BRPI0621098B1 - BICYCLIC HETEROARYL COMPOUNDS - Google Patents

Abstract

COMPOUND OF FORMULA I, COMPOSITION AND METHOD FOR THE TREATMENT OF CANCER IN A MAMMAL. The present invention relates to compounds of formula (I) in which variable groups are defined therein, as well as to their preparation and use.

Description

Protein kinases are a large family of proteins that play an exemplary role in the regulation of a wide variety of cellular processes. A partial, non-limiting list of said kinases include abl, akt, bcr-abl. Blk, Nrk, c-kit, c-met, s-src, CDK1, CDK2, CDK3, CDK4, CDK5, CDK6, CDK7, CDK8, CDK9, CDK10, cRafl, CSK, EGFR, erbB2, erbB2, erbB3, erbB4, erk, Pak, fes, FGFR1, FGFR2 , FGFR3, FGFR4, FGFR5, Fgr, fit-1, Fps, Frk, Fyn, Hck, IGF-1R, IN-S-R, Jak, KDR, Lek, Lyn, MEK, p38, PDGFR, PIK, PKC, PYK2, ros, tié, tie2, TKR and Zap70. Abnormal protein kinase activity has been reported for several diseases, ranging from non-fatal diseases such as psoriasis to extremely serious diseases such as cancers. In view of the large number of protein kinases associated with diseases, there is a great need for new selective inhibitors for several protein kinases that could be useful in the treatment of these diseases. This invention relates to a new family of heteroaryl acetylenic compounds and their use in treatments for cancer, bone diseases, metabolic diseases and other diseases.

1. General Description of the Compounds of the Invention

The compounds of this invention have a wide range of appropriate biological and pharmacological activities, allowing their use in pharmaceutical compositions and methods for treating a variety of diseases. Including, for example, metabolic diseases, bone diseases (such as osteoporosis, Paget's disease, etc.), inflammation (including rheumatoid arthritis, among other inflammatory diseases) and cancer (including solid tumors and leukemias, especially those mediated by one or more kinases , such as Src or kdr, or by the non-regulation of a kinase such as Abl or a mutant variant thereof) including, among others, advanced cases and cases that are resistant or refractory to one or more treatments. Included are the compounds of formula I: or a tautomer or an individual isomer or a mixture of isomers thereof, in which: Ring T is a 5-membered heteroaryl ring containing 1 -2 nitrogens with the remaining 5th ring atom being carbon, substituted on at least two ring atoms (each may be C or N) with R1 groups, only two of which are positioned adjacent to the ring atom, and, together with the atoms to which they are attached, form a saturated, partially saturated, 5-6 membered ring or unsaturated (Ring E), containing 0-3 10 heteroatoms selected from O, N, and S being optionally substituted with 1-4 Re groups.

Ring A represents a 5-6 membered aryl ring or heteroaryl ring being optionally substituted with 1-4 Ra groups;

Ring B represents a 5-6 membered aryl or hereroaryl ring optionally substituted with 1-5 Rb groups; L1 is selected from NR1C (O), C(O)NR1, NR1C(O)O, NR1C(O)NR1 and OC(O)NR1;

Each occurrence of Ra, Rb and Rl being independently selected from groups consisting of halo, -CN, -NO2, -R4, -OR2, -NR2R3, -NR2, -C(O)YR2, 20 -OC(O) YR2, - NR2C(O)YR2, -SC(O)YR2, -NR2C(=S)YR2, -OC(=S)R2, -C(=S)YR2, - YC(=NR3)YR2 , -YR2 , -YP(=O)(YR4)(YR4), -SÍ(R2)3, -NR2SO2R2, -S(O)rR22, - SO2NR2, -SO2R3 and -NR2SO2NR2SO2NR2R3 where each Y is independently a link, -O- , -S- or NR3-; Ra, at each occurrence is independently selected from a selected halo group, =0, -CN, -NO2, -R4, -OR2, -NR2R3, -C(O)YR2, -OC(O)YR2, - NR2C(O)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -(=S)YR2, -YC(=NR3)YR2, - YP(=O)(YR4)(Y R4 ), -SÍ(R2)3, -NR2SO2R2, -S(O)rR2, -SO2NR2R3 and -NR2- SO2NR2R3, where each Y is independently a link, -O-, -S- or -NR3-; R1, R2 and R3 being independently selected from H, alkyl, alkenyl, alkynyl, cycloalcyl, cycloalkenyl, cycloalconyl, aryl, heterocyclic and heteroaryl;

Alternatively, R2 and R3, leading together with the atom to which they are attached, form a saturated, partially saturated or unsaturated 5-6 membered ring, which may be optionally substituted and which contains 0-2 heteroatoms selected from N , O and S(O)r; each occurrence of R4 being independently selected from alkyl, alkenyl, alkynyl, cycloalcyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl; each half of the alkyl, alkenyl, alkynyl, cycloalcyl, cycloalkenyl, cycloalkynyl, aryl, heterocyclic and heteroaryl in its Section 1 being optionally substituted; m being 0, 1,2, 3 or 4; n being 2 or 3; p being 0, 1.2, 3, 4 or 5; and r being 0, 1 or 2; or a pharmaceutically acceptable salt, solvate or hydrate thereof. The above definitions are further elaborated and exemplified below and apply to all subsequent occurrences except to the extent otherwise specified.

2. Highlighted Classes of Compounds and Their Uses Generally the compounds of this invention include those in which the T ring has the following structure: where the E Ring is a saturated 5-6 membered ring (formed by two R* groups together with the T Ring atoms to which they are attached, as described above), and s being 0, 1, 2, 3 or 4. These are illustrated by compounds of Formula I in which the fused T Ring system is one of the following (in which one of the optional Re substituents is represented.

Other classes of particular interest are the compounds of Formula I, as described in Part 1, in which Ring E is a 5-6 membered ring, different from that described above. Illustrative examples thereof include compounds of Formula I in which Anek T (with no Ring E attached) is a fused bicyclic heteroaryl of the following types:

For the above described class and sub-classes of compounds, as well as in all compounds of this invention, Ring A and Ring B are as previously defined in Part 1. Illustrative examples of the substituted Ring A groups are:

Ring B representing a 5-6 membered ring or heteroaryl ring as defined above in Part 1. Illustrative examples of Ring B groups include: of special interest being the class of compounds of Formula I as described above in Part 1, in which one of the substituents Rb is a 5-6 membered ring (Ring C), which may be heteroaryl or heterocyclic, comprising carbon atoms, and 1-3 heteroatoms independently selected from O, N and S(O)r, with Ring C optionally substituted by carbon or heteroatom(s) with 1 to 5 Rc substituents. This class is represented by Formula II: in which the previously defined variables, such as n, m, p, A, B, T, L1, R1, R\ Ra, are as defined above in Part 1, and Rc, in each occurrence, being independently selected at from halo, =0, -CN, -N02, -R4, - OR2, -NR2R3, -C(O)YR2, -OC(O)YR2, -NR2C(O)YR2, -SÍ(R2)3, -SC)O)YR2, - NR2C(=S)YR2, -OC(=S)YR2, -0C( =S)YR2, -C(=S)YR2, -YC(=NR3)YR2, - YP( =O)(YR4)(YR4), -NR2SO2R2, -S(O)rR2, -SO2NR2R3 and -NR2SO2NR2R3, where 5 each Y is independently a link, -O-, -S- or -NR3- er, R2, R3 and R4 being as previously defined in Partel, and v being 0, 1,2, 3, 4 or 5,

Illustrative examples of C Ring systems include but are not limited to the following types: Where Rc and v are as defined above.

Of special interest is the class of compounds of Formula II in which the T Ring has the following structure:

In which the indicated variables, for example, Re seo Ring E are as previously defined. Illustrative subsets of said compounds include those having the following structures: In which various illustrative parts of -[Ring A]-[Ring B]-[Ring] are represented.

Compounds of interest include, among others, those compounds of Formula II in which Ring C is an imidazole ring, optionally substituted with one or more Rc groups. Of particular interest are compounds of this sub-class in which Ring C takes a single lower alkyl (e.g. methyl) from the Rc group. Another feature of the invention relates to compounds of Formula I as described in Part 1, in which an Rb substituent is [L2]-[Ring D]. This class is represented by 10 Formula III:

In which the previously defined variables, such as n, m, p, Ring A, Ring B, L1, R1, Rl, Rae Rb are defined above in part 1, and L2 being selected from (CH2)Z, O(CH2)X, NR3(CH2)X, 15 S(CH2)XNR3C(O)(CH2) and the linker half l_2 including in any direction;

Ring D represents a 5-6 membered heterocyclic or heteroaryl ring comprising carbon atoms and 1-3 heteroatoms independently selected from O, N and S(O)r and Ring D being optionally substituted by carbon or heteroatom(s) with 1-5 Rd groups; Rd, in each occurrence, being independently selected from the halo, =O , -CN, -NO2, -R4, -OR2, -NR2R3, -SÍ(R2)3, -C( O)YR2, -NR2C(O )YR2, - SC(O)YR2, NR2C(=S)YR2, -C(=S)YR2, -YC(=NR3)YR2, -YR2, -YP(=O)(YR4)(YR4), - NR2SO2R2, -S(O)rR2, -SO2NR2R3 and -NR2SO2NR2R3, where each Y is independently a link, -O-, -S- or -NR3- and r, R2, R3, and R4 being as previously defined in Part 1 ; w being 0, 1,2, 3, 4 or 5; x being 0, 1,2 or 3; and z being q, 2, 3 or 4.

Non-limiting illustrative examples of -[Ring B]-[L2]-[Ring D] moieties in compounds of Formula III include among others

Of special interest is the class of compounds of Formula III in which the T Ring has the following structure: in which the previously defined variables, such as Rθ, s and Ring E are as previously defined. Non-limiting examples of said compounds include those having the following structures:

As illustrated by the following examples:

Compounds of interest include among others, compounds of Formula III, in which Ring D is a piperazine ring, substituted by nitrogen with Rd. Of particular current interest are compounds of this sub-class in which Rd is an inferior substitute or irreplaceable ( for example, 1-6 carbons) alkyl as illustrated by the N-methylpiperazine moieties in the same examples 10 above. Of special interest are compounds of Formula II and Formula III in which Ring T is an optionally substituted imidazole [1,2-a] pyridine, imidazole [1,2-b] pyridazine, imidazole [1,2-a] pyrazine, pyrazolo[1,5-a] pyrimidine, pyrazolo[1,5-a]pyridine, pyrazolo[1,5-c]pyrimidine, and pyrazolo[1,5-a][1,3,5]triazine. Also of interest are the compounds of formula II and formula III in which Rings A and B are aryl. Another sub-class of interest are the compounds of Formulas II and III, in which the T Ring is any fused 6/5 heteroaryl ring system, optionally fused with up to three Re groups. Of particular interest are compounds in which s is 0. Also of interest are those in which s is 1 -3 and at least one Re is halo, lower alkyl, alkoxyl, amine, -NH-alkyl, -10 C(O) NH-alkyl, -NHC(O)-alcyl, -NHC(O)NH-alcyl, -NHC(NH)-alkyl, - NHC(NH)NH2, -NH(CH2)x-heteroaxyl, -NH(CH2) X -heterocycle, -NH (CH2) ), cyclic and branched alkyl groups, in which aryl, heteroaryl, heterocyclyl rings are optionally substituted. Illustrative and non-limiting examples of the above compounds include compounds of formulas II and III in which the T Ring is one of the following:

Illustrative but non-limiting examples of this sub-class include compounds of formulas Ila, Ile, Illa, lllb, and lllc:

In which the previously defined variables, for example, Ra, Rb, Rc, Rd, R®, m and p are as previously defined, for example, in part 1, and s being an integer from 0 to 4. A subset of interest includes compounds of Formulas Ha, 5 lib, and lie in which s is 0; m, p m and v are 1; and Ra is CH3, Rb is CF3 and Rc is methyl.

Others include compounds of Formulas IIla, lllb, lllc in which s is 0; m and p are 1; and Ra is CH3, Rb and CF3 and R is CH3 or CH2CH2OH. Compounds of this invention of particular interest include those with one or more of the following characteristics: - a molecular weight of less than 1000, preferably less than 750, and most preferably less than 600 mass units (not including the weight of any solvent or co-species). crystallized, from any ion calculator, in the case of a salt); or - inhibitory activity against an uncultivated or mutant type (especially a clinically relevant mutant) kinase, especially a Src family kinase such as Src, Yes, Lyn, or Lck; a VEGF-R such as VEGF-R1 (Fit-1), VEGF-R2 (kdr), or VEGF-R3; a PDGF-R, an Abl kinase, or other kinase of interest with an IC50 value of 1 μM or less (as determined using any scientifically acceptable kinase inhibition assay), preferably with an IC50 of 500 nM or better, and more precisely with an IC50 value of 250 nM or better; or - inhibitory activity against a given kinase with an IC40 value of at least 100-fold or lower than its IC50 values for another kinase of interest; or - inhibitory activity against both Src and kdr with a 1 μM or better value against each IC59, or; - a cytotoxic or increasing inhibitory effect on cancer cell lines maintained in vitro, or in animal study using a scientifically acceptable xenographic model of cancer cells (especially preferred are compounds of the invention that inhibit K562 cell culture proliferation with a potency at least as Gleevec, preferably with a potential at least twice as Gleevec, and most preferably with a potential at least 10 times as Gleevec, as determined by comparative studies). Also provided is a composition comprising at least one compound of the invention or a salt, hydrate or solvate thereof, and at least one pharmaceutically acceptable excipient or additive. Said compositions may be administered to an individual who needs it to inhibit the growth, development and/or metastasis of cancer, including solid tumors, such as lung, colon, pancreatic, CNS, head and neck cancers, among others) and various forms of leukemia, including leukemias and other cancers that are resistant to other treatment, including those that are resistant to treatment with Gleevec or another kinase inhibitor, and generally for the prophylaxis treatment of or undesirable diseases or conditions mediated by one or more kinases that are inhibited by a compound of this invention. The cancer treatment method of this invention involves administering (as monotherapy or in combination with one or more anti-cancer agents, one or more side effect ameliorating agents, radiation, etc.), a therapeutically effective amount of a compound of the invention in a human or animal in need of inhibiting, slowing or reversing the growth, development or spread of cancer, including solid tumors, or other forms of cancer, such as leukemias, in the recipient. Said administration consists of a method for the treatment or prophylaxis of diseases mediated by one or more kinases including one or more kinases inhibited by one of the disclosed components or pharmaceutically accepted derivatives thereof. The “administration of a compound of this invention involves the release into a recipient of a compound of the order described herein, or a prodrug or other pharmaceutically acceptable derivative, using any suitable formulation or route of administration, as discussed below. Typically, the compound is administered one or more times per month, often one or more times per week, e.g., in the morning every 5 days per week, etc. Oral and intravenous administrations are of current particular interest. The phrase "pharmaceutically acceptable derivative", as used herein, denotes any pharmaceutically acceptable salt, ester or ester salt of said compound, or any other derivative which upon administration to the patient, is capable of providing (directly or indirectly) a compound or otherwise described herein, or a metabolic residue (MW > 300) thereof. Pharmaceutically acceptable derivatives then include, among others, prodrugs. A prodrug is a derivative of a compound, usually with significantly reduced pharmacological activity, that contains a moiety that is susceptible to removal in vivo, revealing the parent molecule as the pharmacologically active species. An example of a prodrug is an ester that is cleaved in vivo to reveal a compound of interest. Prodrugs of a variety of compounds, and materials and methods for derivatizing the parent compounds to create the prodrug are known in the art and may be adapted to the present invention. Particularly favorite derivatives and prodrugs of a parent compound are those derivatives and prodrugs that increase the bioviability of the compound when administered to an animal (e.g. allowing optimization of absorption into the blood following oral administration) or that optimize release to a biological compartment of interest (e.g., the brain or lymphatic system) relative to the parent compound. Preferred prodrugs include derivatives of a compound of this invention with enhanced aqueous solubility or active transport across the intestinal membrane relative to the parent compound. An important aspect of this invention is a method for treating cancer in an individual in need thereof, which comprises administering to the individual an effective treatment amount of a composition containing a compound of this invention. Various cancers that may thus be treated are noted elsewhere herein, and include among others cancers that are or become resistant to another anticancer agent such as Gleevec, Iressa, Tarceva or another agent cited herein. Treatment may be provided in combination with one or more cancer therapies, such as surgery, radiotherapy (e.g. gamma radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, systematic radioactive isotopes, etc. ), endocrine therapy, modified biological responses (such as interferons, interleukins, and tumor necrosis factor (TNF to name mens)) hyperthermia, cryotherapy, agents to mitigate any adverse effects (such as antiemetics) and other chemotherapeutic drugs against cancer. The other agent(s) may be administered using the same or different formulation, route, administration, and dosage schedule as used with the compounds of this invention. Said other drugs include, but are not limited to, one or more of the following: alcylating or intercalating anticancer agent (e.g., mechlorethamine hydrochloride, chlorambucil hydrochloride, cyclophosphamide, melphalan, and ifosfamide); anti-metabolite (e.g. Methotrexate), purine antagonist or pyrimide antagonist (e.g. 6-Mercaptopurine, 5-Fluorouracil, Cytarabil, and Gemcitabine); toxic axis (e.g., Vinblastine, Vincristine, Vinorelbine, and Paclitaxel), podophyllotoxin (e.g., Etoposide, Irinotecan, Topotacan); antibiotics (such as Doxorubicin, Bleomycin and Mitomycin); nitrosourea (e.g. Carmustine, Lomustine); inorganic ion (e.g. Cisplatin, Carboplatin, Oxaliplatin or Oxyplatin); enzyme (e.g. Asparaginase), hormone (e.g. Tamoxifen, Leuprolide, Flutaminde and Megestrol); mTOR inhibitor (e.g., Sirolimus (rapancin), Tensirolimus (CCI779), Everolimus (RAD001), AP23573 or other components disclosed in U.S. Patent No. 7,091,213). proteasome inhibitor, (such as Velcade or another proteasome inhibitor, (see e.g. WO 02/096933) or other NF-kb inhibitor, including for example an IkK inhibitor), other kinase inhibitors (e.g. Src inhibitor, BRC/Abl, kdr, fits, aurora-2, glycogen synthesis kinase 3 (“GSK-3”), EGF-R kinase (e.g., Iressa, Tarceva, etc.), VEGF-R kinase, PDGF-R kinase, etc.) , an antibody, soluble receptor or other receptor antagonist against a receptor or hormone implicated in a cancer (including receptors such as EGFR, ErB2, VEGFR, PDGFR. and IGF-R; and agents such as Herceptin, Avastin, Erbitux, etc.). For a more comprehensive discussion of up-to-date cancer therapies, see http://www.nci.nih.gov/, a list of FDA-approved oncology drugs at http://www.fda.gov/cder/cancer/druqlistframe .htm, and in The Merck Manual, Seventeenth Ed. 1999., the entire contents of which are hereby incorporated herein by reference. Examples of other therapeutic agents are noted herein and include among others, Ziloprim, alenztuzmab, altretamine, amifostine, nastrozole, prostate-specific membrane antigen antibodies (such as MLN-591, MLN591RL and ml_N2704), arsenic trioxide, bexarotene, bleomycin, busulfan , capecitabine, Gliadel Wafer, celecoxib, chlorambucil, cisplatin-epinephrine gel, cladribine, liposomal cytarabine, Elliots B solution, epirubicin, estramustine, etoposide phosphate, etoposide, exemestane, fludarabine, 5-FU, fulvestrant, gemcitabine, gentuzumabo-ozogamycin, acetate of goserelin, hydroxyurea, idarubicin, idamycin, ifosfamide, imatibin mesylate, irinotecan (or other topoisomerase inhibitor, including antibodies such as MLB576 (XR11576), Letraloza, Leucovorin, Levamisole Leucovorin, Liposonal Daunorubicin. Melphalan, L-PAM, Mesna, Methotrexate, methoxalen, mitomycin C, MLN518 or MLN608 (or other fit-3 tyrosine receptor kinase inhibitors, PDGF-R or kit-c), itoxantrone, paclitaxel, Pegademase, pentostatin, porfimer sodium, Rituximab (RITUXAN®), talc, tamoxifen, temozolamide, teniposide, VM-26, topotecan, tretinoin, ATRA, valrubicin, vinorelbine, or pamidronate, zoledronate, or another bisphosphonate. This invention further comprises the preparation of a compound of any of Formulas I, II, III, Ila, lib, llla, lllb, lllc or any other component of this invention. The invention further comprises the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, in the manufacture of a medicament for the treatment of acute or chronic cancer (including leukemias and solid tumors, whether primary or metastasized, including cancers such as those herein). mentioned and including cancers resistant or refractory to one or more therapies). The compounds of this invention are suitable for the manufacture of an anticancer medicine. The compounds of the present invention are also suitable in the manufacture of a medicament for alleviating or preventing diseases by inhibiting one or more kinases such as Src, kdr, abl, etc.. Other diseases that may be treated with a compound of this invention include diseases metabolic diseases, inflammatory diseases, and osteoporosis, and other bone diseases. In these cases, the compound of this invention may be used as a monotherapy or may be administered in conjunction with the administration of another drug for the disease, such as, for example, a bisphosphonate in the case of osteoporosis or other bone-related diseases. This invention further encompasses a composition comprising a compound of the invention, including a compound of any of the described classes or sub-classes, including those of any of the Formulas cited above, among others, preferably in a therapeutically effective amount, in association with at least one pharmaceutically acceptable carrier, adjuvant or diluent. The compounds of this invention are further suitable as standards and reagents for the characterization of various kinases, but not limited to the krd and Src family of kinases, as well as for studying the type of said kinase in biological or pathological phenomenon, for pathway studies for the transport of the intra-cellular signal mediated by the aforementioned kinases, for the comparative evaluation of new inhibitory kinases, and for the study of several other cancers in cell lines and animal models.

3. Definition

When reading this document, the following information and definitions will apply unless otherwise indicated. In addition, as otherwise noted, all occurrences of a functional group are independently chosen, as the reader is in some cases reminded by the use of a printed mark to indicate simply that the occurrences may be the same or different (e.g., R, R ', R”, or Y, Y', Y”, etc.). The term "alkyl" is intended to include linear (i.e. unbranched or acyclic), branched, cyclic or non-polycyclic aromatic hydrocarbon groups, which are optionally substituted by one or more functional groups. Unless otherwise specified, “alkyl” groups contain from one to eight, and preferably one to six, carbon atoms. Ci_6 alkyl is intended to include Ci, C2, C3, C3, C4 and C5 alkyl groups. Lower alkyl refers to alkyl groups containing 1 to 6 carbon atoms. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, pentyl, tert-pentyl, isopentyl, cyclopentyl, hexyl, isohexyl, cyclohexyl, etc.. Alcila may be replaceable or irreplaceable. Illustrations of substitutable alkyl groups include, but are not limited to, fluoromethyl, dufluoromethyl, trifluoromethyl, 2-fluoroethyl, 3-fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, benzyl, substituted benzyl, phenethyl, substituted phenethyl, etc. The term “alkoxyl” represents a subset of alkyl in which an alkyl group as defined above has the indicated number of carbons attached through an oxygen bridge. For example, “alkoxy” refers to —O-alcyl groups, where the alkyl group contains 1 to 8 carbon atoms of a linear, branched, or cyclic configuration. Examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, i-propoxy, t-butoxy, n-butoxy, s-pentoxy and the like. “Haloalcyl” is intended to include both straight and branched saturated hydrocarbon chains, having one or more carbons substituted with a Halogen. Examples of haloalcyl include but are not limited to trifluoromethyl, trichloromethyl, pentafluoroethyl, and the like. The term "alkenyl" is intended to include hydrocarbon chains of straight, branched or cyclic configuration. Unless otherwise specified, “alkenyl” refers to groups usually having two to eight, often two to six, carbon atoms. For example, “alkenyl” could refer to pro-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-5-enyl, 2,3-dimethylabut-2- enila, and the like. Furthermore, alkenyl groups may be substitutable or irreplaceable. The term “alkynyl” is intended to include hydrocarbon chains of linear or branched configuration, having one or more carbon-carbon triple bonds if any point of instability occurs along the chain. Unless otherwise specified, “alkynyl” groups refer to groups having two to eight, preferably two to six carbons. Examples of "alkynyl" include, but are not limited to, prop-2-ynyl, but-2-ynyl, but-3-ynyl, pent-2-ynyl, 3-methylapent-4-ynyl, hex-2-ynyl, hex-5-ynyl, etc.. Furthermore. Alkynyl groups may be substitutable or irreplaceable. Cycloalcyl is a subset of alkyl and includes any stable polycyclic or cyclic hydrocarbon groups of 3 to 13 carbon atoms, any of which are saturated. Examples of said cycloalcyl include, but are not limited to, cyclopropyl, norbornyl, [2.2.2]bibicyclooctane, [4.4.0]bicyclodecane, and the like, which in the case of other alkyl moieties, may optionally be substituted. The term “cycloalcyl” may be used interchangeably with the term “carbocycle”. Cycloalkenyl is a subset of alkeline and includes any polycyclic hydrocarbon groups of 3 to 13 carbon atoms, preferably 5 to 8 carbon atoms, containing one or more carbon-carbon double bonds that are saturated, as they may there may be ruptures, which may occur at any point throughout the cycle. Examples of said cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl and the like. Cycloalkynyl is a subset of alkynyl and includes any stable polycyclic or cyclic hydrocarbon groups of 0 to 13 carbon atoms, preferably 5 to 8 carbon atoms that contain one or more carbon-carbon double bonds, since Ruptures may occur at some point throughout the cycle. Examples of said cycloalkenyl include, but are not limited to, cyclopentenyl, cyclohexenyl and the like. Cycloalkynyl is a subset of alkynyl and includes any stable polycyclic or cyclic hydrocarbon groups of 5 to 13 carbon atoms, which contain an unsaturated carbon-carbon triple bond, since ruptures may occur at some point along of the cycle. As in the case of other alkenyl and alkynyl moieties, cycloalkenyl and cycloalkynyl may optionally be substituted. "Heterocycle", heterocyclyl, or "heterocyclic" as used herein, refers to non-aromatic ring systems having five to fourteen atom rings, preferably five to ten, in which one or more carbon rings, preferably one to four, each being substituted by a heteroatom such as N, O or S. Non-limiting examples of heterocyclic rings include a 3-1 H-benzimidazol-2 (1-substituted)-2-oxo-benzimidazol-3-yl, 2 -tetrahydrofuanyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholine, 3-morpholine, 4-morpholine, 4 - morpholine, 2-thiomorpholine, 3-thiomorpholine, 4-thiomorpholine, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidiline, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-pipθridinyl, 4-piperidinyl , 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 2-phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxoalanyl, benzothiolanyl, and benzothionyl. further include within the scope of the term "heterocyclyl" or "heterocyclic", as used herein, a group in which the non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is the ring containing non-aromatic heteroatom. The terms “heterocycle”, “heterocyclyl”, or “heterocyclic” if saturated or partially saturated also refer to rings that are optionally substituted. The term “aryl”, used alone or as part of a larger moiety such as “aralkyl”, “aralkoxyl”, or “aryloxyalcyl”, refers to groups of aromatic rings having six to fourteen ring atoms, such as phenyl, naphthalene, 2-naphthalene, 1-anthracil and 2-anthracil. An “aryl” ring may contain one or more substituents. The term “aryl” may be used interchangeably with the term “aryl ring”. “Aryl” will also include fused polycyclic aromatic ring systems in which an aromatic ring is fused to one or more rings. Non-limiting examples of suitable aryl ring groups include phenyl, hydroxyphenyl, halophenyl, alloxyphenyl, dialkoxyphenyl, trialkoxyphenyl, alkylenedioxyphenyl, naphthalene, phenanthrile, alkoxyphenyl, dialkoxyphenyl, trialkoxyphenyl, alcylenedioxyphenyl, naphthalene, phenanthrile, anthryl, phenanthro, and the like, as well as, naphthalene-1, naphthalene-2, anthracil-1, anthracil-2. Also included within the scope of the term "aryl", as used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, as in an indanyl, phenanthridinyl, tetrahydronaphthalene, where the radical or point of attachment is the aromatic ring. The term “heteroaryl” as used herein refers to the aromatic moiety of stable polyheterocyclics and heterocyclics, having from 5 to 14 ring atoms. Heteroaryl groups may be substitutable or non-substitutable and may comprise one or more rings. Examples of typical heteroaryl rings include 5-membered monocyclic ring groups such as thienyl, pyrroline, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl and the like; 6-membered monocyclic groups such as pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl and the like; and polycyclic heterocyclic ring groups such as benzo[b]thienyl, naphtho[2-3]thienyl, thianthrenyl, isobenzofuranyl, chromelnyl, xanthenyl, phenoxathienyl, indolizinyl, isidolyl, indolyl, indazolyl, purinyl, isoquonoline, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl , quinazolinyl, benzothiazole, benzimidazole, tetrahydroquinoline, cinolinyl, carbozilyl, betacarbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazianyl, phenoxazinyl, and the like (see for example Katrizky, Handbook of Heterocyclic Chmistry). In addition to specific examples of heteroaryl rings, they also include furanyl-2, furanyl-3. imidazolyl-N, imidazolyl-2, imidazolyl-4, imidazolyl-5, isoxazolyl-3, isoxazolyl-4, isoxazolyl-5, oxadiazolyl- 2, oxadiazolyl-5, oxazolyl-2, oxazolyl-4, oxazolyl-5, pyrrolyl- 1, pyrrolyl-2, pyrrolyl-3, pyridyl-2, pyridyl-3, pyridyl-4, pyrimidyl-2, pyrimidyl-4, pyrimidyl-5, pyridazinyl-3, thiazolyl-2, pyridyl-2, pyridyl-3, pyrimidyl-2, pyrimidyl-4, pyrimidyl-5, pyridazinyl-3, thiazolyl-2, thiazolyl-4, thiazolyl-5, tetrazolyl-5, triazolyl-2, triazolyl-5, thienyl-3, carbozolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl or benzoisoxazolyl. Heteroaryl groups further include a group in which a heteroaromatic ring is fused to one or more aromatic and non-aromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinoline, tetrahydroisoquinoline, pyrido[3,4-d]pyrimidinyl, imidazo[1,2-a]pyrimidyl[1,2- a]pyrazinyl, imidazo[1,2-a]pyridinyls, imidazo[1,2- c]pyrimidyl, pyralozo[1,5- a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidyl, imidazo[1,2-b]pyridazinyl, imidazo[1,5- a]pyrimidyl , pyrazolo[1,5-b][1,2,4]triazine, quinolyl, isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl, triazolopyrimidyl, pyrodopyrazinyl. The term “heteroaryl” further refers to rings that are optionally substituted. The term “heteroaryl” may also be used interchangeably with the term “heteroaryl ring” or the term “heteroaromatic”. An aryl group (including the aryl part of an aralcyl, aralkoxyl, aaryloxyalcyl moiety and the like) or heteroaryl group (including the heteroaryl part of a heteroalkyl or the heteroarylkoxyl moiety and the like) may contain one or more substituents. Examples of suitable substituents on the saturated carbon atom of an aryl or heteroaryl group include halogen (F, Cl, Br or I). -CN, -R4, -OR2, -S(O)R2, (where r is an integer of 0, 1 or 2), -SO2NR2R3, -NR2R3, -(CO)YR2, -O(CO)YR2,- NR2(CO)YR2, -S(CO)YR2, -NR2C(=S)YR2, -OC(=S)YR2, -C(=S)YR2, where each occurrence of Y is independently -O-, -S -, -NR3-, or a chemical link; - (CO)YR2 then representing-C(=O)R2, -C(=O)OR2 and, -C(=O)NR2R3. Additional substituents include -YC(=NR3)YR2, -COCOR2, -COMCOR2 where M is an alkyl group of carbon 1-6), - YP(=0)(YR4)(YR4)(including but not limited to - P(=O )(R4)2), -Si(R2)3, -NO2SO2R2 and -NR2SO2NR2R3. To further illustrate the substituents in which Y is -NR3, we include, among others, -NR3C(=O)R2, - NR3C(=O)NR2R3, -NR3C(=O)OR2 and -NR3C(=NH)NR2R3. R2 and R3 are substituents at each occurrence and independently selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalcyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, and R2 and R3 (and R4) are substituents that must properly be substitutable or irreplaceable. Examples of permitted substituents on R2, R3 and R4 include, among others, amine, alkylamine, dialkylamine, aminocarbonyl, halogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, carbocycle, heterocycle, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, nitro groups. , cyano, carboxyl, alkoxycarbonyl, alkylcarbonyl, hydroxyl, alkoxyl, haloalkoxyl. Additional illustrative examples include protected OH (such as acyloxyl), phenyl, substituted phenyl, O-phenyl, -O- (substituted) phenyl, benzyl, substituted benzyl, -O- phenethyl (i.e. -OCH2CH2C6H5), -O-(substituted ) phenethyl. Non-limiting illustrations of a substituted portion of R2, R3, R4 include haloalcyl and trihaloalcyl, alkoxyalcyl, halophenyl, -M-heteroaryl, -M-heterocycle, -M-aryl, -M- OR2, -M-OR2, -M- SR2, MNR2R3M, -M-NR2R3, -M-NR2R3, -M-OC(O)NR2R3, -M- NR2C(O)OR2, -M-C(O)R2, -M-C(=S)R2, -M-C( =S)NR2R3, -M-C(O)NR2R3, -M- NR2C(O)OR2, -M-C(O)R2, -M-C(O)R2, -M-C(=S)R2, -M-C(=S)NR2R3 , -M-C- (O)NR2R3, -M-C(O)NR2R3, -M-NR2C(NR3)NR2R3C(S)NR2R3, -M-S(O2)R3, -M- C(O)R3, -M-OC( O)R3, -MC(O)SR2, -M-S(O)2NR2R3, -C(O)-M-C(O)R2, -M-C(O)R2, - MC2R2, -MC(=O)NR2R3, -M-C (=NR)NR2R3 and -M-OC(=NH)R2R3 (where M is a carbon 1-6 alkyl group. Some more specific examples include, but are not limited to, chloromethyl, trichloromethyl, trifluoromethyl, methoxyethyl, alkoxyphenyl, halophenyl, -CH2-aryl, -CH2-heterocycle, -CH2C(O)NH2, -C(O)CH2N(CH3)2, - CH2CH2OC(O)NH2, -CH2CH2NH2, -CH2CH2CH2Net2, -CH2OCH3, -C(O)NH2 , - CH2CH2-heterocycle, -C(=S)CH3, -C(=S)NH2, -C(=NH)NH2, -C(=NH)Oet, -C(O)NH- cyclopropyl, C(O )NHCH2CH2-heterocycle, -C(O)NHCH2CH2OCH3, C(O)CH2NHCH3, -CH2CH2F, -CH2F, -C(O)CH2-heterocycle, -CH2C(O)NHCH3, - CH2CH2P(O)(CH3)2, SÍ(CH3) and similar. An aliphatic, that is, alkyl, alkenyl, alkynyl, alacoxyl, haloalcyl, cycloalcyl, cycloalkenyl, cycloalkynyl or non-aortic heterocyclic, the group may then contain one or more substituents. Examples of suitable substituents on said groups include, but are not limited to, those listed above for carbon atoms, an aryl or heteroaryl group and in addition include the following substituents for a saturated carbon atom: =O,=S, =NH, =NNR2R3, =NNHC(O)R2, =BBHCO2R2, OR =NNHSO2R2, where R2 in each occurrence is independently H, alkyl, alkenyl, alkynyl, cycloalcyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl. Illustrative examples of the substituents on an aliphatic, heteroaliphatic or heterocyclic group include amine, alkylaminocarbonyloxy, aminocarbonyl, halogen, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, -CN, carboxyl, alkoxycarbonyl, alkylcarbonyl, -OH, haloalkoxy groups or haloalcyl. Illustrative substituents on a nitrogen, i.e., on an aryl, heteroaryl, or non-aromatic heterocyclic ring, include R4, -NR2R3, -C(=O)R2, - C(=O)OR2, -C(=O)SR2, -C(=O)NR2R3, -C(=NR2)OR2, -C(=NR2)R3, -COCOR2, - COMCOR2, -CN, -SO2R3, S(O)R3, -P(=O)(YR2 )(YR2), -NR2SO2R3 and -NR2- SO2NR2R3, where each occurrence of R2 and R3 is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalcyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl. This invention includes only those combinations of substituents and variables that result in a chemically workable or stable compound. A stable compound or a chemically practicable compound is one that has sufficient stability to allow its preparation and detection. Preferred compounds of this invention are sufficiently stable that they are not substantially changed when maintained at a temperature of 40° C. In the absence of moisture or other chemically reactive conditions for at least one week. Certain compounds of this invention may exist in tautomeric forms, and this invention further includes all said tautomeric forms of these compounds unless otherwise specified. Therefore, unless otherwise stated, the reported structures also aim to include all stereochemical forms of the structure, that is, the R and S configurations for each asymmetric center. Thus, simple stereochemical isomers, as well as enantiomeric and diastereomeric mixtures of the present compounds will be within the scope of the invention. Thus the invention includes each diastereomer or enantiomer free of other isomers (>90% and preferably >95% free of other stereoisomers on a molar basis), as well as a mixture of other isomers. Particular optical isomers may be obtained by resolving racemic mixtures according to conventional processes, such as, for example, the formation of diastereoisomeric salts, by treatment with an optically active acid or base. Examples of suitable acids are tartaric, diacetyltartaric, dibenzoyltartaric, Ditoluoyltartaric and camphorsulfonic acids and then separating the mixture of diastereoisomers by crystallization followed by the release of the optically active bases from these salts. A different process for the separation of optical isomers involves the use of a favorably chosen chiral chromatographic column to maximize the separation of the enantiomers. Yet another method involves the synthesis of covalent diastereoisomeric molecules by reacting the compounds of the invention with an optically pure acid in an activated form or a chemically pure isocyanate. The synthesized diastereoisomers can be separated by conventional means such as chromatography, distillation, crystallization or sublimation, and then hydrolyzed material releases the enantiomerically pure compound. The optical active compounds of the invention can be obtained by the active use of standard materials. These isomers may be in the form of a free acid, a free base, an ester or salt. The compounds of this invention may exist in radiolabeled form, that is, the compounds may contain one or more atoms having an atomic mass or number of masses different from the atomic mass or number of masses, ordinarily found in nature. Radioisotypes of hydrogen, carbon, phosphorus, fluorine, and chloride include 3H, 14C, 32P, 35S, 43Fe36CI, respectively. Compounds of this invention that contain those radiosotopes and/or other radioisotypes of other atoms are within the scope of this invention. Triciate, i.e. 3H, and carbon -14, i.e. 14C, radioisotypes are particularly preferred for their easy preparation and detection. The radiolabeled compounds of this invention may generally be prepared by methods known in the art and identified by one skilled in the art. Conventionally, said radiolabeled compounds may be prepared by carrying out the procedures disclosed in the present application, except by substituting an effective reagent. radiolabeled by a non-radiolabeled reagent.

4. Synthetic Overview

The user will have a very extensive literature on heterocyclic and other relevant chemical transformations, recovery and purification technologies to draw from, in combination with the information contained in the examples that follow, for targeting synthetic strategies, protecting groups, and other materials and methods. suitable for the synthesis, recovery and characterization of the compounds of this invention, including compounds containing the various choices of R', Ra, Rb, Rc, Rd and Rings T, A, B, C and D. The following references, and the references already cited, may be of particular interest: WO 01/27109, WO 02/066478, WO 02/30428, WO 02/080911, WO 02/080914, WO 2004/03345, WO 2004/035578, WO 2004/23972, WO 2005 /105798, US 2003/0119842, US 2004/0023972, US 2004/0122044, US 2004/142961, US 2005/0239822, US 64320365 and US 6703403 are references of the preparation of imizadol[1,2-a]pyridines; WO 05/030218, WO 03/02850 are references to imizadol[1,2-a]pyridines; WO 05/047290, WO 03/089434, US 6589952 relate to imidazol[1,2-b]pyridazines; and WO 05/070431; WO 96/35690; WO 04/089471 refers to pyrazolo[1,5-a]pyrimidines. Various synthetic routes may be used to produce the compounds described here, including those represented schematically below. The user will appreciate that protection groups can be used on these paths. “Protecting groups” are moieties that are used to temporarily block the chemical reaction at a potential reactive site (e.g., an amine, hydroxyl, thiol, aldehyde, etc.) so that the reaction can be carried out selectively at another site into a multifunctional compound. In preferred embodiments, a protecting group selectively reacts in good yield to give a protected substrate that is suitable for designed reactions; the protecting group must be selectively renewable by appropriately viable reagents, preferably non-toxic reagents that do not unduly attack other functional groups; the protecting group preferably forms a separate appropriate derivative (more preferably without the generation of additional stereogenic centers); and the protecting group having a minimum of additional functionality to avoid complication of other reaction sites. A wide variety of protecting groups and strategies, reagents and conditions for organizing and removing them are well known in the art. See, for example, “Protective Groups in Organic Synthesis” Third Ed. Greene, TW and Wuts, PG, Eds., John Wiley & Sons, New York; 1999. For additional practical information on protection group methodologies (materials, methods and strategies, for protection and non-protection) and other appropriate synthetic chemical transformations in the production of the compounds now described; see in R. Larock, Comprehensive Organic Transformations. WCH Publishers (1989); TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L Paquette, Ed. Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995). The entire contents of these references are incorporated into this application by reference. Furthermore, one of the chosen reagents may be enriched for a desired isotope, for example, deuterium in place of hydrogen, to create compounds of this invention containing said isotopes. Compounds containing deuterium in place of hydrogen in one or more locations, or containing various isotopes of C, N, P and O, are covered by this invention and can be used, for example, in the study of metabolism and/or tissue distribution of compounds or to alter the rate or pathway of metabolism or other aspects of biological functioning. The compounds of this invention may be synthesized using the methods described below, together with methods known in the art of synthetic organic chemistry, or by a variation thereof as appreciated by one skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in a solvent appropriate to the reagents and materials used and used for the transformation carried out. It will be understood by a person skilled in the art in organic synthesis that the functionality present in the molecule must be consistent for the proposed transformations. This sometimes requires better analysis to modify the synthetic phases or to select a process scheme to obtain a desired compound of the invention. A compound of the present invention may be prepared as shown in Scheme I to Scheme XIX, via standard methods for one skilled in the art. A Sonogashira catalyzed palladium coupling reaction is used to link the “top” of the AneIT to the bottom of the Ring A]-[Ring B] portion as illustrated in Schemes I and II. In Scheme I, the reaction coupled to Sonogashira is carried out with acetylenic from the “top” of Ring T and with the lower part of [Ring A]-[L1]-[Ring B] that has been activated by the presence of a reactive group W, that is an I, a Br or another reactive group allowing the desired coupling reaction. The variables in W-[Ring A]-[L1]-[Ring B] are as previously defined, that is, Rings A and B being replaced by the permitted groups Ra and Rb, respectively. Scheme I: Sonogashira Coupling Reaction

An alternative coupling reaction is described in Scheme II, in which Ring T is “activated” by the presence of a reactive group W (such as I or Br) and being coupled to the acetylenic “bottom” of [Ring A][L1] under similar catalyzed palladium coupling conditions. Scheme II: Alternative Sonogashira Coupling Reaction

The Sonogashira coupling conditions described in Scheme II are applied to all bicyclic heteroaryl T rings and suitable for synthesizing all compounds of this invention. Several illustrative synthetic pathways for the preparation of the acetylenic T Ring moieties, based on known transformations, are illustrated below, in Schemes III to VIII: Scheme III: Preparation of 3- Ethynylimidazole [1,2-a] pyrazines Scheme IV: Preparation of C-8 Substituted 3- Ethynylimidazole [1,2-a]pyrazines Scheme V: Preparation of 3-Ethynylimidazol[1,2-a]pyridine or 3-Ethynylimidazol[1,2-a]pyridazine Scheme VI: Preparation of C-8 Substituted 3- Ethynylimidazole [1,2-a]pyrazines Scheme VII: Preparation of C-8 Substituted 3-Ethynylimidazol[1,2-a]pyridines

Scheme VIII: Preparation of C-6 and C-8 Substituted 3-Ethynylimidazol[1,2-a]pyridines For the coupling step, see Malleron, J-L., Fiaud, J-C., Legros, J-Y. Handbook_of Palladium Catalyzed Organic Reactions. San Diego: academic Press. 1997.

One skilled in the art will recognize these methods for preparing various substituents of acetylenic T Ring groups, which are widely applied to various other bicyclic ring systems not shown. Schemes IX to XII below represent the synthesis of compounds of Formula W-[Ring A]-[L1][Ring B] that are suitable for intermediate the coupling reaction described in Schemes I and II.

It should be apparent that the intermediates of the formula:

They are of particular interest for their coupling reaction with the “top” of the heteroaryl rings producing the compounds of the present invention. The variable groups A, L1 and B are as previously defined and optionally substituted as described herein, and W being I or an alternative reactant group allowing a desired coupling reaction. Illustrations of said intermediaries include, among others, those of the following structures: where the previously defined variables, that is, Ra, Rb, Rc and Rd are as previously defined. For example, Ra in some embodiments is chosen from F for alkyl, for example, Me, among others, and Rb in some embodiments is chosen from Cl, F, Me, t-butyl, -CF3 or -OCF3 among others. These and other components of the formula W-[Ring A]-[L1]-[Ring B) with the various permitted substituents are suitable for preparing the corresponding compounds of the invention as defined in the various formulas, classes and sub-classes disclosed herein. Some illustrative synthetic routes for the preparation of representative reagents and intermediates are presented below:

Scheme IX describes an illustrative synthesis of W-[RingA]-[L1]-[Ring B] in which Rings A and P are phenyl and L1 is NHC(O). Scheme IX

Scheme X represents the synthesis of a variant of the above scheme in which Ring B is a 2-pyridine and L1 is C(O)NH (that is, in another orientation). Scheme

Schemes X I and XII below illustrate the synthesis of W-[Ring A]-[L1][Ring B] in which Rings A and b are phenyl and Ring C is a heteroaryl ring. These intermediates are suitable for making the compounds of formula II.

More specifically, Scheme Xi describes the preparation of intermediates, 15 in which Ring C is an imized ring.

Scheme XII describes the preparation of intermediates in which Ring C is a pyrrole or an oxazole ring. Scheme XII

Scheme XII illustrates the synthesis of W-[Ring A]-[L1]-[Ring B] in which Rings A and B are phenyl and substituted Rb is L2-[Ring D]. These intermediates are suitable for making compounds of formula III in which Ring D is a 5-6 membered heterocycle, containing one or two heteroatoms.

In this Scheme, non-limiting examples of the Rb substituents on Ring B are halo, for example, Cl; lower alkyl groups, such as isopropyl; and substituted lower alkyl groups, such as -CF3; and non-limiting examples of Ring D being N,N-dimethylapyrolidine, N-(2-hydroxyethyl)piperazine, and N-methylapiperazine. Intermediates W-[Ring A]-[L1]-[Ring B], such as those represented in the various synthetic Schemes shown above, may be reacted with an acetylenic Ring T using Sonogashira coupling conditions described in General Scheme I. An example is depicted in Scheme XIV below, in which the T Ring portion may be further derived after the Sonogashira coupling step, to generate several interesting substituents analogous to this invention. Scheme XIV

Alternatively, the W-[Ring A]-[L1]-[Ring B] may be reacted under Sonogashira conditions with trimethylasilacetylene, prior to coupling with an iodine- or bromine-activated T-Ring unless otherwise described in General Scheme II. . An example represented in Scheme XV: Scheme XV

In other embodiments, the steps may be performed in a different order. For example, the Sonogashira coupling reaction could be used for Ring T and Ring A before linking them to the Ring B part and/or [Ring B]-[L2]-[Ring D] and/or [ Ring B]-[Ring C] as shown in Scheme XVI. Scheme XVI

In a non-limiting example in which Ring A and Ring B are phenyl and L1 is CONH, Scheme XVII describes the Sonogashira coupling of an acetylenic T Ring with 3-iodo-4-methylbenzoic acid (a portion of Ring A) to generate an intermediate [T Ring] that undergoes starch coupling with an optionally substituted portion of the B Ring Scheme XVII

This pathway is illustrated in Scheme XVIII which depicts the coupling of an acetylenic T Ring (i.e., 3-ethynylimodazol[1,2-a]pyridazine with a 5-substituted W-[A Ring](i.e., 3-iodo-4 -methylbenzoic acid), followed by a starch coupling of the resulting [Ring T]-[Ring A]-COOH intermediated with an H2N-[Ring B]-L2[Ring C](i.e., 4-((4- methylpiperazin-1yl)methyl)-3- (trifluoromethylaniline): Alternatively, as another illustration of user set options, the intermediate Ring A with 3-iodo-4-trimethylabenzoic acid, which after being deprotected, may have a second Sonogashira coupling reaction with an activated Ring T as illustrated in Scheme XIX. Scheme XIX with synthetic paths which as mentioned, combined with the examples that follow, and additional information provided herein and conventional materials and methods, will enable the user to prepare a complete extension disclosed herein.

6. Uses, Formulations, Administration Pharmaceutical Uses; Indications This invention provides compounds having biological properties that make them interesting for the treatment or recovery and amelioration of diseases in which the kinase may be involved, symptoms of said diseases, or the effect of other physiological events mediated by kinases. For example, a number of compounds of this invention have been shown to inhibit the tyrosine kinase activity of Src and abl, among other tyrosine kinases that are purported to mediate the growth, development and/or metastasis of cancer. A number of compounds of this invention have also been found to provide potency in vitro activity against cancer cell lines, including among others, K-562 leukemia cells. The observed potencies exceed those of 10-fold, being more powerful than those of Gleevec in conventional anti-proliferation tests with K562 cells. These compounds are therefore of interest for the treatment of cancers, including both primary and metastatic cancers, including solid tumors, as well as lymphomas and leukemias (including CML, AML and ALL), and including cancers that are resistant to other therapies, including other therapies involving the administration of kinase inhibitors such as Gleevec, Tarceva or Iressa. Said cancers include, among others, cancers of the lung, cervical, colon and rectum, breast, ovary, pancreas, prostate, head and neck, gastrointestinal stroma, as well as diseases such as melanoma, multiple myeloma, non-Hodgkin's lymphoma, melanoma, gastric cancers and leukemias (such as myeloid, lymphocyte, myelocyte, and limboblastic leukemias) including cases that are resistant to one or more therapies, including among others, Gleevec, Terceva or Iressa. Resistance to various anticancer agents may lead to one or more mutations in a cancer mediator or effector (e.g., mutation in a kinase such as Src or Abl) that are correlated with alteration of the binding properties of the drug protein, binding phosphate binding, protein binding, self-regulation and other characteristics. For example, in the case of BCR-Abl, the kinase associated with Gleevec-resistant chronic myeloid leukemia has been mapped to a variety of BCR/Abl mutations that are linked to a range of functional consequences, including, but not limited to, sterile impairment. occupancy of the drug, and active site of the kinase, change in deformation of the phosphate loop P bond, effects on the conformation of the activation of the loop around the active site, and others. See, for example, Shah et al, 2002, Cancer Cell 2, 117 - 125 and Azam et al, 2003, Cell 112, 831 - 843 and references cited therein for representative examples of said mutations in Bcr/Abl that correlate with drug resistance. See also the following references for additional practical information on BCR/Abl, its example mechanism in CML and resistance to drug resistance conferring mechanisms and mutations, Kurzrock et al; Philadelphia chromosome-positive leukemias, from basic mechanisms to molecular therapies, Ann Intern Med. 2003 May 20; 138(10):819-30; O’Dwyer et al; Demonstration in Philadelphia of abnormal chromosome-negative clones in patients with chronic myelogenous leukemia during most genetic responses, including imatinib mesylate. Leukemia. 2003 Mar; 17 (3)481-7; Hochhaus et al; Molecular and chromosomal mechanisms os resistance to imatinib (STI571) therapy, Leukemia. 2002. Nov 16(11)2190-6; O’Dwyer et al.. The impact of clonal evolution in response to imatinib mesylate (STI571) in the accelerated CML phase, Blood 220. Sep. 1. 100(5): 1628-33, Braziel et al., Hematopathology and cytology findings in patients with chronic myelogenous leukemia treated with imatinib mesylate; 14 months of experience. Blood. 2002 Ju 15; 100(2)435-41; Corbin et al. Analysis of the structural basis of the specificity of Abl kinase inhibition STI571, J. Bio. Chem. 2002 Aug 30; 277(35):32214-9; Wherteim et al; BCR-ABL induced adhesion effects are independent of tyrosine kinase, Blood 2002 Jun 1 ;99(11): 4122-3-; Kantarijian et al., Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia, N. Engl. J. Med. 2002 Feb 28;346(9):645-32: Erratum in: N, Engl. J. Med. 2002 Jun 13; 346(24):1923; Hochhaus et al., Roots of clinical resistance to STI-571.Science cancer therapy. 2001. Sep 21; 293(5538): 2163; Druker et al.; Activity of a specific tyrosine kinase inhibitor BCR-ABL in severe crisis of chronic myeloid leukemia and acute lymphatic leukemia with the chromosome Philadelphia, N. Engl. J. Med. 2001 Apr 5; 344(14): 1038-42. Erratum in: N. Engl. J. Med. 2001 Jul 19; 345(3): 232: Mauro et al., Chronic myelogenous Leukemia, Curr Opin Oncol. 2001, Jan; 13(1):3-7, Review; Kolibaba et al., CRKL binding to BCR-ABL and BCR-ABL transformation. Leuk Limphoma. 1999 Mar; 33(1-2):119-26. Bhat et al., Interactions of p62(dok) with p210(bcr-abl) and Bcr-Abl-associated proteins. J. Biol. Chem. 1998 Nov 27; 273(48):32360-8. Senechai et al.. Structural requirements for the adapter protein Crkl in strong fibers and hematopoietic cells. Mol Cel Biol. 1998; Sep. 18((0:5082-90; Kolibaba et al., Tyrosine protein kinase and cancer. Biochim Biophis. Acta. 1997 Dec 9; 1333(3):F217-48. Review; Heaney et al., Direct binding of CRKL to BCR-ABL is not required for BCR-ABL transformation. Blood. 1997 Jan 1;89(1):297- 306; Hallek et al; Interaction of the tyrosine receptor kinase kit p-145c with p210bcr/abl kinase in myeloid cells. BR J Haematol. 1996 Jul; 94(1):5-16; Oda et al.. The SH2 domain of ABL is not required for independent BCR-ABL-induced growth in a mature myeloid cell line. Leukemia 1995 Feb;9 (2):295-301; Carlesso et al.. Use of a sensitive temperature mutant to define the biological effects of the p210BCR/ABL tyrosine kinase on the proliferation of a factor-dependent myeloid cell line. Oncogene. 1994 Jan; 9(1 ):149-56. Again we contemplate that the compounds of this invention, both monotherapies and combination therapies, will be suitable against leukemias and other cancers, including those resistant in whole or in part to anticancer agents, specifically including Gleevec and others. kinase inhibitors, and specifically including leukemias involving one or more mutations in BCR/Abl, without or outside the kinase domain, including but not limited to those noted in any publication referenced above. See in particular Azam et al and references cited herein for examples of said mutations in BCR/Abl including, among others, mutations in the drug binding clefts, the P loop in phosphate binding, the activation loop, the VAVK conservation of the kinase beta-3 sheet, the alpha-1 catalytic helix of the small N lobe, the long alpha-3 helix within the large C lobe, and the inner region of the C lobe below the activation loop.

Pharmaceutical Methods

The method of the invention comprises administering by an individual in need thereof a therapeutically effective amount of a compound of the invention. A “therapeutically effective amount” is that amount effective to detect or kill or inhibit the growth or spread of cancer cells; the size or number of tumors; or other measure of cancer level, stage, progression, or severity. The exact amount required will vary from individual to individual, depending on the species, age and general condition of the individual, the severity of the disease, the particular anticancer agent, its mode of administration, combination of treatment with other therapies, and others. The compound or composition containing the compound may be administered using any amount and any route of administration effective to destroy or inhibit the growth of tumors or other forms of cancer. The anticancer compounds of the invention are preferably formulated in unit dosage form to facilitate administration and uniformity of dosage. The term “dosage unit form” as used herein refers to a discrete physical unit of the anticancer agent appropriate for the patient to be treated. As appropriate, the total daily dosage of the compounds of the compositions of the present invention is decided by the attending physician using the confidence of the medical judgment rendered. The level of the specific therapeutically effective dose including the disease being treated, specific composition employed, the age, body weight, general health, sex and diet of the patient, the route and schedule of administration; the degree of metabolism and/or excretion of the compound; the duration of treatment; drugs used in combination or coincident with the administration of the compound of this invention, and similar factors well known in the medical art. Furthermore, after formulation with an appropriate pharmaceutically acceptable carrier in a desired dosage, the compositions of this invention may be administered to humans, or other animals, orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (through intravenous dressings). skin, powders, tablets, capsules) sublingual, buccal, as a nasal or oral spray, or similar. The effective systematic dose of the compound will typically be in the range of 0.01 to 500 mg of the compound per kg of the patient's body weight, preferably 0.1 to 125 mg/kg, and in some cases 1 to 25 mg/kg, administered in single or multiple doses. doses. Generally, the compound can be administered to patients who require said treatment in a daily dose ranging from 50 to approximately 2000 mg per patient. Administration may occur once or multiple times daily, weekly (or even on separate days) or an administration schedule. For example, the compound may be administered one or more times per day or week (for example every Monday) indefinitely or for a period of week, for example 4 to 10 weeks. Alternatively, it may be administered daily for a period of days (e.g. 2 to 10 days) followed by a period of days (e.g. 30 days) without administration of the compound, with the cycle repeated infinitely or for a certain number of repetitions. for example 4 to 10 cycles. As an example, a compound of the invention may be administered daily for 5 days, then discontinued for 9 days, then administered daily for another period of 5 days, and then discontinued for 9 days, and thus repeating the cycle indefinitely, or for a total of from 4 to 10 times. The amount of the compound that will be effective in treating or preventing a particular disease or condition will depend in part on well-known factors affecting the dosage of the drug. In addition, in vitro or in vivo analyzes may optionally be used to help identify the dosage in ideal proportions. A condition to guide effective doses may be extrapolated from dose response curves derived from in vitro analyzes or animal test systems. The precise dosage level will be determined by the clinician or other health care provider and will depend on other known factors, including route of administration, age, body weight, sex and general health of the individual, the nature and severity of the clinical stage of the condition. illness. The use (or not) of concomitant therapies, and the nature and extent of genetic engineering of cells in the patient. When administered for the treatment or inhibition of a particular disease state, the effective dosage of the compound of this invention will vary depending on the particular compound used, the mode of administration, the condition and severity thereof, the condition being treated, as well as various clinical factors relating to the individual being treated. In many cases, satisfactory results may be obtained when the compound is administered at a daily dosage of approximately 0.01 mg/kg-500 mg/kg, preferably between 0.1 and 125 mg/kg, and most preferably between 1 and 25 mg/kg. . The projected daily dosages are expected to vary with the conduct of administration.

Thus parenteral dosages will often be at comparative levels of 10% to 20% of oral dosage levels. When the compound of this invention is used as part of a controlled combination, dosages of each component of the combination are administered over a desired period of treatment. The combination compounds may be administered at the same time, as a unit dosage form containing both components, or separate dosage units; the components of the composition may also be administered at different times during a treatment period, or one may be administered as a pre-treatment for the other.

Relating to compounds

The compounds of the present invention may exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable salt or other derivative. As used herein, the term “pharmaceutically acceptable salt” refers to those salts that are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and small animals without due toxicity, irritation, allergic response and others, and that are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates and other types of compounds are well known in the art. For example, S. M. Berge et al, describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977), incorporated herein by reference. Salts may be prepared in situ during the isolation and purification of compounds of the invention, or separately by reacting the free base of the free acid of a compound of the invention with an appropriate base or acid, respectively. Examples of pharmaceutically acceptable salts are non-toxic acid addition salts and salts of an amine group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid, succinic acid or malonic acid, or by the use of other methods known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfate, benzoate, bisulfate, borate, butyrate, camphorate, camphosulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, hernisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, melate, maleate, malonate, methanesulfate, 2-naphthalesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, parmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propianate, stearate , succinate, sulfate, tartrate, p-tolunelsulfanate, undeconate, valerate salts, and others. Representative alkaline salts, or metal salts of alkaline soil include sodium, lithium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations formed using components such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, low alkyl sulfonate and aryl sulfonate. Additionally, as used herein, the term "pharmaceutically acceptable ester" refers preferentially to esters that hydrolyze in vivo and include those that readily break down in the human body to permit the parent compound or salt thereof. Suitable ester groups include, for example, those derived from alkanedioic carbolic acids, in which each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of particular esters include formates, acetates, propianates, butyrates, acrylates and ethyl succinates. Obviously, esters may be formed with a carboxylic or hydroxylic acid group of the compound of the invention. Furthermore, the term "pharmaceutically acceptable prodrugs" as used in the present application refers to those prodrugs of the compound of the present invention that are, within the scope of medical judgment, suitable for use in contact with the tissues of the present invention. humans or small animals with undue toxicity, allergic response, irritation, and others, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as for zwitteronic forms, where possible, of the compounds of the invention. The term “prodrug” refers to compounds that are transformed in vivo to produce the parent compound of the above formula, for example by hydrolysis in the blood. See for example, T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Sustems, Vol. 14 of the A.C.S. Symposium Series, and Edward B. Roche, ed., Bioversible Carriers in Drug Design, American Pharmaceutical Assocn. And Pergamon Press, 1987, both of which are incorporated into the present application by reference.

Compositions

Compositions are provided comprising any of the compounds described herein (or a prodrug, pharmaceutically acceptable salt, or other pharmaceutically acceptable derivative thereof), and one or more pharmaceutically acceptable carriers or excipients. Such compositions optionally further comprise one or more additional therapeutic agents. Alternatively, a compound of this invention may be administered to a patient in need thereof in combination with the administration of further therapeutic controls (such as Gleevec or other kinase inhibitors, interferon, reduced bone transplantation, farnesyl transferase inhibitors, bisphosphonates, thalidomide, cancer vaccines, hormone therapy, antibodies, radiation, etc.). For example, additional therapeutic agents for joint administration or inclusion in a pharmaceutical composition with a compound of this invention may be any other anticancer agent or agents. As described herein, the compositions of the present invention comprise a compound of the invention together with a pharmaceutically acceptable conductor, which as used herein, may include any solvent, diluent, or other dispersing vehicle or suspension aid, surface active agents, isotonic agents. , and the like as appropriate to the particular dosage desired. Remington’s Pharmaceutical Sciences, Fifteenth Edition. E.W. Martin (Mack Publishing Co., Easton, Pa., 1975) discloses several drivers in the compositions of pharmaceutical formulations and known techniques for preparing them. Unless any conventional conductive medium is incompatible with the compounds of the invention, such as by producing undesirable biological effects or otherwise interacting in a pernicious manner with any other component(s) of the pharmaceutical composition, it uses its contemplation to be within the scope of the invention. Some examples of pharmaceutically acceptable conductive materials include, but are not limited to, sugars such as lactose, glucose and sucrose, starch such as cornstarch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and acetate. cellulose and wax suppositories, oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil, glycols such as propylene glycol, esters such as ethyl and ethyl laurate, agar, insulating agents such as magnesium hydroxide and aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, and phosphate insulating solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, removing agents, sweeteners, aromatic and fragrance agents, preservatives and antioxidants that may also be present in the composition.

Formulations

The invention also encompasses a class of compositions comprising the active compounds of this invention associated with one or more pharmaceutically acceptable conductors and/or diluents and/or adjuvants (collectively referred to hereinafter as “conductive materials”) and, if desired, other active ingredients. The active compounds of the present invention may be administered by any suitable guideline, preferably in the form of a pharmaceutical composition adapted to a guideline or path, and in an effective dose for the intended treatment. The compounds and compositions of the present invention may, for example, be administered orally, mucosally, topically, rectally, pulmonaryly or by spray inhalation, or parentally including intravascularly, intravenously, intraperiotially, subcutaneously, intramuscularly, intratestinally and by infusion techniques, in unit dosage formulations containing conventional pharmaceutically acceptable carriers, adjuvants and carriers. The pharmaceutically active compounds of this invention may be processed in accordance with conventional pharmaceutical methods to produce medicinal agents for administration to patients, including humans and other mammals. For oral administration, the pharmaceutical composition may be in the form of, for example, a capsule, tablet, suspension or liquid. The pharmaceutical composition is preferably made in the form of a unit containing a particular amount of the active ingredient. Examples of said dosage units are capsules or tablets. For example, they may contain an amount of an active ingredient of approximately 1 to 200 mg, preferably of 1 to 500 mg, and more commonly of approximately 5 to 200 mg. An adequate daily dose for a human or other mammal may vary depending on the patient's condition or other factors, but once again, it can be determined using routine methods. The amount of the compounds that are administered and the control of the dosage for a treatment with the compounds and/or compositions of the present invention will depend on a variety of factors, including the age, weight, sex and clinical and medical conditions of the individual, the type of the disease. The severity of the disease, the guideline and frequency of administration, and the particular compound employed. Thus dosage guidelines may vary widely but can be determined routinely using standard methods. A typical daily dose will be in the range of 0.01 to 50 mg of the compound per body weight, preferably between 0.1 and 125 mg/kg per body weight, and in some cases between 1 and 25 mg/kg per body weight. As mentioned previously, the daily dose may be given in one administration or may be divided between 2, 3, 4 or more administrations. For therapeutic purposes, the active compounds of this invention are ordinarily combined with one or more suitable adjuvants, excipients or carriers to indicate the route of administration. If administered orally, the compounds may be mixed with lactose, sucrose, starch powder, cellulose ester of alkonic acids, alkyl esters of cellulose, talc, stearic acid, magnesium stearate, magnesium oxide, calcium and sodium salts, salts phosphoric acids, sulfuric acid, gelatin, acacia gum, sodium, alginate, polyvinyl pyrolidone, and/or polyvinyl alcohol and then encapsulated for convenient administration. Said capsules or tablets may contain a controlled release formulation to be provided in a dispersion of an active compound in hydroxypropylmethyl cellulose. In the case of skin conditions, he may preferably apply a topical preparation of compounds of this invention to the affected area two to four times a day. Formulations suitable for topical administration include liquid preparations, semi-liquid preparations suitable for penetration through the skin (such as liniments, lotions, ointments, creams or pastes), and drops suitable for administration into the eyes, ears or nose. A suitable topical dose of the active ingredient or compound of the invention is 0.1 mg to 150 mg administered one to four times, preferably once or twice a day. For topical administration, the active ingredient may comprise from 0.001% to 10%w/w, for example, from 1% to 2% by weight of the formulation, although it comprises a maximum of 10%w/w, but preferably no more than 5%. %w/w, and more preferably from 0.1% to 1% of the formulation. When formulated into an ointment, the active ingredients may be used either with paraffin or with a water-mixable ointment base. Alternatively, the active ingredients may be formulated into a cream with an oil-in-water cream base. If desired, the aqueous phase of the cream may further include, for example, at least 30% w/w of a polyhydric alcohol such as propylene glycol, butane-1,3-diol, sorbitol, glycerin, glycerol, polyethylene glycol, and mixtures thereof. The topical formulation may desirably include a compound that enhances the absorption or penetration of the active ingredient through the skin and other active areas. Examples of said dermal penetration enhancers include dimethylsulfoxide and related analogues. The compounds of this invention may also be administered by a transdermal device. Preferably, transdermal administration will be accomplished using a patch of the reservoir type and porous membrane, or a solid matrix variety. In each case, the active agent is released continuously from the reservoir or microcapsules through a membrane in the active agent permeable adhesive, which is in contact with the skin or mucosa of the container. If the active agent is absorbed through the skin, a controlled and predetermined flow of the active agent is administered to the recipient. In the case of micro-capsules. The encapsulating agent may also function as a membrane. The oil phase of the emulsions of this invention may be comprised of known ingredients in a known manner. While the phase may comprise merely an emulsifier, it may comprise a mixture of at least one emulsifier with a fat or an oil or both the fat and the oil. Preferably, a hydrofolic emulsifier is included together with a lipophilic emulsifier that acts as a stabilizer. It is even preferred to include both fat and oil. Together, the emulsifier with or without the stabilizer will make the so-called ointment base forming the oil dispersing phase of the creamy formulations. Suitable emulsifiers and emulsion stabilizers for use in the formulation of the present invention include Tween 60, Span 60, cetostearyl alcohol, myristyl alcohol, glycerin, glycerin monostearate, sodium lauryl sulfate, glycerin distearate alone or with wax, or other materials known by the state of the art. The choice of appropriate oils or fats for the formulation is based on the search for the desired cosmetic properties, since the solubility of the active compound in most oils to be used in pharmaceutical emulsion formulations is very low. Therefore, the cream should preferably be non-greasy, non-coloring and washable with an adequate consistency to prevent leakage from tubes and other containers. A straight or branched, mono- or dibasic chain of alkyl esters such as diisoadipate, isocetyl stearate, propylene glycol diether of coconut fatty acids, isopropyl myristrate, decyl oleate, isopropyl palmitate, butyl stearate, palmitate 2-ethylexyl or a combination of straight and branched chains may be used. These can be used alone or in combination depending on the properties required. Alternatively, high melting point lipids as well as soft paraffin and/or liquid paraffin or other mineral oils may also be used. Formulations suitable for topical administration to the eyes may also include eye drops where the active ingredients will be dissolved or suspended in a suitable carrier, especially in an aqueous solvent for active ingredients. The active ingredients are preferably present in said formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% and particularly approximately 1.5%w/w. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. Such solutions and suspensions may be prepared from sterile powders or granules using one or more carriers or diluents mentioned for use in formulations for oral administration or through the use of any other suitable diluent or wetting agents and suspending agents. The compounds may be dissolved in water, polyethylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, Tragracanth gum and/or various insulators. Other adjuvants and modes of administration known in the medical art may also be used. The active ingredient may further be administered by injection as a composition with appropriate carriers including saline, dextrose, or water, or with cyclodextrin (i.e., Captisol), co-solvent solubility (i.e., propylene glycol) or micellar solubility (i.e., propylene glycol) or micellar solubility (i.e., propylene glycol). i.e. Tween 80). The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally non-toxic acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringerm's solution and isotonic sodium chloride solution. In addition, sterile and fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any soft-fixing oil can be used, including monosynthetics or diglycerides. In addition, fatty acids such as oleic acid are also used in injectable preparations. For pulmonary administration, the pharmaceutical composition may be administered in the form of an aerosol, or with an inhaler including a dry powder aerosol. Suppositories for rectal administration of the drug may be prepared by mixing the drug with an appropriate non-irritating excipient such as cocoa butter, and polyethylene glycols which are solid at a certain temperature, but liquid at rectal temperature and thus melt in the rectum releasing the drug. . The pharmaceutical compositions may be subject to conventional pharmaceutical operations such as sterilization and/or containing conventional adjuvants, such as preservatives, stabilizers, wetting agents, emulsifiers, insulators, etc. Capsules and tablets may be further prepared as humectants, sweeteners, and flavoring and cosmetic agents. The pharmaceutical compositions of this invention comprise a compound of the formulas described herein or a pharmaceutically acceptable salt thereof, an additional agent selected from a kinase inhibitory agent (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer agent , an anti-viral agent, an anti-inflammatory agent, an anti-fungal agent, antibiotic, or an anti-vascular or anti-hyperproliferation compound, as well as any other pharmaceutically acceptable carrier or adjuvant. Alternative compositions of this invention comprise a composition of the formulas described in the present patent application, or a pharmaceutically acceptable salt thereof, as well as a pharmaceutically acceptable carrier or adjuvant or carrier. Said compositions may optionally comprise one or more therapeutic agents, including for example, kinase inhibitory agents (small molecule, polypeptide, antibody, etc.), immunosuppressants, anticancer agents, antiviral agents, anti-inflammatory agents, anti-cancer agents, fungi, antibiotics or anti-vascular, and hyperproliferation compounds. The term “pharmaceutically acceptable driver or adjuvant” refers to a driver or adjuvant that can be administered to a patient, together with a compound of this invention, and that does not destroy the pharmacological activity thereof and that is non-toxic when administered in sufficient doses to release the therapeutic amount of the compound. Pharmaceutically acceptable carriers, adjuvants or carrier media that may be used in the pharmaceutical compositions of this invention include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, self-mulsifying drug delivery systems (SEDDS) such as d-atocopherol polyethylene glycol 1000 succinate, surfactants used in pharmaceutical dosage forms, such as Tweens, or other similar polymeric releasing matrices, serum proteins, such as human serum albumin, insulating substances such as phosphates, glycican. Sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, trisicalate magnesium, polyvinyl pyridone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, polyethylene glycol and wool fat. Cyclodextrins, such as u-P-, and y-cyclodextrin, or chemically modified derivatives such as hydroxyalkylacyclodextrins, including 2 and 3-hydroxypropyl-cyclodextrins, or other solubilized derivatives may also advantageously be used to enhance the release of compounds of the formulas described herein. The pharmaceutical compositions may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous emulsions and suspensions, dispersions and solutions. In the case of tablets for oral use, the carriers that are commonly used include lactose and cornstarch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, suitable diluents include lactose and dry cornstarch. When suspensions and/or emulsions are administered orally, the active ingredient may be suspended or dissolved in an oily phase combined with emulsifying and/or suspending agents. If desired, certain sweeteners, aromatics, flavoring agents, and coloring agents may also be added. Pharmaceutical compositions may comprise formulations using liposomes or microencapsulation techniques, several examples of which are known in the art. The pharmaceutical compositions may be administered by inhalation or nasal aerosol. Said compositions are prepared according to well-known techniques in the state of the art of pharmaceutical formulation and may be prepared with saline solutions, using benzyl alcohol, or other suitable preservatives, absorption promoters to enhance bio-viability, fluorocarbons, and/or other solubilizers or dispersing agents, examples of which are well known in the art.

Combinations

While the compounds of the invention may be administered with a single active pharmaceutical agent, they may also be used in combination with one or more compounds of the invention, or with one or more agents. When administered as a combination, therapeutic agents may be formulated in separate compositions that are administered at the same time or sequentially at different times, or therapeutic agents that may be obtained in a single composition. The phrase “therapeutic combination” refers to the use of a compound of this invention together with another pharmaceutical agent, meaning the co-administration of each agent in a substantial subsequent manner, as well as the administration of each agent in a sequential manner, in both cases in a methodical approach that will provide beneficial effects of the drug combination. Co-administration includes inter alia simultaneous release, for example, in a single tablet, capsule, injection or other dosage form having a fixed proportion of active agents, as well as simultaneous release in multiple, separate dosage forms for each agent respectively. . Thus, administration of the compounds of the present invention may be in conjunction with therapies known to one skilled in the art and known by the state of the art in the prevention or treatment of cancer, such as radiation therapy or cytostatic agents, cytotoxic agents, and other anticancer agents. and other drugs to improve cancer symptoms or the side effects of any of the drugs. If formulated as a fixed dose, said combination products employ the compounds of this invention within the limits of acceptable dosages. Compounds of this invention may also be administered sequentially with other anticancer or cytotoxic agents when a formulation is inappropriate. The invention is not limited to the sequence of administration; Compounds of this invention may be administered before, simultaneously with, or after the administration of another anticancer or cytotoxic agent. Currently, the standard treatment of primary tumors consists of surgical excision, when appropriate, followed by radiation or chemotherapy, and typically administered intravenously (IV). Typical chemotherapy regimens consist of DNA-alkylatinizing agents, and DNA-intercalating agents, CDK inhibitors, or micro-tubular toxicants. The doses of chemotherapy used are just below the maximum tolerated doses and therefore, threshold toxicity doses typically include nausea, vomiting, diarrhea, hair loss, neutropenia and others. There are a large number of viable anti-neoplasty agents for commercial use, in clinical evaluation and pre- chemical development, which will be selected for cancer treatment with chemotherapy drug combination. There are also several major categories of said anti-neoplastic agents, notably, antibiotic-type agents, alcilatiating agents, anti-metabolic agents, hormonal agents, immunological agents, interferon-type agents, and a wide variety of agents. A first family of antineoplasty agents that may be used in combination with the compounds of the present invention include thymidylate-type antimetabolic synthase inhibitor antineoplasty agents. Suitable anti-metabolics may be selected, but not limited to, from a group consisting of 5-FU-fibrinogen, acanthifolic acid, aminothiadiazole, brequinar sodium, carmofur, Ciba Geigy CGP-30694, cyclopentyl, cytosine, cytarabine phosphate stearate, conjugates cytarabine, Lilly DATHF, Merrel Dow DDFC, dezaguanine, dideoxycytidine, dideoxyguanosine, didox, Yoshitomi DMCD, doxifluridine, Wellcome EHNA, Merck & CO. EX-015, fazarabine, floxuridine, fludarabine, phosphate, 5-fluorouracil, N-(21-furanidyl), fluroudacil, Daiichi Seyaku FO-152, isopropyl pyrolizine, Lilly LY-188011, Lilly LY-26418, methobenzaprima, methotrexate, Wellcome MZPES, norspermidine, NCI NCS-127716, NCI NSC- 264880, NCI NSC-396661, NCI NSC-612567, Warner-Lambert PLA, pentostatin, pyritrexime, plicamycin, Asahi Chemical PL-AC, Takeda TAC788, thioguanine, thiazofurin, Erbamont TIF , trimetrexate, tyrosine, kinase inhibitors, Tahio LIFT and uricithin. A second family of antineoplastic agents that may be used in combination with the compounds of the present invention consists of alkylatin-type antineoplastic agents. Suitable alkylatin-type antineoplastic agents may be selected but not limited to the group consisting of Shionogi-254-S, aldo-phosphamide analogues, altretamine, anaxirone, Boerhringer Mannheim BBR-2207, bestrabucil, budotitan, Wakumaga CA-102, carboplatin , carmustine, Chinoin-139, Chinoin- 153, chlorambucil, cisplatin, cyclophosphamide, American Cyanamid CL-286558, Sanofi CY-233, ciplatata, Degussa D 384, Sumimoto DACHP(Myr)2, diphenylaspiromustine, cytotastic diplatin, Erba distamycin derivatives , Chungai DWA-2114R, I TI E09, elmustine, Erbamont FCE-24517, estramustine phosphate sodium, fotemustine, Unimed G M, Chinoin GYK-17230, hepsulfam, ifosfamide, iproplatin, lomustine, mafosfamide, mitolactofe Nipon Kayaky NK- 121, NCI NSC-264395, NCI NSC-34215, oxaliplatin, Upjohn PCNU, prednimustine, Proter PTT-119, ranimustine, semustine, SmithKline SK&F-101772, Yakult Honsha SN-22, spiromus-tin, Tanabe Seiyaku TA-077, tauromustine, temozolimide, teroxirone, tetraplatinum and trimelamol. A third family of antineoplasty agents that may be used in combination with the compounds of the present invention consists of antibiotic-type antineoplasty agents. Suitable antibiotic-type antineoplasty agents may be selected from, but not limited to, the group consisting of Taiho 4181-A, aclurubicin, actinomycin D, actinoplanone, Erbamont ADR-456, aerophysin derivative, Ajinomoto NA II, Ajinomoto AN3, Nippon Soda Anisomycin, Anthracycline, Azino-mycin-A, Bisucaberin, Brestol-Meyrs BL-6859, Bristol-Myers BMY-25067, Bristol Myers BNY-25551, Bristol Myers BNY-26605, I BristollMyers BNY-27557, Bristol -Myers BMY-28438, Bleomycin Sulfate, Bryostatin-1, Taiho C-1027, Calichemycin, Chromoxymycin, Dactinomycin, Dactinomycin, Kyowa Hakko DC-102, Kyowa Hakko DC-79, Kyowa Hakko DC-88A, Kyowa Hakko DC89-AI , Kyowa Hakko DC92-B, ditrisarubicin B, Shionogi DOB-41, doxorubicin, doxorubicin-fibrogena, elsamycin-A., epirubicin, erbstatin, esorubicin, esperamycin-AI, esperamycin-Alb, Erbamont FCE21954, Fujisawa FK-973, fostriecin, Fujisawa FR-900482, Glydobactin, Gregatin-A, Grincamycin, Herbimycin, Idarubicin, Iludins, Cazusamycin, Quesarinhodines, K yowa Hakko KM-5539, Kirin Brewery KRN-8602, Kyowa Hakko KT -5432, Kyowa Hakko KT-5594, Kyowa Hakko KT-6149, American Cyanamid LL-D49194, Meiji Seika ME 2303, menogaril, mitomycin, mitoxantrone, Smitk Kline M-TAG, neonactin, Nippon Kayaku NK-313, Nippon Kayaku NKT-01, SRI International NSC-357704, oxalysin, oxaunomycin , pelomycin, pilatin, pirabucine, porotramycin, pyrindanicin A, Tobishi RA-1, rapamycin, rhizoxin, rhodorubicin, sibanomycin, siwenmycin, Sumitomo SM5887, Snow Brand SN-706, Snow Brand SN-07, sorangicin-A, sparsomycin, SS Pharmaceutical SS-21020, SS Pharmaceutical SS-7313B, SS Pharmaceutica SS-9816B, Stefimycin B. Taiho 4181-2, Talisomycin, Takeda TAN-868A, Terpentecin, Trazen, Trichrozarin A, Upjohn U-73975, Kyowa Hakko UCN-10028A, Fujisawa WF-3405, Yoshitomi Y - 25024 and zorubicin. A fourth family of neoplastic agents that may be used in combination with the compounds of the present invention consists of a miscellany of families of antineoplastic agents, including tubulin interacting agents, topoisomerase II inhibitors, topoisomerase I inhibitors, and hormonal agents selected from the from, but not limited to, the group consisting of (xcarotene, (X-difluoromethyl-arginine), acitretin, Biotec-AD-5, Kyorin AHC-52, alstonine, aminafide, amphetinyl, ansacrine, Angiostat, ancinomycin, anti-neoplastica A10, A2 antineoplasty, A3 antineoplasty, antineoplasty, AS1-IF antineoplasty Henkel APD, aphidicolin glycinate, asparaginase, Avarol, bacarin, batracillin, benflurone, benzotript, Ipsen-Beaufour BUM-23015, bisantran, Bristol Myers BNY-40481, Vestar boron-10, bromophosphamide, Wellcome BW-502, Wellcome BW-773, characemide, carmetizole, hydrochloride, Ajinomoto CDAF m chlorsulfacinoxalone, Chemes CHX- 2053, Chemex CHX-100, Werner-Lambert CI-921 , Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI958, clanfenura, claviridenone, compound ICN 1259, compound ICN 4711, Contracan, Yakult Honsha CPT-11, chrysnatol, curaderma, cytochalasin B, cytarabine, cytokine , Merz D-609, DABIS maleate, dacarbazine, dateliptinium, didemin-B, dihaematoporphyrin ether, dihydrolenperone, dynalin, distamycin, Toyo Pharmar DM-341, Toyo Pharmar DM-75, Daiichi Seyaku DN-9693, eliprabine docetaxel, eliptynium acetate , Tsumura EPMTC, epothilnes, ergotamine, etopside, etretinate, fenretidine, Gallium Nitrate Fujisawa FR -57704, Genkwadafinin, Chugai GLA-43, Glaxo GR-63178, Grifolan NMF5N, Hexadecylphosphocholine, Green Cross HO-221, Homoharringtonine, Hydroxyurea, BTG-ICFR-187, Ilmofosine, Isoglutamine, Isotrethionoin, Otsuka JI-36, Ramot K-477, Otsuak K-76COONa, Kureha Chemical K-AM, MECT Corp KI-8110, American Cyanamid L-623, Leuceregulin, Lonidamine, Lundbeck LU 1121, Lilly-LY-186641, NCI (US), MAP, maricin, Merrel Dow MDL-27048, Medco MEDR-340, merbarone, merocyanine derivatives, methylanilinoacridine, Molecular Genetics MGI136, minactivin, mitonafide, mitoquidone, mopidamol, motretinidine . Zenyaku Kogyo MST-16, N-(retinoyl) amine acids, Nisshin Flour Milling N-021, N-acylated-dehydralanines, nafazatrom, Taisho NCU-190, nocodazole derivative, Normosang, NCI NSC-145813, NCI-3614 56, NCI NSC-604782, NCI NSC-95580, Ocreotide, Ono ONO-112, Oquizanicin, Akzo Org-10172, Poclitaxel, Pancrastitatin, Pazeliptidine, Warner-Lambert PD-111707, Warner-Lambert PD-115034, Warner-Lambert PF-121141 , Pierre Fabre PE -1001, ICTR peptide D, pyroxantrone, polyhaematoporphyrin, polypreic acid, Efamol porphyrin, probiman, procarbazzin, proglumide, Invitron protease nexin I, Tobishi RA-7 00, razoxane, Sapporo Breweries RBS, restrictin-P, reteliptin, retinoic acid, Rhone-Poulenc RP-49532, Rhone-Poulenc RP-56976, SmithKline SK&F-104964, Sumitomo SM- 108, Kuraray SMANCS, SeaPharm SP10094, spathol, spirocyclopropane derivatives, spirogermanium, Unimed, SS Pharmaceutical SS-554, estripoldinone , stipoldione, Suntory SUN 2071, superoxide dismutase, Toyama T-506, Toyma T-680. taxol, Tejin TEI-0303, teniposide, taliblastin, Eastman Kodak TJB-29, tocotrienol, topotecan, Topostin, Teijin TT82, Kyowa Hakko UCN-01, Kyowa Hakko UCN-1028, Ukraine, Eastman Kodak USB-006, vinblastine sulfate, vincristine, vindesine, vinestramide, vinorelbine, vintriptol, vinzolidine, withanolides, and Yamanouchi YM. Alternatively, the present compounds may also be used in co-therapies with other antineoplastic agents, such as acemannan, aclarubicin, aldesleukin, alemtuzimab, alitretinoin, altretamine, amifostine, aminolevulinic acid, anrubicin, ansacrine, anagrelide, anastrazole, ANCER, ancestima , ARGLABLIN, arsenic trioxide, BAM 002 (Novelos)< bexatotene, biculatamide, broxuridine, capecitabine, celmoleucine, cetrorelix, cladribine, clotrimazole, cytarabine ocphosphate, DA 3030 (Dong-A), daclizumab, denileukin, difititox, delorelin, dexrazoxane, dilazede , docetaxel, docosanol, doxercalciferol, doxifluridine, doxorubucin, bromocriptine, carmustine, cytarabine, fluoracil, diclofenac HIT, alpha interferon, emitefur, epirubicin, beta epoetin, etopside, phosphate, exemestran, exisulind, fadrozole, filgastrime, finasteride, fludarabine, phosphate, formestane, fotemustine, gallium nitrate, gemcitabine, gentuzumab, zobamycin, gimeracil/oteracil/tegafur combination, glycopine, goserelin, heptaplatin, human chorionic ganadotropin, human fetal alpha fetoprotein, interferon alpha-2, interferon alpha-2a, interferon alpha 2b , interferon alfa-NI, interferon alfa-n3, interferon alfaconl. natural alpha interferon, beta interferon, beta-la interferon, beta-lb interferon, gamma interferon, gamma-la natural interferon, gamma-lb interferon, interleceunin-1-beta, iobenguan, iritotecan, irsogladine, lanreotide, LC 9018 (Yalkult) , leflunomide, lenograstima, lentinan sulfate, letrozole, alpha leukocyte interferon, leuprorelin, viverisole + fluoroacyl, liarazole, lobaplatin, ionidamine, lovastatin, msoprocol, melarsoprol, metoclopramide, mifepristone, miltefosine, mirimostima, mystade double standard RNA, mitoguazone, mitolactol , mitoxantrone, molgramostim, nafarelin, naloxone + pentazocine, nartograstim, nadaplatin, nilutemide, noscapinma, new erythropoiesis stimulating protein, octreotide NSC 631570, oprevelcin, osaterone, oxaliplatin, paclitaxel, pamidronic acid, pegaspargase, peginterferon alfa 2-b, pentos sodium polysulfate year, pentostatin, picibanil, pyrabicin, rabbit antimocyte polyclonal antibody, glycol interferon alfa-2a, porfimer sodium, raloxifene, raltitrexed, rasburicase, etidronate rhenium Re 286, retinamide RH, rituximab, romurtide, samario (153 Sm), lexidronam, sargramostima, sizofran , sobuzonxane, sonermin, strontium-89 chloride, suramin, tasonermin, tazarotene, tegafur, temorphin, temozolomide, teniposide, tetrachlorodecaoxide, thalidomide, thymalfasin, thyrotropin alfa, topotecan, toremifene, tositumomabo-iodine 131, trastuzumab, treosulfan, tretinoin, trilostane , trimetrexate, triptorelin, tumor necrosis factor alpha, natural, ubenimex, gallbladder cancer vaccine, anti-Maruyama vaccine, melan,oma lysate vaccine, valrubicin, verteporfin, vinorelbine, VIRULIZIN, zinostatin stimulator, or zoledronic acid, abarelix; AE 941 (Aeterna), ambamustine, antisense oligonucleotide, bcl-2 (Genta), APC 8015 (Dendreona), cetuximab, decitabine, dexaminoglutethimide, diazicone, EL 532 (Elan), EM 800 (Endorecherche). Eniluracil, etanidazole, filgastrime fenretidine SDO1 (Amgen), fulvestrant, gallocitabine, gastrin 17 immunogen, HLA-B7 gene therapy (Vical), colony factor granulocite macrophage stimulant, histamine dihydrochloride, ibritimoman tiuxetan, ilomstate, IM 862 (Cytran) , iproxifen interleukin, LDI 200 (Mikhaus), leridistima, lintuzumaba, CA 125 Mab, (Biomira), cancer Mab (Japan Pharmaceutical Development), HER-2 and FcMAb (Medarex), idiotypic 105AD7 mAb (CRC Technology), idiotypic CEA Mab (Trilex) porphyromycin, prinomstate, RL 0903 (Shire), rubitecan, satraplastin, sodium phenylacetate, sparphosic acid, DRL 172 (SR Pharma), SU 5416 (SUGEN)y SU 6668 (SUGEN), TA 077 (Tanabe), tetrathiomolibadate, taliblastin, thrombopoitena , ethyltin etiopurpirin, tirapazamine, anticancer vaccine (Biomira), melanoma oncolysate vaccine (New York Medical College), melanoma viral cell lysate vaccine (Royal Newcastle Hospital), or valspodar.

Treatment Kits

In other embodiments, the present invention relates to a kit for conveniently and effectively carrying out the methods according to the present invention. In general, the pharmaceutical package or kit comprises one or more containers comprising one or more of the ingredients of the pharmaceutical compositions of the invention. Said kits are especially suitable for the release of solid oral forms, such as tablets or capsules. A kit preferably includes a number of dosage units, and may include a card having dosages oriented to meet its intended use. If desired, an auxiliary memory may be provided, for example, in the form of numbers, letters, or other marking with the insertion of a calendar, designating the scheduled treatment days on which dosages are to be administered. Optionally associated with the container(s) may have a note in the form prescribed by a governmental agency regulating the manufacture, use or sale of the pharmaceutical products, which reflects notice of the agency's approval of the manufacture, use or sale for human administration. . The following representative examples contain important additional information, exemplification and guidance that may be adapted to the practice of this invention, in its various embodiments and equivalents thereof. These examples are proposed to assist in illustrating the invention, and are not intended and should not be construed to limit its scope. Indeed, various modifications of the invention and many additional embodiments thereof, in addition to those shown and described in the present application, will become apparent to one skilled in the art by reviewing this document, including the examples that follow and the scientific literature references, and cited patents. here. The content of these references is incorporated into the present application by reference to help illustrate the prior art. In addition, for purposes of this invention, chemical elements are identified in accordance with the Periodic Table of Elements, CAS Version, Handbook of Chemistry and Physisc, 75th Ed., Inside cover. Additionally, general principles of organic chemistry, as well as specific functional moieties and reactivity are described in “Organic Chemistry”, Thomas Sorrell, University Science Books, Sausalito: 1999, and “Organic Chemistry”, Morrison & Boud (3d. Ed), whose The entire contents are incorporated into this application by reference.

Examples

Some of the compounds described in the following examples were converted to an HCl salt. The general procedure for generating HCI salts is described below:

At the end of the product, just enough MeOH saturated with HCl (g) was added to dissolve, cooled to 0o C for 0.5-1 hour, filtered and solidly washed with ice-cold MeOH obtaining Et2O, and the resulting solid dried by a vacuum desiccator to provide in most cases the HCI tris salt.

Example 1 N-(3-(1h-imidazol-1-yl)-5-(trifluoromethyl)phenyl-3-(imidazyl[1,2-a]pyrazine-3-ylethynyl)-4-methylabenzamide lmidazol[1,2-a]pyrazine: A solution of aminopyrazine (1g, 10.5 mmol) and chloroacetaldehyde (50% wt in H2O; 1.98 g, 12.6 mmol) in 1.6 mL of EtOH was heated to 90° C in a tube sealed for 5 hours. After cooling to room temperature, the reaction mixture was concentrated and diluted with dichloromethane (DCM). The organic layer washed with saturated aqueous NaHCO3 was then dried with MgSO4 and concentrated. The crude product was purified by flash silica gel chromatography (eluted with 10% MeOH/DCM) to provide 0.8 g of product. 3-((Trimethylasylyl)ethynyl)imidazol[1,2-a]pyrazine: A mixture of 3-bromoimidazol[1,2-a]pyrazine (0.15 g, 0.76 mmol, prepared according to J. Bradac, et al. , and J. Prg. Chem. (1977), 42, 4197 - 4201), 0.09 g (0.p1 mmol) of ethynylatrimethyl asilane, 0.044 g (0.038 mmol) of Pd (PPh3)4, 0.014 g (0.076 mmol) of Cul, and 0.26 mL (1.52 mmol) of disopropylethylamine in 3.8 nL of DMF was heated at 50 ° C overnight under an N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated and the crude product was purified by flash silica gel chromatography (eluted with 50% EtOAc hexanes) to provide 0.15 g of product: 216 m/z(M+ H). 3-Ethynylimidazol[1,2-a]pyrazine: To a solution of 3-((Trimethylasily)ethynyl)imidol[1,2-a]pyrazine (0.15 g, 0.7 mmol) in 3.5 mL of THF was added 1.05 mL (1.05 mmol ) of butylammonium tetrafluoride (1.0M in THF) at room temperature. The solution was stirred for 15 minutes, concentrated, and the crude product purified by flash silica gel chromatography (eluted with 50% hexanes/EtOAc) to provide 0.078 g of product. 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline: A mixture of 3-Amine-5-bromobenzotrifluoride (4.0 g, 0.0167 mol), 8-quinoline hydroxide (0.362 g, 0.0025 mmol), Cui (0.476 g, 0.025 mol). Imidazole (1.36 g, 0.0199 mol), and potassium carbonate (2.52 g, 0.0183 mol) in 17 ml of DMSO (degassed with argon for ~10 minutes) were heated to 120°C under an argon atmosphere for 15 hours, the HPLC indicating the material is not starting. A 14% aqueous solution of ammonium hydroxide was added to the cooled mixture and then stirred for 1 hour at room temperature. Water (50 ml) and etOAc (200 ml) were added and the aqueous layer was extracted with etOAc (3x30 ml). The combined organic layers were dried with Na2SO4 and concentrated. The crude product was purified by flash silica gel chromatography (eluted with hexanes/EtOAc) to provide 2.51 g of the product N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) -3-iodo-4-methylabenzamide: To 3-iodo-4-methylbenzoic acid (3.07 g, 0.0117 mol) was added thionyl chloride (10 ml_) and refluxed for 2 hours. Excess thionyl chloride was carefully removed and the resulting acid chloride was dried under vacuum for 2 hours. The residue was then dissolved in DCM (anhydrous, 25 ml) and cooled on ice. To the cooled solution was added 3-(1H-imidazol-1-yla)-5-(trifluoromethyl)aniline 5 (3.46 g, 0.0152 mol) in DCM followed by the dropwise dosage of disopropylethylamine (8.2 ml_, 0.047 mol). This was stirred at room temperature for 21 hours. The white free solid was separated, filtered and washed with water and dried to provide 4.65 g of product. Additional product may be obtained from the following concentration, filtered and purified by flash silica gel chromatography in hexanes/EtOAc. N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazol[1,2-a]pyrazine-3-ylethynyl)-4-methylabenzamide: A mixture of 3 -Ethynylimidazol[1,2-a]pyrazine (0.075 g, 0.52 mmol), 0.245 g (0.52 mmol) N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3 -iodo-4-methylabenzamide, 0.030 g (0.026 mmol) of Pd(PPH3)4, 0.007 g (0.039 mmol of Cul, and 0.14 ml (0.78 mmol) of disopropylethylamine in 3.0 ml of DMF was stirred at room temperature throughout the overnight under a N2 atmosphere. The reaction mixture was concentrated and the crude product was purified by flash and silica gel chromatography (eluted with 10% hexanes/EtOAc, then 100% EtOAc, then 10% MeOH/EtOAc ) to provide 0.090 g of product as a solid: 487 m/z (M+H) Alternative Synthesis of N-(30(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazole [1,2-a]pyrazine-3-ylethynyl)-4-methylabenzamide: 3-((Trimethylasylyl)ethynyl)imidazol[1,2-a]pyrazine can be prepared as previously described. In a variation, the reaction can also be performed in THF instead of DMF. The crude product can also be purified by flash silica gel chromatography (eluted with hexane/acetate/ethyl) and a brief treatment with charcoal (Darco) can be carried out to further help reduce contamination with the homocoupled product. 3-Ethynylimidazol[1,2-a]pyrazine: For a solution of 3-(trimethylasilyl)ethynyl)imidazol[1,2-a]pyrazine (1.39 mol) in 10 x volume of Ethyl acetate and 1.5 x volume of Methanol was added two and a half times the equivalent of potassium carbonate at room temperature and the solution was then stirred for 1 hour. The potassium carbonate was filtered and the organic stream was washed with water and saturated sodium chloride solution (two or more times). The aqueous phases can be combined under vacuum to approximately 0.5L. Solids may be allowed to precipitate after concentration. The slurry is then cooled, for example, to approximately -5°C, stored overnight, filtered and washed with approximately 0.3L of chilled ethyl acetate. The solids can then be dried under vacuum. 3-(imidazol[1,2-a]pyrazine-3-ylethynyl)-4-methylbenzoic acid can be prepared in a similar way to that described above for the Sonogashira reaction. 3- Ethynylimidazol-1,2-a]pyrazine and 3-iodo-4-methylbenzoic acid used as partner couplers. Alternatively, the solvent (DMF) can be replaced by ethyl acetate and the base (Hunig base) can be replaced by triethylamine. The product can be isolated by filtering the crude reaction mixture. The filter is washed sequentially with a solvent such as ethyl acetate and then water, and dried in a vacuum oven. Purification can also be achieved by fluidizing the solids in water adjusted to pH 3 with the addition of concentrated HCI. After filtering and washing with water, the product can be dried in a vacuum oven.

N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazol[1,2-a]pyrazine-3-ylethynyl)-40methylabenzamide: 3-(imidazol[1 ,2-a]pyrazine-3-ylethynyl)-4-methyl benzoic acid (18 mmol) being dissolved in methylene chloride (100 mL). To this solution, 3 times the equivalent of 4-methylamorpholine (NMM) was added followed by 1.05 equivalents of oxalyl chloride. After stirring at room temperature for 20 minutes, 0.8 equivalents of 3-(1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (prepared as above) is added along with 5 mole% DMAP. After stirring at room temperature, the mixture is brought to reflux and stirred overnight. After 16 hours an additional 0.2 aniline equivalents were added, bringing the total charge to 1 equivalent. The aqueous layer can be extracted with methylene chloride (2 x 50 mL) and the combined extracts can be washed with water. The combined methylene chloride layers may then be evaporated and the residue dissolved in 100 ml of ethyl acetate (20 ml). After waiting for 1 hour, the product can be crystallized. The mixture was cooled, for example, to 0°C, filtered and the solid product washed with cooled ethyl acetate.

N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazol[1,2-a]pyrazine-2-ylethynyl)-4-methylabenzamide mono hydrochloride salt:

N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazol[1,2-a]pyrazine-3-ylethynyl)-4-methylabenzamide (0.94 mmol) may be suspended in MeCN (10 ml) and heated with stirring at a temperature of 45 to 55° C (hot plate temperature). Hydrochloric acid (1.1 eq. 1M solution in EtOH) was added to obtain dissolution. Within a few minutes, a precipitate is formed. The suspension can then be cooled to room temperature and then filtered and washed with MeCN (1 x 1.5 ml of liquid substance + 1 x 1.5 ml of fresh water). The solid can then be dried at 50° C under vacuum at constant weight. Example 2 3-(lmidazol[1,2-a]pyrazine-3-ylethynyl-4-methyl-N-(4-((4-methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide The noble compound was synthesized from 3-ethynylylamidazol[1,2-a]pyrazine and 3-iodo-4-methyl-N-(4-((4-methylapiperazine-1-yla)methyl)-3- (trifluoromethyl )phenyl)benzamide in a similar manner to that described in Example 1. The product was obtained as a solid: 533 m/z (M+H). 1-(Bromomethyl)-4-nitro-2-(trifluromethyl)benzene: A suspension of 2-methyl-5-nitrobenzotrifluoride (3.90 g, 19 mmol), N-bromusuccinimide (NBS, 3.56 g, 20 mmol), 2, 2'-azobis(2-methylapropionitrile) (AIBN, 94 mg, 0.6 mmol) in CCI4 (40 ml_) was refluxed under N2 for 16 hours. The HPLC indicated ca. 50% conversion. More NBS (10 mmol) and AIBN (0.6 mmol) were added, and the mixture was refluxed for another 14 hours. The HPLC indicated ca. 8-% conversion. The reaction mixture was cooled further, and the solid was filtered and washed with etOAc. The combined filter was washed with aq. NaHCO3 dried with Na2SO4, filtered, and concentrated in rotating steam and further dried under vacuum. 1H NMR shows the ratio of the desired product to the unreacted 2-methyl-5-nitrobenzotrifluoride being 75:25. This material was not purified but used directly in the next step. 1-Methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine: For a solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl)benzene bruti (13.33 mmol, 75% pure) in DCM (10 mL) was added Et3N (1.4 mL, 10 mmol) and 1-methylapiperazine (1.1 mL, 10 mmol). After stirring for 3 hours at room temperature, NaHCO3 was added, and the mixture was extracted with DCM. The combined organic layer was washed with Na2SO4, filtered and concentrated and the resulting residue was purified by flash silica gel chromatography (eluted with 10% MeOH/DCM) to provide 2.21 g of product as pale yellow oil. 4-((4-Methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)aniline: A suspension of 1-methyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (1.23 g, 4 mmol ) and sodium hydrosulfite (7.0 g, 85% pure Aldrich, 40 mmol) in acetone and water (1:1.20 ml) was refluxed for 3 hours. After cooling, the volatile components (mainly acetone) were removed in the rotating steam and the resulting mixture was subjected to filtration. The solid was washed completely with EtOAc. The combined filtrate was extracted with n-Bu-OH (4x), and the combined organic layer was washed with aq. Saturated NaHCO3, filtered, concentrated, and the resulting residue was purified by silica gel chromography (eluted with 5% MeOH/DCM, and the MeOH was pre-saturated with ammonia gas) to provide 0.71 g of the product as a pale yellow solid . 3-iodo-4-methyl-N-(4-((4-methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)Benzamide: 3-iodo-4-methylbenzoyl chloride (0.48 g, 1.7 mmol ), prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCI2 (as previously described), was added to a solution of 4-((4-methylpiperazine-1-yl)methyl)-3-(trifluromethyl) aniline (0.47 g, 1.7 mmol), NN-disopropylethylamine (0.26 g, 2.0 mmol) and a catalytic amount of DMAP in THF (10 ml). After stirring at room temperature for 2 hours, the reaction was quenched with water. EtOAc was added and the layers separated. The combined organic layers were concentrated to be dried and purified by silica gel chromatography (eluted with 5% MeOH/DCM, and the MeOH was pre-saturated with ammonia gas) to provide 0.51 g of product as a white-free solid.

Alternative Synthesis of 3-(lmidazol[1,2-a]pyrazine-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluromethyl)phenyl) benzamide and its monohydrochloride salt could be prepared in an alternative synthesis similar to that described in Example 1 of 3-(imidazol[1,2-a]pyrazine-3-ylethynyl)-4-methylbenzoic acid and 4-((4-methylapiperazine -1-yl)methyl)-3-(trifluoromethyl)aniline as prepared above. Example 3 N-(3-2((dimethylamino)methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazol[1,2-a]pyrazine-3-yethynyl)-4 -methylabenzamide

The noble compound was synthesized from 3-ethynimidazol[1,2-a] and N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl -3-iodo-4-methylbenzamide in a similar manner to that described in Example 1, The product was obtained as a solid: 544 m/z (M+H). 1-(1H-imidazol-2-yl)-N, N-dimethylamethanamine: To a two-necked round-bottomed flask equipped with a reflux condenser and a pressure-equalizing adhesion funnel, 2-imidazolecarboxaldehyde (6g, 62.5 mmol) in MeOH (60 mL) was added. To this suspension (room temperature) a solution of dimethylamine (4% aqueous, 60 mL) was added at a rapid drip rate (20 minutes) After completing the addition, the borohydride (7 g, 186.8 mmol) was CAUTIOUSLY added discreetly to each part for 45 minutes. Foaming occurred after each part, and the internal temperature was allowed to be maintained at ~50° C without external cooling. The reaction mixture was then heated to 65° C for 3 hours and cooled at room temperature overnight. The reaction contents were concentrated in vacuo and the resulting residue was placed in etOAc (2 x 30 mL) washed with brine and CHCl3 (4 x 100 mL). The extracted etOAc was discarded. The CHCl3 extract was dried with (NaSO4), filtered and concentrated in vacuo to give 3.7 g of the desired product as a solid wax. 3-(2-(Dimethylamino)methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline: 3-Amine-5-bromobenzotrifluoride (6 g, 25 mmol) and 1-(1H-imidazol-2 -yl)-N,N-dimethylamethamine (3.7 g, 29.6 mmol) were dissolved in anhydrous DMSO (25 mL). To this was added Cul (0.95 g, 7.5 mmol), quinoline 8-hydroxide (0.72 g, 7.5 mmol) and K2CO3 (6.9 g, 50 mmol). The mixture was stirred vigorously and degassed with N2 for 15 minutes. The flask was then equipped with a condenser and heated at 120°C for 18 hours. The resulting heterogeneous mixture was cooled to room temperature, and eluted in 14% aq. NH4OH (100 mL) and extracted with etOAc (3 x 300mL). The combined extracts were dried with NaSO4 and concentrated in vacuo. The residue was chromatographed on silica gel eluting with MeOH/DCN (5:95) to provide 3.5 g of the desired product as a tan colored material: 285 m/z (M+H). N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylanbenzamide: 3-iodo-4-methylbenzoyl chloride (2.2 g, 7.88 mmol), dissolved in anhydrous THF (13 mL), and added dropwise to a solution of 3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl )aniline (1.5 g, 5.5 mmol), DIPEA ((2.1 mL, 11.8 mmol) in THF (30 mL) at -5°C. The resulting solution was stirred at room temperature overnight. The solvent was removed under vacuum and The crude residue was redissolved in CH2Cl2 and washed with 1N NaOH. The organic layer was then washed with water and brine and then dried with NaSO4 before being concentrated in vacuo. The brown colored residue was then triturated in a hexanes/DCM mixture to precipitate 1.4 g of the desired product from a white-free powder: 529 m/z(M+H).

Alternative Synthesis of N-(3-(2-((dimethylamino)methyl)-1 H-imidazol-1-yl)-5- (trifluoromethyl)phenyl)-30(imidazol[1,2-a]pyrazine-3- ylethynyl)-4-methylabenzamide: N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)-3-(imidazol[1,2-a]pyrazine -3-ylethynyl-4-methylabenzamide with its monohydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazol[1,2-a]pyrazine-3-ylethynyl)-4-acid methyl benzoic acid and 3-(2-((Dimethylamino)-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (as prepared above). Example 4 3-(lmidazol[1,2-a]pyridine- 3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide

3-Ethynylamidazol[1,2-a]pyridine: To 3-bromoimidazol[1,2-a]pyridine (5 g, 0.0254 mol) in acetonitrile (50 mL) in a sealed tube was added bisphtriphenylphosphine) palladium(II) dichloride ) (0.445g, 0.634 mmol), Cui (0.17 g, 0.89 mmol), dicyclohexylamine (5.6 ml_, 0.028 mol) and ethynylatrimethylasilane (7.2 mL, 0.051 mol). The solution was cleaned with argon for 15 minutes, sealed and heated at 80° C for 3 hours. At this point, HPLC did not show any onset of bromide. The solvents were concentrated and water and dichloromethane (25 ml each) were added to the residue. The organic layer was separated and the aqueous layer was repeatedly extracted with dichloromethane (3 x 20 ml). The combined extracts were dried (Na2SO4) and concentrated (Rf, 0.47 in 1/1 ethyl acetate/hexanes). The resulting residue was dissolved in THF (100 mL) and treated with tetrabutyl ammonium fluoride monohydrate (8.3 g, 0.032 mol) in water (5 mL) and the mixture stirred at room temperature for 2 hours. The solvents were concentrated and the resulting residue was partitioned between water (25 ml) and dichloromethane (150 ml). The aqueous layer was extracted with dichloromethane (2 X 30mL). The combined extracts were dried (Na2SO4) and concentrated. The resulting residue was purified by combining ethyl acetate/hexane and isolated as a white-free solid: MS M+H)+200.

3-(4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline: A suspension of 3-bromo-5-(trifluoromethyl)aniline (4.8 g, 20 mmol), 4-methylimidazole (1.97 g , 24 mmol), potassium carbonate (3.04 g, 22 mmol), Cul (0.57 g, 3 mmol), and 8-hydroxyquinoline (0.44 g, 3 mmol) in DMSO (20 mL) dried in a pressure tube that was degassed by bubbling N2 into the suspension for 10 minutes while stirring. The tube was sealed tightly. The mixture was heated at 120° C (oil bath temperature) for 15 hours. The mixture was cooled to -45 -50°C and 14% aq. NH4OH(20 mL) was added. The mixture was kept at this temperature for 1 hour. After cooling to room temperature, water and ethyl acetate were added. The aqueous layer was extracted with ethyl acetate and the organic layers were passed through a short column of silica gel to remove most of the green/blue Cu salts. The filtration was dried with sodium sulfate and the concentrate in rotating steam. The crude product was recrystallized from hexanes/EtOAc, yielding pale yellow needles. The mother liquor was concentrated and the residue was purified on a silica gel column (5% methanol chloride; methylene), providing a second group of pale yellow needles.

3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl) Benzamide: 3-iodo-4-methylbenzoic acid (2.62 g, 10 mmol) was refluxed in SOCI2 (10 mL) for 1 hour. The volatile components were removed in a rotating vacuum and the residue was dissolved in benzene (10 mL)), concentrated for drying in a rotating vacuum and still under normal vacuum. The resulting acyl chloride was added to a solution of 3-(4-methyl01H-imidazol-1-yl-5-(trifluoromethyl)benenamine (2.46 g, 10.2 mmol), N,N-disopropylethylamine (1.56 g, 12 mmol), and the catalytic amount of DMAP in THF (20 mL). After stirring for 2 hours, the reaction was quenched with water. etOAc was added and the layers separated. The combined organic layers were concentrated to dryness and used without purification in the next step.

3-(lmidazol[1,2,a]pyridine-3-ylethyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifloromethyl)phenyl)benzamide : For a solution of 3-iodo-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)benzamide (0.11 g, 0.22 mmol) in DMF (i mL), in a sealed tube was added Pd[PPh3)4](0.013 g, 0.011 mmol), Cul (3mg, 0.016 mmol), diethylasopropylamine (0.057 mL, 0.33 mmol), followed by 3-ethynimidazole[1, 2-a]pyridine (0.040 g, 0.28 mmol). The mixture was purged with argon for 15 minutes, sealed and stirred at room temperature for 28 hours. The solvent was concentrated and the residue was taken up in methylene chloride (50 ml). The organic layer was washed with water, dried (Na2,SO4) and evaporated to leave a brown residue which was purified by flash combination of (hexane/ethyl acetate/methanol) to give the desired material: MS(M+H)+ 500.

Alternative Synthesis of 3-(imidazol[1,2-a]pyridine-3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(trifluoromethyl) phenyl)benzamide: 3-(lmidazol[1,2-a]pyridine-3-ylethynyl)-4-methyl-N-(3-(4-methyl-1H-imidazol-1-yl)-5-(fluoromethyl )phenyl)benzmide and its monohydrochloride salt that can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazol[1,2-a]pyridine-3-ylethynyl)-4-methylabenzoic acid and 3-(-4-Methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (as prepared above). ) 3-(imidazol[1,2-a]pyridine-3-ylethynyl)-4-methylbenzoic acid being prepared in a similar manner to that described in Example 1 using 3-Ethynylimidazol[1,2-ajpyridine and 3-iodo-4- methylbenzoic acid as associated Sonogashira couplers. EXAMPLE 5: N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl-3-imidazol[1,2-a]pyridine-3-ethynyl)-4-methylabenzamide

The noble compound was made as in Example 1, using N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylabenzamide and 3-ethynylidazol[1,2 -a]pyridine: MS (M+H)+486. The noble compound can also be prepared according to the alternative synthesis described in Example 1 from 3-(imidazol[1,2-a]pyridine-3-ylethynyl-4-methylbenzoic acid and 3-(1 H-imidazol- 1-yl)-5-(trifluoromethyl)aniline (as prepared in Example 1). Example q using 3-Ethynylimidazol[1,2-a]pyridine and 3-iodo-4-methylbenzoic acid as associates in the Sonogashira coupling. EXAMPLE 6: 3-(lmidazol[1,2-a]pyridine-3-ylethynyl-4 -methyl-N-(4-(trifluoromethyl)pyridine-2-yl(benzamide

The noble compound was made, for example, using 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridine-2-yl)benzamide and 3-ethynimidazol[1,2-a]pyridine: MS (M + H )+421.39. EXAMPLE 7 N-(5-terta-butylisoxazol-3-yl)-3-(-imidazol[1,2-a]pyridine-3-ylethynyl)-4-methylbenzamide

The noble compound was made as in Example 1 using N-(5-terta-butylisoxazol-3-yl_-3-iodo-4-methylabenzide and 3-ethynimidazol[1,2-a]pyridine: MS (M + H)+ 399. EXAMPLE 8 3-(lmidazol[1,2-a]pyridine-3-ylethynyl)-4-methyl-N-(4-((4-methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl )benzamide

3-Ethynylimidazol[1,2-a]pyridine (37 mg, 0.26 mmol), 3-iodo-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl) phenyl)benzamide (103.4 mf, 0.2 mmol), (prepared as in Example 2), Pd[PPh3)4](11.6 mg. 5mol%) and Cul (2.9 mg, 7.5 mmol%) were placed in a vial with a septum of rubber. The mixture underwent 3 vacuum/N2 fill cycles, and DMF (1.5 mL) and N,-N-disopropylethylamine (53 mL, 0.3 mmol) were added. The mixture was stirred at room temperature for 16 hours, and the reaction was mixed with H2O. etOAc and more water were added for extraction. The combined organic layer was dried (Na2SO4), filtered, concentrated, and the remaining residue was purified by silica gel chromatography (eluent: 5% MeOH in methylene chloride, with MeOH pre-saturated with ammonia gas), giving the noble compound as a white free solid (53%, 56 mg): MS (M + H) + 532.

Alternative Synthesis of 3-(lmidazol[1,2-a]pyridine-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl-3-(trifluoromethyl)phenyl)benzamide : 3-(lmidazol[1,2-a]pyridine-3-ylethynyl)-4-methyl-N-(4-((4-methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide and its monohydrochloride salt which can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazol[1,2-a]pyridine-3-ylethynyl)-4-metabenzoic acid and 4-((4-methylpiperazine -1-yl)methyl)-3-(trifluoromethyl)aniline as prepared in Example 2. 3-(imidazol[1,2-a]pyridine-3-ylethynyl)-4-methylbenzoic acid is prepared in a manner similar to that described in Example 1 using 3-Ethynylimidazol[1,2-a]pyridine and 3-iodo-4-methylbenzoic acid as associated Sonogashira couplers EXAMPLE 9: N-(3-(2-((dimethylamino)-1 H-imidazol-1 -yl)-5-(trifluoromethyl)phenyl)-3-(imidazyl[1,2-a]pyridine-3-ylethynyl)-4-methylabenzamide

To 3-ethynimidazol[1,2-a]pyridine (0.032 g, 0.22 mmol) in anhydrous DMF (1.25 mL) was added N-(3-(2-((dimethylamino)methyl)-1H-imidazol-1- yl)-5-(trifluoromethyl)phenyl)-3-iodo-4-methylabenzamide (prepared as in Example 3), Pd(PPh3)4 (0.013 g, 0.011 mmol), Cul (0.0032 mg, 0.0165 mmol) and DIPEA ( 0.064 mL, 0.44 mmol). The solution was degassed with argon for 15 minutes while stirring at room temperature. The solvent was removed and the resulting residue was chromatographed on silica gel eluting initially with EtOAc and then with methanol/methylene chloride (5:95) to give the desired product: (0.07 g, 59%) MS (M + H) +542.

Alternative Synthesis of N-(3-(2-((dimethylamino)methyl-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-(imidazol[1,2-a]pyridine-3- ylethynyl-4-methylabenzmide: N- (3-(2-((dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl)-3- (imidazol[1,2-a] pyridine-3-ylethynyl)-4-methylabenzimide and its monohydrochloride salt which can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazol[1,2-a]pyridine-3-ylethynyl)-4 -methylbenzoic acid and 3-(2-((Dimethylamino)methyl)-1H-imidazol-1-yl)-5-(trifluoromethyl)aniline (as prepared in Example 3). a]pyridine-3-ylethynyl)-4-methylbenzoic acid and being prepared in a similar way to that described in Example 1 using 3-Ethynylimidazol]1,2-a]pyridine and 3-iodo-4-methylbenzoic acid as associates in the Sonogashira coupling EXAMPLE 10: 3-((8-Acetamidoimidazol[1,2-a]pyridine-3-ethynyl)-4-methyl-N-(40(trifluoromethyl)pyridine-2-yl)benzamide

N-(3-Ethynylimidazol[1,2-a]pyridine-8-yl)acetamide: N-(3-Ethynylimidazol[1,2-a]pyridine-8-yl)acetamide was synthesized as in example 1A from N-(3-bromoimidazol=1,2-a]pyridine-8-yl-acetamide (E. Smakula Hand and William W. Paudler, J. Org. Chem., 1978, 43, 2900-2906). The noble compound was isolated as a white free solid, Rf, 0.6 (50/50 hexane/ethyl acetate): MS (M + H)+200.

3-((8-Acetamidoimidazol[1,2-a]pyridine-3-yl)ethynyl)-4-methyl-N-(4-(trifluoromethyl)pyridine-2-yl)benzamide: The noble compound was made as in example using 3-iodo-4-methyl-N-(e-(trifluoromethyl)pyridine-2-yl)benzamide and N-(3-ethynimidazol]1,2-a]pyridine-8-yl)acetamide> MS (M + H)+ 478.4. EXAMPLE 11: N-3-(1H-lmidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((8-acetamidoimidazol[1,2- a]pyridine-3-yl)ethynyl)-4 -methylabenzamide

The noble compound was made as in Example 10 using N-(3-(1H-imidazol-1-yl)-5-(trifluoromethyl)phenyl-3-iodo-4-methylabenzamide and N-(e-ethynimidazol[1, 2- a]pyridine-8-yl)acetamide: MS (M + H)+ 543. EXAMPLE 12 4-Methyl-3-((8-(4(methylasulfonyl)phenylamine(imidazol[1,2-a]pyridine- 3-yl)ethynyl)-N- (4-(trifluromethyl)pyridine-2-yl)benzamide

8-(Benzyloxyl)-3-bromoimidazol[1,2-a]pyridine: For a solution of 2-amine-3-benzyloxypyridineM (25.0 g, 124.9 mmol) and chloroacetaldehyde (50% by weight in H2O: 16.7 mL, 131 .2 mmol) in 250 mL of etOH was heated at reflux in a sealed tube for 19 hours. After cooling to room temperature, the reaction mixture was concentrated and to the resulting brown oil added 125 mL of 1N NaOH and then extracted with dichloromethane (DCM). The combined organic layers were washed with H2O, dried with Na2SO4 and concentrated. After concentration the solution, in tan solid form, was filtered and dried to provide 25.8 g of crude product. To a solution of 8-(benzyloxyl)imidazol[1,2-a]pyridine (8.73 g, 38.9 mmol) in 100 mL of EtoH was added dropwise, 4.8 mL (46.7 mmol) of a 1:1 Br2 solution /H2O at room temperature under an N2 atmosphere. The resulting dark orange suspension was stirred at room temperature for 30 minutes, 60 mL of 1N NaOH was added, and the reaction mixture was extracted with DCM. The combined organic layers were dried with Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 30% hexanes/EtOAc) to provide 7.04 g of product

8-(Benzyloxy(-30((trimethysyl)ethynyl)imidazol[1,2-a]pyridine: A mixture of 80(benzyloxyl)-3-bromoimidazol[1,2-a]pyridine (10.0 g, 33.0 mmol), 9.39 m L (66.0 mmol) of ethynylatrimethylasilane, 0.580 g (0.825 mmol) of Pd(PPh3)CI2, 0.230 g (1.19 mmol) of Cul, and 5.09 mL (36.3 mmol) of disopropylamine in 100 mL of acetonitrile was heated at reflux for 3 hours under an N2 atmosphere. After cooling to room temperature, the reaction mixture was concentrated and the pure product was purified by silica gel flash chromatography (eluted with 20-50% hexanes/etOAc) to provide 6.74 g of product: 321 m/z (M + H).

3-((Trimethylasylyl)ethynyl)imidazol[1,2-a]pyridine-8-yl-trifluoromethanesulfate: For a cooled (0o C) solution of 8-(benzyloxyl)-3-((trimethylasily)ethynyl)imidazol[1 ,2-a]pyridine (3.44 g, 10.7 mmol) in 400 mL of DCM, under an N2 atmosphere, 100 mL (100 mmol) of barium trichloride (1.0M solution in hexanes) were added via cannula. . The reaction solution was stirred at 0o C/N2 for 30 minutes, to which 200 mL of H2O was added (0o C) followed by extraction with DCM. The combined organic layers were washed with brine, dried with Na2SO4 and concentrated. The crude product was purified by silica gel flash chromatography (eluted with 30% hexanes/EtOAc then 10% MeOH/DCM) to provide 2.32 of the unprotected product: 231 m/z(M+H). For a cooled (-78° C) solution of 8-(hydroxyl)-3-((trimethylasilyl)ethynyl)imidazol[1,2-a]pyridine (2.32 g, 10.1 mmol) and 1.63 mL (20.1 mmol) of pyridine in 50 mL of DCM, under an atmosphere of N2, 2.03 (12.1 mmol) of trifluoromethanesulfonic anhydride was added via a syringe. After removal by a cold bath, the reaction solution was stirred at room temperature (N2) for 2 hours. The reaction mixture was flowed into a stirred solution of 100 mL 1.0N HCl, the layers separated, and the organic layer washed successively with 1.0N HCl, H2O, saturated aqueous liquid NaHCO3 and brine. The organic layer was dried with Na2SO4 and concentrated. The crude product was filtered through a small plug of silica gel (eluted with 30% hexanes/EtOAc), concentrated, and further vacuum dried to provide 3.63 m/z (M+H) product.

N-(-4-(Methylsulfonyl)phenyl)-3-((trimethylasylyl)-3-(ethynylline)imidazol[1,2-a]pyridine-8-amine: A mixture of 3-((trimethylasylyl)imidazol[1 ,2-a]pyridine-8-yl-trifluoromethanesulfonate (0.329 g, 0.91 mmol), 0.186 (1.09 mmol) 4-(methylsulfonyl)aniline, 0.083 g (0.091 mmol) Pd2(dba)2, 0.087 g (. 0181 mmol) of 2-dicyclohexylphosphine-2',4',6'-trisopropylbiphenyl, and 0.385 g (1.81 mmol) of potassium phosphate in 8 mL of DME were heated at 80° C in a sealed tube overnight under an atmosphere of N2. After cooling to room temperature, the reaction mixture was concentrated and the crude product purified by silica gel flash chromatography (triethylamine-treated silica gel, eluted with 0.80% hexanes/EtOAc) to provide 0.058 g of product: 384 m/z (M+H).

3-Ethynyl-N-4-(methylasulfinyl)phenyl)imidazol[1,2-a]pyridine-8-amine: For a solution of N-(4-(methylasulfonyl)phenyl)-3-((trimethylasylyl)ethynyl) imidazol[1,2-a]pyridine-8-amine (0.058 g, 0.15 mmol) in 1.5 mL of THF was added 0.23 mL (0.23 mmol) of tetrabutylammonium fluoride (1.0M in THF) at room temperature. The solution was stirred for 15 minutes, concentrated and the crude product purified by silica gel flash chromatography (silica gel treated with triethylamine; eluted with 100% DCM and then 5% MeOH/DCM) to provide an amount of product (0.047g) of product: 312 m/z: M+H).

4-Methyl-3-((8-(4-methylasulfonyl)phenylamine)imidazol[1,2-a]pyridine-3-yl)ethynyl)-N- (4-(trifluoromethyl)pyridine-2-yla)benzamide: A mixture of 3-ethynyl-N-(4-(methylasulfonyl)phenyl)imidazyl[1,2-a]pyridine-8-amine 5 (0.048 g, 0.154 mmol), 0.069 g (0.0170 mmol) of 3-iodo- 4-methyl-N-(-4-(trifluoromethyl)pyridine-2-yl)benzamide, 0.009 g (0.008 mmol) of pd(PPh3)4, 0.002 g (0.012 mmol) of Cull, and 0.04 mL (0.23 mmol) ) of disopropylethamine in 0.8 mL of DMF which was stirred at room temperature overnight under an N2 atmosphere. The reaction mixture was concentrated and the crude product purified by silica gel flash chromatography (triethylamine-treated silica gel, eluted with 10% hexanes/EtOAc to 100% EtOAc) to provide 0.047 g of product as a solid: 590 m/z (M+H). EXAMPLE 13 4-methyl-3-((8-(4-sulfamoylphenylamine)imidazol[1,2-a]pyridin-3-yl)ethynyl)-N-(-4-(trifluoromethyl)pyridine-2-yl)- benzamide

The noble compound was synthesized from 3-ethynyl-N-(4-sulfamoylphenyl)imidazol[1,2-a]pyridine-8-amine and 3-iodo-4-methyl-N-(4-(trifluoromethyl)pyridine -2-ylb)benzamide in a similar manner to that described for Example 12. The product was obtained as a solid: 591 m/z (M+H). EXAMPLE 14 (R)-N-(4-((3-(Dimethylamine)pyrolidin-1-ylb)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazol[1,2-b]pyridazine-3- ylethynyl)-4-methylabenzamide

3-((Trimethylasylyl)ethynyl)imidazol[1,2-a]pyridazine: A mixture of 3-bromoimidazol[1,2-b]pyridizine (36.78 g, 0.186 mol: prepared according to Stanovnik, B. et al, Synthesis (1981) mol) in 150 L of DMF was stirred at room temperature under an atmosphere of N2m for 1 hour. The reaction mixture was concentrated and the crude product purified by silica gel flash chromatography (eluted with 0-5% Me)H/DCM) to provide 28.4 g of product.

3-Ethynylimidazol[1,2-b]pyridine (28.46 g, 0.132 mol) in 200 mL of THF with 145 mL (0.145 mol) of tetrabutylammonium fluoride (1.0M in THF) added at room temperature. The solution was stirred for 15 minutes, concentrated, and the crude product purified by silica gel flash chromatography (eluted with 0-5% MeOH/DCM) to provide 17.84 g of product.

1-(Bromomethyl)-4-nitro-2-(trifluoromethyl)benzene: A suspension of 2-methyl-5-nitrobenzotrifluoride (3.90 g, 19 mmol), N-bromusicimide (NBS, 3.56 g, 10 mmol) and 2,2'-azobis(2-methylapropionitrile) (AIBN, 0.094 g, 0.6 mmol) in 40 mL of CCI4 was heated at reflux under N2 for 16 hours. HPLC indicated ca. with 50% conversion; Additionally NBS (10 mmol) and AIBN (0.6 mmol) were added and the mixture was heated at reflux for another 14 hours. HPLC indicated ca. 80% conversion. The reaction mixture was cooled to room temperature, and the solid filtered and washed with EtOAc. The combined filtrate was washed with aq. NaHCO3, dried with Na2SO4, filtered, concentrated under rotary vacuum, and further dried under vacuum. 1N NMR indicated the ratio or radius of the desired product to the unreacted 2-methyl-5-nitrobenzotrifluoride to be 75:25. This material was used directly in the next step. (R)-N,N-Dimethyl-1 -(4-nitro-2-(trifluoromethyl)benzyl)pyrolidine-3-amine: For a crude solution of 1-(bromomethyl)-4-nitro-2-(trifluoromethyl) benzene (17.5 mmol, 75% pure) in 40 mL of DCM was added Et3N (2.69 mL, 19.3 mmol) and (R)-(+)-3-(dimethylamine)pyrolidine (2.0 g, 17.5 mmol). After stirring overnight at room temperature under an N2 atmosphere, the reaction solution was concentrated, added aq. NaHCO3 (100 mL), and the resulting mixture extracted with DCM (4 x 50 mL). The combined organic layer was dried with Na2SO4, filtered, concentrated and the resulting residue was purified by silica gel chromatography (eluted with 0 -10% MeOH/DCM) to provide 3.35 g of the product as a yellow oil. (R)-1-(4-Amine-2-(trifluoromethyl)benzyl)-N.N-dimethylapirolidine-3-amine: For a solution of (R)-N,N-dimethyl-1-(4-nitro-2( trifluoromethyl)benzyl)pyrolidine-3-amine (1.20 g, 3.79 mmol) in 20 mL of moistened EtOH was added 0.26 Pf/C (10% Pd in C) and the mixture stirred in a Parr apparatus (reaction vessel pressure topped up with H2 and pressure regulated to 45 psi completely) for 2-3 hours. The reaction mixture was filtered through a small pad of celite, washed with etOAc, and the combined organics concentrated to provide a quantitative yield of a light yellow oil. This material was used directly in the next step. (R)-N-(4((3-(Dimethylamine)pyrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylabenzamide: For a cooled solution (0o C) of ( R)-1-(4-amine-2-(trifluoromethyl)benzyl)-N,N-dimethylapyrolidine-3-amine (3.79 mmol) in 14 mL of DCM, under an atmosphere of N2, 3-iodo-4 was added -methylbenzoyl chloride (1.17 g, 4.17 mmol; CAS# 52107-98-9, prepared from the reaction of 3-iodo-4-methylbenzoic acid and SOCI2) followed by dropwise addition of N,N-disopropylethylamine (2.64 mL, 15.2 mmol). After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated and the crude product purified by silica gel chromatography (eluted with 0.8% MeOH/DCM, the MeOH being pre-saturated with ammonia gas) to provide 0.71 g of the product with a strong yellow oil. (R)-N-(-4-((3-(dimethylamine)pyrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazol[1,2-b]pyridazine-3-ylethynyl )-4-methylabenzamide: A mixture of 3-ethynimidazol[1,2-bJpyridazine (0.051 g, 0.34 mmol), 0.150 g (0.28 mmol) of (R)-N-(4-((3-(dimethylamine)pyrolidine (0.051 g, 0.34 mmol), 0.150 g (0.28 mmol) of (R)-N-(4-((3-(dimethylamine)pyrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3- iodo-4-methylabenzamide, 0.016 g (0.014 mmol) of Pd(RPh3)4, 0.004 g (0.021 mmol) of Cui, and 0.09 mL (0.51 mmol) of N,N-disopropylethylamine in 3.5 mL of DMF stirred at temperature ambient, under an atmosphere of N2, for 3 days (reaction boosted for complementation with additional equivalent reagents and heated to 80° C.) The reaction mixture was concentrated and the crude product purified by silica gel chromatography (eluted with 0- 10% MeOH/DCM; MeOH being pre-saturated with ammonia gas) to provide 0.020 g of product as a solid: 547 m/z (M+H).

Alternative Synthesis of (R)-N-(4-((3-(Dimethylamine)pyrolidin-1-yl)methyl)-3-(trifluoromethyl)phenyl)-3-(imidazol[1,2-b]pyridazine-3 -ylethynyl)-4-methylabenzamide: (R )-N-(4-((3-(DimethylamineOpyrolidine-1-yla)methyl-3-(trifluoromethyl)phenyl-3-(imidazol[1,2-b]pyridazine -3-ylethynyl)-4-methylabenzamide and its monohydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazol[1,2-b]pyridazine-3-ylethynyl-4-acid methylbenzoic acid and (R)-1-(4-Amine-2-(trifluoromethyl)benzyl)-N,N-dimethylapirolidine-3-amine (as prepared above). 3-ylethynyl)-4-methylbenzoic acid is prepared in a manner similar to that described in Example 1 using 3-Ethynylimidazol[1,2-b]pyridazine and 3-iodo-4-methylbenzoic acid as associated Sonogashira couplers. EXAMPLE 15 N-( 3-(lmidazol[1,2-b]pyridazine-3-ylethonyl)-4-methylaphenyl)-4-((4-methylapiperazine-1-iia)-3-(trifluoromethyl)benzamide

The noble compound was synthesized from 3-ethynimidazol[1,2-b]pyridazine and N-(3-iodo-4-methylaphenyl)-4-((methylapiperazine-1-yl)methyl)-3-(trifluoromethyl) benzamide in a manner similar to that described for Example 14. The product was obtained as a solid: 533 m/z: (M+H.

N-(3-lodo-40methylaphenyl)-4-((methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)benzamide: For one vial containing 1.0 g (2.67 mmol) of 4-[(4-methyl-1 -piperazine)methyl]-3-(trifluoromethyl)-benzoic acid (CAS# 859027-02-4; prepared according to Asaki, T. et al., Bioorg. Med. Chem. Lett. (2006), 16, 1421 -1425), 0.62 g (2.67 mmol) of 3-iodo-4-methylaniline, 0.77 g (4.0 mmol) of N-(3-dimethylaminopropyl)-N'-ethylcarbodimide hydrochloride (EDAC) and 0.43 g (3.2 mmol) of hydroxybenzotriazole N-monohydrate (HOBt + H2O) was added 5 mL of DCM and 5 mL of triethylamine. The solution was stirred at room temperature under an N2 atmosphere for days, concentrated and the crude product purified by silia gel chromatography (illuted with 100% etOAc and 10% MeOH/EtOAc), to provide 0.69 g of product as a white solid. EXAMPLE 16 3-(lmidazol[1,2-b}pyridazine-3-ylethynyl)-4-methyl-N-(4-((4-methylapiperazine-1-yl)methyl-3-trifluoromethyl)phenyl)benzamide

The noble compound was synthesized in a similar way to that described for Example 14, using 3-ethynimidazol[1,2-b]pyridazine and 3-iodo-4-methyl-N-(4-((4-methylapiperazine- 1yl)methyl-3-(trifluoromethyl)phenyl)benzamide (prepared as described in Example 2) The product was obtained as a solid 533 ./z (M+H).

Alternative Synthesis of 3-(lmidazol[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide: 3-(lmidazol[1,2- b]pyridazine-3-ylethynyl)-4-methyl-N-(4-((4-methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)enzamide and its monohydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 3, from 3-(imidazol[1,2-b]pyridazine-3-ylethynyl)-4-methylbenzoic acid and 4-(( 4-methylpiperazine-1-yl)methyl)-3-(trifluoromethyl)aniline (as prepared in Example 2). 3-(imidazol[1,2-b]pyridazine-3-ylethynyl)-4-methylbenzoic acid is prepared in a similar manner to that described in Example 1 using 3-Ethynylimidazol[1,2-b]pyridazine and 3-iodo- 4-methylbenzoic acid as associated Sonogashira couplers. EXAMPLE 17: N-(3-Chloro-4-((4-methylapiperazine-1-yl)methyl)phenyl)-3-(imidazol[1,2-b]pyridazine-3-ylethynyl)-4-methylabenzamide

The noble compound was synthesized according to Example 14, from 3-ethynylimidazol[1,2-b]pyridazine and N-(3-chloro-4-((methylapiperazine-1-yl)methyl)phenyl)-3 -iodo-4-methylabenzamide. The product was obtained as a solid: 499 m/z (M+H).

1-(Bromomethyl)-2-chloro-4-nitro-benzene: A suspension of 2-chloro-4-nitrotoluene (10.0 g, 58.3 mmol), N-bromuscinimide (NBS, 10.9 g, 61.2 mmol) and 2 ,2'-azobis(2-methylapropionitrile) (AIBN, 0.29 g, 1.75 mmol) in 120 mL of CCI4 was heated at reflux under an N2 atmosphere for 12 hours. The reaction mixture was cooled to room temperature, and the solid was filtered and washed with EtOAc. The filtrate was washed with aq. NaHCO3, dried with Na2SO4, filtered, concentrated by rotary vacuum and dried again under vacuum. 1H NMR indicated the ratio of the desired product to the unreacted material 2-chloro-4-nitrotoluene to be 50:50. This material was used directly in the next step.

1-(2-Chloro-4-nitrobenzyl)-4-methylpiperazine: To a solution of crude 1-(bromomethyl)-chloro-4-nitro-benzene (29.1 mmol; 50% pure) in 30 mL of DCM was added Et3N (4.2 mL, 30 mmol) and 1-methylapiperazine (3.4 mL, 30 mmol). After stirring for 3 hours at room temperature, aq. NaNHCO3 was added and the mixture was extracted with DCM. The combined organic layer was purified by silica gel chromatography (eluted with 5% MeOH/DCM) to provide 6.80 g of product as a dark yellow oil. 3-Chloro-4-((4-methylapiperazine-1-yl)-methyl)aniline: For a solution of 1-(2-chloro-4-nitrobenzyl)-4-methylapiperazine (0.96 g, 3.6 mmol) in MeOH/ Water (4:1. 50 mL) was added 1.80 g (33.7 mmol) of NH4CI and 1.47 g (26.3 mmol) of Fe pollen and the mixture heated at reflux under an atmosphere of N2 for 2 hours (HPLC indicated no progress) . To this was added 4 mL of glacial acetic acid and the mixture heated at reflux for an additional 2 hours. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The residue was partitioned between EtOAc and aq. NaHCO3 was saturated, the separated aqueous layer was extracted with EtOAc, and the combined organics were washed with brine and dried with Na2SO4. After concentration, the crude product was purified by silica gel chromatography (eluted with 5-7% MeOH/DCM) and silica gel deactivated with 1% triethylamine/DCM to provide 0.53 g of product.

Alternative Synthesis of N-(3-Chloro-4-((4-methylapiperazine-1-yl)methyl)phenyl)-3-imidazol[1,2-b]pyridazine-3-ylethynyl)-4-methylabenzamide: N- (3-Chloro-4-((4-methylpiperazine-1-yl)methyl-phenyl)-3-(imidazol[1,2-b]pyridazine-3-ylethynyl-4-methylbenzamide and its monohydrochloride salt can be prepared in an alternative synthesis similar to that described in Example 1 from 3-(imidazol[1,2-b]pyridazine-3-ylethynyl)-4-methylabezoic acid and 3-Chloro-4-((4-methylpiperazine-1- yl)methyl)aniline (as prepared above). 1,2-b]pyridazine and 3-iodo-4-methylbenzoic acid with associated Sonogashira couplers. [1,2- b]pyridazine-3-ylethynyl)-4-methylabenzamide

The noble compound was synthesized from 3-ethynimidazol[1,2-b]pyridazine and N-(3-cyclopropyl-4-((4-methylapiperazine-1-yl)methyl)phenyl)-3-iodo-4- methylbenzamide in a similar way to that described for Example 14 (nitro reduction carried out in a similar way to that described in Example 17; 0.25M and m MeOH/10%AcOH). The product was obtained as a solid: 505 m/z (M+H).

1-(2-Cyclopropyl-4-nitrobenzyl)-4-methylpiperazine: A mixture of 1-(2-bromo-4-nitrobenzyl)-4-methylpiperazine (0.94 g, 3.0 mmol), 0.77 g (9.0 mmol) acid cyclopropyllaboronic acid, 0.067 g (0.30 mmol) of Pd(Oac)2, 2.87 g (13.5 mmol) of K3PO4, and 0.168 g (0.60 mmol) of tricyclohexylphosphine in 18 mL of water/toluene (5:1) being heated at reflux under an N2 atmosphere for 19 hours. The reaction mixture was then concentrated and the crude product purified by silica gel chromatography (eluted with 5% MeOH/DCM; MeOH being pre-saturated with ammonia gas) to provide 0.80 g of product. EXAMPLE 19: 3-(lmidazyl[1,2-b]pyridazine-3-ylethynyl)-N-(4-((4-methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

The noble compound was synthesized from 3-ethynimidazol[1,2,-b]pyridazine and 3-iodo-N-(4-((4-methylapiperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl) benzamide in a manner similar to that described for Example 14. The product was obtained as a solid > 519 m/z (M+H). The noble compound may also be prepared according to the alternative synthesis described in Example 1 from 3-(imidazol[1,2-b]pyridazine-3-ylethynyl)-4-methylbenzoic acid and 4-((4-methylpiperazine- 1-yl)methyl)-3-(trifluoromethyl)aniline (as prepared in Example 2). 3-imidazol[1,2-b]pyridazine-3-ylethynyl)-4-methylbenzoic acid is prepared in a similar manner to that described in Example 1, using 3-Ethynylimidazol[1,2-b]pyridazine and 3-iodo- 4-methylbenzoic acid as associated Sonogashira couplers. EXAMPLE 20: N-(4-((4-(2-Hydroxyethyl)piperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl-3- (imidazol[1,2-b]pyridazine-3-ylethynyla- 4-methylabenzamide.

The noble compound was synthesized from 3-ethynimidazol[1,2-b]pyridazine and N-(4- ((4-(2-hydroxyethyl)piperazine-1-yl)methyl)-3-(trifluoromethyl)phenyl)- 3-iodo-4-methylbenzamide in a similar manner to that described for Example 14. The product was obtained as a solid: 563 m/z (M+H). EXAMPLE 21: 3-(lmidazol[1,2-b]pyridazine-3-ylethynyl)-4-methyl-N-(4-(piperazine-1-yl-methyl)-3-(trifluoromethyl)phenyl)benzamide

The noble compound was synthesized from 3-ethynimidazol[1,2-b]pyridazine and tertabutyl 4-(4-(3-iodo-4-methylabenzamido)-2-(trifluoromethyl)benzyl)piperazine-2-carboxylate of a similar way to that described for Example 14. Using saturated MeOH/HCI(g), the product was obtained with a tri-HCI salt: 519 m/z (M+H). EXAMPLE 22: Biological Evaluation of Compounds

The compounds of this invention are evaluated in a variety of analyzes and tests to determine their biological activities. For example, compounds of the invention may be tested for their abilities to inhibit various protein kinases of interest. Some of the compounds tested showed potential nanomolar activity against the following kinases: Abl, Abl, T3 151, Src and FGFR. Furthermore, several of these components have been designed for antiproliferative activity and have demonstrated activity in the range of 1-100nM. Compounds may further be evaluated for their cytotoxic or growth inhibitory effects on tumor cells of interest, as, for example, described in more detail below and as shown above for the same representative compounds. See for example, WO 03/00188, pages 115-136, 10 the full content of which is incorporated into the present application by reference. Some representative compounds are described below:

Kinase Inhibition

More specifically, the compounds described here are designed to inhibit kinase activity as will be shown. Suitable kinases for use in the following protocol include, but are not limited to: Abl, Lck, Lyn, Src, Fyn, Syk, Zap-70, Itk, Tec, Btk, EGFR, ErB2, Kdr, Fit1, Fit3, Tek, c-Met, InsR, and AKT. Kinases are also expressed within the kinase framework or constructed in large sizes fused to fusion proteins labeled as poly-Histidine or glutathione S-transferase (GST) or as E. coli or Baculovirus-High Five Expression systems. They are purified to near homogeneity by chromatographic affinity as previously described (Lehr et al., 1996; Gish et al., 1995). In some examples, kinases are expressed or mixed with purified or partially purified regulatory polypeptides before measuring their activity. Kinase activity and inhibition can be measured by established protocols (see for example, Braunwalder et al., 1996). In some cases, the transfer of 33PO4 from ATP to polysynthetic (Glu, Tyr) 4:1 or poly (Arg, Ser) 3:1 substrates attached to the bioactive surface of the micro-pattern plates which is given as a measure of enzyme activity. After a period of incubation, the amount of phosphate transferred is measured by first washing the plate with 0.5% phosphoric acid, adding liquid scintillation, and counting in a liquid scintillation detector. The IC50 is determined by the concentration of the compound that causes a 50% reduction in the amount of 33P incorporated when binding the substrate to the plate. In one method, the kinase is incubated with a biotinylated substrate peptide (continued tyr) with or without the presence of a compound of the invention. After the incubation period of the kinase test, excess kinase inhibitor is added to destroy along the kinase feed with a Europium labeled anti-phosphotyrosine antibody (Eu-Ab) and Streptavidin Alloficicyanin (AS-APC). The biotinylated substrate peptide (with or without phosphorylated Tyrosine) in solution binds to the AS-APC through the Biotin-Avidin coupler. Eu-Ab bonds only transfer energy from Europium to APC when they are in close proximity (i.e., attached to the same molecule as the phosphorylated and biotinylated substrate peptide. APC when fluoresces at a wavelength of 665 nm. Excitation and emission occurs in a Vitor2V plate reader where the plate is read fluoretrically and the absorbances at 615 and 665 nm are recorded. This data is then processed by an Excel processor board that calculates the IC505 of the tested compounds by converting the fluorescent into amounts of phosphorylated substrate which are made by determining the concentration of the tested compound that may be required to inhibit the development of the phosphorylated substrate by 50% (IC50) Other reliable methods relating to the transfer of phosphate to the peptide or polypeptide substrate containing tyrosine, serine, threonine or histidine alone or in combination with another, or in combination with other amino acids, in solution or immobilized (i.e. in the solid phase are also suitable. For example, phosphate transfer in a peptide or polypeptide may also be detected using proximity scintillation, Polyratio Fluorescence, or time-resolved homogeneous fluorescence. Alternatively, kinase activity may be measured using an antibody-based method in which an antibody or polypeptide is used as a reagent to detect the phosphorylated labeled polypeptide. For more information on the tests of these methodologies, see, for example, Braunwalder et al., 1996, Anal Biochem, 234(l):32. Cleveland et al., 1990, Anal Biochem, 190(2):249 Gish et al. (1995), Protein Eng. 8(6):609 Kolb et al (1998), Drug Discov. Toda V. 3:333 Lehr et al., (1996), Gene 169(2):27527 - 87 Seethala et al. (1998), Anal Biochem, 255 (2): 257 We et al (2000). IC5a values in the low namolar range have been observed for compounds of this invention against several kinases, including Src, Abl and Kdr.

Cell-based tests

Certain compounds of this invention have also been demonstrated to have cytotoxic or growth-inhibiting effects on tumors and other cancer cell lines and thus may be suitable in the treatment of cancer and other proliferative cell diseases. Compounds are tested for antitumor activity using in vivo and in vitro assays that are well known in the art. Generally, initial screenings of compounds to identify candidate anticancer drugs are carried out in cellular analyses. Compounds identified as having antiproliferative activity in said cell-based tests may be subsequently tested in whole organisms for antitumor activity and toxicity. Generally speaking, cell-based projections could be performed more quickly and at a relatively lower cost than tests used for whole organisms. For purposes of this invention, the terms “antitumor” and “anticancer” activity are used interchangeably. Cell-based methods for measuring antiproliferative activity are well known and can be used for comparative characterization of the compounds of this invention. In general, cell proliferation and cell viability tests are designed to provide a detectable signal when cells are metabolically active. Compounds may be tested for antiproliferative activity by measuring any observed decrease in the metabolic activity of cells following exposure of cells to the compound. Commonly used methods, for example, are measurement of membrane integrity (as a measure of cell viability) (e.g. using trypan blue exclusion) or measurement of DNA synthesis (e.g. measurement by incorporation of Brdll or 3H-thymidine). Some methods for analyzing cell proliferation use a reagent that is converted into a detectable compound during cell proliferation. Particularly preferred compounds are the tetrazzolium salts and include without limitation MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenylatetrazolium bromide; Sigma-Aldrich, St. Louis, MO), MTS (3 -(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethylaphenyl)-2-(4-sulfonyl)-2H- tetrazolium), XTT (2,3-bis(2-Methoxyl-4-nitro- 5-sulfonyl)-2H-tetrazolium-5-carboxanilide), INT, NBT and NTV (Bernas et al. Biochim Biophys Acta 1451(1):73-81, 1999). Preferred are assays using tetrasolium salts to detect cell proliferation by detecting the product of the enzymatic conversion of tetrazolium salts to blue formazan derivatives, which are readily detected by spectroscopic methods (Mosman. J. Immunol. Methods. 65:55-63, 1983 ). Generally, preferred methods for testing cell proliferation involve incubating cells in the desired growth medium with or without the compound being tested. The growth conditions for various prokaryotic and eukaryotic cells are well known to one skilled in the art, with respect to the prior art (Ausubel et al. Current Protocols in Molecular Biology. Wiley and Sons, 1999; Bonifacino et al. Current Protocols in Cell Biology. Wiley and Sons 1999, both incorporated herein by reference). To detect cell proliferation, tetrazolium salts are used to incubated cultured cells to allow enzymatic conversion to the product detected by active cells. The cells are processed, and the optical density of the cells is determined to measure the amount of formazan derivatives. Additionally, commercially viable kits including reagents and protocols are available, for example, from Promega Corporation (Madiso, WI), Signma-Aldrich (St. Louis, MO), and Trevigen (Gaithersburg, MD). More specifically, assays or tests for cell proliferation typically use a CelITiter 96 Single Aqueous Solution Cell Proliferation test kit (Promaga, Ca#G3581). This analysis is a colorimetric method to determine the number of living cells in proliferation or cytotoxic analyses. Analysis using tetrazolium salts detects cell proliferation by detecting the product of the zymatic conversion of tetrazolium salts into formazn azyl derivatives, which can be measured by absorption at 490 nm on a reader plate, Wallac Victor2V (PerkinElmer). An example of a cell-based test will be shown below. The cell lines used in the test are Ba/F3, a murine pro-B cell line, which has stably transfected with a broad-sized wild-type Bcr-Abl or Bcr-Abl with multiple spots in the kinase field (including T 3511 , Y253F, E255K, H369P, M351T, etc.) The parental Ba/F3 cell line is used as a control. These cell lines were obtained from Brina J. Druker (Howard Hughes Medical Institute, Oregon Health and Science University, Portland, Oregon, USA). Ba/F3 cells expressing Bcr-Abl or mutant Bcr-Abl were maintained in PRMI 1640 growth medium with 200 μM L-gultamine, 10% FCS, penicillin (200 U/mL), and streptomycin (200 μg/mL). Parental Ba/F3 cells were cultured in the same medium supplemented with 10 ng/ml IL-3. Parental cells (supplemented with IL-3) or Bas/F3 cells expressing WT or Bcr-Abl mutants are plated in duplicate on 1x104 cell plates in 96 plates complete with the compounds at different concentrations in the medium. The compounds are first dissolved and diluted in DMSO by preparing 4-fold dilution; then equal volumes of the compounds with DMSO are transferred into the medium and then transferred to the cell plates. The final concentrations of the compounds range from 10 μM to 6 nM. DNSO in the same percentage is used as control. After the compound is incubated with cells for 3 days, the number of active cells are measured using the CelITiter 96 Single Aqueous Solution Cell Proliferation kit following the kit instructions. Basically, tetrazolium salts are added to incubated cultured cells to allow enzymatic conversion to the product detected by active cells. The cells are processed, and the optical density of the cells is determined to measure the amount of formazan derivatives. The mean +/- SD is generated in the duplicate springs and reported as the control absorption percentage. IC50s are calculated on well-fitted curves using Microsoft Excel-fit software. In addition, a wide variety of cell types can be used to engineer compounds for antiproliferative activity, including the following cell lines; among others: COLO 25 (colon cancer), DLD-1 (colon cancer). HCT-15 (Colon Cancer), HT29 (Colon Cancer), HEP G2 (Hepatoma), K-562 (Leukemia). A549 (Lung). NCI-H249 (Lung), MCF7 (Breast), MDA- MB-231 (Breast), OSAS-2 (Osteosarcoma), OVCAR-3 (Ovary), PANC-1 (Pancreas), DU-145 (Prostate), PC -3 (Prostate), ACHN (Renal), CAKI-1 (Renal), MG-63 (Sarcoma). While the cell line is preferably mammary, lower order eukaryotic cells such as fermented cells could also be used to design the compounds. Preferred mammary or mammalian cell lines are derived from humans, rats, mice, rabbits, monkeys, hamsters, guinea pigs, since cell lines from these organisms are very well studied and characterized. However, many others can also be used. Suitable mammalian cell lines are often derived from tumors. For example, the following types of tumor cells could be sources of cell culture, such as: melanoma, myeloid, leukemia, carcinomas of the lung, breast, ovary, colon, kidney, prostate, pancreas and others), cardiomyocytes, endothelial cells, epithelial cells, lymphocytes (T-cell and B-cell), mast cells, eosinophils, intimal vascular cells, hepatocytes, leukocytes including mono-nuclear leukocytes, stem cells such as haemopetic, neural, skin, lung, liver stem cells, and kidney, and myocyte (for use in projection for differentiation and non-differentiation factors), osteoclates, chondrocytes and other connective tissue cells such as keratinocytes, melanocytes, liver cells, kidney cells and adipocytes. Limited examples of mammalian cell lines that have been widely used in research include HeLa, NIH/3T3, HT1080, CHO, COS-1, 293T, WI-38, and CV1/EBNA-1. Other cell tests that report a gene can be used to detect metabolically active cells. Non-limiting examples of a gene reporting expression system include green fluorescent protein (GFP) and luciferase. As an example of using GFP to design potential antitumor drugs, Sandman et al. (Chem. Biol. 6:541-51, incorporated herein by reference) used HeLa cells containing an inducible variant of GFP to detect compounds that inhibit the expression of GFP, and thus inhibit cell proliferation. Compounds identified by said cellular tests having anti-cell proliferation activity are then tested for antitumor activity in all organisms. Preferably, the organisms are mammals. Well-characterized mammalian systems for studying cancer include rodents such as rats and mice. Typically, a tumor of interest is transplanted into a mouse having a reduced ability to mount an immune response to the tumor to reduce the possibility of rejection. Said mouse includes, for example, nude (athymic) mice and SCI D (severe combined immunodeficiency) mice. Other transgenic mice such as oncogen-containing mice may be used in the present tests (see, for example, US Patent No. 4,736,866 and US Patent No. 5,175,383). For a review and discussion on the use of rodent models for antitumor drug testing see Kerbel (Cancer Metastasis Ver. 17:303-304, 1998-99). In general, tumors of interest are implanted into a test organism, preferably subcutaneously. The organism containing the tumor is treated with doses of candidate antitumor compounds. Tumor size is periodically measured to determine the effects of the tested compound on the tumor. Some tumor types are implanted in sites other than subcutaneous sites (e.g., intraperironal sites), and survivorship is measured as the endpoint. Parameters to be analyzed with routine projection include different tumor models, various tumors, and drug routines, and dose amounts and schedules. For a review of the use of mice in the detection of antitumor compounds see Corbett et al. (Invest New Drugs. 15:207-218, 1997); herein incorporated by reference.

Example 23: Pharmaceutical Compositions

Pharmaceutical dosage forms representative of the compounds of this invention (the active ingredient being referred to as “Compound”) are provided for therapeutic or prophylactic use in humans: Note: These formulations can be prepared using conventional procedures well known in the pharmaceutical art. Tablets (a)-(c) may be enteric coated by conventional means, if desired to provide a cellulose acetate phthalate coating, for example. Aerosol formulations (h)-(k) may be used in conjunction with standard dispensers, metered aerosol dispensers, and soy lecithin sorbitan trioleate suspending agents which may be substituted as an alternative suspending agent such as sorbitan monooleate, sorbitan sesquiolate, polysorbate 80, polyglycerol oleate or oleic acid 10.

Claims (6)

1 .- “COMPOUND” characterized by being selected from Formulas IIa, IIb, IIc, IIIa, IIIb, and IIIc. in which Ra, Rb, Rc and Re is independently selected from the group consisting of halo, -CN, -NO2, -R4, -OR2, -NR2R3, -NR 2C(=S)YR2, -OC(=S )YR2, -C(=S)YR2, -YC(=NR3)YR2, - YP(=O)(Y R4)(YR4 ), -Si(R2)3, - NR2SO2R2, -S(O)rR2, -SO2NR2R3 and -NR2SO2NR2R3; where each Y is independently a bond, -O-, -S- or -NR3 -; R1, R2 and R3 are independently selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-6 cycloalkyl, C3-6 cycloalkenyl, C5-6 cycloalkynyl, aryl, and heterocyclic and heteroaryl substituents ; alternatively, R2 and R3, taken together with the atom to which they are attached, form a 5- or 6-substituted ring containing 0-2 heteroatoms selected from N, O and S(O)r; each occurrence of R4 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alcohol, C3-6 cycloalkyl, C3-6 cycloalkenyl, C5-6 cycloalkynyl, aryl, and the heterocyclic and heteroaryl substituents, where the heterocyclic substituents are chosen from 3-1H-benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1- piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanil, benzothiolanil, benzothianyl, indolinyl, cromanyl, phenanthridinyl and tetrahydroquinolinyl; and the heteroaryl substituents are chosen from thienyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, isothiazolyl, furazanyl, isoxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, benzo[b]thienyl, naphtho[2,3-b]thienyl , tianthrenyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxatienyl, indolizinyl, isoindolyl, indolyl, indazolyl, purinyl, isoquinolyl, quinolyl, phthalazinyl, naphtiridinyl, quinoxalinyl, quinazolinyl, benzothiazole, benzimidazole, tetrahydroquinoline cinnolinyl, pteridin yl, carbazolinyl, quinoxalinyl, quinazolinyl, benzothiazole, benzimidazole, tetrahydroquinoline cinnolinylyl, pteridinyl, carbazolinyl, benzothiazole, benzimidazole, tetrahydroquinoline cinnophenyllinyl, beta- carbolanthridinyl, beta acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, isothiazolyl, phenothiazinyl, phenoxazinyl, 2-furanyl, 3-furanyl, nimidazolyl , 2-imidazolyl, 4 - imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl , 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-triazolyl, 5 -triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, isoindolyl, acridinyl, benzoisoxazolyl, tetrahydroquinoline, tetrahydroisoquinoline, pyrido[3 , 4 -d)pyrimidinyl, imidazo[1,2-a]pyrimidyl, imidazo[1,2-a]pyrazinyl, imidazo[1,2-a]pyridinyl, imidazo[1,2-c]pyrimidyl, pyrazolo[1,5 -a][1,3,5]triazinyl, pyrazolo[1,5-c]pyrimidyl, imidazo[1,2-b]pyridazinyl, imidazo[1,5-a]pyrimidyl, pyrazolo[1,5-b] [1,2,4]triazine, quinolyl, isoquinolyl, quinoxalyl, imidazotriazinyl, pyrrolo[2,3-d]pyrimidyl, triazolopyrimidyl and pyridopyrazinyl in is 0, 1, 2, 3 or 4; p is 0, 1, 2, 3 or 4; r is 0, 1 or 2; s is 0, 1, 2, 3, or 4 and v is 0, 1, 2, 3, 4, or 5; or a pharmaceutically acceptable salt thereof.” two . “COMPOUND” according to claim 1 characterized in that s is 0; m, p and v are 1; Ra and Rc are methyl; and Rb be CF3. 3.- “COMPOUND” according to claim 1 characterized in that s is 0, m is 1, p is 1, Ra is methyl, Rb is CF3, and Rd is methyl or -CH2CH2OH. 4.- “COMPOSITION” characterized in that it comprises a compound according to any one of the preceding claims or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent or carrier. 5.- “COMPOUND” any one of the preceding claims or a pharmaceutically acceptable salt thereof characterized by its use in the treatment of cancer in a mammal in such need. 6.- “COMPOUND” according to claim 1, characterized by being used in the treatment of cancer in a mammal with such need, has the following structure: