilyl)amide (140.2 mg, 0.702 mmol) was added and the resulting yellow solution was heated at 80*C for 15 min. Then solid K 2 C0 3 (19.4 mg, 0.140 mmol) was added, followed by 4-chloro-2-pyridine-carboxamide (52.7 mg, 0.309 mmol). The 106 reaction mixture was microwaved at 200 C for 15 min. Then it was diluted with 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitnile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected; solvent was removed in vacuo to give the title product as a white solid (67.5 mg). 102641 ESI-MS: [M+H]* 490.4, 491.3. i' NMR (DMSO-d,): 6 2.79-2.80 (d, J= 4.9 Hz, 3H), 7.26-7.28 (dd, J, = 5.6 Hz, J2= 2.6 Hz, 1H), 7.43-7.44 (d, J= 6.8 Hz, 2H), 7.49 (d, J= 2.6 Hz, 1H), 7.72-7.74 (d, J= 8.8 Hz, lH), 7.85-7.86 (dd, J, = 8.8 Hz, J 2 = 2.6 Hz, IH), 8.01 8.03 (d, J = 6.8 Hz, 2H), 8.19 (d, J= 2.6 Hz, IH), 8.57-8.58 (d, J= 5.7 Hz, IH), 8.79-8.81 (q, J= 4.9 Hz, I H), 11.28 (s, I H). Example 68. Synthesis of 4-f5-(4-chloro-3-(trifluoromethyll-phenyl)-4H-1.2,4-triazol-3 yLminolphenol N-N H H CI

CF

3 102651 4-chloro-3-trifluoromethylbenzoic acid hydrazide (2.89 g, 12.1 nmol) and S methyl N-(4-hydroxyphenyl)isothiourea hydroiodide (3.75 g, 12.1 mmol) were suspended in 40 mL of anhydrous pyridine. The reaction mixture was refluxed for 18 hours, during which time it changed color from yellow into dark-red. Then it was cooled down to ambient temperature and poured with stirring into 250 mL of ice-water. The aqueous solution was decanted and the oily residue was purified by silica gel chromatography using 1:1 mixture of ethyl acetate/hexane. Solvent was removed in vacuo to give the title product as a white solid (1.95 g). Yield 45.5%. Example 69. Synthesis of 6-f4-((5-[4-chloro-3-(trifluoromethyl)phenvl-4H-1,2,4-triazol-3 yl amino)phenoxylpyrimidine-2,4-diamine trifluoroacetate salt

H

2

H

2

F

3

CF

3

COOH

107 102661 4 -{5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazol-3-ylamino]phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 mmol) was added and the resulting solution was heated at 80*C for 15 min. Then solid K 2 C0 3 (20 mg, 0.141 mmol) was added, followed by 4-chloro-2,6-diamino-pyrinidine (61.1 ng, 0.422 mmol). The reaction mixture was microwaved at 200 *C for 20 min. Then it was diluted with I mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected, solvent was removed in vacuo to give trifluoroacetate salt of the product as a white solid (28.6 mg). {02671 ESI-MS: {M+H]* 463.4, 464.

4 . 1H NMR (DMSO-d6): 5 5.24 (s, 1H), 7.14-7.16 (d, J= 8.8 Hz, 2H), 7.65-7.66 (d, J= 8.8 Hz, 2H, 7.81 (br s., 4H), 7.88-7.90 (d, J =8.4 Hz, 1H), 8.23-8.25 (dd, J = 8.4 Hz, J 2 = 1.7 Hz, 1H), 8.37 (s, IH), 9.66 (br s., 1H). Example 70. Synthesis of 5-[4-chloro-3-(trifluoromethvl)phenl-N4 4 4Pydine- 4 yloxy)phenyll-4H-1,2,4-triazol-3-amine trifluoroacetate salt H H

F

3

CF

3 COOH {02681 4 -[5-(4-chloro-3-(trifluoromethyl)-phenyl)- 4 H-1,2,4-triazol-3-ylamino]phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF. Solid potassium bis(trimethylsilyl)amide (196.2 mg, 0.983 mmol) was added and the resulting solution was heated at SO 0 C for 15 min. Then solid K 2

CO

3 (20 mg, 0.141 mmol) was added, followed by 4-chloropyridine hydrochloride (63.2 mg, 0.421 mmol). The reaction mixture was microwaved at 220 *C for 30 min. Then it was diluted with I mL of MeOH, filtered through 0.22 urn syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected, solvent was removed in vacuo to give trifluoroacetate salt of the product as a light-brown solid (23.5 mg). {02691 ESI-MS: [M+H)* 432, 433. 'H NMR (DMSO-d 6 ): 8 7.23-7.25 (d, J= 8.8 Hz, 2H), 7.39-7.40 (d, J =7.2 Hz, 2H), 7.74-7.77 (d, J= 8.8 Hz, 2H), 7.89-7.90 (in, IH), 8.24-8.26 108 (dd,Jj = 8.4 Hz,J2=2.0 Hz, 1H), 8.38 (s, 1H), 8.73-8.74 (d,J= 7.2 Hz, 2H), 9.75 (brs., 1H-). Example 71. Synthesis of 5-[4-chloro-3-(trifluoromethyl)phenyll-N-f4-(pyimidin-5 yloxy)phenyll-4H-1,2,4-triazol-3-amine trifluoroacetate salt H H I .

F

3

CF

3 COOH 102701 4 -[5-(4-chloro-3-(trifluoromethyl)-phenyl)-4H-1,2,4-triazol-3-ylamino]phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF. Solid potassium bis(trimethylsilyl)amide (84.1 mg, 0.421 mmol) was added and the resulting solution was heated at 80 *C for 15 min. Then solid KEC0 3 (20 mg, 0.141 mmol) was added, followed by 5-bromopyrimidine (67.0 mg, 0.421 mmol). The reaction mixture was microwaved at 220 'C for 20 min. Then it was diluted with I mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected; solvent was removed in vacuo to give trifluoroacetate salt of the product as a light-brown solid (25.0 mg). [02711 ESI-MS: [M+H]* 432.9, 435. 'H NMR (DMSO-d 6 ): 5 7.14-7.16 (d, 1 8.9 Hz, 2H), 7.63-7.67 (d,J= 8.9 Hz, 2H), 7.87-7.89 (d, J= 8.4 Hz, IH), 8.22-8.24 (dd,J/ = 8.4 Hz, J2= 2.0 Hz, IH), 8.36 (s, 1H), 8.54 (s, 2H), 8.93 (s, IH), 9.57 (br s., 1H). Example 72. Synthesis of 6-{4-({5-f4-chloro-3-(trifluoromethyl)phenyll-4H-1,2,4-triazol-3 yl anino)phenoxylpyridazin- 3 -amine trifluoroacetate salt H H

F

3

CF

3 COOH [02721 4-[5-(4-chloro-3-(trifluoromethyl)-phenyl)- 4 H-1,2,4-triazol-3-ylamino]phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 mmol) was added and the resulting solution was heated at 80 C for 15 min. Then solid K 2 C0 3 (20 mg, 0.141 mmol) was added, followed by 109 3-amino-6-chloropyndazine (54.6 mg, 0.421 mmol). The reaction mixture was microwaved at 220 *C for 40 min. Then it was diluted with I mL of MeOH, filtered through 0.22 urn syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected; solvent was removed in vacuo to give trifluoroacetate salt of the product as a light-brown solid (23.1 mg). [02731 ESI-MS: [M+H)* 448, 449. 'HNMR (DMSO-d 6 ): 57.16-7.18 (d, J= 8.9 Hz, 2H), 7.51-7.53 (d, J= 9.7 Hz, 11), 7.62-7.66 (d, J = 8.9 Hz, 2H), 7.73-7.75 (d, J= 9.7 Hz, 1H), 7.88 (d, J= 8.4 Hz, 111), 8.23-8.25 (dd, J/ 8.4 Hz,J 2 = 2.0 Hz, IH), S.36 (s, 111), 8.48 (br s., 2H), 9.62 (br s., 1H). Example 73. Synthesis of 4-[4-({5-[4-chloro-3-(trifluoromethyl)pheflMl- 4 H-,2,4-triazol-3 yUl amino)phenoxy-N-methylpyridine-2-carboxaniide trifluoroacetate salt N AiI HMe H H

F

3

CF

3 COOH [02741 4 -[5-(4-chloro-3-(trifluoromethyl)-phenyl)- 4 H-I ,2,4-triazol-3-ylaminolphenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 mmol) was added and the resulting solution was heated at 80 *C for 15 min. Then solid K 2 C0 3 (20 mg, 0.141 mmol) was added, followed by 4-chloro-2-pyridine-carboxamide (71.9 mg, 0.421 mmol). The reaction mixture was microwaved at 220 *C for 20 min. Then it was diluted with I mL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product .was collected; solvent was removed in vacuo to give trifluoroacetate salt of the product as yellow solid (25.4 mg). [02751 ESI-MS: [M+H] 489, 490. 'H NMR (DMSO-d 6 ): 52.77-2.78 (d, J= 4.8 Hz, 3H), 7.14-7.15 (dd, J, = 5.6 Hz, J 2 = 2.5 Hz, 1H), 7.15-7.17 (d, J= 9.0 Hz, 2H), 7.40 (d, J= 2.5 Hz, 111), 7.68-7.71 (d, J= 9.0 Hz, 2H), 7.87-7.89 (d, J= 8.4 Hz, 1H), 8.23-8.25 (dd, J = 8.4 Hz, J 2 = 2.0 Hz, 1H), 8.37 (s, 1H), 8.49-8.50 (d, J= 5.6 Hz, 1H), 8.75-8.78 (q, J= 4.8 Hz, 1H), 9.65 (br s., 11).

110 Example 74. Synthesis of 5-[4-chloro-3-(trifluorometyll)phenvll-N-[4-(pyridine-3 yloxy)phenyll-4H-1,2,4-triazol-3-amine trifluoroacetate salt N / \ H H F

CF

3 COOH F [02761 4-[5-(4 chloro-3-(trifluoromethyl)-phenyl)-4H- 1,2,4-triazol-3-ylamino]phenol (200 mg, 0.562 mmol) was dissolved in 2 mL of anhydrous DIvF. Solid potassium bis(trimethylsilyl)amide (280.3 mg, 1.405 mmol) was added and the resulting solution was heated at 80"C for 15 min. Then solid K 2 C0 3 (40 mg. 0.282 mmol) was added, followed by 3-bromopyridine (177.6 mg, 1.12 mmol). The reaction mixture was microwaved at 250 "C for 20 min. Then it was diluted with I muL of MeOH, filtered through 0.22 um syringe filter and purified by preparative reverse-phase chromatography using acetonitrile/water gradient with 0.1 % TFA. The major peak having the mass of the product was collected, solvent was removed in vacuo to give trifluoroacetate salt of the product as a yellow solid (17.0 mg). [02771 ESI-MS: [M+HI 432, 433. 'H NMR (DMSO-d 6 ): 5 7.09-7.11 (d, J= 9.0 Hz, 2H), 7.50-7.52 (m, 2H), 7.63-7.66 (d, J= 9.0 Hz, 2H), 7.87-7.89 (d,J= 8.4 Hz, lH), 8.22-8.25 (dd. J/ = 8.4 Hz, J1= 2.0 Hz, 1H), 8.37-8.38 (m, 2H), 8.43 (in, 1H), 9.56 (br s., IH). Example 75. Synthesis of 4-(5-{{ 3-(Trifluoromethylphenyl1amino} -1,3,4-oxadiazol-2 yllphenol H F3 HO- HF [02781 Mercury (11) oxide yellow (5.33 g, 24.60 mmol) was suspended in ca. 70 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (3.74 g, 24.60 mmol) was added to this bright-orange suspension, followed by 3-triflurormethylphenylisothiocyanate (5.0 g, 24.60 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite, then through a short pad of silica gel. Then methanol was removed in vacuo and the resulting grey precipitate was re-crystallized from ca. 100 mL of EtOAc. The formed white crystalline solid was filtered, 111 washed with a small amount of EtOAc and dried in vacuo to give the title product as white crystals (7.182 g). Yield 71.3%. [02791 ESI-MS: [M+H)V 322.0. 'H NMR (DMSO-d 6 ): 5 6.92-6.95 (d, J= 8.7 Hz, 2H), 7.33-7.35 (d. J= 8.3 Hz, 1H), 7.57-7.60 (t, J= 8.0 Hz, 1H), 7.72-7.75 (d, J= 8.7 Hz, 2H), 7.80-7.82 (dd, J; = 8.0 Hz, J. = 1.8 Hz, 111), 8.06 (s, 1H), 10.21 (s, 1H), 10.99 (br s., 1 H). 3 C NMR (DMSO-d6) 112.9, 114.5, 116.1, 117.9, 120.6, 127.6, 129.7, 130.0, 130.3, 139.6, 158.3, 158.9, 160.1. Example 76. Synthesis of 6-[4-(5- j[3-(trifluoromethyl)phenyllaminio}-1,3,4-oxadiazol-2 yl)phenoxy pyrimidine-2,4-diamine

H

2

H

2

F

3 H {02801 4-(5-{[3-(trifluoromethyl)-pheny1]amino}-1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (119.7 mg, 0.6 mmol) was added and the reaction mixture was stirred with heating at 80 *C for 10 min, then 6-chloro-2,4-diamino pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous

K

2 C0 3 (69.1 mg, 0.5 mm-rol). Then the vial was capped and microwaved at 200 *C for 20 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.0 1% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na 2 SO4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (81.0 mg). Yield 37.7%. [02811 ESI-MS: [M+HI 430.29. 'H NMR (DMSO-d6): 8 5.19 (s, 1H),6.04 (s, 2H), 6.33 (s, 2H), 7.27-7.30 (d, J= 8.7 Hz, 2Ff), 7.36-7.37 (d, J= 7.9 Hz, 1H), 7.59-7.63 (t, J= 8.0 Hz, lH), 7.82-7.83 (dd, Jr = 8.0 Hz, J 2 = 1.8 Hz, 1H), 7.89-7.92 (d, J= 8.7 Hz, 2H), 8.08 (s, 1H). 11.11 (s, 1H1).

112 Example 77. Synthesis of 5-[4-(Pvrimidin-5-yloxy)phenl-N-[3-(trifluoromethvl)phenvl] 1,3.4-oxadiazol-2-amine H

F

3 102821 4-(5-{[3-(trifluoronethyl)-phenyl]amino} -1,3,4-oxadiazol-2-yl)phenol (160.6 mg, 0.5 mnol) was dissolved in 3 mL of anhydrous DMiF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (149.6 mg, 0.75 mmol) was added and the reaction mixture was stirred with heating at 80 "C for 10 min, then 5-bromopyrimidine (119.2 mg, 0.75 mmol) was added, followed by anhydrous K 2 C0 3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 200 *C for 20 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHC0 3 . EtOAc layer was washed with brine, dried over anhydrous Na 2

SO

4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (87.0 ng). Yield 43.5%. [0283] ESI-MS: [M+H]* 400.16. 'H NMR (DMSO-d,): 6 7.31-7.33 (d, J= 8.7 Hz, 2H), 7.35-7.37 (d, J= 7.9 Hz, 1H), 7.59-7.62 (t, J = 8.0 Hz, IH), 7.81-7.83 (dd, J, = 8.0 Hz, J2 = 1.8 Hz, IH), 7.93-7.95 (d, J= 8.7 Hz, 2H), 8.07 (s, 1H), 8.76 (s, 2H), 9.08 (s, 1H), 11.11 (s, 1H). Example 78. Synthesis of 4- {5-[(4-chlorophenvlaminol- 1,3,4-oxadiazol-2-yllphenol HO [02841 Mercury (11) oxide yellow (6.38 g, 29.47 mmol) was suspended in ca. 70 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (4.48 g, 29.47 mmol) was added to this bright-orange suspension, followed by 4-chlorophenylisothiocyanate (5.0 g, 29.47 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite, then through a short pad of silica gel. Then methanol was removed in vacuo and the resulting grey precipitate was re- 113 crystallized from ca. 40 mL of EtOAc. The formed white precipitate was filtered, washed with a small amount of EtOAc and dried in vacuo to give the title product as a white powder. (02851 ESI-MS: [M+H)* 287.94. 'H NMR (DMSO-d 6 ): 8 6.91-6.94 (d, J= 8.7 Hz, 21H), 7.39-7.41 (d, J= 8.9 Hz, 2H), 7.61-7.63 (d, J 8.9 Hz, 2H), 7.71-7.74 (d, J= 8.7 Hz, 2H), 10.19 (s, LH), 10.73 (s, 1H). "C NIVIR (DMSO-d6) 114.6,116.1, 118.5, 125.3, 127.5, 128.9, 137.8, 158.1, 159.1, 160.0. Example 79. Synthesis of 6-(4-{5-f(4-chloropheny1)aminol-1,3,4-oxadiazol- 2 -yll phenoxy) pyrimidine-2,4-diamine

H

2

H

2 / H2H 4- - H [02861 4- {5-[(4-chlorophenyl)amino]- 1,3,4-oxadiazol-2-yli phenol (144.0 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)anide (100.0 mg, 0.5 mmol) was added and the reaction mixture was stirred with heating at 80 "C for 10 min, then 6-chloro-2,4-diamino-pyrimidine (72.3 mg, 0.5 mmnol) was added, followed by anhydrous

K

2 C0 3 (34.5 mg, 0.25 mmol). Then the vial was capped and microwaved at 200 "C for 15 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na 2

SO

4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (24.5 mg). 102871 ESI-MS: [M+H]* 396.25. 'H NMR (DMSO-d6): 8 5.19 (s, 1H), 6.04 (s, 2H), 6.33 (s, 21H), 7.26-7.29 (d, J =8.7 Hz, 211), 7.41-7.43 (d, J= 8.9 Hz, 211), 7.63-7.65 (d, J= 8.9 Hz, 2 H), 7 .88-7.90 (d, J= 8.7 Hz, 21), 10.85 (s, 111). Example 80. Synthesis of 5-14-(Pyimidin-5-yloxy)phenyll-N-.4-chloro-phenyll-1,3,4 oxadiazol-2-amine 114 [02881 4-{5-[(4-chlorophenyl)amino]- 1,3,4-oxadiazol-2-yl}phenol (144.0 mg, 0.5 mnmol) was dissolved in 3 m.L of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trunethylsilyl)amide (100.0 mg, 0.5 mmol) was added and the reaction mixture was stirred with heating at 80 *C for 10 min, then 5-bromopyrimidine (79.5 mg, 0.5 mmol) was added, followed by anhydrous K 2 C0 3 (34.5 mg, 0.25 mmol). Then the vial was capped and microwaved at 200 "C for 15 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing product, were partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated NaHCO 3 . EtOAc layer was washed with brine, dried over anhydrous Na2SO 4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (61.6 mg). [02891 ESI-MS: [M+Hj 366.24. 'H NMR (DMSO-d 6 ): 8 7.30-7.32 (d, J = 8.7 Hz, 21), 7.41-7.43 (d, J= 8.9 Hz, 2H), 7.63-7.65 (d, J= 8.9 Hz, 2H), 7.92-7.94 (d, J= 8.7 Hz, 2H), 8.76 (s, 2H), 9.08 (s, 1H), 10.85 (s, 1H). Example 81. Synthesis of 4-(5- . 2-cliloro-5-(trifluoromethyllphenyll amino} -1,3,4 oxadiazol-2-yl)phenol H F3 102901 Mercury (II) oxide yellow (1.82 g, 8.41 mmol) was suspended in ca. 50 mL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (1.28 g, 8.41 mmol) was added to this bright-orange suspension, followed by 2-chloro-5-trifluoromethyl-phenylisothiocyanate (2.0 g, 8.41 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite, then through a short pad of silica gel. Then methanol was removed in vacuo and the resulting grey solid was re-crystallized from ca. 20 nL of EtOAc. The formed white precipitate was filtered, washed with anhydrous Et 2 O and dried in vacuo to give the title product as a white solid (2.638 g). Yield 88.1% 102911 ESI-MS: [M+H)* 356.22. 'H NMR (DMSO-d 6 ): S 6.93-6.96 (d, J= 8.7 Hz, 2H), 7.41-7.43 (dd, J = 8.3 Hz, J = 1.7 Hz, 1H), 7.72-7.75 (m, 3H), 8.61 (s, 1H), 10.23 (s, 1H), 10.30 (s, 1H).

115 Example 82. Synthesis of 6-(4-{5-{(2-chloro-5-trifluoromethl-phenvl)aminol-1,3,4 oxadiazol-2-yllphenoxy) pyrimidine-2.4-diamine

H

2

F

3

H

2 {0292) 4-(5-([2-chloro-5-(trifluoromethyl)phenyl-amino}-1,3,4-oxadiazol-2-yl)phenol (177.85 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMIF in a 2-5 muL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80 'C for 10 min, then 6 chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mmol) was added, followed by anhydrous

K

2 C03 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180 "C for 30 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. EtOAc layer was washed with brine, dried over anhydrous Na 2 SO4 and filtered. Solvent was removed in vacuo to give the title product as an off-white solid (131.1 mg). Yield 56.5%. {02931 ESI-MS: [M+H)* 464.21. 1 H NMR (DMSO-d6): 3 5.20 (s, lH), 6.05 (s, 2H), 6.34 (s, 2H), 7.28-7.

3 1 (d, J= 8.7 Hz, 2H), 7.46-7.48 (dd, J, = 8.3 Hz,J 2 = 1.8 Hz, IH), 7.76-7.78 (d, J= 8.3 Hz, 1H), 7.90-7.92 (d, J = 8.7 Hz, 2H), 8.62 (s, 1H), 10.47 (s, IH). Ehsi of 5-{4-(Pyr-imidin-5-yloxyjphenyl--{-hloro-5-(trifluo®romethyl) Example 83. Snthei ofl -- 2 phenyll-1,3.4-oxadiazol-2-amine

F

3 ..- H {02941 4-(5-([ 2 -chloro-5-(trifluoromethyl)phenyllamino}-1,3,4-oxadiazol-2-yl)phenol (177.85 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80 "C for 10 min, then 5 bromopyrimidine (95.4 mg, 0.6 mmol) was added, followed by anhydrous

K

2 C0 3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180 "C for 40 min. Then the 116 reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.0 1% TFA. Fractions, containing the product, were partitioned between ca. 50 m1L of EtOAc and ca. 50 mL of saturated aqueous NaHCO 3 . EtOAc layer was washed with brine, dried over anhydrous Na 2

SO

4 and filtered. Solvent was removed in vacuo to give the title product as a beige solid (129.1 mg). Yield 59.5%. [0295] ESI-MS: [M+H] 434.20. 'H NMR (DMSO-d 6 ): 6 7.32-7.35 (d, J= 8.7 Hz, 2H), 7.46-7.48 (dd, J = 8.3 Hz, J2 1.8 Hz, IH), 7.76-7.78 (d, J= 8.3 Hz, 1H), 7.94-7.96 (d, J= 8.7 Hz, 2H), S.61 (s, lH), 8.77 (s, 2H), 9.09 (s, 1H), 10.47 (s, IH). Example 84 . Synthesis of 4-{,5-[(3-chlorophenyl)aminol-1,3.4-oxadiazol-2-yl phenol HO- H [02961 Mercury (11) oxide yellow (6.38 g, 29.47 mmol) was suspended in ca. 100 niL of anhydrous methanol. 4-Hydroxybenzoic acid hydrazide (4.48 g, 29.47 mmol) was added to this bright-orange suspension, followed by 3-chlorophenylisothiocyanate (5.0 g, 29.47 mmol). The reaction mixture was brought to reflux and refluxed for 2 hours. The reaction mixture turned pitch-black in color and formed black precipitate. Then it was cooled down to ambient temperature and filtered through a short pad of Celite. Then it was purified by silica gel chromatography using 0% to 20 % methanol gradient in EtOAc. Solvent was removed in vacuo and the resulting grey precipitate was re-crystallized from ca. 50 mL of EtOAc. The formed white crystalline solid was filtered, washed with a small amount of EtOAc, anhydrous Et 2 O and dried in vacuo to give the title product as a white powder (7.606 g). Yield 89.7%. 102971 ESI-MS: [M+H]* 288.26. 'H NMR (DMSO-d 6 ): 6 6.92-6.94 (d, J= 8.7 Hz, 2H), 7.00-7.02(dd,J;=7.9Hz,J 2 1.8 Hz, 1H),7.33-7.36 (t,J= 8.1 Hz, IH),7.47-7.49 (dd,J; = 8.1 Hz,J 2 = 1.8 Hz, IH), 7.72-7.74 (d, J= 8.7 Hz, 2H), 7.76-7.78 (t, J= 2.1 Hz, IH), 10.19 (s, IH), 10.81 (s, 1H). "C NMR (DMSO-d6) 114.6,115.5, 116.1, 116.4, 121.3, 127.6, 130.6, 133.5, 140.3, 158.3, 159.0, 160.1.

117 Exam le85. Synthesis of 6-(4-{5-[(3-chlorophenyl)aminol-1.3,4-oxadiazol-2-yllphenoxy) pyrimidine-2.4-diamine

H

2 Hz H 102981 4- {5-[(3-chlorophenyl)aminio)- 1,3,4-oxadiazol-2-yl}phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimnethylsilyl)amide (200.0 img, 1.0 mrnol) was added and the reaction mixture was stirred with heating at 80 "C for 10 min, then 6-chloro-2,4-diamino-pyrimidine (86.7 mg, 0.6 mol) was added, followed by anhydrous

K

2 C0 3 (69.1 mg, 0.5 mmol). Then the vial was capped and microwaved at 180 *C for 40 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of saturated aqueous NaHCO3. FtOAc layer was washed with brine, dried over anhydrous Na 2 SO4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (62.0 mg). Yield 31.3%. [02991 ESI-MS: {M+H]* 396.22. 'H NMR (DMSO-d 6 ): 5 5.19 (s, 1H), 6.04 (s, 2H), 6.33 (s, 2H), 7.06-7.08 (m, 1H), 7.27-7.29 (d,J= 8.7 Hz, 2H), 7.37-7.41 (t,J= 8.1 Hz, 1H), 7.50 7.52 (dd,J, = S.1 Hz, J 2 = 1.8 Hz, 1H), 7.78-7.79 (t, J= 2.1 Hz, lH), 7.89-7.90 (d,J= 8.7 Hz, 2H), 10.95 (s, IH). Example 86. Syntesis of 5-f4-(Pyrimidin-5-yloxy)phenyll-N-[3-chloro-phenyll-1,3,4 oxadiazol-2-amine \lX H ci [03001 4- {5-[(3-chlorophenyl)amino)- 1,3,4-oxadiazol-2-yl) phenol (143.8 mg, 0.5 mmol) was dissolved in 3 mL of anhydrous DMF in a 2-5 mL microwave vial (Personal Chemistry). Solid potassium bis(trimethylsilyl)amide (200.0 mg, 1.0 mmol) was added and the reaction mixture was stirred with heating at 80 "C for 10 min, then 5-bromopyrimidine (95.4 mg, 0.6 nmol) was added, followed by anhydrous

K

2 C0 3 (69.1 mg, 0.5 mnol). Then the vial was 118 capped and inicrowaved at 180 *C for 30 min. Then the reaction mixture was diluted with ca. I mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. Fractions, containing the product, were partitioned between ca. 50 mL of EtOAc and ca. 50 mL of -turated aqueous NaHCO 3 . EtOAc layer was washed with brine, dried over anhydrous Na 2

SO

4 and filtered. Solvent was removed in vacuo to give the title product as a light-yellow solid (74.7 mg). Yield 40.8%. [03011 ESI-MS: [M+H]* 366.23. 'H NMR (DMSO-d 6 ): 5 7.06-7.08 (m, 1H), 7.31-7.33 (d, J= 8.7 Hz, 2H), 7.37-7.41 (t, J= 8.1 Hz, I H), 7.50-7.52 (dd, J1, = .1 Hz, J, = L.S Hz, 111), 7.77-7.79 (t, J= 2.0 Hz, 1H), 7.93-7.94 (d, J= 8.7 Hz, 2H), S.77 (s, 2H), 9.09 (s, 1H), 10.96 (s, 1H). Example 87. Synthesis of 5-[4-(Pyridin-3-yloxy)phenyll-1,3,4-oxadiazol-2-amine hydrobromide salt \I j\ H 2 HBr [03021 4-(pyridine-3-yloxy)benzohydrazide (3.7 g, 16.14 mmol) was dissolved in 100 mL of anhydrous THF and 3.0 M solution of cyanogen bromide (5.38 mL, 16.14 mmol) was added via syringe. Within 5-10 min of stirring an orange precipitate started to form. The reaction mixture was brought to reflux and refluxed for I hr. Then it was cooled down to ambient temperature and filtered. The collected orange precipitate was washed with ca. 100 mL of TIF, ca. 100 mL of EtOAc, anhydrous Et20 and dried in vacuo to give the title product as an orange solid (4.40 g). Yield 81.4%. [03031 ESI-MS: [M+H)H 255.05. 'H NMR (DMSO-d 6 ): 8 7.27-7.29 (d, J= 8.8 Hz, 2H), 7.75-7.78 (dd, J = 8.5 Hz, J = 5.0 Hz, 1H), 7.85-7.87 (d, J= 8.8 Hz, 2H), 7.92-7.94 (m, I H), 8.59-8.60 (dd, J, = 5.0 Hz, J, = 1.0 Hz, IH), 8.69-8.70 (d, J= 2.7 Hz, lH).

119 Example 88. Synthesis of N-{5-f4-(pyridin-3-yloxy)phenyll-1,3,4-oxadiazol-2-yl}-4 (trifluoromethoxy)benzamide -- H

CF

3 103041 5-[4-(Pyridin-3-yloxy)phenyl]- 1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 4-Trifluoromethoxybenzoyl chloride (167.2 mg, 117 uL, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of precipitate. It was left to stir for 6 hours. Then it was diluted with ca. I mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (89.0 mg). Yield 40.2%. [03051 ESI-MS: (M+H]* 442.82. 'H NMR (DMSO-d 6 ): 5 7.20-7.22 (d, J =8.8 Hz, 2H), 7.44-7.46 (d, J = 8.6 Hz, 2H), 7.48-7.51 (dd, J, = 8.4 Hz, J.1 = 4.6 Hz, lH), 7.59-7.62 (ddd, J, = 8.4 Hz, 12= 2.8 Hz,J3 = 1.2 Hz, IH), 7.94-7.96 (d, J= 8.8 Hz, 2H), 8.17-8.19 (d, J= 8.6 Hz, 211), 8.45-8.46 (dd, J, = 4.6 Hz, J = 1.2 Hz, 1H), 8.48-8.49 (d, J= 2.8 Hz, 1H). Example 89. Synthesis of N-{5-[4-(pyridin-3-yloxylphenyll-1.3.4-oxadiazol-2-yll -3 (trifluoromethvl)benzamide H F3 [03061 5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 3-Trifluoromethylbenzoyl chloride (156.4 mg, 0.75 mmol) was added to the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. I mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of 120 TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 niL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (50.0 mg). Yield 23.4%. 103071 ESI-MS: [M+f)* 426.94. 1 H NMR (DMSO-d 6 ): 8 7.21-7.23 (d, J= 8.8 Hz, 2H), 7.49-7.51 (dd, J, = 8.4 Hz, 12 = 4.6 Hz, 1H), 7.60-7.62 (ddd, J, = 8.4 Hz, 12 = 2.8 Hz, J3 = 1.2 Hz, 1H), 7.75-7.76 (t, J= 7.7 Hz, 1H), 7.95-7.98 (in, 3H), 8.33-8.34 (d, J= 7.7 Hz, 1H), 8.39 (s, 1H1), 8.46-8.47 (dd, J, = 4.6 Hz, 12 = 1.2 Hz, 1H), 8.48-8.49 (d, J= 2.8 Hz, IH). Example 90. Synthesis of 4-Bromo-N-{*5-[4-(pyridin-3-vloxylphenvl)-1.3,4-oxadiazol-2-yl benzamide H r [03081 S-(4-(Pyridin-3-yloxy)phenyll-1,3,4-oxadiazol-2-anine hydrobromide salt (167.5 mi 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. 4-Bromobenzoyl chloride (164.6 mg, 0.75 mmol) was added to the solution. The reaction mixture formed an orange red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. I mL of MeOH, filtered through 0.22 u syringe filter and puri--d by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (46.5 mg). Yield 21.2%. [03091 ESI-MS: [M+H) 438.84. 'H NMR (DMSO-d 6 ): S 7.20-7.22 (d, J= 8.8 Hz, 2H), 7.49-7.51 (dd, J, = S.4 Hz, J = 4.6 Hz, IH), 7.60-7.62 (ddd, J, = 8.4 Hz, J, = 2.8 Hz, J 3 = 1.2 Hz, 1H), 7.68-7.70 (d, J 8.4 Hz, 2H), 7.95-7.97 (d, J= 8.8 Hz, 2H), 8.00-8.02 (d, J= 8.4 Hz, 2H), 8.45-8.46 (dd, J, = 4.6 Hz, 12= 1.2 Hz, IH), 8.48-8.49 (d, J= 2.8 Hz, 1H).

121 ExamPle 91. Synthesis of N-f5-[4-(pyridin-3-yloxy)phenyll-1,3,4-oxadiazol-2-Vl}-3 (trifluoromethoxy)-benzamide -- H

CF

3 [03101 5-{4-(Pyridin-3-yloxy)phenyl)-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 3 trifluoromethoxybenzoyl chloride (117 uL) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. I mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (38.8 mg). Yield 17.5%. 103111 ESI-MS: [M+H]* 442.85. 'H NMR (DMSO-d 6 ): 8 7.22-7.24 (d, J= 8.8 Hz, 2H), 7.49-7.51 (dd, J; = 8.4 Hz, Jf = 4.6 Hz, 1H), 7.60-7.62 (ddd, J, = 8.4 Hz, J 2 = 2.8 Hz, J3 = 1.2 Hz, 1H), 7.61-7.63 (in, 1H), 7.68.-7.71 (t,J= 7.7 Hz, 1H), 7.97-7.98 (m, 3H), 8.08-8.10 (d, J = 7.7 Hz, 1H), 8.46-8.47 (dd, J, = 4.6 Hz, J2= 1.2 Hz, 1H), 8.48-8.49 (d, J= 2.8 Hz, 1IH). Example 92. Snthesis of 4-methoxy-N-{5-[4-(pvridin-3-yloxylphenyll-1.3,4-oxadiazol-2 vl -3-(trifluoromethyl)-benzamide - H I Me

F

3 103121 5 -[4-(Pyridin-3-yloxy)phenyl]- 1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 nunol) was suspended in 2 mL of anhydrous pyridine. Neat 4-methoxy-3 trifluoromethylbenzoyl chloride (179.0 mg, 0.75 nunol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. I mL of MeOH, filtered through 122 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (37.0 mg). Yield 16.2%. [03131 ESI-MS: [M+H] 456.85. 'H NMR (DMSO-d 6 ): 8 3.97 (s, 31H), 7.21-7.23 (d, J= 8.8 Hz, 2H), 7.38-7.40 (d, J= 9.1 Hz, 111), 7.49-7.51 (dd, J1 = 8.4 Hz, J 2 = 4.6 Hz, 1H), 7.60 7.62 (ddd, Ji = 8.4 Hz, J2= 2.8 Hz, J3= 1.2 Hz, IH), 7.95-7.97 (d, J= 8.8 Hz, 2H), S.34-8.35 (m, 2H), 8.46-8.47 (dd, J, 4.6 Hz, J2 = 1.2 Hz, 1H), 8.48-8.49 (d, J= 2.8 Hz, 1H). Example 93. Synthesis of 2.2-Difluoro-N-{5-f4-(pyridin-3-yloxy)phenyll-1,3.4-oxadiazol-2 Vl - 1,3-benzodioxole-5-carboxamide H [03141 5-[4-(Pyndin-3-yloxy)phenlyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 2,2-difluoro-1,3 benzodioxole-5-carbonyl chloride (165.4 mg, 0.75 mmol) was added directly into the solution. The reaction mixture formed an orange-red solution with a small amount of white precipitate. It was left to stir for 3 hours. Then it was diluted with ca. 1 mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (27.0 mg). Yield 12.3%. [03151 ESI-MS: [M+H)* 456.85. 'H NMR (DMSO-d 6 ): 8 7.19-7.21 (d, J= 8.8 Hz, 2H), 7.47-7.51 (m, 2H), 7.58-7.60 (ddd, J, = 8.4 Hz, J= 2.8 Hz, J 3 = 1.2 Hz, 1H), 7.93-7.95 (d, J = 8.8 Hz, 2H), 7.99-8.01 (n, 2H), 8.45-8.46 (dd, J, = 4.6 Hz, J2= 1.2 Hz, 1H), 8.48-8.49 (d, J= 2.8 Hz, 1H).

123 Example 94. Synthesis of 3-Chloro-2-fluoro-N-(5-[4-(pyridin-3-yloxy)Phenyl1-1,3,4 oxadiazol-2-yl}-5-(trifluoromethyl)-benzamide - H

F

3 (03161 5-[4-(Pyridin-3-yloxy)phenyl}-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 3-chloro-2-fluoro-5 trifluoromethylbenzoyl chloride (250 uL) was added directly into the solution. The reaction mixture formed a red solution with a small amount of white precipitate. It was left to stir for 18 hours. Then it was diluted with ca. I mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (83.4 mg). Yield 34.8%. 103171 ESI-MS: [M+H}* 480.71. 'HNMR(DMSO-d6): 5 7.18-7.20 (d,J= 8.8 Hz, 2H), 7.47-7.50 (dd, Ji = 8.4 Hz, J 2 = 4.6 Hz, 1H), 7.58-7.60 (ddd, J, = 8.4 Hz, J, = 2.8 Hz, J 3 1.2 Hz, 1H), 7.92-7.94 (d., J= S.8 Hz, 2H), 8.13-8.16 (in, 2H), 8.44-8.45 (dd, J, = 4.6 Hz, J, = 1.2 Hz, lH), 8.47-8.48 (d, J= 2.8 Hz, lH). Example 95. Synthesis of 4-Fluoro-N-{5-[4-(pyridin-3-yloxV)phenyl I ,3,4-oxadiazol-2-ylI 3-(trifluoromethyl)-benzanide - H

F

3 103181 5-[4-(Pyridin-3-yloxy)phenyl}-1,3,4-oxadiazol-2-anline hydrobromide salt (167.5 mg, 0.5 mmnol) was suspended in 2 mL of anhydrous pyridine. Neat 4-fluoro-3 trifluoromethylbenzoyl chloride (200 uL) was added directly into the solution. It was left to stir for IS hours. The reaction mixture formed a red solution with a yellow precipitate. Then it was diluted with ca. I mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA.

124 Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 mL of saturated aqueous NaHCO3. The EtOAc layer was washed with bnne, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a yellow solid (105.1 mg). Yield 47.3%. [03191 ESI-MS: [M+H]* 444.79. 1 H NMR (DMSO-d 6 ): 6 7.18-7.20 (d, J= 8.8 Hz, 2H), 7.47-7.50 (dd, Jj = 8.4 Hz, J2= 4.6 Hz, IH), 7.53-7.60 (m, 2H), 7.93-7.94 (d, J= 8.8 Hz, 21H), 8.40-8.43 (m, 1H), 8.43-8.45 (dd, Jr = 4.6 Hz, J2 = 1.2 Hz, 1H), 8.47-8.48 (d, J= 2.8 Hz, IH). Example 96. Synthesis of N-f5-[4-(pyridin-3-yloxy)phenyll-1,3.4-oxadiazol-2-vl}-2 (trifluoromethoxy)-benzamide

CF

3 [03201 5-[4-(Pyridin-3-yloxy)phenyl]-1,3,4-oxadiazol-2-amine hydrobromide salt (167.5 mg, 0.5 mmol) was suspended in 2 mL of anhydrous pyridine. Neat 2 trifluoromethoxybenzoyl chloride (100 uL) was added directly into th. solution. It was left to stir for 18 hours. The reaction mixture formed an orange solution with a yellow precipitate. Then it was diluted with ca. I mL of MeOH, filtered through 0.22 u syringe filter and purified by reverse phase preparative HPLC using acetonitrile/water mixture containing 0.01% of TFA. Fractions, containing the product, were combined and partitioned between ca. 40 mL of EtOAc and ca. 40 nL of saturated aqueous NaHCO3. The EtOAc layer was washed with brine, dried over anhydrous sodium sulfate and filtered. Solvent was removed in vacuo to give the title product as a bright-yellow solid (20.2 mg). Yield 9.1%. 103211 ESI-rVfS: [M+H]* 443.04. 'H NMR (DMSO-d 6 ): S 7.22-7.24 (d, J= 8.8 Hz, 2H), 7.48-7.54 (m, 4H, 7.60-7.63 (ddd, J1 = 8.4 Hz, J2= 2.8 Hz, J3 = 1.2 Hz, 1H), 7.69-7.71 (t, J = 7.8 Hz, IH), 7.80-7.SI (d, J= 7.5 Hz, IH), 7.94-7.96 (d, J 8.8 Hz, 2H), 8.47-8.49 (m, 2H).

125 Example 97. Synthesis of N-amino-N'-(4-chloro-3-trifluoromethyl-phenyl-guanidine hydroiodide H E) cq [03221 A mixture of 2.54 g 4-chloro-3-trifluoromethyl-phenylthiourea, 0.62 ml of iodomethane in 50 mL of anhydrous EtOH was refluxed for I hr to give 1-[4-chloro-3 (trifluoromethyl)phenyl]-S-methylisothiourea hydroiodide. Then it was cooled down to ambient temperature and treated with 0.35 g of 98 % hydrazine, heated gently with stirring until the initial vigorous evolution of MeSH subsided and then refluxed for additional I hour. Example 98. Synthesis of 4-(3-f[4-chloro-3-(trifluoromethyl)phenyllaminol -1,2,4-triazin-5 yl)phenol Ho H H [03231 N-amino-N-[4-chloro-3-(trifluoromethyl)phenyl]-guanidine hydroiodide can be reacted with about 1.0-1.5 equivalents of 4-hydroxy-phenylglyoxale in 1:1 mixture of methanol/water to yield the title product. The product can be isolated by precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography. Example 99. Synthesis of 4-[4-(3- f4-chloro-3-(trifluoromethyl)phenyllamino} f ,2,4]triazin-5-vl)-phenoxyl-N-methylpyridinie-2-carboxamiide H

F

3 HMe [03241 7.23 g (19.73 mmol) of 4-(3- {[4-chloro-3-(trifluoromethyl)phenyl]amino} -1,2,4 triazin-5-yl)phenol can be dissolved in 80 mL of anhydrous DMF under argon atmosphere. 2.44 g (21.71 mmol, 1.1 equivalent) of solid potassium tert-butoxide can be added to the solution. The resulting mixture can be heated to about 100"C and stirred at that temperature for 15 min. Then a solution of 3.7 g (21.71 mmol, 1.1 equivalent) of 4-chloro-pyridine-2 carboxylic acid methylamide in 10 mL of anhydrous DMF can be added, followed by 3.28 g (23.68 mmol, 1.2 equivalent) of anhydrous

K

2 C0 3 . The reaction mixture can be heated at 126 140 *C for 30 hrs. The progress of the reaction can be monitored by LC/MS. Then it can be allowed to cool down to ambient temperature. The resulting mixture can be poured into 500 mL of water and 100 mL of ethyl acetate. The aqueous layer can be extracted with a number of solvents, such as ethyl acetate, methylene chloride or ether. The combined extracts can be washed 3 times with 100 mL of water, then with brine and dried over anhydrous sodium sulfate. Solvent can be removed in vacuum to yield crude 4-[4-(3-phenylamino [1,2,4]triazin-6-yl)-phenoxy]-pyridine-2-carboxylic acid methylamide. The product can be than purified using silica gel column chromatography. Those having ordinary skill in the art can determine which solvent system can be used as an eluents in the chromatographic purification. Example 100. Synthesis of 4-(3-ethylsulfanyl-F .2.41triazin-5-yl)-phenol WO Et H [03251 1.0-1.5 equivalent of 4-hydroxyphenylglyoxale can be reacted with l-amino-S ethylisothiourea hydrobromide in 1:1 mixture of methanol/water with 1.0-2.0 equivalent of

K

2

CO

3 to yield 4-(3-ethylsulfanyl-[1,2,4]triazin-5-yl)-phenol. The product can be isolated by a number of methods known to one skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or dietl -l ether or by silica gel column chromatography. Example 101. Synthesis of 4-(3-amino-[1.2,41triazin-5-yl)-phenol N CH 2 H 103261 1.0 equivalent of 4-(3-ethylsulfanyl-[1,2,4]triazin-6-yl)-phenol can be reacted with 1-5 equivalent of ammonia in dioxane to give 4-(3-amino-[1,2,4]triazin-5-yl)-phenol. The product can be isolated by a number of methods known to one skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography.

127 Example 102. Synthesis of 4-[4-(3-amino-[ 1,2,4 1triazin-5-yl)-phenoxvl -N-methvlpvridine-2 carboxamide

H

2 HMe 103271 3.71 g (19.73 mmol) of 4-(3-amino-{l,2,4]triazin-5-yl)-phenol can be dissolved in 80 mL of anhydrous DIF under argon atmosphere. 2.44 g (21.71 mnol, 1.1 equivalent) of solid potassium tert-butoxide can be added to the solution. The resulting mixture can be heated to about 100 "C and stirred at that temperature for 15 min. Then a solution of 3.7 g (21.71 mmol, 1.1 equivalent) of 4-chloro-pyridine-2-carboxylic acid methylamide in 10 mL of anhydrous DMF can be added, followed by 3.28 g (23.68 mmol, 1.2 eq.) of anhydrous

K

2 C03. The reaction mixture can be heated at 140 "C for 30 hrs. The progress of the reaction can be monitored by LC/MS. Then it can be allowed to cool down to ambient temperature. The resulting mixture can be poured into 500 mL of water and 100 mL of ethyl acetate. The aqueous layer can be extracted with a number of solvents, such as ethyl acetate, methylene chloride or ether. The combined extracts can be washed 3 times with 100 mL of water, then with brine and dried over anhydrous sodium sulfate. Solvent can be removed in vacuum to give crude 4-[4-(3-amino-[1,2,4]triazin-5-yl)-phenoxy]-N-mehylpy carboxamide. The product can be than purified using silica gel column chromatography. Those having ordinary skill in the art can determine which solvent system can be used as an eluents in the chromatographic purification. Example 103. Synthesis of 4-f4-(3- {f4-chloro-3-(trifluoromethl)benzovllamino, [l2]_triazini-5-vl)-phienoxyl-N-miethylpvridine-2-carboxamide H HMe F 3 10328] 108.6 mg (0.337 mmol, 1.0 eq) of 4-[4-(3-amino-[1,2,4]triazin-5-yl)-phenoxy]-N methylpyridine-2-carboxamide can be dissolved in 2 mL of anhydrous DMF with heating to about 100 "C. 45.4 mng (0.405 mmol, 1.2 equivalent) of solid t-BuOK can be added to the solution, followed by 0.405 mmol (1.2 equivalent) of 4-chloro-3-trifluoromethylbenzoyl 128 chloride. It can be allowed to stir at ambient temperature for 1-2 hours. The product can be isolated by a number of methods known to those skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography, or by reverse-phase pi ap-F[PLC chromatography. Example 104. Synthesis of 4-{4-[3-({ [4-chloro-3-(trifluorometlyl)phenyllsulfonyl} amino) f[1,2,4]triazin-5-yl)-phenoxy} -N-methylpyridine-2-carboxamide N H H Me F 103291 108.6 mg (0.337 mmol, 1.0 equivalent) of 4

-[

4

-(

3 -amino-[1,2,4]triazin-5-yl) phenoxy)-N-methylpyridine-2-carboxamide can be dissolved in 2 mL of anhydrous pyridine with heating to about 100 *C. 0.405 mmol (1.2 equivalent) bf 4-chloro-3-trifluoromethyl benzenesulfonyl chloride can be added. The reaction mixture can be allowed to stir at ambient temperature for 1-2 hours. The product can be isolated by a number of methods known to one skilled in the art, such as precipitation or by extraction with a number of solvents, such as ethyl acetate, methylene chloride or diethyl ether or by silica gel column chromatography, or by reverse-phase preparative HPLC. Example 105. Testing of Inhibition of MAPK Pathway in Cellular Assay [03301 Some compounds described by the general structure (B) were tested for inhibition of MAPK pathway in cellular assay. Western Blot Early passage primary human umbilical vein endothelial cells (HUVECs) were maintained in EGM-2 containing SingleQuots (Cambrex, East Rutherford, NJ), 10% FBS, 10mM HEPES, and 50 sig/ml gentamicin. Prior to treatment of the cells with inhibitor, the HUVECs were starved for 1 Sh by replacing serum-containing complete media with serum-free and SingleQuot-free media. The starved cells were pre-treated with inhibitors for 60 min at various concentrations (0-20 gM). Next the HUVECs were treated with 50 ng/ml VEGF or FGF (Peprotech, Rocky Hill, NJ) for 6 min and the cells were immediately washed with ice-cold PBS. Cells were lysed with ice cold RIPA buffer containing 100mM Tris pH 7.5, 150 mM NaCl, 1 mM EDTA, 1% deoxycholate, 1% Triton X-100, 0.1% SDS, 2 mM PMSF, one Complete-Mini protease inhibitor tablet (Roche, Indianapolis, IN; 1 tablet/ 7 ml of lysis buffer) and the phophatase inhibitors NaF (500 mM) and orthovanadate (1 mM). The cells were scraped and lysates 129 transferred and centrifuged at 15,000 g for 10 min. Supernatants were transferred to new tubes and protein concentration was quantitated using the BCA protein reagent (Pierce, Rockford, IL). Cell lysates containing 20 gg of total protein were separated by 10% SDS PAGE, transferred to nitrocellulose, and blocked in 5% milk in TBST. Anti phospho-ERK Thr 202/Tyr 204 (Cell Signaling, Beverly, MA), anti-phospho-MEK Ser217/221 (Cell Signaling), and c-Raf (BD Biosciences Pharmingen, San Diego, CA) used as primary antibodies were detected with horseradish peroxidase-conjugated goat anti-mouse or rabbit secondary antibodies and bands were visualized using the SuperSignal West Pico chemiluminescence reagent system (Pierce) and Kodak X-ray film (Rochester, NY). 103311 Bay 43-9006 (Raf/FGF inhibitor) showed reduction of expression of p-MEK and p-ERK with IC50 between 200 and 300 nM when tested in this assay. U0126 (MEK inhibitor) showed reduction in p-Erk levels with ICSO between 200 and 300 nM, while p MEK levels were unaffected. The results are shown in Table 1. As can be seen, compounds of the invention showed reduction in p-MEK and p-ERK levels with ICso between 400 nM and 20 .M. Example 106. Cell Viability Assay 103321 Some compounds described by the general structure (B) were tested for cell viability. XTT assay: HUVECs were seeded at 10,000 cells/well of a tissue culture treated 96-well plate treated with collagen type I and grown overnight in the complete EGM-2 media as described above. The following morning, the inhibitors were serial diluted with DMSO and added to the cells with a final DMSO concentration of 1%. After 72 hours cell viability was measured with an XTT assay (Sigma, St. Louis, MO). The cells were also photographed to compare morphological differences to the XTT trends observed. Determination of the IC 50 values was performed with quantitative software (Prism software package, GraphPad Software, San Diego CA). Several inhibitors blocked cell proliferation and induced apoptosis at concentrations below 1 p.M and experiments were repeated three times to confirm the observations. The compounds of the invention displayed IC 30 between 100 nM and 40 uM in this assay (Table 2).

130 Table 2. Test Results for Examples 105 and 106 Examples Western Blot Inhibition of HUVEC cell prolifiration (1050) 4 $-(4ds5-4-dtorto-3-tdfluoaromcthvl-phenylantlnoH4H- t,2,4jrtud-3- active at It0 uMV 2.85 uNI ytj-phcno~xyl-pyrIdtflt--Cio~xyic adid aetttytamlde .444.-4trIntuoromethoxr-phmfytHH-11,A1tfl~ot-3-yim0l- not active 2.2 ott!I phcoyj-pyridiOO-2-OrbOXyttt acid methytantide (4-chor.3truormthy-ptfl)-(51-pyrtdb-3-yOaY)-PhfYll- atv tsut .1ut 4H11.2.4Itrtnzo.-vtli)amtnoatv t5 N113 I 4.(4IS.4trifluoroflttcy-pbehftifl0H-lI,2.dltrot3YIl- not active > 40 uM phcenocyI-pyrldtoe--carbaxy1c acid mathyamide tSI14.pyrdifl-oxy)-phtoyl fHtl2A41trdsoi3-yW(4- not active > 40 aiM trlfloormothonx-pcny)-1ne 6 f4(I(4rtdolncthphetoamtno)HP,2A41trizot3-ylI- not active > 20 aM ptacnory)-pyrtdazin.3-yiamtflt 6-{4IN5.4dri~luoronitehoxvphttflttiofOHHl,4tl-3-ytI- not active 6.0 UiM phenoxyl-pyfltoidint-2,t-diatinfl &[-(.4(rnaoehy-hy4 -,,-r-o.3 not active 6.53 aiM yk)amtflo)phitioylpytflhlttc2.4-dIamhtO 5.(4- 1 54(Chloro-3-trtJ~uoraiithiyt-phtaino)-.tN-tt,2A4)trtnot- active at 5 ttM 0.089 a MV yfl~pheooxy)-pyrlmdilt2,4-di=Ittl &1-5( i 3ttloochl-hntLo4fl~ttzl3 not active 1.79 uN! yt)-plienoryl-pyridazin-3ytaifC 4.(3.IS5t(ctetor 3-trifloromtl-phtii3Trlo)4HI., 4 tdazob) not active > 20 0itt ytj-phenoxvy)-pyridin-2caioytc add methytamide 6(3-($4 charo.3.taitzbcaorthyt-piIcflyiattiLloHWf/]tA 4 1trnot4. active at 5 aM 044nt yt(-pheno.yIpyFTtdhntt-24t3mtiCe044 iv 131 (4W o3tiloo hlp~yMS1.pTdn4YOYP'Yl active at 5 UM 1.79 uNI ~~~~~activ a u .6u 6-4(.1-W r3tiloo ehy-hoi2~O-.,-~ l 12 active at 5 tNI 1.57 uM N-4doo3- normthphnll5[-pTii--lxypeyl active 40 tm172u I 3 44 lor -Otuot~hyIf nlfl -5qme p)wyu4ytlxyf l - active at tM 8.1 u N-4boo4tiu ty~hni51-prmdnS active at url .5 I ytia)phn~ y IP lda21n.

3 .azmntn>40u

(

4 .i((S 4 .dtoo 4 3(trno ttholeihmyt)t4 tH-1, ,-rut-3 active 40 95 M ylamino)phbflOXINplth1IP r2I-d Oitd 4H1lW~l3wit active i > 40 uM 132 6.[4-(5-3-(rifnuoromet by)pheytlamino)-1,3,4-oxadizot-2- active at 5 uN > 10 Ui yI)phenoxy)yIm~idine-2,4-dIs3mine 5-1 4 -(Pyrimidin-S-yfoxy)phenyl)-?N-3-(trifluoromethyt)phenytl-,34 active at uM >10 oM oxadlazol-2-amine 6-(4-(s-l(4-chlropheny)aInl-1.3r-adaol-2-yiphnosy) active at 5uM 2.6 uM pyrimldine-2,4-diamne 5-I4-Pyimidin5-ytoxy)penyt-N-4hloro-phenyt, 3 4oadiazl-2 active at 5 uM > 20 M amine 6-(4-(S-(2chloro-5-rifluormethyl-pheny)aminol-1,3

,

4-oadiaol-- notactive ~20uM yi)phenoy) pyrlmidine-2,4-dlmnnei 5-[4-(Pyrimldin-5-yloxy)phenyI-N-{2-ch)loro-5-(trifluoromethyl)- not active 20 uM phenyl-I,3,4-oxadlazol-2-amine 6.(4-5-t(3-chlorophenyt)amino)-t,3,4-oxdizol-2-yl)phenoxy) active at S uM -20 uM pyrimidine-2,4-diamine - active at 5 uM - 20 Um ammne S-14-(Pyridin-3-loxy)phenyll-N-|4-choro-phenyll-1.3,4-xdlazol-2- atv t1 M96u 2rdn active at to oN! 9.6 oN! amine 5-{ 4 -(Pyridin-3-ytoxy)phenyll-N-13-trfluormiethyl-phenyll-1,3,4- active at to oNM > 20 uM oxadiazo-2-minea S-{4.(P)Tidin-3-ioxy)phenyll..3,4-oadazol-2-andine not active at 10 UM > 40 uM N4-(5-[4-(pyridin-3-yloxy)phenyli-1,3,4-exdiazel-2-yt)--ntatv 0u 0 rlIuorothoy)bnz de not active at >40M N-{5-14-(pyridi-3-yo active at l 0ouM > 40 oM (trifluoromethyla)benzaide 133 not active at 10 uI >40 uM benzamilde 5 a-3-yloxy)Phenyll-1,3o -2-yQ-3- not active at 10 uM >40 uM (trinuoromethoxy)-benzaide ..Meth - ydin-3-XYPheny d -2y-3-active at 10 uM >40cO (trinuoromethyl)-benza1 2,2.DifluoroM[5-14-(Pydi-3-yloxy)phenyll-1,4.oxdiazol--2-yl)- not active at 10 UM >40 uNI 1,3-benzodIoxole5-arboxarnId 3 - - dt active at 10 uiL >40 aM (trinl.ormetyl).benz4n ,,i~yldin-3--yloxy)Phe"7'l1)..,4.ox d12zo-2-yl}-2- Dot 2CliVe 2t 10 UM -20 uMI (trinu~oromethoxy I {0333] Although the invention has been described with reference to the above examples, it will be understood that modifications and variations are encompassed within the spirit and scope of the invention. Accordingly, the invention is limited only by the following claims.

Claims (26)

1. A compound having the structure (B) or an N-oxide, N,N'-dioxide, N,N',N" trioxide, or a pharmaceutically acceptable salt thereof: X2 0 2 3 3 5 (B) wherein: each of Zi, Z 2 and Z 3 is independently selected from a group consisting of N, CH, N=CH, 0, S and N-R 4 , wherein R 4 is hydrogen or lower alkyl, with the further proviso that at least one of ZI, Z 2 and Z 3 is not CH; 10 X is absent or is NH; and Y is absent or is selected from a group consisting of the following moieties: Ri is an unsubstituted or a substituted C 3 -C 12 heteroaryl having 1-3 heteroatoms; R 2 is selected from a group consisting of of hydrogen, halogen, Ci-C 18 alkyl, -OH, 15 NO 2 , -CN, Ci-Cis alkoxy, -NHSO 2 R 5 , -SO 2 NHR', -NHCOR', -NH 2 , -NR 5 R 6 ,-S(O)R, S(O) 2 R 5 , -C0 2 R 5 , -CONR 5 R 6 , wherein R 5 and R 6 are independently selected from a group consisting of hydrogen, a CI-C 18 alkyl, and a substituted C 1 -C 1 2 alkyl; and R 3 is selected from a group consisting of a Ci-C 18 alkyl, a substituted Ci-C 1 2 alkyl, a Ci-C 12 cycloalkyl, a substituted CI-C 1 2 cycloalkyl, a substituted C 3 -C 10 cycloalkyl having 0-3 20 heteroatoms, an C 6 -C 1 2 aryl, a substituted C 6 -C 1 2 aryl, a heterocycle, a substituted heterocycle, a C 3 -Cl 2 heteroaryl having 1-3 heteroatoms, a substituted C 3 -C 1 2 heteroaryl having 1-3 heteroatoms, a C 7 -C 2 4 aralkyl, a substituted C 7 -C 24 aralkyl, a C 7 -C 2 4 alkylaryl, and a substituted C 7 -C 24 alkaryl. 135

2. The compound of claim 1, wherein R, is selected from the group consisting of: ti~J 6 6 NH 2 k51NH 2 K6IN.H 2 I~NLH2 H 2 eI 1NH 2 '~I~ H 2 IJ~~ 2 N~~H 2 l~NH 2 Me2"I 5 N H 2 NILe ~HWe 6Y ~Me 2 6Y .~H2 l~1gHMe l1AMe 2 1NH 2 H H H H H ~ JH I H H N- NN HN H2 H Hn HN H HI n H n H2 H2 R H 2 H H 2 H H 136 H n HH H n H n Hn H Ht -'nH nH HnH NR H H 6 H n H n H n H n H n Me Me H H H H H Me Me H H H H H; R 3 is selected from the group consisting of: F3 CF3 F F 5 C kFC MeC H I 137 Ir eF 3 6 'W Me Me Me meMe e ~F 3 F 3 FF3~e H H H ~ F3 H ~AHH aMe 2 r I N ~ CF3 ~'CF3 CF., CF.,CF CF 3 '. CF 3 138 r Me Me F 3 F 3 F 3 33 F 3 ~N F 3 ~N F 3 ~F 3 F 3 F 3 F 3 Me H H2H I %( ( ( 139 R R R ) n R )n R R R H R R R )nn H R nn R H R jn R )n R jn R jn R n R ) H. 5 n is an integer selected from a group consisting of 0, 1, 2, and 3, and R' is selected from a group consisting of hydrogen, a CI-CI8 alkyl, and a substituted C 1 -Ci 8 alkyl.

3. The compound of claim 1, wherein the compound having structure (B) is selected from a group consisting of compounds having formulae (17)-(3 5): F 3 1HMe (1 10 (17) 140 -O H F 3 (18) NH 2 H12 - H H F 3 (19) H 2 5 H 2 - H H F (20) - I 0 - H H F 3 (21) NH 2 H 2 N H F 3 10 (22) 0 H 3 141 (23) F 3 (24) 5 (25) - H F 3 NHMe (26) H2N (27) 10 (28) 142 (29) H2H 2 H 2 H F (30) 5 F3 (31) NH 2 H 2 H (32) 10 (33) 143 NH 2 H 2 - H (34) (35) 5

4. The compound of claim 1, wherein the compound has the formula: Me F3 H 2 -- H H or a pharmaceutically acceptable salt thereof.

5. A method for treating a disorder comprising administering to a subject in need 10 thereof an effective amount of a compound of any one of claims 1 to 4 or a combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof.

6. The method of claim 5, wherein the disorder is selected from a group consisting of cancer, eye disease, inflammation, psoriasis, and a viral infection. 15

7. The method of claim 6, wherein the cancer is an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer. 144

8. The method of claim 5, wherein the disorder is associated with a kinase.

9. The method of claim 8, wherein disorder is associated with a MAPK kinase pathway.

10. A pharmaceutical composition comprising a compound of any one of claims 1 to 5 4, in a pharmaceutically acceptable carrier.

11. A method of treating a disorder comprising the administration of a therapeutically effective amount of at least one compound as set forth in any one of claims 1 to 4, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with a chemotherapeutic agent, 10 immunomodulatory agent, therapeutic antibody or a protein kinase inhibitor, to a subject in need of such treatment.

12. A process for making a pharmaceutical composition comprising combining a combination of a compound of any one of claims 1 to 4 or any combination thereof or its pharmaceutically acceptable salts, hydrates, solvates, crystal forms salts and individual 15 diastereomers thereof, and a pharmaceutically acceptable carrier.

13. A method for treating cancer or a tumor in a subject, comprising administering to a subject in need thereof an effective amount of a therapeutic agent, in combination with a compound of any one of claims 1 to 4, or any combination thereof, thereby treating the cancer or tumor in the subject. 20

14. The method of claim 13, wherein the cancer is an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer, breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or brain cancer.

15. The method of claim 14, wherein the cancer is colon cancer or lung cancer. 145

16. The method of any one of claims 13 to 15, wherein the therapeutic agent is an antimetabolite; a DNA cross-linking agent; alkylating agent; topoisomerase I inhibitor; microtubule inhibitors, a vinca alkaloid, mitomycin-type antibiotic, and a bleomycin-type antibiotic. 5

17. The method of any one of claims 13 to 15, wherein the therapeutic agent is methotrexate, cisplatin/carboplatin; canbusil; dactinomicin; taxol (paclitaxel), antifolate, colchicine, demecoline, etoposide, taxane/taxol, docetaxel, doxorubicin, anthracycline antibiotic, doxorubicin, daunorubicin, carminomycin, epirubicin, idarubicin, mithoxanthrone, 4-dimethoxy daunomycin, 11-deoxydaunorubicin, 13-deoxydaunorubicin, adriamycin- 14-benzoate, 10 adriamycin-14-octanoate or adriamycin-14-naphthaleneacetate, irinotecan, topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab.

18. The method of claim 17, wherein the therapeutic agent is doxorubicin, docetaxol, or taxol. 15

19. The method of any one of claims 13 to 15, wherein the therapeutic agent is trastuzumab, bevacizumab, erlotinib, or Vitaxin.

20. Use of an effective amount of a compound of any one of claims I to 4, or a combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diasteromers thereof in the manufacture of a medicament for treating a disorder. 20

21. The use of claim 20, wherein the disorder is selected from a group consisting of cancer, eye disease, inflammation, psoriasis, and a viral infection.

22. The use of claim 21, wherein the cancer is an alimentary/gastrointestinal tract cancer, colon cancer, liver cancer, skin cancer , breast cancer, ovarian cancer, prostate cancer, lymphoma, leukemia, kidney cancer, lung cancer, muscle cancer, bone cancer, bladder cancer or 25 brain cancer. 146

23. Use of an effective amount of a compound according to any one of claims 1 to 4, or any combination thereof, or pharmaceutically acceptable salts, hydrates, solvates, crystal forms and individual diastereomers thereof, in combination with a chemotherapeutic agent, immunomodulatory agent, therapeutic antibody or a protein kinase inhibitor in the manufacture 5 of a medicament for treating a disorder.

24. Use of an effective amount of a therapeutic agent, in combination with a compound of any one of claims I to 4, or any combination thereof in the manufacture of a medicament for treating cancer or a tumor in a subject.

25. A compound according to claim 1, substantially as hereinbefore described. 10

26. A method of claim 5, substantially as hereinbefore described.