BRPI0615615A2 - pharmaceutical compositions and treatment of a neoplastic disease or proliferative disorder in humans based on theramutein modulators - Google Patents

Abstract

PHARMACEUTICAL COMPOSITIONS AND TREATMENT OF A NEOPLASTIC DISEASE OR A RPOLIFERATIVE DISORDER IN HUMANS BASED ON THERAMUTEIN MODULATORS. This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and new methods of identifying those variants. Of particular interest are inhibitors and activators of endogenous protein variants, encoded by mutated genes, whose variants always appear or are at least identified as arising after exposure to a chemical agent that is known as an inhibitor or activator of the protein endogenous without corresponding mutation.

Description

FAEMACEUTIC COMPOSITIONS, TREATMENT OF A NEOPLASTIC DISEASE OR A RPOLIFERITIVE DXSXUBE IN HUMANS BASED ON HUMAN HUMAN MODUATORS

This application is a partial continuation of International Application PCT / US2005 / 18412, filed May 23, 2005, and claims US patent no. 60/712/742, filed August 29, 2005, US Patent No. 60 / 739,477, filed November 23, 2005, US Patent No. 60 / 715,517, filed September 9, 2005, U.S. Patent No. 60 / 739,476, filed on November 23, 2005, U.S. Patent No. 60 / 741,767, filed on December 2, 2005, U.S. Patent No. 60 / 751,030, filed on December 16 2005, U.S. Patent No. 60 / 783,106, filed March 13, 2006, U.S. Patent No. 60 / 785,904, filed March 23, 2006, U.S. Patent No. 60 / 785,817, filed March 23, 2006, U.S. Pat. 60 / 785,817, filed March 32, 2006 and U.S. Pat. 60 / 789,379, filed April 4, 2006.

Background of the invention

The progressive development of drug resistance in a patient is the hallmark of chronic treatment with many classes of drugs, especially in the therapeutic areas of cancer and infectious diseases. Molecular mechanisms have been identified that mediate certain types of drug resistance phenomena considering that in other cases the acquired as well as initial resistance mechanisms remain unknown today.

One mechanism of induced (acquired) drug resistance originally considered relevant in the area of cancer therapy involves increased expression of a protein known as P-glycoprotein (P-gp). P-gp is located on the cell membrane and acts as a drug efflux pump. The protein is able to pump toxic chemical agents, including many classic anticancer drugs, out of the cell. Consequently, up-regulation of P-glycoprotein usually results in resistance to various drugs. Up-regulation of P-glycoprotein in tumor cells may represent a defense mechanism that has evolved in mammalian cells to prevent damage from toxic chemicals. Other related drug resistance proteins have now been identified with P-gp-like functions, including members of the drug resistance-associated protein family, such as MRP1 and ABCG2. In any case, with the advent of the development of compounds that are specific for a particular target protein, e.g. less toxic, the importance of P-glycoprotein and related ATP-binding cassette proteins in clinically significant drug resistance has decreased.

Another possible molecular mechanism of acquired drug resistance is that alternative signal pathways are responsible for the continued survival and metabolism of cells, even though the original drug is still effective against its target. In addition, changes in the intracellular metabolism of the drug may lead to loss of therapeutic efficacy as well. In addition, changes in gene expression as well as gene amplification events may occur, resulting in increased or decreased expression of a given target protein and often requiring high dosages of the drug to maintain the same effects. (Adcock and Lane, 2003)

Mutation-induced drug resistance is a frequently occurring event in the area of infectious disease. For example, various drugs have been developed that inhibit reverse viral transcriptase or viral protease encoded in the HIV viral genome (human immune deficiency). It is well established in the literature that repeated treatment of HIV-infected AIDS patients using, for example, a reverse transcriptase inhibitor ultimately provides an increase in mutant forms of the virus that have reduced drug sensitivity. Increased mutations in the gene that encodes reverse transcriptase show the mutant form of the enzyme less affected by the drug.

The appearance of drug resistance during the course of HIV treatment is not surprising considering the rate at which errors are introduced into the HIV genome. The HIV reverse transcriptase enzyme is known to be particularly error prone, with an advanced mutation rate of about 3.4 χ 10-5 base pair mutations per replication cycle (Mansky et al., J. Virol 69: 5087-94 (1995)). However, analogous mutation rates for endogenous genes encoded in mammalian cells are more than an order of magnitude lower.

New evidence shows that drug resistance may also arise from a mutational event involving the gene that encodes the drug target (Gorre et al., Science, 2001; PCT / US02 / 18729). In this case, exposure of the patient to a specific therapeutic substance such as a particular cancer drug that targets a protein of interest (POI or target protein) may be followed by the result of a host cell group of a mutation occurring in the gene that encodes the protein that is the target of the therapeutic substance. The fact . whether the result of this cell population results from a small percentage of pre-existing cells in the patient already hosting a mutation that provides growth to the drug-resistant POI, or these mutations reappear during or after exposure of the animal or human to a The therapeutic agent capable of activating or inhibiting the mentioned POI is currently unknown. In either case, the events of this mutation may result in an altered protein (defined below with theramutein) that is less affected, or perhaps completely unaffected, by the aforementioned therapeutic substance.

Chronic myelogenous leukemia (CML) is characterized by excessive proliferation of myeloid progenitors that retain the ability to differentiate during the stable or chronic phase of the disease. Several lines of evidence have established Abl tyrosine kinase dysregulation as the causative oncogene in certain forms of CML. Dysregulation is usually associated with a chromosome translocation known as the Philadelphia (Ph) chromosome, which results in the expression of a fusion protein consisting of the Abelson tyrosine kinase fused BCR gene product, forming P210B "" Abl which has the activity tyrosine kinase. A related fusion protein, called p190Bcr-AbI, which arises from a different major point in the BCR gene, occurs in patients with Philadelphia Chromosome positive (Ph +) Acute Lymphoblastic Leukemia (ALL) (Melo, 1994; Ravandi et al., 1999). The transformation appears to result from the activation of various signal paths, including those involving RAS, MYC, and TUN. Imatinib mesylate ("STI-571" or "Gleevec®") is a 2-phenylamino pyrimidine intended for the Abl kinase domain ATP binding site (Druker et al, NEJM 2001, p. 1038). Subsequently, it has also been found by other methods to be a platelet-derived growth factor (PDGF) receptor inhibitor, and the Tyrosine kinase Kit, the latter being involved in the development of gastrointestinal stromal tumors (see below).

Until recently, it has not been observed that during the course of treatment with a specific inhibitor of a particular endogenous cellular protein that a mutation in its corresponding endogenous gene could lead to the expression of protein variants whose cell function is resistant to the inhibitor. The work of Charles Sawyers and his colleagues (Gorre et al., Science 293: 876-80 (2001); PCT / US02 / 1872 9) demonstrated for the first time that treatment of a patient with a drug capable of inhibiting tyrosine P210Bcr "Abl kinase (i.e., STI-571) could be followed by the emergence of a clinically significant population of patient cells harboring a mutation in the p210Bcr ~ Abl cancer-targeting protein coding gene that contains the tyrosine domain Several of these mutations elevated the mutant forms of p210Bcr_Abl that were less responsive to the treatment of gleevec, which was the original cancer-causing version.Notably, the mutations that emerged gave the mutant protein a relative resistance to the effects of the drug. protein kinase, while maintaining a certain degree of original substrate specificity of the mutant protein kinase. Prior to the work of Gorre et al., those skilled in the art believed The types of resistance that would be observed in patients exposed to a compound that inhibited Abelson protein kinase, such as STI-571, would have resulted from one or more of the drug resistance mechanisms listed above or some other unknown mechanism. that in any case resistance would involve a target (protein or otherwise) that was distinct from the drug's target POI.

Consequently, the ability to treat clinically resistant relevant mutant protein forms that are different from the targets of an existing therapy would be extremely useful. These changed proteins (theramuteins as defined below) are beginning to be recognized and understood as important targets in recurrent cancers, and will become important in other diseases as well. There is a need for therapeutic agents that are active in relation to these forms of drug resistant variant cell proteins which may therefore arise during or after normally effective drug therapies. An important object of this invention is to provide compounds that may serve as potential therapeutic agents useful in overcoming drug resistance induced by mutation in endogenously occurring proteins.

Brief Summary of the Invention

This invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins. Of particular interest are inhibitors and activators of endogenous protein variants encoded by mutated genes, the variants of which always arise or are at least identified as arising upon exposure to a chemical agent that is known as a protein inhibitor or activator. endogenous protein without corresponding mutation. These types of protein variants (mutant proteins) are referred to herein as "theramuteins" and may occur spontaneously in an organism (and may be pre-existing mutations in some cases), or the mutants cited may arise as a result of the selective pressure that results when the organism is treated with a certain chemical agent capable of inhibiting the mutated form of theramutein cited (hereinafter referred to as "prototheramutein"). It will be understood that in some cases prototheramutein may be a "wild type" form of a POI (eg, a protein arising at an illness owing to dysregulation). In other cases, prototheramutein will be a disease-causing variant of a "wild-type" protein, having already changed and thus contributing to the development of the diseased state as a result of the above mutation. An example of the latter type of prot otheramutein is oncorprotein P210BCR "ABL, and a mutant form of this protein that hosts a threonine (T) mutation to isoleucine (I) at position 315 is called p210BCR_ABL_ T3151 and is an example of theramutein. As used herein, the designation "P210 BCR" ABL "is synonymous with the term" p210Bcr_Abl ", the" wild-type Bcr-Abl protein "and the like.

Theramuteins are a rare class of endogenous proteins that host mutations that reproduce said drug resistant proteins that are known to effectively inhibit or therapeutically activate their mutant counterparts. Endogenous genes encoding certain proteins of this type are currently known to exhibit such mutations under certain circumstances. This invention is directed to compositions which. inhibit certain drug resistant mutants (theramuteins) of Abelson protein tyrosine kinase, originally called P210-Bct-Abl in the literature, which is involved in the development of chronic myelogenous leukemia.

The present invention is particularly directed to the identification of specific inhibitors or specific activators of theramuteins. Ò use of the term "specific" in the context of the terms "inhibitor" or "activator" (see definitions below) means that the aforementioned inhibitor or activator binds to theramutein and inhibits or activates theramutein's cellular functioning without also binding it. whether and activating or inhibiting a wide variety of other proteins or non-target proteins in the cell. The experienced examiner will also be aware that there is a certain degree of variability in the medical literature regarding the concept of a specific inhibitor or specific activator and the related concept of target protein "specificity" when discussing the actions of inhibitors or activators. Accordingly, for purposes of this invention, a substance will be a specific inhibitor or specific activator of a given theramutein if the cited substance is capable of inhibiting or activating the cited theramutein at a given concentration, such that a corresponding response is appropriately modulated without having an appreciable effect at the same concentration provided in the hay-response (if any) of a corresponding control cell that does not essentially express theramutein or its corresponding prototheramutein.

In certain representations, a substance can be a prototheramutein and also theramutein modulator. In other embodiments, in addition to being a modulator of prototheramutein and theramutein, a substance can also modulate the activities of proteins that have similar functions. As described above, in addition to inhibiting p210Bcr Abl tyrosine kinase, imatinib mesylate is also capable of inhibiting the c-kit innogenous product (also a tyrosine kinase) which is overexpressed in certain gastrointestinal stromal tumors as well as the β receptor. PDGF (also a tyrosine kinase), which is expressed in certain chronic myelomonocytic leukemias (CMML). This compound is sometimes referred to as a "moderately specific" inhibitor.

The invention also provides a general method that can be used to identify substances that will activate or inhibit a theramutein at the same intensity, and preferably at an even higher intensity than a known drug substance is capable of inhibiting the "wild type" form. corresponding to that protein. (The expert is also aware that the "wild-type" forms of these proteins may already have changed in the course of the onset of the corresponding disease in which the protein participates.)

In a preferred embodiment, the present invention provides theramuthein p210BCR-ABL-T3151 inhibitors having formula I

<formula> formula see original document page 10 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O ) N (R 12) R 13), - (CH 2) p C (O) O (CH 2) q R 11, - (CH 2) p N (R 11) (CH 2) q C (O) R 11, "(CH 2) p N (R 12) (R 13) , - (CH 2) p N (Rix) (CH 2) q + R 11, -N (R 11) SO 2 R 11, -OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and additionally or alternatively, two R 1 groups on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocyclic ring; or R12 and R13 can be used together

one with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain an additional heteroatom; wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo aryl and a heterocyclic ring;

P is 0 to 4;

q is 0 to 4;

R2 is selected from -CR21a-, -NR22b- and - (C = R23) -; each R21 is independently selected from H, halo, -NH2, -N (H) (C1-3 alkyl), -NIC1-, alkyl) 2, -O- (C1-3 alkyl), OH and C1-3 alkyl;

each R 22 is independently selected from H and CX-3 alkyl; R23 is selected from 0, S, N-R0 and N-OR0;

-, 3

R3 is selected from -CR31 and-, -NR32 d-, -SO2- and - (C = R33) -; each group of R 31 is selected from H, halo, -NH 2, -N (H) (R c), -N (R 0) 2, -O-R 0, OH and C 1-3 alkyl;

each group R 32 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, aryl and a heterocyclic ring;

R33 is selected from O, S., N-R34 and N-OR0;

R34 is selected from H, NO2, CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

R4 is selected from -CR41-, -NR42r, - (C = R43) -, -SO2- and -O-; each R41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO2 R0, C (O) R0, aralkyl, aryl and a heterocyclic ring;

each group R42 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0, C (O) R0, aryl and a heterocyclic ring;

each R43 is selected from 0, S, N-R0 and N-OR0; provided that when R2 is -NR22 b- and R4 is -NR42 / -, R3 will not be - NR32 d-; that R3 and R4 are not simultaneously selected from - (C = R33) - and - (C = R43) - respectively; and that R3 and R4 are not simultaneously selected from -SO2-;

R5 is selected from -Y-R6 and -Z-R7;

Y is selected from a chemical bond, O, NR0, R6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and a heterocyclic ring;

Z is a hydrocarbon chain of 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, C (O) N (R 0) 2 CN, CF3, N (R0) 2, NO2 and OR0; R is H or is selected from aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;

a is 1 or 2;

b is 0 or 1;

c is 1 or 2;

d is 0 or 1;

e is 1 or 2; and

f is 0 or 1.

The invention provides a fundamentally novel way of treating cancer and other diseases wherein treatment with an existing drug compound by any mechanism is followed by identifiable (clinically significant) theramutein-mediated drug resistance by providing alternative drugs that may be administered when theramuteins arise and are identified as such (Wakai et al., 2004, report an example where a theramutein may arise during the course of an ongoing treatment regimen) or early before the result of clinically significant cell populations that express theramutein. In addition, where drug treatment for a particular disease is less effective in a subset of individuals expressing a particular theramutein of a drug-targeted protein, the invention allows for the customization of treatments for such cases by providing alternative drug substances which will be effective against the cited theramutein.

The invention provides a method for determining whether a chemical agent is at least as effective as a modulator of a theramutein in a cell as a known substance is a modulator of a corresponding prototheramutein. One representation of the method involves contacting a control cell that expresses prototheramutein and is capable of exhibiting a responsive phenotypic characteristic (linked to the functioning of prototheramutein in the cell). with the known prototheramutein modulator in contact with a test cell that expresses theramutein and is also capable of exhibiting the phenotypic responsive characteristic (linked to theramutein's function in the cell) with the chemical agent and comparing the response of the test cell treated with the response of the treated control cell; To determine that the chemical is at least as effective as a theramutein modulator as the known substance is a prototheramutein modulator. In other given representations, a control cell type may not actually express prototheramutein. In other embodiments, the control cell may express approximately the same amount of prototheramutein as the expressed test cell of theramutein. In still other embodiments, the control cell may be capable of responsive phenotypic characteristic to approximately the same intensity as the test cell under certain conditions.

The theramuteins of the invention which are of specific interest are those involved in regulatory function, such as enzymes, protein kinase, tyrosine kinase, receptor tyrosine kinase, serine threonine kinase protein, dual specificity protein kinase, proteases, matrix metalloproteinases, phosphatases, cell cycle control, docking proteins such as IRS family members, cell surface receptors, G proteins, ion channels, DNA and RNA binding proteins, polymerases and the like. No limitations should be considered on the type of theramutein that may be used in the invention. At present, three theramuteins are known: BCR-ABL, c-Kit and EGFR.

Any responsive phenotypic characteristics that may be linked to the presence of theramutein (or prototheramutein) in the cell may be employed for use in the method, including, for example, growth or culture properties, the phosphorylation (or other modification) state of a substrate of the cell. theramutein and any type of cell transient characteristic, as will be defined and described in detail.

Description of the figures

Figure 1 shows the effect on growth and viability of different concentrations of Compound 2 (C2) for untransformed vector control Ba / F3 cells (which depend on IL-3) as well as Ba / F3 cells expressing " wild type "p210Bcr" Abl (called p210Bcr-Abl-wt cells) and Ba / F3 cells expressing the drug resistant mutant p2ioBcr-Abl-T3151. Cell counts and viability were determined in an automated cell counter as described. cell counts are shown by solid colored bars, cell viability is shown by dotted bars Note that STI-571 potentially inhibits the growth of cell line P210 (gray bar) as it is impossible to inhibit growth cell line T315I (white bar) even at 10 μΜ concentration C2 500 nM shows the highest specificity range in this dose response series Compare STI-571 at 10 μΜ with C2 at 500 nM in the T315I cell line (white bars). Abbreviations:

DMSO: dimethyl sulfoxide (solvent used for drug dissolution).

Figure 2 shows the effect on growth and viability of different concentrations of Compound 6 (C6) for untransformed vector control Ba / F3 cells as well as Ba / F3 cells expressing the drug resistant mutant P210Bcr-Abl-T3151. All other details are in accordance with figure 1.

Figure 2 shows the various determinations of the specificity range by comparing the effects of various compounds identified on screen, considering their effects on prototheramutein and theramutein expressing cell lines. Compound 3 (C3) shows the best example of the method's ability to identify a compound that has an even greater effect on theramutein than its corresponding prototheramutein. (Panel E). Panel A: control DMSO treatments: B: heterologous specificity range; C: slightly positive heterologous specificity range; D: very positive homologous specificity range; E: positive heterologous specificity range. See the text for explanations.

Figure 4 shows a wild-type autoradiography of recombinant P210 Bcr-Abl and T31r1 mutant kinase domains analyzed by autophosphorylation activity. 200 ng of protein was preincubated with test substances for 10 minutes under autophosphorylation reaction conditions and then radio-labeled ATP was added, and reactions continued for 30 minutes at 30 ° C, after which samples were separated. by SDS-PAGE. The gels were silver stained, vacuum dried and exposed to X-ray film. Note that as long as 10 μ STI 571 is effective against wild type P210 Bcr-Abl, it is virtually ineffective against T315I kinase domain, even at concentrations up to 100 μΜ. C2 and C6 are the best identified compounds, followed by C5, C7 and C4.

All compounds were tested positively to some degree. "P210 cell line" refers to cells expressing p210 bcr-abl-wt. "T3151 line" refers to cells expressing p210 bcr "abl-T315I

Figure 5 shows the chemical structures of representative compounds of the present invention.

Figure 6 shows the chemical structures of representative compounds of the present invention.

Figure 7 shows the chemical structures of representative compounds of the present invention.

Figure 8 shows the chemical structures of representative compounds of the present invention.

Figure 9 shows the chemical structures of representative compounds of the present invention.

Figure 10 shows the chemical structures of representative compounds of the present invention.

Figure 11 shows the chemical structures of representative compounds of the present invention.

Figure 12 shows the chemical structures of representative compounds of the present invention.

Figure 13 shows the chemical structures of representative compounds of the present invention.

Detailed Description of the Invention

The term "halo" or "halogen" as used herein includes fluorine, chlorine, bromine and iodine.

The term "alkyl" as used herein refers to substituted and unsubstituted straight chain and branched alkyl radicals having from 1 to 6 carbon atoms. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. In addition, the alkyl group may be optionally substituted by one or more substituents selected from halo, CN, CO2R, C (O) R, C (O) NR2, NR2, cyclic amino, NO2 and OR.

The term "cycloalkyl" as used herein refers to unsubstituted / substituted cyclic alkyl radicals. Preferred cycloalkyl groups are those with a single ring containing from 3 to 7 carbon atoms and include cyclopropyl, cyclopentyl, cyclohexyl and the like. Other cycloalkyl groups may be selected from C7 to C10 bicyclic systems or from C9 to C14 tricyclic systems. In addition, the cycloalkyl group may be optionally substituted by one or more substituents selected from halo, CN, CO2R, C (O) R, C (O) NR2, NR2, cyclic amino, NO2 and OR.

The term "alkenyl" as used herein refers to substituted and unsubstituted straight chain and branched alkene radicals. Preferred alkenyl groups are those containing from two to six carbon atoms. In addition, the alkenyl group may be optionally substituted by one or more substituents selected from halo, CN, CO2R, C (O) R, C (O) NR2, NR2, cyclic amino, NO2 and OR.

The term "alkynyl" as used herein refers to substituted and unsubstituted straight and branched chain alkyne radicals. Preferred alkynyl groups are those containing from two to six carbon atoms. In addition, the alkynyl group may be optionally substituted by one or more substituents selected from halo, CN, CO2R, C (O) R, C (O) NR2, NR2, cyclic amino, NO2 and OR.

The term "aralkyl" as used herein refers to an alkyl group having as an substituent an aromatic group, the group of which may be substituted and unsubstituted. The aralkyl group may be optionally substituted on aryl by one or more substituents selected from halo, CN, CF3, NR2, cyclic amino, NO2, OR, CF3, - (CH2) x R, - (CH2) x C (O) ( CH2) yR, - (CH2) xC (O) N (R ') (R' '), - (CH2) x C (O) O (CH2) yR, - (CH2) xN (R') (R " ), -N (R) SO 2 R, -0 (CH 2) x C (O) N (R ') (R "), - SO 2 N (R') (R"), - (CH 2) x N (R) - (CH 2 ) y -R - (CH 2) X N (R) -C (O) - (CH 2) y R, - (CH 2) x N (R) -C (O) -O- (CH 2) y -R, - (CH 2 ) XC (O) -N (R) - (CH 2) y R, - (CH 2) XC (O) N (R) - (CH 2) y R, -O- (CH 2) XC (O) -N (R) - (CH2) yR, substituted and unsubstituted alkyl cycloalkyl, aralkyl, alkenyl, alkynyl, aryl and a substituted heterocyclic ring, wherein the substituted heterocyclic alkyl, cycloalkyl, aralkyl, alkenyl, aryl ring may be substituted by a or more between halo, CN, CF 3, CO 2 R, C (O) R, C (O) NR 2, NR 2, cyclic amino, NO 2, and OR.

The term "heterocyclic group" or "heterocyclic ring" as used herein refers to aromatic and non-aromatic cyclic radicals having at least one heteroatom as a member of the ring. Preferred heterocyclic groups are those containing 5 or 6 ring atoms that include at least one heteroatom and include cyclic araines such as morpholine, piperidine, pyrrolidine and the like and cyclic ethers such as tetrahydrofuran, tetrahydropyran and the like. Aromatic heterocyclic groups, also called "heteroaryl" groups, include single ring heteroaromatic groups which may include one to three heteroatoms, for example, pyrrole, furan, thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine and the like. The term heteroaryl also includes polycyclic heteroaromatic systems having two or more rings in which two atoms are common to two adjacent rings (the rings are "fused") wherein at least one ring is a heteroaryl, for example, the other rings may be cycloalkyls, cycloalkenes, aryl, heterocycles and / or heteroaryls. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran. purine, imidazopyridine, benzotriazole and the like. In addition, heterocyclic groups may optionally be substituted by halo, CN, CF3, NR2, cyclic amino, NO2, OR, CF3, - (CH2) x C (O) (CH2) y R, - (CH2) XC (0) N (R ') (R "), - (CH 2) x C (O) O (CH 2) y R, - (CH 2) X N (R') (R"), -N (R) SO 2 R, -0 (CH 2) X C (0) N (R ') (R "), -SO 2 N (R-) (R"), - (CH 2) x N (R) - (CH 2) y R, - (CH 2) x N (R) -C (O ) - (CH2) yR, (CH2) x N (R) -C (O) -O- (CH2) yR, - (CH2) xC (O) -N (R) - (CH2) yR- (CH2) xC (O) N (R) - (CH 2) y R,

-O- (CH2) xC (O) -N (R) - (CH2) yR, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic ring, wherein the substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted alkenyl, substituted aryl and substituted heterocyclic ring may be substituted by a or more between halo, CN, CF3, CO2R, C (O) R, C (O) NR2, NR2, cyclicamino, NO2 and OR.

The term "cyclic amino" as used herein refers to aromatic and non-aromatic cyclic radicals that have at least one nitrogen as a ring member. Preferred cyclic amino groups are those containing 5 or 6 ring atoms, which includes at least one nitrogen and includes morpholine, piperidine, pyrrolidine, piperazine, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine pyridazine. pyrimidine. and the like. In addition the cyclic amino may be optionally substituted by halo, GN, CF3, NR2, NO2, 0R, CF3, substituted and unsubstituted alkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted alkynyl and unsubstituted, substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic ring, wherein the substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted alkenyl, substituted aryl and substituted heterocyclic ring may be substituted by one or more of halo, CN, CF3, CO2R, C (O) R, C (O) NR2, NR2, NO2 and OR.

The term "aryl" or "aromatic group" as used herein refers to single ring aromatic groups (e.g., phenyl, pyridyl, pyrazole, etc.) and polycyclic ring systems (Cnaphthyl, quinoline, etc.). Polycyclic rings may have two or more rings in which two atoms are common to two adjacent rings (rings are "fused") wherein at least one ring is aromatic, for example, the other rings may be cycloalkyls, cycloalkenes, aryl heterocycles and / or heteroaryls. In addition, aryl groups may be optionally substituted by: one or more substituents selected from halo, CN, CF3, cyclic amino NR2, NO2, OR, CF3, - (CH2) x C (O) (CH2) yR, (CH2) XC (O) N (R1) (R "), - (CH2) xC (O) O (CH2) y R, - (CH2) xN (R1) (Rn), -N (R) SO2R , -O (CH 2) x C (0) N (R ') (R "), SO 2 NiR') (R"), - (CH 2) x N (R) - (CH 2) y R, - (CH 2) x N ( R) -C (O) - (CH 2) y R, "(CH 2) X N (R) -C (O) -O- (CH 2) y R, - (CH 2) X C (O) -N (R) - (CH 2 ) yR, CH2) XC (O) N (R) - (CH2) yR, -O- (CH2) XC (O) -N (R) - (CH2) y -R, substituted and unsubstituted alkyl, substituted cycloalkyl and unsubstituted, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic ring, wherein substituted alkyl / substituted cycloalkyl, substituted aralkyl, substituted alkenyl, substituted alkynyl, substituted o-aryl and heterocyclic ring are Substituted may be substituted by one or more of halo, CN, CF3, CO2R, C (O) R, C (O) NR2, NR2, cyclic-amino, NO2 and OR.

The term "heteroatom", particularly as a ring heteroatom, refers to N, 0 and S.

Each R is independently selected from H, unsubstituted alkyl, substituted, unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aryl and a substituted unsubstituted heterocyclic ring, wherein the substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl and substituted heterocyclic ring may be substituted by one or more halo, CN, CF3, 0H, CO2H, NO2, C1-Salkyl, -O- (C1-6 alkyl), - NH 2, -NH (C 1-6 alkyl) and -N (C 1-6 alkyl) 2 · Each R 'and R "are independently selected from H or substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl substituted and unsubstituted aryl and a substituted and unsubstituted heterocyclic ring wherein the substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl and substituted heterocyclic ring may be substituted by one or more halo, CN, CF3, OH, CO2H, NO2, C1-6 alkyl, -O- (C1-6 alkyl), -NH2, -NH (C1-6 alkyl) and -N (C1-6 alkyl) 2; or R 'and R "may be used together with the nitrogen to which they are attached to form a 5 to 7 membered ring which may optionally contain up to three additional heteroatoms, whose heteroatoms may be substituted with C1-6 alkyl. Each χ and each y are independently selected from 0 to 4.

In a preferred embodiment, the present invention provides theramutein p210BCR-ABL-T3151 inhibitors having formula I

<formula> formula see original document page 22 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, - (CH 2) p C (O) (CH 2) q R 11 - (CH 2) p C (O) N (R 12) (R 13), - (CH 2) PC (0) 0 (CH 2) q R 11, - (CH 2) p N (R 11) (CH 2) q C (O) R 11, (CH 2) p N (R 13) (R 13), -N (R 11) SO 2 R 11, - OC (O) N (R 12) (R 13), - SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and additionally or alternatively, two R 1 groups on adjacent ring atoms form a fused 5 or 6 membered ring which contains from 0 to 3 heteroatoms; η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom; wherein the 5- to 7-membered ring may optionally be substituted by one to three substituents which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2 OR0, CO2 R0, C (O) R0, halo, aryl and a heterocyclic ring;

P is 0 to 4;

q is 0 to 4;

R2 is selected from -CR21a-, -NR22b- and - (C = R23) -; each R21 is independently selected from H, halo, -NH2, -N (H) (C1-3 alkyl), -N (C1-3 alkyl) 2, -O- (C1-3 alkyl), OH and C1. 3 alkyl;

each R22 is independently selected from He C1-3 alkyl; R23 is selected from O, S, N-R0 and N-OR0; R3 is selected from -CR31c-, -NR32d-, -SO2- and - (C = R33) -; each group of R 31 is selected from H, halo, -NH 2, -N (H) (R 0), -N (R 0) 2, -O-R 0, OH and C 1-3 alkyl;

each group R 32 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, aryl and a heterocyclic ring;

R33 is selected from O, S, N-R34 and N-OR0;

R34 is selected from H, NO2, CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; R4 is selected from -CR41 and -, -NR42f, - (C = R43) -, -SO2- and -O-; each R41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO2 R0, C (O) R0, aralkyl, aryl and a heterocyclic ring;

each group R42 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0, C (O) R0, aryl and a heterocyclic ring;

each R43 is selected from 0, S, N-R0 and N-OR0; provided that when R2 is -NR22b- and R4 is -NR42f-, R3 will not be - NR32 d - that R3 and R4 are not simultaneously selected from - (C = R33) - and - (C = R43) -, respectively; and that R3 and R4 are not simultaneously selected from -SO2-;

R5 is selected from -Y-R6 and -Z-R7; Y is selected from a chemical bond, 0, NR0,

R6 is selected from alkyl,. cycloalkyl, alkenyl, alkynyl, aryl and a heterocyclic ring;

Z is a hydrocarbon chain of 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl-, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, C (O) N (R 0) 2, CN, CF3, N (R0) 2, NO2 and OR0 / R7 is H or is selected from aryl and a heterocyclic ring; each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; a is 1 or 2; b is 0 or 1; c is 1 or 2; d is O or 1; e is 1 or 2; and f is 0 or 1.

An important component and conceptual explanation of the invention described herein is that neither the R 2 nor R 3 positions of the compounds of this invention are members of any aromatic or non-aromatic ring structure. We have found that compounds having positions R2 and / or R3 as members of any aromatic or nonaromatic ring structure do not effectively inhibit theramutein T315I, whereas compounds of the invention which require such a ring component at these positions, in addition to having other preferred chemical groups, are potent inhibitors of theramutein T315I.

In preferred embodiments of the invention, ring A is an aromatic ring.

In preferred embodiments of the invention, X1 or X2 is N. In another preferred embodiment, X1 and X2 are N. In particularly preferred embodiments of the invention, Ring A is a biridine ring or a pyrimidine ring. Still in preferred representations, Ring A is selected from the following structures: <formula> formula see original document page 25 </formula>

In preferred embodiments of the invention, R 5 is a moiety. the formula

<formula> formula see original document page 25 </formula>

on what:

X 3 is N or CH;

R61 is selected from aryl and a heterocyclic ring; Q is selected from a chemical bond or a group having the formula -a-, "(CH 2) i -, - (CH 2) i C (O) (CH 2); j -, - (CH 2) i -N (R62) - (CH2) - - (CH2) iC (O) -N (R62) - (CH2) 3, - (CH2) i (C) O (CH2) r, "(CH2) iN ( R62) C (O) - (CH2) j -, - (CH2) iOC (O) N (R62) - (CH2) f- and -0- (CH2) iC (O) N (R62) - (CH2) j;

R62 is selected from H, alkyl, aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; h is 0 to 4;

i is 0 to 4; and

j is 0 to 4;

In further preferred embodiments of the invention, R 5 is a group having the formula

<formula> formula see original document page 25 </formula>

on what:

X 3 is N or CH;

Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O ) -, -OC (O) NH-, and -OC (O) NH-; each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3,

each R71 is selected from H, alkyl, aryl, aralkyl and a heterocyclic ring; and k is 0 to 4.

In further preferred embodiments of the invention, R 5 is a group having the formula

<formula> formula see original document page 26 </formula>

on what

X 3 is N or CH;

Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O ) -, -OC (O) NH- and -OC (O) NH-; R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3; and each R71 is selected from H, alkyl, aryl, aralkyl and a heterocyclic ring.

In particularly preferred embodiments, one or more of the following selections are made: Q1 is α-NH-; X 3 is -N; each R71 is independently selected from H, methyl and ethyl and preferably each R71 is methyl; and / or R70 is selected from OH, OCH3, halo and CF3.

In a preferred embodiment, if R2 or R4 is selected to be -NR22b- or -NR42-, respectively, R31 will not be selected from halo, -NH2, -N (H) (R0), -N (R0) 2, -0- R0 or 0H.

In an additional preferred embodiment,. the present invention provides theramutein p210BCR "ABL-T315I inhibitors having the formula Ia <formula> formula see original document page 27 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O ) N (R 12) (R 13), "(CH 2) p C (O) O (CH 2) q R 11, (CH 2) p N (R 11) (CH 2) q C (O) R 11, - (CH 2) p N (R 12) (R 13) , -N (Rn) SO 2 R 11, OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on ring atoms adjoining form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms; η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom; wherein the 5- to 7-membered ring may optionally be substituted by one to three substituents which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR0, CO2 R0, C (O) R0, halo aryl and a heterocyclic ring;

P is 0 to 4;

q is 0 to 4;

each R 22 is independently selected from H and C 1-3 alkyl; R3 is selected from -CR31c-, -NR32d-, -SO2- and - (C = R33) -; each group of R31 is selected from H, halo. -NH 2, -N (H) (R 0), -N (R 0) 2, -O-R 0, OH and C 1-3 alkyl;

each group R 32 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, aryl and a heterocyclic ring;

R33 is selected from O, S, N-R34 and N-OR0; R34 is selected from H, NO2, CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; R4 is selected from -CR41-, -NR42f, - (C = R43) -, -SO2- and -O-; each R41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO2 R0, C (O) R0, aralkyl, aryl and a heterocyclic ring;

each group R42 is: selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0, C (O) R0, aryl and a heterocyclic ring;

each R43 is selected from 0, S, N-R0 and N-OR0; provided that when R4 is -NR42f-, R3 will not be -NR32d-; and that R3 and R4 are not simultaneously selected from - (C = R33) - and - (C = R43) -, respectively; and that R3 and R4 are not simultaneously selected and -SO2-;

R5 is selected from -Y-R6 and -Z-R7;

Y is selected from a chemical bond, O, N-R0,

R6 is selected from alkyl, cycloalkyl, alkenyl,

alkynyl, aryl and a heterocyclic ring;

Z is a hydrocarbon chain of 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, C (O) N (R 0) 2 CN, CF3, N (R0) 2, NO2 and OR0;

R 7 is H or is selected from aryl and a heterocyclic ring; each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; a is 1 or 2;

b is O or 1; c is 1 or 2; d is O or 1; e is 1 or 2; and f is 0 or 1.

In a further preferred embodiment, the present invention provides theramutein P210BCR "inhibitors having the formula Ib

<formula> formula see original document page 29 </formula>

on what:

ring Δ is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring; X1 is selected from N, N-R0 or C-R1; X is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O ) N (R 12) (R 13), - (CH 2) p C (O) O (CH 2) q R 11,

(CH 2) p N (R 11) (CH 2) q C (O) R 11, - (CH 2) PN (R 12) (R 13), -N (R 11) SO 2 R 11, -OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms; η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom; wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo aryl and a heterocyclic ring;

P is 0 to 4;

q is 0 to 4;

each R 22 is independently selected from H and Ch alkyl; each group R 32 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, aryl and a heterocyclic ring;

R4 is selected from -CR41-, - (C = R43) -, -SO2-, and -O-;

each R41 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO2 R0, C (O) R0, aralkyl, aryl and a heterocyclic ring;

each R43 is selected from 0, S, N-R0 and N-OR0;

R5 is selected from -Y-R6 and -Z-R7;

Y is selected from a chemical bond, O, N-R 0, R 6 is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aryl and a heterocyclic ring;

Z is a hydrocarbon chain of 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, C (O) N (R 0) 2 CN, CF3, N (R0) 2, NO2 and OR0;

R 7 is H or is selected from aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; a is 1 or 2;

b is 0 or 1;

c is 1 or 2;

d is 0 or 1;

e is 1 or 2; and

f is 0 or 1.

In an additional preferred representation, the

The present invention provides theramutein p210BCR "ABL-T315I inhibitors having the formula Ic

<formula> formula see original document page 31 </formula>

or 7 members or a ring

on what

ring A is a ring of 5,

fused bicyclic from 7 to 12 members;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl,

aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) q R11, (CH2) pC (O) N (R12) (R> 13. - (CH2) pC (O) O (CH2 ) qR11, (CH2) pN (Rn) (CH2) gC (O) R11, - (CH2) PN (R12) (R13) -N (R11) SO2R11, OC (0) N (R12) (R13-SO2N ( R12) (R13),

halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

ρ is 0 to 4;

q is 0 to 4;

X 3 is N, CH or C-R 2;

each R2 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR21, - (CH2) rC (O) (CH2) sR21, - (CH2) rC (O) N (R 22) (R 23) r - (CH 2) t C (O) O (CH 2) s R 21, -

(CH 2) r N (R 21) C (O) R 21, - (CH 2) r N (R 22) (R 23) 7 -N (R 21) SO 2 R 21, OC (O) N (R 22) (R 23), -SO 2 N (R 22) ( R 2a), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 2 on adjacent ring atoms form a fused 5- or 6-membered ring containing from 0 to 3 heteroatoms;

each R21 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R 22 and R 23 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R22 and R23 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring; r is 0 to 4;

s is 0 to 4;

m is 0 to 4;

each R 4 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO 2 R 0, C (O) R 0, aryl and a heterocyclic ring;

a is 0 or 1;

X4 is selected from

<formula> formula see original document page 33 </formula>

each R 3 is independently selected from the group consisting of H, -N (R 0) 2, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0, C (O) R 0, aralkyl, aryl and a heterocyclic ring,

R 3 is selected from H, -N (R 0) 2, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring, and each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

In preferred embodiments of the invention, R 2, R 3 and R 4 of formula I are selected to produce the following chemical groups:

-N (R22) -N = C (R41) -

-N (R22) -N (R32) -C (= 0) -

-N (R22) -N (R32) -C (R41) (R41) -

-N (R22) -C (R3x) (R31) -C (R41) (R41) -

-N (R22) -C (R31) (R31) -C (= 0) -

-N = N-C (R41) (R41) ~

-C (R21) = C = C (R41) -

-C (R21) = C (R31) -C (= 0) -

-C (R21) = C (R31) -C (R41) (R41) -

-C (R21) (R21) -C (R31) -C (R41) -

-C (R21) (R21) -C (R31) (R31) -C (O) -

-C (R21) (R21) -C (R3x) (R31) -C (R41) (R41) -C (R21) (R21) -N (R32) -C1 = O) -C (R21) ( R21) -N (R32) -C (R41) (R41) -N - (R22) -C (= O) -C (R41) (R41) -N (R22) -C (= 0) -N ( R41) -N (R22) -C (= O) -0- -C (R21) (R21) -C (= O) -C (R41) (R41) -C (R21) (R21) -C (= 0) -N (R42) -N - (R22) -C (= NR34) -N (R42) -C (= O) -N (R32) -N (R42).

Particularly preferred chemical groups for R2, R3 and R4 include:

-N (R22) -N = C (R4x) -N (R22) -N (R32) -C (= 0) -N (R22) -C (R31) (R31) -C (R41) (R41 ) -. -N (R22) -C (R31) (R31) -C (= O) -C (R21) (R21) -C (= O) -C (R41) (R41) -C (R21) (R21 ) -C (= O) -N (R 42) -N (R 22) -C (= NR 34) -N (R 42) -C (= O) -N (R 32) -N (R 42). .

In other preferred embodiments, R 6 or R 7 is an aryl group which may be optionally substituted. Particularly preferred aryl groups include substituted or unsubstituted phenyl and pyridyl. In additional or alternative embodiments, it is preferred that substituents R21 and R22 are independently selected from groups having small steric mass and which are preferably selected from H and CH3, and more preferably being H.

In a further preferred embodiment, the present invention provides theramutein p210BCR?

ABL-T315I having formula II <formula> formula see original document page 35 </formula>

on what

ring A is a 5-, 6- or 7-membered ring or. a fused 7 to 12 membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, (CH2) pC (O) N (R 12) (Ris), - (CH 2) p C (O) O (CH 2) q R 11, (CH 2) p N (R 11) (CH 2) q C (O) R 11, - (CH 2) p N (R 12) (Rla), -N (R 11) SO 2 R 11, - OC (O) N (R 12) (R 13) (-SO 2 N (R 12) CR 13), halo, aryl and a heterocyclic ring are, yet or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl. alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom; wherein the 5-7 membered ring may optionally be substituted by one to three substituents which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR0, CO2 R0, C (O) R0, halo aryl and a heterocyclic ring;

ρ is 0 to 4;

q is 0 to 4;

R 8 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0, C (O) R 0, aralkyl, aryl and a heterocyclic ring;

R 9 is selected from -Y-R 6 and -Z-R 7;

Y is selected from a chemical bond, O, N-R 0, R 6 is known from someone, cycloalkyl, someone else, someone else, aryl and a heterocyclic ring;

Z is a hydrocarbon chain of 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0, C (O) R0, C (O) N (R0) 2 CN, CF3, N (R0) 2, NO2 and OR0;

R 7 is H or is selected from aryl and a heterocyclic ring; each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

In a further preferred embodiment, the present invention provides theramutein P210BCR "ABL-T315I tendQ inhibitors of formula IX

<formula> formula see original document page 36 </formula>

on what

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds; each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, (CH2) pC (O) N (R 12) (R a), - (CH 2) p C (O) O (CH 2) q R 11, (CH 2) p N (R 11) C (O) R 11, - (CH 2) p N (R 12) (Rib), -N ( R 11) SO 2 R 11, OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 11), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on adjacent ring atoms form a ring fused 5 or 6 membered containing 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

ρ is 0 to 4;

q is 0 to 4;

R 8 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0, C (O) R 0, aralkyl, aryl and a heterocyclic ring;

X 3 is N, CH or C-R 50;

each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 51, - (CH 2) r C (O) (CH 2) s R 51 / (CH 2) r C (0) N ( R52) (R53), - (CH2) rC (O) O (CH2) 3R51, - (CH2) rN (R51) C (O) R51, - (CH2) rN (R52) (R5s), -N (R51) ) SO2 R51, OC (O) N (R52) (R53), -SO2N (R52) (R53) 7 halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of R50 on adjacent ring atoms form a ring 5- or 6-membered fusion containing 0 to 3 heteroatoms;

each R51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R52 and R53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R52 and R53 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CNf CF3, NO2, OR0, CO2R0, C (O) R0, halo, aryl and a heterocyclic ring;

r is 0 to 4;

s is 0 to 4;

m is 0 to 4; and

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

In a further preferred embodiment, the present invention provides theramutein P210BCR "ABL-T3i5i inhibitors having formula IIb.

<formula> formula see original document page 38 </formula>

on what:

R14 is selected from H and F;

R 8 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, CO 2 R 0, C (O) R 0, aralkyl, aryl and a heterocyclic ring;

X 3 is N, CH or C-R 60;

each R 60 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, halo, aryl and a heterocyclic ring;

R is selected from aryl and a heterocyclic ring;

Q is selected from a chemical bond or a group having the formula -0-, - (CH2) i -, - (CH2) iC (O) (CH2) j -, - (CH2) i-NiR62) - (CH2 ) j -, - (CH 2) i C (O) -N (R 62) - (CH 2) j, - (CH 2) i C (O) O (CH 2) r ,. - (CH2) jN (R62) C (O) - (CH2) j-, - (CH2) iOC (O) N (R62) - (CH2) j- and 0- (CH2) iC (O) N (R62) ) - (CH 2) j -;

R62 is selected from H, alkyl, aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;

h is 0 to 4;

i is 0 to 4; and

j is 0 to 4;

In preferred embodiments of the compounds of formula IIb, R 60 is selected from halo, CF 3 and OH. In other preferred embodiments, R 8 is selected from H and CH 3.

In the preferred representations of the compounds of formula IIb / X3 is N. In the additional preferred embodiments, Q is selected to be - (CH2) i-NiR62) (CH2) f-, and particularly in the preferred embodiments, Q is -N (R62) -.

In a further preferred embodiment, the present invention provides theramutein P210BCR "RBL" T3151 inhibitors having formula IIc wherein:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 11, - (CH 2) p C (O) (CH 2) q R 11, (CH 2) p C (O ) N (R 12) (R 13), - (CH 2) PC (O) O (CH 2) q R 11, (CH 2) p N (R 11) C (O) R 11, - (CH 2) pN (R 12) (Ris), -N (R11) SO2R11, - OC (O) N (R12) (Ria), -SO2N (R12) (Ris), halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of 1R1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from Η, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from Η, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

ρ is 0 to 4;

q is 0 to 4;

R8 is selected from H and methyl;

X 3 is N or CH; R is selected from aryl and a heterocyclic ring; Q is selected from a chemical bond or a group having the formula -0-, - (CH2) i -, - (CH2) iC (O) (CH2) f -, - (CH2) i -N (R62) - (CH 2) j -, - (CH 2) i C (O) -N (R 62) - (CH 2) f -, - (CH 2) i C (O) O (CH 2) j -, (CH 2) j N (R 62) C (O) - (CH2) j -, - (CH2) iOC (O) N (R62) - (CH2) j-, and -0- (CH2) iC (O) N (R62) - (CH2) j ,.

R62 is selected from H, alkyl, aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;

h is 0 to 4;

i is 0 to 4, and

j is 0 to 4;

In a further preferred embodiment, the present invention provides theramutein P210BCR "ABL-T315I inhibitors having formula IId

<formula> formula see original document page 41 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a 7 to 12-membered fused bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, (CH2) pC (O) N (Ria) (R 13), - (CH 2) p C (O) O (CH 2) q R 11, (CH 2) p N (R 11) C (O) R 11, - (CH 2) p N (R 12) (Ris), -N ( Ru) SO 2 R 11, - OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

ρ is 0 to 4;

q is 0 to 4;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;

R8 is selected from H and CH3;

X 3 is N or CH;

Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O ) -, -OC (O) NH- and -OC (O) NH-;

each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3,

each R71 is selected from H, alkyl, aryl, aralkyl and a heterocyclic ring; and

k is 0 to 4.

In a further preferred embodiment, the present invention provides theramutein P210BCR-ABL-T315I inhibitors having the formula IIe <formula> formula see original document page 43 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

dotted lines represent optional double bonds;

consists of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11. - (CH2) pC (O) (CH2) q R11, (CH2) pC (O) N (R12) (R13) f - (CH2) pC (O) O (CH2) q R11, - (CH2) pN (R11) C (O) R 11, - (CH 2) p N (R 12) (Ris), -N (R 11) SO 2 R 11, - OC (O) N (R 12) (Ria), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5- or 6-membered ring containing from 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R and R are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

each R 1 is independently selected from the group p is 0 to 4;

q is 0 to 4;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;

R8 is selected from H and CH3;

X 3 is N or CH;

Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH- ,. -C (O) -NH-, -C (O) O-, -NH-C (O) -, -OC (O) NH- and -O-C (O) NH-;

each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3; and

each R71 is selected from H and alkyl.

In a further preferred embodiment, the present invention provides theramütein P210BCR-ABL-T315I inhibitors having formula IIf.

<formula> formula see original document page 44 </formula>

on what

R14 is selected from H and F;

R8 is selected from H and CH3;

each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3,

each R71 is selected from H, alkyl, aryl, aralkyl and a heterocyclic ring; and

k is 0 to 4.

Example compounds of formula II, IIa, IIb, IIc, Hd, IIe or IIf include the following structures: <formula> formula see original document page 45 </formula> <formula> formula see original document page 46 </formula> < formula> formula see original document page 47 </formula> <formula> formula see original document page 48 </formula> <formula> formula see original document page 49 </formula> <formula> formula see original document page 50 </ formula > <formula> formula see original document page 51 </formula> <formula> formula see original document page 52 </formula> <formula> formula see original document page 53 </formula> <formula> formula see original document page 54 < / formula> <formula> formula see original document page 55 </formula> <formula> formula see original document page 56 </formula> <formula> formula see original document page 57 </formula> <formula> formula see original document page 58 </formula> <formula> formula see original document pag and 59 </formula> <formula> formula see original document page 60 </formula> <formula> formula see original document page 61 </formula> <formula> formula see original document page 62 </formula> <formula> formula see original document page 63 </formula> <formula> formula see original document page 64 </formula> <formula> formula see original document page 65 </formula> <formula> formula see original document page 66 </formula> <formula> formula see original document page 67 </formula> <formula> formula see original document page 68 </formula> <formula> formula see original document page 69 </formula> <formula> formula see original document page 70 </formula> < formula> formula see original document page 71 </formula> <formula> formula see original document page 72 </formula> <formula> formula see original document page 73 </formula> <formula> formula see original document page 74 </ formula > <formula> formula see original document page 75 </formula> <form ula> formula see original document page 76 </formula> <formula> formula see original document page 77 </formula> <formula> formula see original document page 78 </formula> <formula> formula see original document page 79 </ formula > <formula> formula see original document page 80 </formula> <formula> formula see original document page 81 </formula> <formula> formula see original document page 82 </formula> <formula> formula see original document page 83 < / formula> <formula> formula see original document page 84 </formula> <formula> formula see original document page 85 </formula> <formula> formula see original document page 86 </formula> <formula> formula see original document page 87 </formula> <formula> formula see original document page 88 </formula> <formula> formula see original document page 89 </formula> <formula> formula see original document page 90 </formula> <formula> formula see original document page 91 </formula>

In a further preferred embodiment, the present invention provides theramutein P210BCR-ABL-T315I inhibitors having the formula III <formula> formula see original document page 92 </formula>

(IIΙ)

on what

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O ) N (R 12) (R n), - (CH 2) p C (O) O (CH 2) q R 11, (CH 2) p N (R 11) C (O) R 11, - (CH 2) p N (R 12) (Ris), -N (R11) SO2R11, OC (O) N (R12) (Rs), -SO2N (R12) (Rs), -SO2N (R12) (Rs), halo, aryl and a heterocyclic ring and, still or alternatively, two groups of R 1 on adjacent ring atoms form a 5- or 6-membered fused ring containing from 0 to 3 heteroatoms; n is from 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom; wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo aryl and a heterocyclic ring;

p is 0 to 4;

q is 0 to 4;

R10 is selected from -Y'-R18;

Y 'is selected from a chemical bond, O, NR0-, and a hydrocarbon chain having from 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0 C (O) R 0, C (O) N (R 0) 2, CN, CF 3, N (R 0) 2, NO 2 and OR 0; each R 18 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF 3, aryl and a heterocyclic ring; and

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

In a further preferred embodiment, the present invention provides theramutein P210BCR "ABL-T315I inhibitors having formula IIIa

<formula> formula see original document page 93 </formula>

(IIIa)

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds:

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, (CH2) pC (O) N (R 12) (R 13), - (CH 2) p C (O) O (CH 2) q R 11, - (CH 2) p N (Rii) C (O) R 11, - (CH 2) pN (R 12) (R 13), -N (R 11) SO 2 R 11, -CO (0) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

n is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

foot 0 to 4;

q is 0 to 4;

X 3 is N, CH or C-R 50;

each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 51, - (CH 2) r C (O) (CH 2) s R 51, (CH 2) r C (0) N ( R52) (R53), - (CH2) rC (0) 0 (CH2) SR51, - (CH2) rN (R51) C (O) R51, - (CH2) rN (R52) (R53) fN (R51) SO2R51 , OC (O) N (R · 52) (R53), -SO2 N (R52) (R53), halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of R50 on adjacent ring atoms form a fused ring 5- or 6-membered containing 0 to 3 heteroatoms;

each R51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R52 and R53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R52 and R53 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

r is 0 to 4;

s is 0 to 4;

m is 0 to 4; and

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

In a further preferred embodiment, the present invention provides theramutein P210BCR "ABL-T315I inhibitors having formula IIIb

<formula> formula see original document page 95 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, (CH2) pC (O) N (Ria). (R13),

- (CH2) pC (O) O (CH2) qR (CH2) PN (R11) C (O) R11, - (CH2) pN (R12) (Ris), -N (R11) SO2R11, OC (0) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing 0 to 3 heteroatoms; η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring;

ρ is 0 to 4;

q is 0 to 4;

X 3 is N or CH;

R61 is selected from aryl and a heterocyclic ring; Q is selected from a chemical bond or a group having the formula -0-, - (CH2) i -, - (CH2) iC (O) (CH2) j -, - (CH2) iNi R62) - (CH2) j -, - (CH2) iC (0) -N (R62) - (CH2) j-, - (CH2) iC (0) 0 (CH2) j-, (CH2) iN (R62) C (O) - ( CH2), (CH2) iOC (O) N (R62) - (CH2) j, and -0- (CH2) iC (O) N (R62) - (CH2) j-;

R62 is selected from H, alkyl, aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; h is 0 to 4; i is 0 to 4; and j is 0 to 4;

In a further preferred embodiment, the present invention provides theramutein P210BCR "abl-t3151 inhibitors having formula IIIc.

<formula> formula see original document page 97 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11i (CH2) pC (O) (CH2) qR11, - (CH2) pC (O) N (R 12) (Ris), - (CH 2) p C (O) O (CH 2) q R 11, - (CH 2) p N (R 11) C (O) R 11, - (CH 2) pN (R 12) (Ria), - N (R 11) SO 2 R 11, OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring:

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which may be substituted. are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2. OR0, CO2 R0, C (O) R0, halo, aryl and a heterocyclic ring;

p is 0 to 4;

q is 0 to 4;

X 3 is N or CH;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O ) -, -OC (O) NH- and -OC (O) NH-;

each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3,

each R71 is selected from H, alkyl, aryl, aralkyl and a heterocyclic ring; and k is 0 to 4.

In a further preferred embodiment, the present invention provides theramutein P210BCR-ABL-T3151 inhibitors having formula IIId.

<formula> formula see original document page 98 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N3, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O ) N (R 12) (R 13), - (CH 2) p C (O) O (CH 2) q R 11, (CH 2) pN (Rii) C (O) R 11, - (CH 2) pN (R 12) (Ría), -N (R11) SO2Rn OC (O) N (R12) (Ría), -SO2N (R12) (Ría), halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of R1 on adjacent ring atoms form a ring 5- or 6-membered fusion containing 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from Η, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 10 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R12 and RIA may be used together with the nitrogen to which they are attached form a 5 to 7 membered ring which may optionally contain an additional heteroatom, wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO2 R 0, C (O) R, halo, aryl and a heterocyclic ring;

foot 0 to 4;

q is 0 to 4;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring;

R8 is selected from H and CH3;

X 3 is N or CH;

Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O ) -, -OC (O) NH- and -OC (O) NH-;

each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3;

and each R71 is selected from H and alkyl.

In a further preferred embodiment, the present invention provides theramutein P210BCR 'ABL-T315I inhibitors having formula IIIe.

<formula> formula see original document page 100 </formula>

on what

R14 is selected from H and F;

each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic amino, NO2, OR71 and CF3,

each R71 is selected from H, alkyl, aryl, aralkyl and a heterocyclic ring; and

k is 0 to 4.

Example compounds of formula III, IIIa, IHb, IHc, IIId, or IIIe include the following structures: <formula> formula see original document page 101 </formula> <formula> formula see original document page 102 </formula> <formula > formula see original document page 103 </formula> <formula> formula see original document page 104 </formula> <formula> formula see original document page 105 </formula> <formula> formula see original document page 106 </formula> <formula> formula see original document page 107 </formula> <formula> formula see original document page 108 </formula> <formula> formula see original document page 109 </formula> <formula> formula see original document page 110 </ formula> <formula> formula see original document page 111 </formula> <formula> formula see original document page 112 </formula> <formula> formula see original document page 113 </formula> <formula> formula see original document page 114 </formula>

In another preferred embodiment, the present invention provides theramutein p210BCR-ABL-T315I inhibitors having the formula IV <formula> formula see original document page 115 </formula>

(IV)

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, (CH2) pC (O) N (R 12) (Ria), - (CH 2) p C (O) O (CH 2) q R 11, (CH 2) p N (R 11) C (O) R 11, - (CH 2) p N (R 12) (Ris), -N ( Rn) SO 2 R 11, OC (O) N (R 12) (Ría), -SO 2 N (R 12) (Ría), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on adjacent ring atoms form a ring 5- or 6-membered fusion containing 0 to 3 heteroatoms;

n is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

p is 0 to 4; q is 0 to 4;

R22 is selected from H and C1-3 alkyl;

R34 is selected from H, NO2, CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R44 is selected from H, alkyl, cycloalkyl, - (C = O) R0, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; R45 is selected from -Y '' - R19;

Y "is selected from a chemical bond, O, NR0-, and a hydrocarbon chain having from 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0 , C (O) R 0, C (O) N (R 0) 2, CN, CF 3, N (R 0) 2, NO 2 and OR 0, each R 19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF3, aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

Example compounds of formula IV include the following structures:

<formula> formula see original document page 116 </formula>

In a further preferred embodiment, the present invention provides theramutein P210BCR "abl-t315i inhibitors having the formula V

<formula> formula see original document page 116 </formula>

(V)

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) q Ru, (CH2) pC (O) N (R 12) (R 13), - (CH 2) p C (O) O (CH 2) q R 11, - (CH 2) PN (R n) (C) (0) R 11, - (CH 2) PN (R 12) (R 13), -N (R 11) SO 2 R 11, - OC (O) N (R 12) (Ru), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on ring atoms adjacent form a fused 5 or 6 membered ring containing 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

ρ is 0 to 4;

q is 0 to 4;

R22 is selected from H and C1-3 alkyl;

R34 is selected from H, NO2, CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

R56 is selected from -Y "-R19;

Y "is selected from a chemical bond, O, NR0-, and a hydrocarbon chain having from 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0 C (O) R 0, C (O) N (R 0) 2, CN, CF 3, N (R 0) 2, NO 2 and OR 0;

each R19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF3, aryl and a heterocyclic ring; and

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

In another preferred embodiment, the present invention provides theramutein p210BCR-ABL-T315I inhibitors having the formula Va

<formula> formula see original document page 118 </formula>

(Go)

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, (CH2) pC (O) N (R 12) (R 13), - (CH 2) p C (O) O (CH 2) q R 11, - (CH 2) p N (R 11) C (O) R 11, - (CH 2) PN (R 12) (R 13), -N (R 11) SO 2 R 11, OC (O) N (R 12) (Ris), -SO 2 N (R 12) (R 13), halo, aryl and a heterocyclic ring and, alternatively or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

n is 0 to 6, each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

ρ is 0 to 4;

q is 0 to 4;

Each R55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

X 3 is N or C-R 50;

each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 51, - (CH 2) r C (O) (CH 2) s R 51, (CH 2) r C (0) N ( R52) (R53), - (CH2) rC (0) 0 (CH2) SR51, - (CH2) rN (R51) C (O) R51, - (CH2) rN (R52) (R53) fN (R51) SO2R51 , OC (O) N (R52) (R53) r -SO2N (R52) (Rss), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R50 on adjacent ring atoms form a fused ring of 5 - or 6 members containing from 0 to 3 heteroatoms;

each R51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R52 and R53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R52 and R53 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

r is 0 to 4;

s is 0 to 4;

m is 0 to 4; and each R is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

Example compounds of formula V or Va include the following structures:

<formula> formula see original document page 120 </formula>

In another preferred embodiment, the present invention provides theramutein p2ioBCR_ABL "T3151 inhibitors having formula VI

<formula> formula see original document page 120 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R 1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl,

aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR ", (CH2) PC (O) N (R12) (R13), - (CH2) pC (O) O (CH2 ) qR11, - (CH2) pN (Rii) C (O) R11, - (CH2) pN (R12) (Ria), -N (R11) SO2 R11, OC (O) N (R12) (R13) i -SO2N (R 12) (R a), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R 1 on adjacent ring atoms form a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms;

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

ρ is 0 to 4;

q is 0 to 4;

each R55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

R56 is selected from -Y '' -R19;

Y "is selected from a chemical bond, O, NR0-, and a hydrocarbon chain having from 1 to 4 carbon atoms and optionally substituted by one or more of halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2 R0 C (O) R 0, C (O) N (R 0) 2, CN, CF 3, N (R 0) 2, NO 2 and OR 0;

each R19 is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF3, aryl and a heterocyclic ring;

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

In another embodiment, the present invention provides theramutein P210BCR_ABL "T3151 inhibitors having the formula VIa <formula> formula see original document page 122 </formula>

on what:

ring A is a 5, 6 or 7 membered ring or a fused 7 to 12 membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O ) N (R 12) (Ris), - (CH 2) p C (O) O (CH 2) q R 11, (CH 2) p N (R 11) C (O) R 11, - (CH 2) pN (R 12) (Ris), -N (R11) SO2R11, OC (O) N (R12) (Ris), -SO2N (R12) (Ris), halo, aryl and a heterocyclic ring and, alternatively or even, two groups of R1 on adjacent ring atoms form a fused 5 or 6 membered ring containing 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R12 and Rxs may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

ρ is 0 to 4;

q is 0 to 4; each R55 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

X 3 is N or C-R 50;

each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 51, - (CH 2) r C (O) (CH 2) s R 51, - (CH 2) r C (O) N (R52) (R5a), - (CH2) rC (O) O (CH2) sR51, - (CH2) rN (R51) C (O) R51, - (CH2) rN (R52) (R5s), -N (R51) SO2R51, -OC (0) N (R52) (R53), SO2N (R52) (R53) fhalo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R50 on adjacent ring atoms form a 5- or 6-membered fused ring containing 0 to 3 heteroatoms;

each R51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R52 and R53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R52 and R53 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

r is 0 to 4;

s is 0 to 4;

m is 0 to 4; and

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

Example compounds of formula VI or VIa include the following structures: <formula> formula see original document page 124 </formula> present invention provides theramutein P210BCR "abl-t3151 inhibitors having formula VII

<formula> formula see original document page 125 </formula>

on what:

ring A is a 5-, 6- or 7-membered ring or a fused 7 to 12-membered bicyclic ring;

X1 is selected from N, N-R0 or C-R1;

X 2 is selected from N, N-R 0 or C-R 1;

dotted lines represent optional double bonds;

each R1 is independently selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) q R11, (CH2) pC (O ) NiR 12) (R 13), - (CH 2) p C (O) O (CH 2) q R 11 (CH 2) p N (R 1) C (O) R 11, - (CH 2) PN (R 12) (R 13), -N (R 11) SO2R11 -OC (O) N (R12) (R16), -SO2N (R12) (Rn), halo, aryl and a heterocyclic ring and, alternatively or even, two groups of R1 on adjacent ring atoms form a fused ring of 5 or 6 members containing 0 to 3 heteroatoms;

η is 0 to 6,

each R 11 is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring;

each R 12 and R 13 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R 12 and R 13 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom; p is 0 to 4;

q is 0 to 4;

ring B is selected from a cycloalkyl group having 5 or 6 ring atoms and a heterocyclic group containing 5 or 6 ring atoms that includes one to three heteroatoms: each R 50 is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR51, - (CH2) rC (O) (CH2) sR51, (CH2) rC (0) N (R52) (R53), - (CH2) rC ( 0) 0 (CH2) SR51, - (CH2) rN (R51) C (O) R51, - (CH2) rN (R52) (R53), -N (R51) SO2R51, OC (O) N (R52) ( R53), -SO2N (R52) (R5s), halo, aryl and a heterocyclic ring and, yet or alternatively, two groups of R50 on adjacent ring atoms form a 5- or 6-membered fused ring containing 0 to 3 heteroatoms; each R51 is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R52 and R53 are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; or R52 and R53 may be used together with the nitrogen to which they are attached and form a 5 to 7 membered ring which may optionally contain an additional heteroatom;

r is 0 to 4;

s is 0 to 4;

m is 0 to 4; and

each R 0 is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring.

Example compounds of formula VII include the following structures: <formula> formula see original document page 127 </formula>

As used herein, the definition of each expression, for example alkyl, m, n, R ', etc., when occurring more than once in any structure, must be independent of its definition elsewhere in the same structure.

For each of the above descriptions of compounds having structures I, Ia, Ib, II, IIa, etc., each citation of the terms halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heterocyclic group or ring is independently selected from the above. definitions of these terms as provided at the beginning of this section.

It will be understood that the chemical structures provided herein include the condition that the substitution is in accordance with the permitted valence of the substituted atom and substituent (s), and that the results of substitution in a stable compound, for example, do not undergo transformation such as rearrangement, cyclization, disposal etc.

When one or more chiral centers are present in the compounds of the present invention, the individual isomers and mixtures thereof (e.g. racemates, etc.) should be included by the formulas represented herein.

When one or more double bonds are present in the compounds of the present invention, the useful and trans isomers should be included by the formulas represented herein. Although chemical structures (such as structures II, IIa, V, Va, VI and VIa) are represented here in the eis or trans configuration, the two configurations must be included by all formulas.

In certain embodiments, the compounds of the invention may exist in various tautomeric forms. Therefore, the chemical structures depicted herein include all tautomeric forms of the illustrated compounds.

The compounds of the invention may generally be prepared from commercially available starting materials and known chemical techniques. Representations of the invention may be synthesized as follows. A person skilled in the art of medicinal or synthetic chemistry would be familiar with the procedures and techniques required to perform the synthetic approaches provided below.

Compounds of formula II may be prepared by reaction of an appropriate hydrazine compound such as A and an appropriate aldehyde such as Br under conditions similar to those described on page 562 of Gineinah. etal. (Arch. Pharm. Med. Chem. 2002, 11, 556-562).

<formula> formula see original document page 129 </formula>

For example, heating A with 1.1 equivalents of B for 1 to 24 hours as a C1 to C6 alcohol, followed by cooling and collecting the precipitate, would yield C. Alternatively, product C could be isolated by evaporation of the solvent and purification by chromatography using silica gel, alumina or C4 to C18 reverse phase medium.

Similar methodology would be applicable where "Aryl" is replaced by other groups defined under R5.

Ring compounds of formula III may be prepared by reaction of a suitable hydrazine compound such as D and an activated carboxylic acid such as Er wherein LG is a leaving group such as halo, 1-oxybenztriazole, pentafluorophenoxy, p-nitrophenoxy or the like or Compound E may also be a symmetric carboxylic acid anhydride, whereby conditions similar to those described on p. 408 from Nair and Mehta (Indian J. Chem. 1967 5, 403-408) may be applied.

<formula> formula see original document page 129 </formula>

For example, treating D with an active ester such as Aryl-C (O) -OC6F5 in an inert solvent such as dichloromethane, 1,2-dichloroethane or N, N-dimethylformamide, optionally in the presence of a base such as pyridine or other amine. optionally in the presence of a catalyst such as 4-N, N-dimethylaminopyridine, at an appropriate temperature of 0 ° C to the boiling point of the solvent would yield F, which can be isolated by evaporation of the solvent followed by chromatography using silica gel. , alumina or reverse phase medium from C4 to C18. The above example of active ester of E would be readily prepared from the corresponding carboxylic acid and pentafluorophenol using a carbodiimide as dicyclohexylcarbodiimide as a condensing agent.

Precursors such as AeD may be prepared by reacting an appropriate nucleophile, for example a hydrazine derivative, with a heteroaromatic compound carrying a halo substituent at a position adjacent to a nitrogen atom. For example, using methods analogous to those described by Wu, et al. (J. Heterocyclic Chem. 1990, 27, 1559-1563), Breshears, et al. (J. Am. Chem. Soc. 1959, 81, 3789-3792) or Gineinah, et al. (Arch. Pharm. Med. Chem. 2002, 11, 556-562), examples of AeD compounds can be prepared from of, for example, a 2,4-dihalopyrimidine derivative, many of which are commercially available or readily prepared by one skilled in the art. Therefore, treatment of a 2,4-dihalopyrimidine G derivative with an amine or other nucleophile (Z), optionally in the presence of an included base, selectively displaces the 4-halo substituent on the pyrimidine ring. Subsequent treatment of the product with the second nucleophilic reagent, such as hydrazine or the hydrazine derivative, optionally in a solvent such as C1 to C6 alcohol and optionally in the presence of an included base, displaces the 2-halo substituent on the pyrimidine ring to produce compounds which are examples of AeD structures. <formula> formula see original document page 131 </formula>

Representations wherein R2 is -NR22 and R3 is -C (= R33) may be synthesized by the methods as follows or their direct modifications. The synthesis may be conducted from an appropriate ring A derivative J which leads an leaving group (LG) adjacent to the required ring nitrogen. The above structure G and the product of the reaction of structure G with nucleophile Z, as illustrated above, are examples of such derivatives of Ring A. Suitable LG groups are halo, alkylthio, alkylsulfonyl, alkylsulfonate or arylsulfonate. Treatment of J with an amine R12NH2 effects displacement of LG 'to yield intermediates K. An example of such chemical transformation where R12 is H and LG' is CH3SO2- is reported by Capps, et al. J. Agric. Food Chem. 1993, 41, 2411-2415, and an example where R12 is H and LG 'is Cl is reported in Marshall, et al. J. Chem. Soc. 1951, 1004-1015.

<formula> formula see original document page 131 </formula>

Intermediates of structure K are transformed into compounds of the invention by simultaneous or sequential introduction of the elements of R3, R4 and R5. For example, treatment of structure K intermediates with isocyanates R6-N = C = O yields in one step compounds of structure M, which are compounds of the invention wherein R2 = -NR22-, R3 = -C = O-, R4 = -NH- and R5 = -chemical bond-R6. Alternative methods for converting compounds of structure K to compounds of structure M are well known in the art, where R 3 together with an leaving group (e.g., p-nitrophenoxy or chlorine) is introduced first, followed by subsequent displacement of the group of compounds. output, for example, an amine R6-NH2, to introduce R5 and R6.

<formula> formula see original document page 132 </formula>

Alternatively, treatment of intermediates of structure K with (NH2-CN), usually under heating conditions and optionally in the presence of acid in a solvent such as ethyl acetate or dioxane, yields N intermediates. Alternatives to cyanamide are nitroguanidine or starch sulfonic acid. (NH 2 -C (= NH) -SO 3 H). An example of such a transformation using cyanamide is reported by Latham et ah, J. Org. Chem. 1950, 15, 884. An example using nitroguanidine is reported by Davis, Proc. Natl. Acad. Know. USA 1925, 11, 72. The use of amidine sulfonic acid has been reported by Shearer, et al. Bioorg. Med. Chem. Lett. 1997, 7, 1763.

<formula> formula see original document page 132 </formula>

In analogy to the conversion of intermediates A or D to representations represented by C or Fr the intermediates K are converted respectively to compounds represented by P or Qr which are still representations of the invention. <formula> formula see original document page 133 </formula>

Treatment of A or K with a ketone S1 wherein R is as defined above in place of an aldehyde B in the above schemes produces compounds of structure T or U, respectively, which are still embodiments of the invention.

<formula> formula see original document page 133 </formula>

The non-guanidine carbon-nitrogen double bond of U can be selectively reduced by appropriately reducing the agent as a metal (baro, aluminum, silicon etc.), hydride reagents, preferably one with basic properties, to produce compounds of the invention. <formula> formula see original document page 134 </formula>

Embodiments of the invention wherein R 2 = CO, R 3 = -NR 32 -, R 4 = N- and R 5 = ZR 7, wherein Z is a hydrocarbon chain and R 7 is defined above, may be prepared as follows. When R32 = H, a carboxylic acid W derived from Ring A is activated by conversion to the corresponding acid chloride, or alternatively into an active ester, or analog activated derivative, many of which are well known in the art. Treatment of the hydrazine-activated carboxylic acid yields the corresponding hydrazide Y. Treatment of Y with an aldehyde or ketone (under heating and / or moderate acid catalysis if necessary) yields the desired final product Z. aldehyde u (or chain of

<formula> formula see original document page 134 </formula>

If not commercially available, carboxylic acids W derived from Anela A may be prepared by treating the above starting material J above with cyanide ion, optionally with heating or transition metal catalysis, to replace the leaving group LG 'with a residue. of cyan. Basic or acidic hydrolysis of the cyano group yields the desired carboxylic acid intermediate W.

When R32 is not H, the protected form of monosubstituted hydrazine may be used in the above scheme in place of hydrazine. Therefore, treatment of W-activated carboxylic acid with R32NHNH-PG, where PG is is a nitrogen protecting group such as benzyloxycarbonyl or t-butyloxycarbonl, followed by deprotection and treatment with an appropriate aldehyde or ketone as above yields Z ', a further representation of the invention.

<formula> formula see original document page 135 </formula>

It will be apparent to a person skilled in the art of organic molecule synthesis that the reaction processes illustrated above are representative of a broad set of methods that are logical extensions of the illustrated processes. Therefore, additional embodiments of the invention that incorporate additional R2, R3, R4 and R5 variants claimed by this invention are prepared by obvious modifications of the above processes.

As would be recognized by a person of ordinary knowledge, it may be advantageous to employ a temporary protection group to obtain the final product. The phrase "protecting group" as used herein means temporary modifications of a potentially reactive functional group that protects it from unwanted chemical transformations. Examples of such protecting groups include carboxylic acid esters, alkali and acetal silyl ethers and aldehydes and ketones ketals, respectively. The field of chemistry of the protecting group has been reviewed (Greene, T.W .; Wuts, P.G.M. Protective Groups in Organic Synthesis, 2nd ed .; Wiley: New York, 1991).

A "mutein" is a protein that has an amino acid sequence that is altered as a result of a mutation that occurred in its corresponding gene (Weigel et al, 1989). These mutations may result in changes in one or more characteristics of the encoded protein. For example, an enzyme variant that has modified catalyst activity resulting from a change in or more amino acids is a mutein.

This invention relates to proteins hosting an alteration of at least one amino acid residue (the terms "amino acid sequence change" or "amino acid sequence change" include changes, deletions or inclusions of at least one amino acid residue or any combination of exclusions, inclusions, alterations) such that the resulting mutein has become (as a result of the mutation) resistant to a therapeutic agent relative to the mutation-free version sensitivity of the cited protein to the therapeutic agent. This specialized class of mutein will be referred to hereafter as theramutein, and the corresponding protein without the mutation will be referred to as aphototheramutein.

As used herein, the term "prototheramutein" refers to a protein that occurs endogenously in a cell that is susceptible to mutation, which confers relative intensity (ie resistance) to a therapeutic compound that inhibits or activates the protein. . Therefore, "theramutein" refers to an endogenously occurring protein or part of a protein in a cell that contains at least one amino acid sequence change relative to an endogenous protein form, wherein the amino acid sequence change is or has been identified or will become identifiable, and is or has been considered clinically significant for the development or evolution of a particular disease following exposure of at least one human to the substance known to inhibit or activate prototheramutein. Exclusively for the purpose of defining the previous sentence, a substance need not be limited to a chemical agent for the purpose of first defining the existence of a theramutein. Therefore, by definition, a theramutein is a protein that hosts a mutation in its corresponding endogenous gene wherein the said mutation is associated with the development of clinical resistance in a patient to a drug that is generally capable of activating or inhibiting the protein without mutation. With respect to a particular theramutein, the term "corresponding prototheramutein" refers to prototheramutein which, by mutation, provides the origin of the cited theramutein. Similarly, with respect to a particular protheramutein, "the corresponding theramutein" refers to the theramutein that originated by mutation from said prototheramutein.

Therefore, it is apparent to a skilled practitioner that since theramutein-encoding genes are limited to endogenously occurring genes, the definition of a theramutein excludes proteins encoded by infectious agents that cause diseases such as viruses and bacteria. As used herein, the term "endogenous gene" refers to a gene that has been present on the organism's chromosomes, at least in their unchanged form, from the beginning. The term "cell" as used herein refers to a eukaryotic cell living in an organism or maintained under appropriate laboratory tissue or organ culture conditions outside an organism.

In one aspect of the invention theramutein is a protein that is altered for the first time relative to a commonly occurring "wild-type" protein form (i.e. prototheramutein). In another aspect of the invention, a theramutein is a variant of a protein (prototheramutein) which is itself a mutein. In yet another embodiment, a theramutein may still mutate as compared to a previously existing theramutein. In these instances, the first theramutein (such as the P210 BCR-ABL mutant T315I (see below) may be considered a "primary" theramutein, while subsequent mutations of the T315I variant (which has already mutated) may be called a secondary theramutein, tertiary theramutein, etc. As exemplified below, a mutein of the invention is a Bcr-Abl tyrosine kinase variant that provides inhibition by a "wild-type" Bcr-Abl inhibitor. A mutein Bcr-Abl is altered from one form more common or "wild-type" Bcr-Abl (which is also a mutein) so that a property of the protein is altered.

It will be understood that a mutein of primary interest is a theramutein which may have the same, increased or decreased specific activity relative to its prototheramutein and which is not inhibited or insufficiently inhibited by an agent that is capable of inhibiting prototheramutein. Likewise, another theramutein of major interest is one which has the same increased or decreased specific activity (relative to prototheramutein) and which is not activated or insufficiently activated by an agent that is capable of activating prototheramutein. Other variations are obvious to the skilled practitioner. It will further be appreciated that theramuteins may include naturally occurring or normally observed variants of a protein, for example variants that are expressed from different alleles of a given gene. In some cases, these variants may not be noted for their normal cellular function, with functional differences that become apparent only in the presence of agents that differently inhibit or activate the cellular function of the variants. For example, variants of a given naturally occurring enzyme may have activity profiles that are not considerably different, but a therapeutic agent that modulates one may be ineffective in modulating the other. It will be appreciated that, whereas one aspect of the invention is the identification of an active agent in relation to a theramutein that originates or becomes dominant (by any mechanism) before or during the course of treatment of a particular disease, another aspect is the identification of an active agent in relation to a mutein that is common in a population of unaffected individuals, but in which the cited mutein is less susceptible to modulation by an approved drug and where variation in mutein activity profile becomes important (and is therefore first identified as a theramutein) in a disease state such as that in which it is overexpressed or participates in a signaling process that has become irregularly regulated. For example, a neoplastic disease may be caused by irregular regulation of a cellular component other than theramutein or its prototheramutein and may still be treatable with a prototheramutein inhibitor, since the same treatment is less effective or ineffective where theramutein was present. This may be a problem where it is observed that the response of a given tumor type to an anticancer agent varies between individuals who express different variants of an enzyme against which the anticancer agent is directed (Lynch et al., 2004). Here, variants would not have appeared or become prevalent during the course of treatment of the disease, but would be pre-existing in the healthy population and detected only by their altered responsiveness in a particular course of established therapeutic treatment.

As used herein, the terms "agonist" and "activator" of a protein are used interchangeably. An activator (agonist) is limited to a substance that binds to and activates the functioning of a particular protein. Unless explicitly stated, an "activator", "agonist" and "activator of a protein" are identical in meaning. Activation by an activator may be partial or complete. Similarly, as used herein, the terms "antagonist" and "inhibitor" of a protein are used interchangeably. An inhibitor (antagonist) is limited to a substance that binds to and inhibits the function of a particular protein. To state that a substance "inhibits" a protein means that the substance binds to the protein and reduces the activity of that protein in the cell without materially reducing the amount of protein in the cell. Similarly, to state that a substance "activates" a protein, such as a prototheramuthein or theramutein, is to state that the substance enhances the defined function of the protein in the cell without significantly altering the protein level in the cell. Except when explicitly stated, an "inhibitor", an "antagonist" and an "inhibitor" of a protein are also synonymous. Inhibition by an inhibitor may be partial or complete. A modulator is an activator or an inhibitor. As an example, a "PKCpi activator" should be constructed to indicate a substance that binds to and activates PKCpi. Similarly, a "p210Bcr_Abl inhibitor" is a substance that binds to and inhibits the functioning of p210Bcr_Abl. Claiming that a substance "inhibits a protein" requires the substance to bind to the protein to manifest its inhibitory effect. Similarly, to state that a substance "activates protein X" is to state that the substance binds to and activates protein X. The terms "bind (m)", "binding" and "bind to" have their common meanings. in the field of biochemistry in terms of describing the interaction between two substances (eg enzyme-substrate, protein-DNA, receptor-ligand, etc.). As used herein, the term "binds to" is synonymous with "interacts with "in the context of discussing the relationship between a substance and its corresponding target protein. As used here, to state that a substance "acts on" a protein, "affects" a protein, "manifests its effect on" a protein, etc., and all uniformly related terms, means (as the skilled examiner will perceive) that the cited substance activates or inhibits the cited protein.

The concept of inhibition or activation, in a way that has mutated an endogenous protein to a greater extent than the counterpart protein that has not mutated correspondingly, is first defined and cited here as a "specificity range". In general terms, and using an inhibitory case as an example, the specificity range refers to the difference between the ability of a given substance under comparable conditions to inhibit theramutein in a cell-based assay system of the invention when compared to:

(a) the ability of the same substance under comparable conditions to inhibit prototheramutein; or

b) the ability of a second substance (usually a known prototheramutein inhibitor) to inhibit theramutein under comparable conditions; or

c) the ability of the second substance to inhibit prototheramutein under comparable conditions.

When a comparison is made between the effects of two distinct substances (individually tested) on theramutein alone, the result is termed a homologous specificity interval determination.

Alternatively, when a comparison is made between the effects of two distinct substances (usually, but not always), one of which is tested on theramutein and the other on prototheramutein, respectively, the result is called heterologous specificity interval determination. (SG). Therefore (a) and (c), as above, are examples of heterologous specificity range (SG) determinations (although (a) uses the same substance in both instances), since (b) is an example of a determination of homologous specificity range.

The reference to figure 3 is informative to understand and elucidate these concepts.

Similar questions apply when the case refers to an activator. It will be readily apparent to the skilled practitioner that the term "comparable conditions" includes testing two different compounds, for example at the same concentration (as when comparing two related compounds in detail to determine relative potency) or when comparing the effects of two different compounds. tested at their respective IC50 values on prototheramutein and the corresponding theramutein. The experienced researcher will readily recognize other useful variations and comparable conditions.

Therefore, in a representation of the application of this approach, substances that are most effective against theramutein have a "positive specificity range". A "zero, zero or none" specificity range indicates that there is no significant measurable difference between the effect of a substance on theramutein compared to its effect on prototheramutein (but these compounds can be very useful in their ability to inhibit or activate a theramutein. and its corresponding prototheramutein), and a "negative specificity range" indicates a substance that at a given concentration is less effective against the cited theramutein than against the corresponding prototheramuein form or its comparative form of theramutein (such as one that can host a different mutation). This latter category is generally of less interest than previous categories of compounds, except where the compound is so potent that its relatively minor effect on theramutein is not of real interest from the perspective of therapeutic efficacy. The seasoned researcher can easily recognize a variety of approaches to quantifying the specificity range assessment in ways tailored to their needs.

The invention also provides a means for identifying compounds exhibiting a desired range of specificity. These compounds can be identified, and their ability to inhibit or activate theramutein is determined using an in vitro cell-based assay system in which the effect of a substance on the cellular functioning of the endogenous protein-mutated form is compared to the effect on same drug in cellular functioning in an endogenous way without protein mutation.

Therefore, the system allows the discovery of compounds capable of binding to a Theramutein and exerting a greater modulating effect on the cellular functioning of the mentioned theramutein than on its corresponding prototheramutein. Furthermore, the system allows the discovery of compounds capable of binding to a theramutein and exerting at least one modulating effect as large or greater on the cellular functioning of a theramutein than previously known compounds are capable of exerting on the corresponding prototheramutein. In a particular embodiment of the invention, a compound may be screened and identified so that 1) is at least as effective against theramutein as the parent drug is against prototheramutein, and / or 2) is similarly effective against prototheramutein as against theramutein. (ie, exhibit a small or essentially zero specificity range).

In one embodiment of the invention, cells expressing excess theramutein of interest are used to identify chemical agents that are inhibitors or activators of (ie, bind to and inhibit or bind to and activate) at least the selected theramutein. Chemical agents may also be prototheramutein inhibitors or activators or even other theramuteins of the same prototheramutein. As used herein, the terms "chemical agent" and "compound" are used interchangeably, and both refer exclusively to substances that have a molecular weight of up to, but not including, 2000 atomic mass units (Daltons). These substances are occasionally referred to as "small molecules". Except as otherwise specified, the term substance as used herein refers exclusively to chemical agents / compounds and does not refer to biological agents. As used herein, "biological agents" are molecules that include proteins, polypeptides and nucleic acids and have molecular weights equal to or greater than 2000 atomic mass units (Daltons).

In one embodiment of the invention, a theramutein is selected and used in a cell response-based cellular assay system of the present invention for identifying agents that are theramutein inhibitors or activators. Where two or more distinct theramuteins originate from the same prototheramutein are known, it is preferable to select the most resistant theramutein available for use in the assay system. In general, the degree of resistance of a theramutein to a given chemical agent is determined relative to its mutant counterpart (prototheramutein), using the drug that was first administered and known to inhibit or activate the prototheramutein against which theramutein "arose. " Methods of determining the degree of such resistance, for example by analyzing IC 50 or AC 50 values, are well known and standard in the art and will not be reiterated here. However, no causal relationship is necessary or must be concluded between the patient's treatment with a particular therapeutic agent alone and the subsequent appearance of a theramutein. What is required to practice the invention is that a true theramutein must be correctly selected according to the explanations herein.

Therefore, for example, randomly generated site-directed known protein mutants that are created in the laboratory but have not been clinically relevant are not suitable muteins for use within the scope of this invention. These muteins would not be properly classified as theramuteins.

For example, in an effort to obtain potential inhibitors of p210Bcr-Abl mutants, Huron et al. (2003) used a recombinant c-abl preparation and screened a number of compounds known to inhibit c-src tyrosine kinase activity. The authors performed c-abl kinase assays on their compounds and identified the most potent compound as an 8 nM inhibitor against c-abl. However, when this compound (PD 166326) was tested against several p210Bcr_Abl theramuteins, it showed activity against some of the mutants, such as p2ioBcr-Abl_E255K, but theramutein p2ioBcr_Abl-T3151 remained 10 times more resistant (Huron et al. 2003, Table 3). . Furthermore, in each case, the compound was still notably less effective on p210Bcr-Abl theramuteins than it was against wild-type p210Bcr-Abl. When the compound was tested against the activity of the p210Bcr ~ Abl ~ T3151 mutant, it did not inhibit activity at any considerable level (p. 1270, left column, second paragraph; see also Figure 4). Therefore, the disclosed compound inhibited a theramutein that is partially resistant to STI-571, but showed no activity against the Bcr-AbL T315I mutant, which was already known at the time to be theramutein that exhibited most resistance to STI-571. Therefore, Huron's methodology failed to identify an effective theramutein p210Bcr-Abl-T315I inhibitor.

However, prior to the disclosure of this invention, including the detailed methodology first described and also the compositions provided herein, there was no success anywhere in the world in identifying a chemical agent, not to mention a methodology that is capable of identifying a chemical agent that effectively inhibits theramutein p2ioBcr-Abl "T3151 at an intensity equal to or greater than that of STI-571 is able to obtain relative to wild-type p210Bcr" Abl protein. (See Shah et al, Science, July 2004; OHare et al., Blood, 2004; Tipping et al., Leukemia, 2004; Weisberg et al., Leukemia, 2004).

There can be no overemphasis on saying that such compounds would be immensely useful, because at the moment there is no alternative for patients progressing to imatinib mesylate-resistant status mediated by theramutein p2ioBcr "Abl" T3151. Once patients develop this resistance, there is no other effective alternative treatment and death is certain. The method described here provides the first reported approach to identify, pharmacologically characterize and chemically synthesize the effective inhibitors of theramutein p210Bcr "Abi-T315I. In addition, the experienced researcher will immediately recognize the applicability and generalization of his approach to any highly resistant to theramutein. damn it.

In the present invention, a test cell that exhibits a carefully selected phenotypic trait (as defined below) that is linked to the presence and functional activity of theramutein of interest (TOI) in the cell under appropriate conditions is used. This must be qualitatively equal to the phenotypic characteristic exhibited by a cell expressing prototheramuein. A phenotypic characteristic (ie, a non-genotypic characteristic of the cell) is a property that is observed (measured), selected and / or defined for subsequent use in an assay method as described herein. The expression of the phenotypic characteristic is responsive to the total activity of theramutein in the cell and is a result of the absolute amount of theramutein and its specific activity. Often the phenotypic characteristic is observed as a result of

High levels of theramutein activity are not apparent in cells expressing low amounts of theramutein or low amounts of their corresponding prototheramutein. In addition, it can always be demonstrated that the phenotypic characteristic is modulated by modulating theramutein specific activity with a theramutein inhibitor or activator, although this is not always the case, as a TOI inhibitor or activator may not always be available in moment when the experienced researcher is in charge of such project. Therefore, for the purpose of defining the phenotypic characteristic to be used subsequently with a given test cell

For testing purposes, the experienced researcher may also use a substance capable of increasing or decreasing theragene expression, which in turn leads to increases or decreases in the corresponding theramutein level. This allows the seasoned researcher to simulate the effects of certain types of theramutein activators or inhibitors (such as a suicidal theramutein inhibitor, which is a class of chemical agent that binds irreversibility and co-modifies TOI, making it permanently inactive), without actually having access to this compound, for the purpose of refining the appropriate phenotypic characteristic to subsequently establish a useful cellular assay system. Known examples of a person of common knowledge that would be useful for such purposes include the use of antisense DNA oligonucleotides, low interference RNAs, other RNA interference-based methodologies, and induction promoter systems that contain vector structures. Thus, the phenotypic characteristic selected is linked to theramutein activity in the test cell.

Particularly for theramuteins, the selected phenotypic characteristic is generally also exhibited by a cell expressing prototheramutein in excess and this phenotypic characteristic is modulated by known prototheramutein inhibitors or activators.

A phenotypic trait is simply a trait of a cell in addition to a genotypic trait of the cell. Except for specific requirements of a suitably defined phenotypic characteristic as disclosed herein for the purpose of creating cellular assay systems useful in accordance with the instructions of the embodiments of the invention, no further limitation on the phenotypic characteristic of any kind or nature is intended or appropriate for use. proper and effective practice of the invention. Indeed, the seasoned practitioner should be able to select any cell trait that maximizes the usefulness of establishing the appropriate cell-based assay for his needs. The phenotypic characteristic may be quantitative or qualitative and may be observable or measurable directly (eg observable with the naked eye or with a microscope), but more commonly, the characteristic is measured indirectly using standard automated laboratory equipment and assay procedures that are known. by an expert in the art. The term "observable" means that a characteristic may be measured or detectable under appropriate conditions by any means, including the use of any available laboratory instrumentation. The term "detectable" is not the same as "detected". A feature may be detectable to an experienced practitioner undetected at any time, depending upon the mode chosen by the researcher to designate the assay system. For example, when looking for activators of a prototheramutein (or theramutein), it may be better to have the relevant phenotypic characteristic detected only after the inclusion of a known activator or to test the substance capable of activating the POI. This provides the ability to maximize the signal strength generated by the test cell in the assay.

Phenotypic characteristics include, but are not limited to, growth characteristics, transformation state, differentiation state, substrate phosphorylation state, catalytic activity, ion flux across the cell membrane (calcium, sodium, chloride, potassium, hydrogen ions, etc. .), pH changes, fluctuations of second messenger molecules or other intracellular chemical species such as cAMP, phosphoinositides, cyclic nucleotides, gene expression modulations and the like. The cell characteristic can be observable or measurable continuously (e.g., the growth rate of a cell), either after a period (eg terminal density of a cell culture) or in a transient manner (eg modulation of a cell culture). mutein causes transient change in phosphorylation of a mutein substrate or transient flux in ion flux across the membrane (or increases or decreases in intracellular cAMP levels). In certain embodiments, a phenotypic feature can be detected only in the presence of a prototheramutein or theramutein modulator. No limitations are determined with respect to a characteristic that can be selected for measurement. As used herein, the terms "cell characteristic" and "phenotypic characteristic" and simply "characteristic", when used to refer to the particular measurable property of the intact cell or a subcellular fraction of the cell after treatment of a test cell. with one substance, are identical. For example, a phenotypic feature may be focus formation that becomes observable when a cell expressing an excess of a selected protein is cultured in the presence of a protein activator or may be a transient increase or decrease in the level of a metabolite or ion. such as cAMP, calcium, sodium chloride, potassium, lithium, phosphatidylinositol, cGMP, bicarbonate, etc. It is obvious to one of ordinary skill in the art that after a cell is exposed to a test substance, the measured (analyzed) characteristic can be determined in a subcellular fraction of the cell. However, initial treatment of the cell with a substance, which causes the substance to come into contact with the cell, should be performed on the intact cell, not on a subcellular fraction.

The characteristic selected for measurement within the cell should not be an intrinsic physical or chemical property of theramutein or prototheramutein (such as the simple amount (mass) of protein within the cell), but should be a characteristic that results from theramutein activity within the cell. affecting a cell characteristic that is distinct from theramutein itself, as described in detail above. For example, where theramutein is a protein kinase that is capable of autophosphorylation, a process by which the enzyme is able to catalyze its phosphorylation by transferring a group of ATP terminal phosphates to itself would NOT be appropriate. select the TOI phosphorylation state as an appropriate phenotypic cell characteristic for measurement. This is because this type of trait does not reflect TOI activity in other cellular components. As the experienced researcher knows, autophosphorylation is not necessarily a reflection of the activity of a protein kinase in a cell, since protein kinase mutants are known to retain sufficient enzyme activity to undergo autophosphorylation, even though they lose their ability to engage. transduction events within the cell. The classic paper by White et al. (1988) is educational and noteworthy in this regard.

The term "responsive phenotypic characteristic" means a cell characteristic that is responsive to inhibitors or activators of a given protein (including, for example, a prototheramutein or theramutein). The term "known therapeutic agent" is defined as any agent that has been administered to a human for treating a disease in a country of the world.

A useful phenotypic feature, as exemplified herein, in association with p210Bcr "Abl and its theramuteins, is the deregulation of cell growth and proliferation. It is noted that the same or similar assay may be appropriate for use with many different proteins of interest. For example, growth, proliferation and / or differentiation dysregulations are common phenotypic characteristics that may result in overexpression of a variety of different cellular proteins.It is an important instruction of this invention that in overexpressing a protein selected to obtain the appearance of a phenotypic trait, the trait becomes linked to the presence, amount, and specific activity of that selected protein under appropriate conditions, and this binding allows the experienced researcher to identify inhibitors or activators of a theramutein of interest (TOI) as desired. character Phenotypic eristics is responsive to changes in the level and / or specific activity of the selected protein. This responsive phenotypic feature is referred to herein as "fenorresponse," and the conception and recognition of this highly useful property of a cell represents one of the considerable advances of this invention over the prior art, including the Applicant's own original work in the general area of cell-based assays (U.S. Patent Nos. 4,490,281; 5,266,464; 5,688,655; 5,877,007). Identification is the selection of the phosphorus provide the experienced researcher with a cellular assay system that is extremely sensitive in terms of its ability to identify TOI inhibitors or activators and thus identifies chemicals with a much higher degree of assurance than any other related assay method disclosed in the prior art.

Although not always necessary, it will always be advantageous to employ cells expressing high levels of theramutein and to select a phenotypic trait that results from overexpression of theramutein. This is because the phenotypic characteristics linked to the functioning of theramutein generally become more distinguishable (easier to measure) when a theramutein is overexpressed at a higher level. In addition, the phosphorus responses observed in response to theramutein modulators are always magnified when the theramutein functional level is elevated. In other words, the phosphorus observed in theramutein-overexpressing cells is particularly sensitive to theramutein modulators.

Preferably theramutein is firmly expressed in a test cell. Stable expression results in a level of theramutein in the cell that remains relatively unchanged during the course of an assay. For example, stimulation or activation of a component of a signaling pathway may be followed by an immune period during which signaling is inhibited due to down-regulation of the component. For theramuteins of the invention, such down-regulation is generally far exceeded by the artificially over-expression of theramutein. Expressed otherwise, the expression is sufficiently maintained that changes in a phenotypic trait observed during the course of an assay occur mainly because of theramutein inhibition or activation, not a change in its level, even if down modulation of theramutein occurs subsequently. For these reasons, although stable expression of theramutein is preferred, transfection after transient expression of theramutein may be employed provided that the selected phenotypic characteristic is measurable and the duration of the assay system is short relative to the progressive decline in levels. of the transiently expressed theramutein that is expected in these systems over time. For these reasons, stably expressing cell lines is preferred (U.S. Patent No. 4,980,281).

A preferred drug screening method of the present invention involves the following:

1) Identification of a theramutein for which a new inhibitor or activator is intended. Identification of an appropriate theramutein can be performed using standard techniques (See, Gorre et al., Science, 2001; see also PCT / US02 / 18729). In summary, patients who have participated in a therapeutically effective treatment using a known or suspected prototheramutein activator or inhibitor and who have subsequently shown clinical signs and symptoms consistent with disease recurrence are identified, and cell or tissue samples derived from these patients are obtained. Using standard laboratory techniques such as RT-PCR, the prototheramutein sequence is determined and compared to the nucleic acid sequence previously determined from the known prototheramutein gene or cDNA sequence. Mutations, if present, are identified and correlated with the functional resistance of prototheramutein function in cell-based or, more commonly, cell-free assay systems using the standard methodology. Once the resistance-inducing mutations are confirmed, then one or more confirmed mutants consist of a theramutein which can be used in subsequent methods as described herein.

2) Provision of a test cell that expresses a theramutein of interest and exhibits an observable (measurable) phenotypic characteristic that was previously considered responsive to theramutein inhibitors or activators or, more commonly, the corresponding prototheramutein. This type of phenotypic characteristic that has previously been shown to be responsive to theramutein inhibitors or activators of interest (TOI), and / or prototheramutein of interest (pTOI, prototheramutein of interest) is defined herein as "fenesponse". One embodiment of this invention is the definitive use of the phosphorus for the purpose of identifying compounds that are likely TOI inhibitors or activators. This can be achieved through the use of high throughput screening using a cell line that produces a particular TOI and for which an appropriate response has been identified and characterized. Alternatively, high throughput primary screening may be used using a more generic phenotypic feature of a cell line (which is not qualified as a response in accordance with the instructions provided here) and then using secondary screening. according to the instructions provided herein to distinguish between compounds that are true positive "hits", ie theramutein inhibitors or activators of interest, from false positive compounds that are not theramutein inhibitors or activators of interest. In one embodiment, a cell is selected to naturally express theramutein so that a responsive phenotypic trait is present under appropriate culture conditions that are obvious to a person of ordinary skill in the art. In other representations, theramutein is overexpressed, in some cases in a hosting cell that does not express theramutein. This usually involves the construction of an expression vector from which theramutein can be introduced into a suitable and overexpressed hosting cell using standard vector systems and methodology. (Gorre et al., 2001; Housey et al., 1988). In one representation, overexpression results in a level of theramutein that is at least about 3 times the amount of protein generally present in a cell. Alternatively, the amount is at least about 10 times the amount usually present in a cell. In another embodiment, the amount is at least about 20 times or more, preferably at least 50 times, the amount generally present in the cell.

3) Provision of a control cell expressing the corresponding prototheramutein for theramutein of interest. Since some of the muteins described herein are also enzymes, they generally retain catalytic activity and therefore the control cell generally exhibits considerably the same phenotypic characteristic as the test cell. However, the phenotypic characteristic need not be quantitatively similar in both cells. For example, a mutation that leads to prototheramutein reactivation may also increase, decrease, or affect its specific activity with respect to one or more substrates in the cell. As a result, it can display the phenotypic trait to a greater or lesser extent. Therefore, it may be desirable in some cases to adjust the expression of either or both prototheramutein and theramutein so that the test and control cells exhibit a phenotypic characteristic to approximately the same degree. This can be done, for example, by expressing promoter proteins whose activity can be adjusted by adjusting the amount of inducer present, all using standard methodology (see, for example, Sambrook et al. 1989 and 2001).

It will be obvious to a person of ordinary skill in the art that a properly defined phosphorus may be quantitatively different between the prototheramutein and theramutein expressing cell lines as a result of differences in specific activity (if any) between theramutein and its corresponding prototheramutein. Mutations that induce theramutein may increase or decrease the specific activity of the cited theramutein relative to the corresponding prototheramutein. When comparing a theramutein expression cell to a prototheramutein expression cell line, it is preferable that the selected phosphorus be qualitatively the same in both cell types. Therefore, the experienced researcher may choose to normalize the activity of the theramutein-expressing cell line to the prototheramutein-expressing cell line, or vice versa. These normalization methods are standard in the art. See, for example, Bolstad et al. (2003).

Alternatively, the experienced researcher may also use unmodified host cells or host cells that host only the expression vector as control cells for certain experimental procedures. (Host cells are cells into which an expression vector encoding theramutein has been introduced to generate the test cells.) This may be the case where the researcher is solely interested in identifying the specific theramutein inhibitor or activator of interest, without considering whether or not the compound cited is also effective against prototheramutein of interest (pTOI).

4) Test and control cells are maintained or propagated (though not necessarily at the same time) in the growth medium (or even in intact animals) under appropriate conditions such as that the response can be expressed and analyzed. Control cells expressing prototheramutein can be treated with a known prototheramutein modulator, or with a test substance, and test cells are treated with test compounds to determine if they are active against theramut ein when measured by their ability. of the aforementioned substances in modulating the phosphorus in the expected manner. Alternatively, control cells that do not express prototheramutein may also be replaced, depending on the particular response that the experienced researcher has chosen to study. Substances can be analyzed in the test cells and optionally in the control cells at the same time, or at another time, and the results compared.

In one embodiment of the invention, substances that are active with respect to test cells can be readily identified by their ability to modulate the test cell phosphorus in the same way that, for example, the known prototheramutein modulator alters the phosphorus cell response. control expressing prototheramutein. In another embodiment, active substances can be identified by their ability to modulate theramutein activity in test cells, although they have little or no effect on unmodified control cells (prototheramutein and / or theramutein). The skilled researcher will readily notice the many variations of this approach that can be used to identify, for example, modulators that are most effective against theramutein or that are equally effective against prototheramutein and one or more corresponding specific theramuteins.

Other phenoresponders may be observed and / or measured and include, for example, detection of prototheramutein substrates and detection of gene expression changes that are regulated by theramutein activity. In simplest terms, any cell characteristics that the experienced researcher has previously correlated with theramutein functional activity may be suitable for use with these methods. However, when selecting a particular trait, the experienced researcher must first verify that the cited trait meets the criteria of being a response in accordance with the instructions presented in detail here. The experienced researcher may also normalize the repertoire with theramutein-expressing cells to those of prototheramutein-expressing cells.

Suitable detection characteristics can be measured by a variety of methods well known to one skilled in the art. Such methods include, but are not limited to, fluorescence detection of appropriately labeled proteins (FACS), immunohistochemistry (IHC) for detection of protein expression, competitive radioligand binding assays, solid matrix blotting techniques such as " Northern ", Southern" and "Western blot" cell extracts, reverse transcriptase polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assays (ELISA), phosphorylation assays, gel retardation assays, potential membrane disorders and the like. The relevant phenotypic characteristic can be detected in the intact cell after treatment with a test substance, or alternatively in a subcellular fraction of the cell after treatment of the intact cell with a test substance.

Once the compounds are identified to have the desired effect on theramutein-expressing test cells, it may be desirable (but not necessary) to independently verify whether the identified compounds exert their effects on theramutein by a direct binding mechanism, or that is, whether the compounds meet the criteria of being theramutein inhibitors or activators (as desired) according to the instructions of the invention (definitions of the terms "activator" and "inhibitor" are explained to the reader as mentioned above). This can be accomplished with a number of standard binding assays known to one of ordinary skill in the art involving purified protein samples or intact cell binding assays using appropriate prototheramutein or theramutein transfected cells together with appropriate controls. as decreed by the scientific methods presented. Since such methods are well established in the art, they will not be reiterated here. Several reference texts widely discuss such techniques (see, for example, Foreman and Johansen, 2002; Enna SJ. Et al. (1991) Current Protocols in Pharmacology, Wiley & Sons, Incorporated; Bonifacino, JS et al. (1999) Current Protocols in Cell Biology, Wiley & Sons, Incorporated). See also Housey, G.M. 1988, Chapters 4, and references; see also Horowitz et al., 1981.

In a particular embodiment of the invention, the method is used to identify substances that are theramutein p210Bcr "Abl_T3151 inhibitors. Protheramutein and theramutein are each expressed in Ba / F3 (murine) cells using standard methodology, and the phosphorus that is observed are growth characteristics (terminal cell density for a carefully defined cell culture and growth in the absence of interleukin-3 (IL-3). Unmodified host cells, or host cells that contain only the expression vector or both, may also In yet another embodiment, the test cells alone may be used with or without reference to a known inhibitor or activator.

Another useful test is the determination of the phosphorylation state of a p2ioBcr "Ab1" 3151 direct substrate. Such a substrate is Crk1 (Gorre et al., Science 293: 876-80 (2001)), an adapter protein that mediates the connection between Bcr-Abl and Ras. The CRKL phosphorylation state is representative of p210Bcr_Abl signaling activity in a cell. Another downflow substrate is p62DOK. Any substrate would be sufficient for these purposes as long as phosphorylation of said substrate occurred within the cell and was not simply a TOI or PTOI autophosphorylation event as described above. Other cascade components of signal transduction may also be monitored, including src family kinases, STAT5, Kinase PD, raf kinase, RAS, MEK, ERK1 and ERK2, JNK1, 2 and 3, MLK1, 2 and 3, ΜΚΚ4 , ΜΚΚ7, ΑΚΤ, mTOR, HSP90 and others.

As exemplified herein, theramutein T315I inhibitors have been identified. In addition, these inhibitors are also active at different levels from wild type prototheramutein p210Bcr-Abl-wt.

In accordance with the present invention, a therapeutically effective amount of one or more compounds that modulate the functional activity of a theramutein p210Bcr_Abl is administered to a mammal in need thereof. The term "administration" as used herein means applying the compounds of the present invention to a mammal by any method that can achieve the intended result. They may be administered, for example, orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation. The term "mammal" as used herein includes, but is not limited to, humans, laboratory animals, domestic animals, and farm animals. "Therapeutically effective amount" means an amount of a compound which, when administered to a mammal is effective in producing the desired therapeutic effect, such as inhibition of kinase activity, inhibition of cancer cell growth and division, etc.

The invention provides a method of treating disease in a mammal by administering to the mammal an effective amount of a theramutein modulator. Diseases to be treated in accordance with the present invention include, but are not limited to, recurrent neoplasia or other proliferative disorders that have become resistant to previously administered drugs. The method is also useful for overcoming the variation among individuals regarding susceptibility to drug treatment that results from allelic differences between therapy targets. For example, the tyrosine kinase function of pML10Bcr_Abl signaling in CML has been extensively demonstrated as it has the function of p210Bcr "Abl theramuteins in CML drug resistant recurrence. In addition, the different p210Bcr_Abl muteins exhibit varying sensitivity to CML inhibitors. p210Bcr "Abl. Although some theramuteins appear during drug therapy, others may pre-exist in the population. These latter examples will not be recognized as theramuteins until this time, as the disease state continues and is followed by treatment with a known class of therapeutic agents. Only after the aforementioned treatment will such pre-existing theramuteins prove clinically significant in terms of unresponsiveness leading to disease progression in the theramutein host patient.

In one embodiment of the invention, theramutein modulators are administered in combination with one or more antineoplastic agents. Any suitable antineoplastic agent may be used, such as a chemotherapeutic agent, its radiation or combinations. The antineoplastic agent may be an alkylating agent or an antimetabolite. Examples of alkylating agents include, but are not limited to, cisplatin, cyclophosphamide, melphalan and dacarbazine. Examples of antimetabolites include, but are not limited to, doxorubicin, daunorubicin and paclitaxel, gemcitabine and irinotecan of topoisomerase inhibitors (CPT-Il), aminocamptothecin, camptothecin, DX-8951f, topotecan (topoisomeride inhibitor I-VP) and etoposide 16; topoisomerase II) and teniposide (VM-26; topoisomerase II inhibitor). When an antineoplastic agent is radiation, the source of radiation may be external (external beam radiation therapy - EBRT) or internal (brachiotherapy - BT) to the patient being treated. The dose of antineoplastic agent administered depends on a number of factors, including, for example, the type of agent, the type and severity of the tumor being treated and the route of administration of the agent. However, it should be emphasized that the present invention is not limited to any dose, route of administration or combination of chemotherapeutic agents or other particular therapeutic control that is combined with administration of theramutein modulators.

Antineoplastic agents that are currently known in the art or in the art may be grouped into several classes, including, for example, mitotic inhibitors, alkylating agents, antimetabolites, intercalation antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes. , topoisomerase inhibitors, anti-survival agents, biological response modifiers, anti-hormone agents and anti-angiogenesis, all of which may be administered with theramutein inhibitors or activators.

A modulator of theramutein may be administered with antibodies that neutralize other receptors involved in tumor growth. In addition, a theramutein modulator may be administered with a compound that modulates a component of a signal transduction pathway, preferably a component of the signal transduction pathway in which theramutein is active and which is common for one or more pathways. of signal transduction. In one embodiment of the invention, a theramutein modulator is used in combination with a receptor antagonist that specifically binds to the Epidermal Growth Factor Receptor (EGFR). Particularly preferred are antigen binding proteins that bind to the extracellular domain of EGFR and block the binding of one or more of these ligands and / or neutralize ligand-induced activation of EGFR. An EGFR antagonist may be an antibody that binds to EGFR or an EGFR ligand and inhibits EGFR binding to its ligand. Ligands for EGFR include, for example, EGF, TGF-α, anfiregulin, heparin binding EGF (HB-EGF) and betacellulin. EGF and TGF-α are considered to be the major endogenous ligands that result in EGFR-mediated stimulation, although TGF-a has been shown to be more potent in promoting angiogenesis. It should be noted that the EGFR antagonist may bind externally to the extracellular portion of EGFR, which may or may not inhibit ligand binding or internally to the tyrosine kinase domain in the case of chemical agents. Examples of EGFR antagonists that bind EGFR include, but are not limited to, biological agents such as EGFR-specific antibodies (and their functional equivalents) and chemical agents (small molecules) such as synthetic kinase inhibitors that act directly on the EGFR cytoplasmic domain.

Other examples of growth factor receptors involved in tumorigenesis are receptors for vascular endothelial growth factor (VEGFR-I and VEGFR-2), platelet-derived growth factor (PDGFR), nerve growth factor (NGFR), fibroblast growth factor (FGFR) and others.

In a combination therapy, theramutein inhibitor is administered before, during or after initiation of therapy with another agent and also as a combination thereof, ie before and during, before and after, during and after or before, during and after. starting antineoplastic agent therapy. For example, the theramutein inhibitor may be administered between 1 and 30 days, preferably 3 and 20 days, more preferably between 5 and 12 days, prior to initiating radiation therapy. In a preferred embodiment of the invention, chemotherapy is administered prior to, concurrently with or more preferably after antibody therapy.

In the present invention, any suitable method or route may be used for administering theramutein inhibitors of the invention and optionally co-administering antineoplastic agents and / or antagonists of other receptors. Antineoplastic agent regimens used in accordance with the invention include any regimen believed to be suitable for treating the patient's neoplastic condition. Different malignancies may require the use of specific antitumor antibodies and specific antineoplastic agents that will be determined on a patient-by-patient basis. Routes of administration include, for example, oral, intravenous, intraperitoneal, subcutaneous or intramuscular administration. The dose of antineoplastic agent administered depends on a number of factors, including, for example, the type of agent, the type and severity of the tumor being treated and the route of administration of the agent. However, it should be emphasized that the present invention is not limited to any particular method or route of administration.

Suitable carriers include, for example, one or more of water, saline, phosphate, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof. Carriers may consist of smaller amounts of auxiliary substances, such as wetting and emulsifying agents, preservatives and buffers, which may enhance the life or effectiveness of the theramutein modulator as an active ingredient. The compositions may, as is well known in the art, be formulated to provide rapid, sustained or delayed release of the active ingredient upon administration to a mammal.

The compositions of this invention may be of various forms. They include, for example, solid, semi-solid and liquid dosage forms such as tablets, pills, powders, liquid solutions, dispersions or suspensions, liposomes, suppositories, injectable and infusion solutions. The preferred form depends on the intended mode of administration and therapeutic application.

Such compositions of the present invention are prepared in a manner well known in the pharmaceutical art. In the manufacture of the composition, the active ingredient will generally be mixed with a carrier which may, for example, be in the form of a capsule, sachet, paper or other container. When the carrier acts as a diluent, it may be a solid, semi-solid or liquid material that acts as a carrier, excipient or medium for the active ingredient. Therefore, the composition may be in the form of tablets, lozenges, sachets, capsules, elixirs, suspensions, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of active compound, capsules. soft or hard gelatin, suppositories, injection solutions, suspensions, sterile post-packs and as a topical adhesive.

It should be noted that the methods and compositions of the present invention may be administered to any suitable mammal, such as rabbit, rat or mouse. More preferably, the mammal should be a human being.

The compounds according to the invention may also be present as salts. In the context of the invention, preference is given to pharmaceutically acceptable salts. Pharmaceutically acceptable salts refer to an acid addition salt or basic addition salt of a compound of the invention wherein the resulting counter ion is understood in the art to be generally acceptable for pharmaceutical uses. Pharmaceutically acceptable salts may be salts of the compounds according to the invention with inorganic or organic acids. Preference is given to salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid or salts with organic or sulfonic carboxylic acids such as acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts may also be metal or ammonium salts of the compounds according to the invention. Particular preference is given to, for example, sodium, potassium, magnesium or calcium salts and also ammonium salts which are derived from ammonia or organic amines, such as, for example, ethylamine, di- or triethylamine, di- or triethanolamine, dicyclohexylamine. dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine. (see Bhadra et al. J Pharm. Sd. 1977, 66, 1-19).

Throughout this application, various publications, reference texts, textbooks, technical manuals, patents and patent applications have been consulted. The instructions and disclosures of these publications, patents and patent applications in their entirety are included herein by reference in this application to more fully describe the latest in the field to which this invention belongs.

It should be understood and expected that variations in the principles of the invention disclosed herein may be made by one skilled in the art and such modifications should be included within the scope of the present invention.

The following examples also illustrate the invention, but should not be construed as limiting the scope of the invention. Detailed descriptions of conventional methods, such as those employed in constructing vectors and plasmids, insertion of genes encoding polypeptides into these vectors and plasmids, introduction of plasmids into host cells, and expression and determination of gene and gene products may available from various publications, including Sambrook, J et al., (1989) Molecular Cloning: A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory Press; Coligan, J. et al. (1994) Current Protocols in Iminunology, Wiley & Sons, Incorporated; Enna, SJ. et al. (1991) Current Protocols in Pharmacology, Wiley & Sons, Bonifacino, J.S. et al. (1999) Current Protocols in Cell Biology, Wiley & Sons and U.S. Patent 4,980,281. All references mentioned here are included in their entirety.

Examples

It should be understood and expected that variations in the principles of the invention disclosed herein may be made by one skilled in the art, and such modifications should be included within the scope of the present invention.

The following examples of the invention are explained to illustrate the invention and should not be construed as limiting the invention.

EXAMPLE 1: IDENTIFICATION OF A THERAMUTEIN MODULATOR p210Bcr_Abl "T3151 is a theramutein of the protein p210Bcr-Abl (p210Bcr-Abl) that is resistant to inhibition by imatinib mesylate (Gleevec, STI-571). The modulation at position 315 converts is an isoleucine residue and is one of several mutations observed among resistant or relapsing patients, but this particular mutant is the most resistant theramutein ever identified.

A response has been determined for a Ba / F3 cell line designed to overexpress theramutein p2ioBcr ~ Abl_T3151. Phenoresponse was determined for untransformed Ba / F3 cells and Ba / F3 cells expressing prototheramutein p210Bcr-Abl-wt. Phenoresponse was the ability of T315I mutants to grow at a higher cell saturation density under analogous culture conditions as compared to the control untransformed Ba / F3 cell line and grow in the absence of interleukin 3 (IL-3). , which is required for maintenance of the untransformed control Ba / F3 cell line. The response has been defined and characterized according to the explanations given above.

The detection system used was a high-speed cell counting and imaging system in which sample volumes of 3 μl of cells were sequentially injected through a 5 μl optical microcell with a digitally generated and electronically stored image. swept and then counted, all in a microcomputer-based control system. The system has the ability to perform direct cell counts on sample cultures as small as 500 μl and provides statistically significant total counts from culture samples containing only 12,500 cells. All figures displaying cell viability and count analyzes used this system for data collection and analysis. Simultaneously with the performed cell count, the system is also able to determine cell viability by distinguishing contacted and image generated cells that have been excluded by trypan blue (contacted as "viable" cells) from cells that have used staining. trypan blue (counted as "non-viable" cells). Trypan blue injection into the cell sample occurs just before the sample is sequentially injected into the microcell for cell counting and simultaneous cell generation.

The system can be integrated into the workflow of high throughput screening devices to provide a more accurate, sensitive and accurate cell count and viability analysis system that is less prone to confusing effects of metabolic viability-based cell analysis such as XTT or Blue wing.

Initially, approximately 113,000 compounds were screened at concentrations generally from 10 to 20μΜ to identify a subset that was capable of affecting the growth of Ba / F3 cells (Ba / F3 T315I cells) that overexpressed theramutein p2ioBcr-Abl-T3151 by any one. middle.

A total of approximately 11,760 compounds showed growth inhibition above 50%, which was considered to correspond to approximately 4,500 distinct chemical classes. Retesting these compounds with the same cell line yielded a composite responsiveness database that was rated, and the rating was sorted according to the compounds that exhibit the highest overall growth inhibition. From this ranked database, compounds scoring 130 (based on the highest degree of growth inhibition observed at the lower concentrations that the compounds were tested) were re-screened in a cell-based analysis system using Ba / F3 T315I as test cells and wild type Ba / F3 as control cells according to the methods of the present invention. Compounds of interest were those that inhibited the growth of Ba / F3 cells expressing theramutein p210Bcr-Abi-T315I relative to wild type Ba / F3 cells.

unprocessed. Six compounds were identified and met the desired criteria and some of these compounds were further analyzed using Ba / F3 p210Bcr-Abl-wt cells (Ba / F3 P210 cells). A compound was unavailable for further testing due to the unavailability of additional material from the chemical supplier. The remaining five compounds were independently evaluated in additional cell-based analyzes using the aforementioned cell lines and also in a cell-free purified protein kinase analysis using recombinantly produced human 120 kd domain kinase domain fragments. of the wild-type P210 Bcr-Abl mutant kinase domain and also P210 T315I.

All five compounds inhibited the 120 Kd activity of p2χoBcr "Abl ~ T3151 r according to the measurement by inhibition of autophosphorylation activity, as shown in Figure 4. Therefore, of the six highest-scoring compounds among more than 113,000 compounds. screened, at least five of these six directly inhibited the p2IOecr "^ -" 151 mutant directly. It is worth noting that compound 5 appears to distribute the recombinant protein range in the SDS page gel. TMs were also evident in the gel It is possible that this compound may indeed be a "suicidal" inhibitor that is capable of covalently cross-linking the POI to permanently inhibit its activity, but this will require further study.

Taken together, the explanations and results described here provide conclusive proof that the system is capable of identifying selected theramutein inhibitors or activators, and experienced researchers will immediately recognize that such a system can be easily applied to any other theramutein or another protein with only minor obvious modifications.

Representative examples of cell-based analysis results demonstrating selective growth inhibition of the BA / F3 T315I cell line relative to wild-type untransformed Ba / F3 cells are shown in Figures 1 and 2. The compounds inhibited growth and reduced cell growth. viability of cells expressing theramutein T315I at concentrations at which growth and viability of wild-type untransformed Ba / F3 cells (not expressing p210Bcr-Abi-wt nor P210Bcr-Abl-T31S1) were not relatively affected, while cells expressing prototheramutein as well as theramutein were considerably inhibited. In some instances, T315I expression cells were inhibited to a greater extent than prototheramutein P210 expression cells. See, for example, Figure 3 on the right side for Compound 3 results for cells P210 and T315I.

In short, the methods presented here provide a fundamental breakthrough in the form of a generalizable approach to creating or identifying the modulators of any theramutein. The results conclusively demonstrate the method's power to critically identify the compounds needed to overcome a specific type of acquired drug resistance that is regularly fatal in certain patient groups and currently untreatable. Furthermore, it is apparent to one skilled in the art that the techniques and methods described herein can, using obvious modifications, be directly generalized to any potential theramutein of clinical significance.

It is noteworthy that, out of a primary screening of over 100,000 compounds in which about 10,000 compounds exhibited some degree of growth inhibition, when the most potent growth inhibitory substances were screened again using the method described in detail here, 6 compounds. distinct compounds were identified, and all compounds that were subsequently tested showed inhibitory activity in a cell-free purified protein kinase analysis using the T315I mutant (one compound was unavailable for further testing). Based on these remarkable results, it is immediately clear to the skilled practitioner that the method can be effectively applied to the identification of inhibitors and activators of any theramutein based on the proper selection and definition of the corresponding response according to the explanations in the previous sections and the documents included here. For reference. For example, with knowledge of the foregoing, one of ordinary skill in the art could easily designate and analyze the system to identify theramutein inhibitors derived from another prototheramuteins that exhibit drug resistance mutations, such as the c-kit gene product. or the Epidermal Growth Receptor Factor (EGF) or the Platelet Derived Growth Receptor Factor (EGF) α and β. No limitation should be considered in the utility of the method with respect to its ability to be used with any theramutein expressed in a mammalian cell type for which the corresponding phosphorus is detectable.

Representative compounds of the invention corresponding to various chemical formulas provided above were tested in the cellular analysis system described herein (see Example 1) and assigned activity categories as shown in Table I. The assigned activity categories are represented by the following designations, in IC50 for a given cell line is concentration at which a given compound inhibits growth of that cell line by 50% in the cell analysis system. Compounds tested on a given cell line that had an IC 50 value that was <300 nM (less than 300 nanomolar) were designated as Category "A" compounds. Compounds tested on a given cell line that had an IC50 value that was <1 ΙμΜ (less than 1 micromolar) were designated as Category "B" compounds. Compounds tested on a given cell line that had an IC 50 value that was <10 μΜ (less than 10 micromolar) were designated as Category "C" compounds. Compounds tested on a given cell line that had an IC50 value of> 10 μΜ (greater than or equal to 10 micromolar) were designated as "D" Category compounds.

Table 1

<table> table see original document page 174 </column> </row> <table> <table> table see original document page 175 </column> </row> <table> <table> table see original document page 176 < / column> </row> <table> The <table> table see original document page 177 </column> </row> <table> <table> table see original document page 178 </column> </row> <table > <table> table see original document page 179 </column> </row> <table> <table> table see original document page 180 </column> </row> <table>

EXAMPLE 2:

1. Synthesis of compound 2:

<formula> formula see original document page 180 </formula>

Reaction Scheme:

<formula> formula see original document page 180 </formula>

Experimental Details:

The mixture of compound 1 (25 g) and N, N-dimethylaniline (24.2 g) in POCl 3 (110 mL) was refluxed for 5 hours. POCl 3 was removed by evaporation under reduced pressure, and the residue was poured into ice water (500 g) carefully and stirred for 1 hour. The mixture was filtered, and the solid was washed with water to yield compound 2 as a yellowish solid. 2. Synthesis of compound 3: Reaction scheme:

<formula> formula see original document page 181 </formula>

Experimental Details: To a solution of compound 2 (1.04 g) in 15 ml ethanol, 1.08 g (2 eq.) Of morphine was added dropwise at -10 ° C in 15 minutes. The mixture was stirred for 0.5h and heated at 50 ° C for 15 minutes. After cooling and dilution with water (50 ml), compound 3 was obtained as a yellowish solid powder, then filtration.

3. Synthesis of compound 4: Reaction scheme:

<formula> formula see original document page 181 </formula>

Experimental Details: To 1.1 g of compound 3 was added 8 ml of NH2NH2H2O. The mixture was refluxed for 2 h. After cooling, the crude product was obtained after filtration. Purification by column chromatography afforded pure compound 4 as a light yellow solid.

4. Synthesis of compound 6: Reaction scheme: <formula> formula see original document page 182 </formula>

Experimental Details: To the solution of compound 5 (1.0 g, 1.0 eq) and DMF (0.05 g, cat. Quantity) in 20 mL of dichloromethane was added (COCl) 2 (0.81 g, 1, 1 eq) in drops. The reaction mixture was stirred at room temperature for 2 hours and then concentrated to yield 1.2 g of crude product of compound 6, which was used for the next step without further purification.

5. Synthesis of compound 7:

Reaction Scheme:

<formula> formula see original document page 182 </formula>

Experimental details: To the crude product of compound 6 (1.2 g, 1.0 eq) in 20 mL of dichloromethane was added 3-trifluoromethyl phenylamine (0.94 g, 1.0 eq) and triethylamine (0.71 g 1.2 eq). The reaction mixture was stirred at room temperature overnight, washed with 1 N NaOH solution, 1 N HCl solution and brine. The organic layer was collected, dried over Na 2 SO 4 and concentrated to yield crude product of compound 7. After purification by column chromatography, 1.1 g of compound 7 was obtained.

6. Synthesis of compound 8: Reaction scheme: <formula> formula see original document page 183 </formula>

Experimental Details: To the mixture of compound 7 (0.3 g, 1.0 eq) and 3 mL of trifluoroacetic acid was added hexamethylenetetramine (0.53 g, 4.0 eq). The reaction mixture was immediately sealed and heated at 90 ° C for 20 h. After cooling, the reaction mixture was adjusted to pH 8 with 1 N NaOH solution, extracted with dichloromethane, and the organic phase was dried and concentrated to yield a brown solid. Purification by preparative TCL yielded compound 8 as a yellowish solid. 7. Synthesis of Final Compound:

<formula> formula see original document page 183 </formula>

Experimental Details: The mixture of compound 4 (30 mg, 1.0 eq) and compound 8 (19 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature overnight. The precipitates were collected and washed thoroughly with dichloromethane and dried under vacuum to yield the desired compound.

EXAMPLE 3: <formula> formula see original document page 184 </formula>

1. Reaction scheme:

<formula> formula see original document page 184 </formula>

Experimental Details: Mixture of compound 1 (1.0 g, 1.0 eq), compound 2 (0.92 g, 1.0 eq), Na 2 CO 3 (0.77 g, 1.5 eq) in 15 mL of Dioxane was added Pd (PPh3) 4 (0.56 g, 0.1 eq), and the reaction mixture was refluxed under N2 for 16 hours. After cooling, the mixture was filtered, and the filtrate was evaporated to dryness and purified by column chromatography to yield compound 3.

2. Reaction scheme:

<formula> formula see original document page 184 </formula>

Experimental Details: To the mixture of compound 3 (0.3 g, 1.0 eq) and 3 mL of trifluoroacetic acid was added hexamethylenetetramine (0.62 g, 4.0 eq). The reaction mixture was immediately sealed and heated at 90 ° C for 20 hours. After cooling, the reaction mixture was adjusted to pH 8 with 1 N NaOH solution, extracted with dichloromethane, and the organic phase was dried and concentrated to yield a brown solid. Purification by preparative TCL yielded compound 4 as a yellowish solid.

3. Reaction scheme:

<formula> formula see original document page 185 </formula>

Experimental Details: The mixture of compound 4 (30 mg, 1.0 eq) and compound 5 (19 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature overnight. The precipitates were collected and washed with dichloromethane and dried under vacuum to yield the desired compound.

EXAMPLE 4

<formula> formula see original document page 185 </formula>

1. Reaction scheme:

<formula> formula see original document page 185 </formula>

Experimental Details: To the solution of compound 1 (0.6 g, 1.0 eq) in 10 mL of methanol was added 4 mL of 1 N NaOH solution, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was acidified to pH 6 with 5% citric acid, extracted with dichloromethane. The organic layer was dried and concentrated to yield compound 2.

2. Reaction scheme: <formula> formula see original document page 186 </formula>

Experimental Details: The mixture of compound 2 (0.4 g, 1.0 eq), trifluoromethyl phenylamine (0.39 g, 1.0 eq), EDC (0.71 g, 1.5 eq), HOBt (33 mg, 0.1 eq) in 10 mL of dichloromethane was stirred at room temperature overnight. The mixture was washed with 1 N NaOH solution, water and extracted with dichloromethane. The organic layer was dried over Na 2 SO 4, concentrated to dryness and purified by column chromatography to yield compound 3.

Experimental Details: The solution of compound 3 (0.2 g, 1.0 eq) in 10 mL of dioxane was treated with 4 mL of 1 N HCl, and the mixture was heated at 60 ° C for 2 hours. After cooling, the pH was adjusted to 8 with the addition of NaHCO3. The mixture was extracted with dichloromethane, the organic layer was washed with water, dried with Na 2 SO 4 and evaporated to dryness. The crude product was purified by column chromatography to yield compound 4.

3. Reaction scheme:

<formula> formula see original document page 186 </formula>

4. Reaction scheme:

<formula> formula see original document page 186 </formula>

Experimental Details: The mixture of compound 4 (40 mg, 1.0 eq) and compound 5 (30 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature overnight. The mixture was concentrated to dryness and purified by preparative HPLC to yield the desired compound.

EXAMPLE 5

<formula> formula see original document page 187 </formula>

1. Reaction scheme:

Experimental Details: The mixture of compound 2 (0.3 g, 1.0 eq), 2-chloro-6-methylphenylamine (0.26 g, 1.0 eq), EDC (0.53 g, 1, 5 eq), HOBt (25 mg, 0.1 eq) in 10 mL of dichloromethane was stirred at room temperature overnight. The mixture was washed with 1 N NaOH solution, water and extracted with dichloromethane. The organic layer was dried over Na 2 SO 4, concentrated to dryness and purified by column chromatography to yield compound 3.

2. Reaction scheme:

<formula> formula see original document page 187 </formula>

Experimental Details: The solution of compound 3 (0.2 g, 1.0 eq) in 10 mL of dioxane was treated with 4 mL of 1 N HCl, and the mixture was heated at 60 ° C for 2 hours. After cooling, the pH was adjusted to 8 with the addition of NaHCO3. The mixture was extracted with dichloromethane, the organic layer was washed with water, dried with Na 2 SO 4 and evaporated to dryness. The crude product was purified by column chromatography to yield compound 4.

3. Reaction scheme:

<formula> formula see original document page 188 </formula>

Experimental Details: The mixture of compound 4 (40 mg, 1.0 eq) and compound 5 (30 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature overnight. The mixture was concentrated to dryness and purified by preparative HPLC to yield the desired compound.

EXAMPLE 6

<formula> formula see original document page 188 </formula>

1. Reaction scheme:

<formula> formula see original document page 188 </formula>

Experimental Details: To a solution of 1 g (5.5 mmol) of 5-bromo-2-cyanopyridine, 0.97 g of (6.05 mmol 1.1 eq) 3- (trifluoromethyl) aniline in 100 mL of toluene was added. 3 eq t-BuONa, 0.2 eq BINAP and 0.1 eq Pd 2 (dba) 3. Then the solution was heated to reflux overnight. The reaction was monitored by LC / MS. The volatiles were removed under reduced pressure. The crude product was purified by flash chromatography to yield compound 2.

2. Reaction scheme: <formula> formula see original document page 189 </formula>

Experimental Details: 250 mg (0.95 mmol) of compound 2 was added to 20 mL of concentrated HCl, then the solution was heated to reflux until the starting material disappeared. The mixture was concentrated under reduced pressure to obtain compound 3 as a yellow solid without purification.

3. Reaction scheme:

<formula> formula see original document page 189 </formula>

Experimental Details: A solution of 50 mg (0.18 mmol) of compound 3 in 3 mL dichloromethane was added to 0.5 mL thionyl dichloride. The mixture was heated and stirred for 3 hours. Finally, the solution was evaporated under reduced pressure. Compound 4 was obtained and used in the next step without purification.

4. Reaction scheme:

<formula> formula see original document page 189 </formula>

Experimental Details: A solution of 50 mg of compound 4 and 43 mg (1.2 eq) of hydrazine in 5 mL of DCM was stirred at 25 ° C for 3 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to yield the desired compound.

EXAMPLE 7 <formula> formula see original document page 190 </formula>

1. Reaction scheme:

<formula> formula see original document page 190 </formula>

Experimental Details: A suspension of compound 1 (25 g, 0.145 mol) and SeO2 (27.5 g, 0.247 mol) in acetic acid (1200 mL) was heated to reflux for 12 hours. The reaction mixture was concentrated under reduced pressure to dryness. The residue was dissolved in water and adjusted to pH = 9 by adding K 2 CO 3. The resulting mixture was extracted with EA (100 mL * 3). The combined EA was dried over Na 2 SO 4. After filtering Na 2 SO 4, the filtrate was concentrated under reduced pressure to yield crude product 2, which was used in the next step without purification.

2. Reaction scheme:

Experimental Details: A solution 2 prepared above in triethyl orthoforniato ethanol (10 mL) was refluxed for 4 hours. After removing the solvent, the residue was separated by column to yield product 3 as oil.

3. Reaction scheme: <formula> formula see original document page 191 </formula>

Experimental Details: To a stirred and degassed mixture of compound 3 (73 mg, 0.28 mmol) and compound 4 (50 mg, 0.28 mmol) and tBuONa (27 mg, 0.56 mmol) and BINAP (70.4 mg, 1.12 mol) in toluene (15 mL) was added Pd 2 (dba) 3 (26 mg, 0.028 mmol) under N 2 atmosphere and stirred at 80 ° C for 48 hours. After filtering the solid, the filtrate was concentrated to yield crude product 5, which was used in the next step without purification.

4. Reaction scheme:

Experimental Details: A solution of compound 5 (335 mg, 0.1 mmol) in dichloromethane (10 mL) was treated as BBr3 (146 mg, 0.6 mmol) at -30 ° C under N 2 atmosphere and then It was stirred at room temperature for 4 hours. The reaction was poured into ice water and was then obtained by adding Na2CO3. The resulting mixture was extracted with dichloromethane (25 mL * 3), the combined organic layer was dried over Na 2 SO 4. After filtering Na 2 SO 4, the filtrate was concentrated to yield crude product 6, which was done in the next step without purification.

5. Reaction scheme: <formula> formula see original document page 192 </formula>

Experimental Details: A solution of compound 6 (27.74 mg, 0.1 mmol) and compound 7 (21 mg, 0.1 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

EXAMPLE 8

<formula> formula see original document page 192 </formula>

1. Reaction scheme:

Experimental Details: To a stirred and degassed mixture of compound 1 (5 g, 25 mmol) and compound 2 (3.4 g, 27 mmol) in DMF (50 mL) and aqueous Na 2 CO 3 (20 mL, 2 M) was added Pd 2 ( dbbf) 3 (26 mg, 0.028 mmol) under N 2 atmosphere and stirred at 100 ° C for 18 hours. After cooling to room temperature and filtering the solid, the filtrate was extracted with EA (200 mL). The organic layer was concentrated to dryness. The residue was purified by column to yield crude product 3.

2. Reaction scheme: <formula> formula see original document page 193 </formula>

Experimental Details: A mixture of compound 3 (2 g, 0.1 mol) and Na 2 S 2 O 4 (5.2 g, 0.3 mol) in methanol (80 mL) and H 2 O (20 mL) was heated to reflux for 3 hours. . The reaction was concentrated under reduced pressure to dryness.

The residue was dissolved in water and then extracted with EA (150 mL). The organic layer was washed with brine twice and dried with Na 2 SO 4. After filtering Na 2 SO 4, the filtrate was concentrated to yield product 4.

Experimental Details: To a stirred and degassed mixture of compound 5 (228 mg, 88 mmol) and compound 4 (150 mg, 88 mmol) and tBuONa (170 mg, 176 mmol) and BINAP (210 mg, 176 mol) in toluene ( 25 mL) Pd 2 (dba) 3 (79 mg, 0.88 mmol) was added under N 2 atmosphere and stirred at 80 ° C for 48 hours. After filtering the solid, the filtrate was concentrated to yield crude product 6.

3. Reaction scheme:

<formula> formula see original document page 193 </formula>

4. Reaction scheme:

<formula> formula see original document page 193 </formula>

Experimental Details: A solution of compound 6 (140 mg, 4 mmol) in dichloromethane (20 mL) was treated as BBr3 (600 mg, 10.6 mmol) at -30 ° C under N 2 atmosphere and then stirred at room temperature for 4 hours. The reaction was poured into ice water and then brought to pH = 9 by adding Na 2 CO 3. The resulting mixture was extracted with dichloromethane (25 mL * 3), the combined organic layer was dried over Na 2 SO 4. After filtering out the Na 2 SO 4, the filtrate was concentrated to dryness. The residue was column purified to yield product 7.

5. Reaction scheme:

<formula> formula see original document page 194 </formula>

Experimental Details: A solution of compound 7 (98 mg, 0.36 mmol) and compound 8 (64 mg, 0.3 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

EXAMPLE 9

<formula> formula see original document page 194 </formula>

1. Reaction scheme:

<formula> formula see original document page 194 </formula>

Experimental Details: To a stirred and degassed mixture of compound 1 (5.9 g, 25 mmol) and compound 2 (3.3 g, 27 mmol) in DMF (50 mL) and aqueous Na 2 CO 3 (20 mL, 2 M) was Pd 2 (dbbf) 3 (26 mg, 0.028 mmol) is added under N 2 atmosphere and stirred at 100 ° C for 18 hours. After cooling to room temperature and filtering the solid, the filtrate was extracted with EA (200 mL). The organic layer was concentrated to yield crude product 3 obtained in the next step without purification.

2. Reaction scheme:

<formula> formula see original document page 195 </formula>

Experimental Details: A mixture of 3 (6.5 g, 27.9 mmol) and Pd (OH) 2 (10%, 0.5 g) in ethanol (200 mL) was stirred under a hydrogen atmosphere (20 psi) at room temperature. room temperature for 2 hours. The catalyst was filtered off, and the filtrate was removed in vacuo to yield product 4 as a colorless oil.

3. Reaction scheme:

<formula> formula see original document page 195 </formula>

Experimental Details: To a stirred and degassed mixture of compound 4 (406 mg, 20 mmol) and compound 5 (520 mg, 20 mmol) and tBuONa (170 mg, 176 mmol) and BINAP (210 mg, 176 mol) in toluene ( 25 mL) Pd 2 (dba) 3 (79 mg, 0.88 mmol) was added under N 2 atmosphere and stirred at 80 ° C for 48 hours. After filtering the solid, the filtrate was concentrated to yield crude product 6, which is used in the next step without purification.

4. Reaction scheme: <formula> formula see original document page 196 </formula>

Experimental Details: A solution of compound 6 (383 mg, 10 mmol) in dichloromethane (20 mL) was treated as BBr3 (600 mg, 10.6 mmol) at -30 ° C under N 2 atmosphere and then stirred at room temperature for 4 hours. The reaction was poured into ice water and then brought to pH = 9 by adding Na 2 CO 3. The resulting mixture was extracted with dichloromethane (25 mL X 3), the combined organic layer was dried over Na 2 SO 4. After filtering out the Na 2 SO 4, the filtrate was concentrated to dryness. The residue was column purified to yield product 7.

5. Reaction scheme:

<formula> formula see original document page 196 </formula>

Experimental Details: A mixture of 7 (60 mg, 0.22 mmol) nicotinaldehyde (33 mg, 0.15 mmol) in dichloromethane (10 mL) was heated to reflux for 3 hours. After removing the solvent, the residue was purified by chromatography to yield the desired compound 7.

EXAMPLE 10

<formula> formula see original document page 196 </formula> 1. Reaction scheme:

<formula> formula see original document page 197 </formula>

Experimental Details: A solution of DMAP (9.3 g, 0.077 mol) and compound 1 (10 g, 0.051 mol) and Boc20 (12 g, 0.051 mol) in tBuOH (200 mL) was stirred at room temperature during night. The solvent was removed under reduced pressure, and the residue was purified by flash chromatography on silica gel. (ethyl acetate / petroleum ether = 10: 1) to yield 2 as a colorless oil.

2. Reaction scheme:

<formula> formula see original document page 197 </formula>

Experimental Details: A mixture of 2 (6.17 g, 27.9 mmol) and Pd (OH) 2 (10%, 1 g) in ethanol (200 mL) was stirred under a hydrogen atmosphere (50 psi) at room temperature. for 4 hours. The catalyst was filtered off, and the filtrate was removed in vacuo to yield product 3 as a colorless oil.

3. Reaction scheme:

<formula> formula see original document page 197 </formula>

Experimental Details: A mixture of compound 3 (2.65 g, 12 mmol) and compound 4 (2.6 g, 10 mmol) and tBuONa (1.34 g, 14 mmol) and Pd2 (dba) 3 (46, 5 mg, 50 mmol) and DCHPB (70 mg, 0.2 mmol) in dry toluene (50 mL) was heated at 80-90 ° C under N 2 for 24 hours. Precipitation was filtered, and The filtrate was removed in vacuo, and the residue was purified by silica gel chromatography (ethyl acetate / petroleum ether = 10: 1) to yield 5 as a yellowish oil.

4. Reaction scheme:

<formula> formula see original document page 198 </formula>

Experimental Details: To a solution of 5 (0.9 g, 2.24 mmol) in CHCl 3 (50 mL), CF 3 COOH (40 mL) was added at 0 ° C. After completing the addition, the resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure to dryness. The residue was recrystallized from ether to afford an off-white solid. The solid was dissolved in ammonia (10 mL). The mixture was brought to pH = 7.0 by adding IM HCl and precipitate. The precipitate was collected and washed with cold water (5 mL) and dried under reduced pressure to yield 6 as a dark solid.

5. Reaction scheme:

<formula> formula see original document page 198 </formula>

Experimental Details: A mixture of 6 (60 mg, 0.22 mmol), nicotine Idehyde (33 mg, 0.15 mmol) in dichloromethane (10 mL) was heated to reflux for 3 hours. After removing the solvent, the residue was purified by chromatography to afford the desired compound as a yellow solid.

EXAMPLE 11 <formula> formula see original document page 199 </formula>

1. Reaction scheme:

<formula> formula see original document page 199 </formula>

Experimental Details: To a stirred and degassed mixture of compound 1 (6.7 g, 25 mmol) and compound 2 (4.1 g, 27 mmol) in DMF (50 mL) and aqueous Na 2 CO 3 (20 mL, 2 M) was Pd 2 (dbbf) 3 (26 mg, 0.028 mmol) is added under N 2 atmosphere and stirred at 100 ° C for 18 hours. After cooling to room temperature and filtering the solid, the filtrate was extracted with EA (200 mL). The organic layer was concentrated to yield crude product 3.

2. Reaction scheme:

<formula> formula see original document page 199 </formula>

Experimental Details: A mixture of 3 (3.2 g, 10 mmol) and Pd (OH) 2 (10%, 0.5 g) in ethanol (200 mL) was stirred under a hydrogen atmosphere (20 psi) at room temperature. for 2 hours. The catalyst was filtered off, and the filtrate was removed in vacuo to yield product 4 as a colorless oil.

3. Reaction scheme: <formula> formula see original document page 200 </formula>

Experimental Details: To a stirred and degassed mixture of compound 4 (297 mg, 10 mmol) and compound 5 (259 mg, 10 mmol) and tBuONa (170 mg, 17.6 mmol) and BINAP (210 mg, 17.6 mol ) in toluene (25 mL) was added Pd 2 (dba) 3 (79 mg, 0.88 mmol) under N 2 atmosphere and stirred at 80 ° C for 48 hours. After filtering the solid, the filtrate was concentrated to yield crude product 6, which is used in the next step without purification.

4. Reaction scheme:

<formula> formula see original document page 200 </formula>

Experimental Details: A solution of compound 6 (446 mg, 10 mmol) in dichloromethane (20 mL) was treated as BBr3 (600 mg, 10.6 mmol) at -30 ° C under N 2 atmosphere and then stirred at room temperature for 4 hours. The reaction was poured into ice water and then brought to pH = 9 by adding Na 2 CO 3. The resulting mixture was extracted with dichloromethane (25 mL * 3), the combined organic layer was dried over Na 2 SO 4. After filtering out the Na 2 SO 4, the filtrate was concentrated to dryness. The residue was column purified to yield product 7.

5. Reaction scheme: <formula> formula see original document page 201 </formula>

Experimental Details: A mixture of 7 (67 mg, 0.15 mmol), nicotinaldehyde (33 mg, 0.15 mmol) in dichloromethane (10 mL) was heated to reflux for 3 hours. After removing the solvent, the residue was purified by chromatography to afford the desired compound as a yellow solid.

EXAMPLE 12

<formula> formula see original document page 201 </formula>

1. Reaction scheme:

<formula> formula see original document page 201 </formula>

Experimental Details: To a stirred and degassed mixture of compound 1 (3 g, 0.02 mol) and compound 2 (3.4 g, 0.02 mol) and KOH (5.28 g, 0.1 mol) and TBBA (6.44 g, 0.02 mol) in anhydrous THF (100 mL) was added Pd (PPh3) 4 (2.31 g, 2 mmol) under N 2 atmosphere and stirred at reflux for 12 hours. After filtering the solid, the filtrate was concentrated to dryness. The residue was column purified to yield product 3, which is used in the next step without purification. 2. Reaction scheme:

<formula> formula see original document page 202 </formula>

Experimental Details: To a stirred and degassed mixture of compound 3 (334 mg, 1.7 mmol) and compound 4 (434 mg, 1.7 mmol) and t-BuONa (322 mg, 3.4 mmol) and BINAP (420 mg, 0.67 mol) in toluene (60 mL) was added Pd 2 (dba) 3 (156 mg, 0.017 mmol) under N 2 atmosphere and stirred at 80 ° C for 48 hours. After filtering the solid, the filtrate was concentrated to dryness. The residue was column purified to yield product 5.

3. Reaction scheme:

<formula> formula see original document page 202 </formula>

Experimental Details: A solution of compound 5 (100 mg, 0.3 mmol) in dichloromethane (10 mL) was treated as BBr3 (393 mg, 0.6 mmol) at -30 ° C under N 2 atmosphere and then It was stirred at room temperature for 4 hours. The reaction was poured into ice water and was then obtained by adding Na2CO3. The resulting mixture was extracted with dichloromethane (25 mL X 3), the combined organic layer was dried over Na 2 SO 4. After filtering Na 2 SO 4, the filtrate was concentrated to yield crude product 6.

4. Reaction scheme:

<formula> formula see original document page 202 </formula>

Experimental Details: A mixture of 6 (39 mg, 0.13 mmol), nicotinaldehyde (29 mg, 0.13 mmol) in dichloromethane (10 mL) was heated to reflux for 3 hours. After removing the solvent, the residue was purified by chromatography to afford the desired compound as a yellow solid.

EXAMPLE 13

<formula> formula see original document page 203 </formula>

1. Reaction scheme:

<formula> formula see original document page 203 </formula>

Experimental Details: Paraformaldehyde (1.8g, 59.3 mmol) was added to a solution of compound 1 (1.0 g, 5.9 mmol) in acetic acid (40 mL), followed by NaCNBH3 (1.8 g, 28.8 'mmol) at 10 ° C. After stirring for 16 hours at room temperature, the solution was poured into ice water (100 mL), and the pH was adjusted to 10 with concentrated NaOH. The solution was extracted with DCM (3 x 100 mL). The combined organic layers were dried (MgSO 4), filtered and concentrated in vacuo to yield compound 2.

2. Reaction scheme:

<formula> formula see original document page 203 </formula>

Experimental details: 0.84 g (4.3 mmol) of compound 2 was hydrogenated under 1 atm hydrogen with Pd / C for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to yield compound 3 without further purification.

3. Reaction scheme:

<formula> formula see original document page 204 </formula>

Experimental Details: A 250 mg (1.51 mmol) solution of compound 3, 0.2 eq BINAP, 0.1 eq Pd2 (dba) 3, 3 eq Cs2CO3 and 5-Bromo-2-diethoxymethyl pyridine (0.783g, 3.01 mmol) in 10 mL of 1,4-dioxane reacted at 150 ° C in microwave for 2 hours. The reaction was monitored by LC-Ms. The mixture was monitored by LC-Ms. The mixture was concentrated, and the residue was purified by preparative TCL to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 204 </formula>

Experimental Details: At 1 mg (0.55 mmol) of compound 4 in 5 mL DCM was included 4 mL TFA. The reaction mixture was stirred for 30 minutes at room temperature. Ice water was added to the mixture and basified by NaHCO 3 at PH = 10 and extracted with DCM (15 mL * 3). The combined organic layer was washed with water and brine, dried over MgSO 4, filtered and concentrated to yield compound 5.

5. Reaction scheme: <formula> formula see original document page 205 </formula>

Experimental Details: A solution of 80 mg (0.295 mmol) of compound 5 and (5-Fluoro-4-morpholin-4-yl-pyrimidin-2-yl) -hydrazine (125 mg, 0.59 mmol) in 10 mL of DCM was stirred at 25 ° C for 15 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to yield compound 6.

6. Reaction scheme:

<formula> formula see original document page 205 </formula>

Experimental Details: To a solution of compound 6 (40 mg, 0.086 mmol) in DCM (5 mL) was added dropwise BBr (22 mg, 0.258 mmol) at 0 ° C. The reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with methanol, and the mixture was concentrated. The residue was purified by preparative HPLC to yield the desired compound.

EXAMPLE 14

<formula> formula see original document page 205 </formula>

1. Reaction scheme: <formula> formula see original document page 206 </formula>

Experimental Details: To a stirred solution of 3 - Bromoaniline (0.86 g) in 30 ml of toluene was added 0.1 eq Pd (PPh3) 4.5 ml of sat. aq. Na 2 CO 3 and a solution of 3-boronic acid methoxyphenyl (0.75g) in 10 ml EtOH under N 2 atmosphere. The mixture was vigorously stirred at reflux for 15 hours and cooled, 10 mL of H 2 O was added, and the mixture was extracted with CH 2 Cl 2 (20 mL * 3). The combined organic layers were dried over Na 2 SO 4 and concentrated. The residue was purified by column chromatography (PE / EA = 10: 1) to obtain pure compound 2.

2. Reaction scheme:

<formula> formula see original document page 206 </formula>

Reaction Details: A mixture of compounds 2 (59.5mg), 5-bromo-2-diethoxymethyl pyridine (116.7mg), t-BuONa (8 6.4mg), BINAP (36.7mg) and Pd2 (dba ) 3 (27.4mg) in dioxane (2ml) was microwaved for 2 hours at 150 ° C, the solution was filtered and concentrated. The residue was purified by preparative TCL to yield compound 3.

3. Reaction scheme: <formula> formula see original document page 207 </formula>

Reaction Details: To a solution of compound 3 (120 mg) in 5 ml DCM was added 1 ml BBr3, the reaction was stirred overnight at room temperature. Then 5 ml of H 2 O were added to the mixture, extracted with EtOAc and concentrated. The crude product was purified by preparative TLC to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 207 </formula>

Experimental Details: A mixture of 43.5 mg of compound 4 and 32 mg of hydrazine in 5 ml DCM was stirred overnight at room temperature and concentrated. The crude product was purified by pre-preparative TLC to yield the desired compound.

EXAMPLE 15

<formula> formula see original document page 207 </formula>

1. Reaction scheme:

<formula> formula see original document page 207 </formula> Experimental Details: A solution of 2.0 g (16.2 mmol, 1.0 eq) of compound 1, 0.05 eq of BINAP, 0.05 eq of Pd 2 (dba) 3, 1.2 eq t-BuONa and 1-Bromo-3-nitro-benzene (3.28 g, 16.2 mmol, 1.0 eq) in 20 mL of anhydrous toluene reacted at 100 ° C by 24 hours. The reaction was monitored by LC-MS. The mixture was concentrated and the residue was purified by column chromatography to yield compound 2.

2. Reaction scheme:

<formula> formula see original document page 208 </formula>

Experimental details: 2.5 g of compound 2 was hydrogenated under 1 atm hydrogen with Pd / C (0.25 g) for 16 hours. The reaction mixture was filtered, and the filtrate was concentrated to yield compound 3 without further purification.

3. Reaction scheme:

<formula> formula see original document page 208 </formula>

Experimental Details: A 500 mg (2.33 mmol) solution of compound 3,5-Bromo-2-diethoxymethylpyridine (607 mg, 2.33 mmol), 0.05 eq xantphos, 0.05 eq Pd2 (dba ) 3 and 1.5 eq t-BuONa in 10 mL of toluene was refluxed at 100 ° C for 24 hours. The reaction was monitored by LC-MS. The mixture was concentrated and the residue was purified by column chromatography to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 208 </formula> Experimental details: 100 mg of compound 4 was treated with 1 mL HCl (aqueous 1 N solution) in 10 mL dioxane. The mixture was stirred at room temperature for 4 hours, adjusted to pH 8-9 with 0.5 N NaOH solution. After extracted with DCM, the organic layer was dried with Na 2 SO 4 and concentrated to yield compound 5.

5. Reaction scheme:

<formula> formula see original document page 209 </formula>

Experimental Details: A solution of 50 mg (0.16 mmol) of compound 5 and (5-Fluoro-4-morpholin-4-yl-pyrimidin-2-yl) -hydrazine (50 mg, 0.23 mmol) in 5 mL of DCM was stirred at 25 ° C for 15 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to yield compound 6.

6. Reaction scheme:

<formula> formula see original document page 209 </formula>

Experimental Details: To a solution of dry compound 6 (50 mg, 0.09 mmol) in DCM (5 mL) was added BBr3 (20 mg, 0.25 mmol) in drops at 0 ° C. The reaction mixture was stirred for 3 hours at room temperature. The reaction was quenched with methanol, and the mixture was concentrated. The residue was purified by preparative HPLC to yield the desired compound.

EXAMPLE 16 <formula> formula see original document page 210 </formula>

1. Reaction scheme:

<formula> formula see original document page 210 </formula>

Experimental Details: A solution of 10 g (70.92mmol) of 3-fluoro-nitrobenzene, 1 eq imidazole and 2eq K2CO3 in 100 ml DMSO was heated at 130 ° C for 5 hours. The reaction mixture was monitored by LC-MS. Then 500 mL of water was added and the precipitate was filtered off and the solution was washed with water and dried to yield compound 2 without further purification.

2. Reaction scheme:

<formula> formula see original document page 210 </formula>

Experimental details: 5 g (31.4 mmol) of compound 2 was hydrogenated under 1 atm of hydrogen with Pd / C for 0.5 hours. The reaction mixture was filtered, and the filtrate was concentrated to yield compound 3 without further purification.

3. Reaction scheme:

<formula> formula see original document page 210 </formula>

Experimental Details: A solution of 500 mg (3.14 mmol) of compound 3, 0.1 eq xantphose, 0.1 eq Pd2 (dba) 3 and 1.5 eq t-BuONa in 10 mL toluene was refluxed. at 130 ° C for 15 hours. The reaction was monitored by LC-Ms and washed with water and extracted with EtOAc. The organic layer was washed with brine and dried over MgSO4. Filtered and concentrated, the residue was purified by preparative TCL to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 211 </formula>

Experimental Details: To a solution of 200 mg of compound 4 in 5 mL of 1,4-dioxane was added 8 mL of 4N HCl and heated at 80 ° C for 2 hours. The reaction mixture was basified by 2N NaOH at ph = 10 and extracted with DCM (15 mL * 3). The combined organic layer was washed with water and brine, dried over MgSO 4, filtered and concentrated to yield 250 mg of crude product. The crude product was purified by preparative TLC to yield compound 5.

5. Reaction scheme:

<formula> formula see original document page 211 </formula>

Experimental Details: A solution of 80 mg of compound 5 and 1 eq of compound 6 in 5 mL of DCM was stirred at 25 ° C for 15 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to yield the desired compound.

EXAMPLE 17 <formula> formula see original document page 212 </formula>

1. Reaction scheme:

<formula> formula see original document page 212 </formula>

Experimental Details: A 1.50 g solution of 1-Bromo-3-methyl-5-nitro-benzene and 1.60 g (1.2 eq) of Piperazine-I-tert-butyl ester, 0.1 xantphos eq, 0.1 eq Pd 2 (dba) 3 and 1.5 eq t-BuONa in 20 mL toluene was refluxed at 130 ° C for 4 hours. The reaction was monitored by LC-Ms and washed with water and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na 2 SO 4. Filtered and concentrated, the residue was purified by silica gel column chromatography using 10: 1 PA: EA as an eluent. Appropriate fractions were combined and concentrated under reduced pressure to yield intermediate 1.

2. Reaction scheme:

<formula> formula see original document page 212 </formula>

Experimental details: 1.6 g of intermediate 1 was hydrogenated under 1 atm of hydrogen with Raney / Ni by 2 filtrate.

hours The reaction mixture was filtered, and concentrated to yield intermediate 2 without further purification.

3. Reaction scheme:

<formula> formula see original document page 213 </formula>

Experimental Details: A 1.20 g solution of Intermediate 2, and 1.30 g (1.20 eq) of 5-Bromo-2-diethoxymethyl pyridine, 0.1 eq xantphose, 0.1 eq Pd2 (dba) 3 and 1.5 eq t-BuONa in 20 mL toluene was refluxed at 130 ° C for 4 hours. The reaction was monitored by LC-MS and washed with water and extracted with EtOAc. The combined organic layer was washed with brine and dried over Na 2 SO 4. Filtered and concentrated, the residue was purified by silica gel column chromatography using 4: 1 PA: EA as an eluent. Appropriate fractions were combined and concentrated under reduced pressure to yield intermediate 3.

4. Reaction scheme:

<formula> formula see original document page 213 </formula>

Experimental Details: 200 mg of intermediate 3 was dissolved in 10 ml of DCM. 130 mg of TFA was added to the reaction mixture solution dropwise and stirred for 3 hours at room temperature. The reaction mixture was based on NaHCO 3 solution as neutral and brine, dried over Na 2 SO 4, filtered and concentrated to yield 220 mg of crude product. The crude product was purified by preparative TLC to yield intermediate 4.

5. Reaction scheme:

<formula> formula see original document page 214 </formula>

Experimental Details: A solution of 50 mg of intermediate 4 and 1.0 eq of (5-Fluoro-4-morpholin-4-yl pyrimidin-2-yl) hydrazine in 5 mL of DCM was stirred at room temperature for 3 hours. . The reaction mixture was washed with water and brine, concentrated to yield the residue and purified by preparative HPLC to yield the desired compound.

EXAMPLE 18

<formula> formula see original document page 214 </formula>

1. Reaction scheme: <formula> formula see original document page 215 </formula>

Experimental details: 15 added dropwise to a solution of 3 g (13.95 mmol) of 4-bromo-2-methyl benzoic acid in 20 ml of THF at 0 ° C. The reaction solution was left at room temperature for 1 hour and quenched by the dropwise addition of 50 ml of 50% aqueous THF. The mixture was treated with Na 2 CO 3 and concentrated. The residue was extracted with Et 2 O. The organic layer was dried to yield compound 2.

2. Reaction scheme:

<formula> formula see original document page 215 </formula>

Experimental Details: A solution of 2.4 g (11.9 mmol) of compound 2 in 20 ml DCM was added to a slurry of 5.1 g (23.8 mmol) PCC in 60 ml DCM. The reaction solution was stirred for 1 hour at room temperature, diluted with 300 mL of Et 2 O and filtered. The filtrate was concentrated to yield compound 3.

3. Reaction scheme:

<formula> formula see original document page 215 </formula>

Experimental Details: A solution of 2.1 g (14 mmol) was added in an ethanol solution containing 1.9 g (9.55 mmol) of compound 3. The reaction solution was heated to reflux for 3 hours and, It was then concentrated. The solid was washed with NaHCO 3 and extracted with acetic ether. The organic layer was dried to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 216 </formula>

Experimental details: 0.7 g of compound 4, 0.41 g of 3-trifluromethyl phenylamine 0.32 g of Pd2 (dba) 3, 0.21 g of binap and 0.02 g of t-BuONa were added in 35 ml of toluene. The reaction solution was heated to reflux overnight and concentrated. The crude product was purified by column chromatography (ethyl acetate / hexane = 1: 1) to yield compound 5.

5. Reaction scheme:

<formula> formula see original document page 216 </formula>

Experimental Details: The solution of compound 5 (0.2 g, 1.0 eq) in 10 mL of dioxane was treated with 4 mL of 1 N HCl, and the mixture was heated at 60 ° C for 2 hours. After cooling, the pH was adjusted to 8 with the addition of NaHCO3. The mixture was extracted with dichloromethane, the organic layer was washed with water, dried with Na 2 SO 4 and evaporated to dryness. The crude product was purified by column chromatography to yield compound 6.

6. Reaction scheme: <formula> formula see original document page 217 </formula>

Experimental Details: A solution of 80 mg of compound 6 and 1 eq of compound 7 in 5 mL of DCM was stirred at 25 ° C for 15 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to yield the desired compound.

Example 19.

<formula> formula see original document page 217 </formula>

1. Reaction scheme:

Experimental Details: To the mixture of compound 1 (0.5 g, 1.0 eq), c3-trifluoromethyl phenyl boronic acid (0.63 g, 1.0 eq), Na2 CO3 (0.46 g, 1.5 eq) In 15 mL dioxane Pd (PPh3) 4 (0.33 g, 0.1 eq) was added, and the reaction mixture was refluxed under N2 for 16 hours. After cooling, the mixture was filtered, and the filtrate was evaporated to dryness and purified by column chromatography to yield compound 2.

2. Reaction scheme: <formula> formula see original document page 218 </formula>

Experimental Details: A mixture of compound 2 (0.2 g, 1.0 eq), SeO2 (0.19 g, 2.0 eq) in 10 mL of acetic acid was refluxed under N2 for 48 h. The solvent was removed by evaporation, and the residue was dissolved in water and adjusted to pH 6 with saturated NaHCO 3 solution, extracted with dichloromethane. The organic layers were collected, dried and evaporated to dryness. The crude product was purified by column chromatography to yield compound 3.

3. Reaction scheme:

<formula> formula see original document page 218 </formula>

Experimental Details: The mixture of compound 3 (30 mg, 1.0 eq) and compound 4 (19 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature overnight. The mixture was concentrated to dryness and purified by preparative HPLC to yield the desired compound.

EXAMPLE 20

<formula> formula see original document page 218 </formula>

1. Reaction scheme: <formula> formula see original document page 219 </formula>

Experimental Details: The mixture of compound 1 (0.5 g, 1.0 eq), trifluoromethyl phenylamine (0.58 g, 1.0 eq), EDC (1.05 g, 1.5 eq), HOBt (50 mg, 0.1 eq) in 15 mL of dichloromethane was stirred at room temperature overnight. The mixture was washed with 1 N NaOH solution, water and extracted with dichloromethane. The organic layer was dried over Na 2 SO 4, concentrated to dryness and purified by column chromatography to yield compound 2.

2. Reaction scheme:

<formula> formula see original document page 219 </formula>

Experimental Details: A mixture of compound 2 (0.2 g, 1.0 eq), SeO2 (0.16 g, 2.0 eq) in 10 mL of acetic acid was refluxed under N2 for 48 h. The solvent was removed by evaporation, and the residue was dissolved in water and adjusted to pH 6 with saturated NaHCO 3 solution, extracted with dichloromethane. The organic layers were collected, dried and evaporated to dryness. The crude product was purified by column chromatography to yield compound 3.

3. Reaction scheme:

<formula> formula see original document page 219 </formula> Experimental details: The mixture of compound 3 (40 mg, 1.0 eq) and compound 4 (30 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature. room temperature at night. The precipitates were collected and washed with dichloromethane and dried under vacuum to yield the desired compound.

EXAMPLE 21

<formula> formula see original document page 220 </formula>

1. Reaction scheme:

<formula> formula see original document page 220 </formula>

Experimental Details: The solution of compound 1 (3.0 g, 1.0 eq) and 2 mL 98% H2SO4 in 10 mL EtOH was refluxed for 4 hours, cooled to room temperature to dryness, diluted with water, adjusted to pH 8 with NaHCO 3 extracted with dichloromethane. The organic layer was dried and concentrated to yield compound 2.

2. Reaction scheme:

<formula> formula see original document page 220 </formula>

Experimental Details: A mixture of compound 2 (1.7 g, 1.0 eq), SeO2 (2.29 g, 2.0 eq) in 80 mL of acetic acid was refluxed under N2 for 48 h. The solvent was removed by evaporation, and the residue was dissolved in water and adjusted to pH 6 with saturated NaHCO 3 solution, extracted with dichloromethane. The organic layers were collected, dried and evaporated to dryness. The crude product was purified by column chromatography to yield compound 3.

3. Reaction scheme:

<formula> formula see original document page 221 </formula>

Experimental Details: The solution of compound 3 (1.1 g, 1.0 eq), diethoxymethoxyethane (2.3 g, 2.5 eq) and TsOH-H2O (0.12 g, 0.1 eq) in 20 mL of ethanol was refluxed for 5 hours. The solvent was evaporated, and the solid was dissolved in EtOAc, washed with water. The organic layer was dried over Na 2 SO 4 and evaporated to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 221 </formula>

Experimental Details: To the solution of compound 4 (0.6 g, 1.0 eq) in 10 mL of methanol was added 4 mL of 1 N NaOH solution, and the mixture was stirred at room temperature overnight. The solvent was evaporated, and the residue was acidified to pH 6 with 5% citric acid, extracted with dichloromethane. The organic layer was dried and concentrated to yield compound 5.

5. Reaction scheme:

<formula> formula see original document page 221 </formula>

Experimental Details: The mixture of compound 5 (0.4 g, 1.0 eq), trifluoromethyl phenylamine (0.29 g, 1.0 eq), EDC (0.51 g, 1.5 eq), HOBt (25 mg, 0.1 eq) in 10 mL of dichloromethane was stirred at room temperature overnight. The mixture was washed with 1 N NaOH solution, water and extracted with dichloromethane. The organic layer was dried over Na 2 SO 4, concentrated to dryness and purified by column chromatography to yield compound 6.

6. Reaction scheme:

<formula> formula see original document page 222 </formula>

Experimental Details: The solution of compound 6 (0.2 g, 1.0 eq) in 10 mL of dioxane was treated with 4 mL of 1 N HCl, and the mixture was heated at 60 ° C for 2 hours. After cooling, the pH was adjusted to 8 with the addition of NaHCO3. The mixture was extracted with dichloromethane, the organic layer was washed with water, dried with Na 2 SO 4 and evaporated to dryness. The crude product was purified by column chromatography to yield compound 7.

7. Reaction scheme:

<formula> formula see original document page 222 </formula>

Experimental Details: The mixture of compound 7 (30 mg, 1.0 eq) and compound 8 (19 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature overnight. The precipitates were collected and washed with dichloromethane and dried under vacuum to yield the desired compound.

EXAMPLE 22 <formula> formula see original document page 223 </formula>

1. Reaction scheme:

<formula> formula see original document page 223 </formula>

Experimental Details: A mixture of compound 1 (2.0 g, 1.0 eq), SeO2 (2.6 g, 2.0 eq) in 80 mL of acetic acid was refluxed under N2 for 36 hours. The solvent was removed by evaporation, and the residue was dissolved in water and adjusted to pH 6 with saturated NaHCO 3 solution extracted with dichloromethane. The organic layers were collected, dried and evaporated to dryness. The crude product was purified by column chromatography to yield compound 2.

2. Reaction scheme:

<formula> formula see original document page 223 </formula>

Experimental Details: The solution of compound 2 (0.5 g, 1.0 eq), diethoxymethoxyethane (1.0 g, 2.5 eq) and TsOH-H2O (0.05 g, 0.1 eq) in 8 mL of ethanol was refluxed for 3 hours. The solvent was evaporated, and the solid was dissolved in EtOAc, washed with water. The organic layer was dried over Na 2 SO 4 and evaporated to yield compound 3.

3. Reaction scheme: <formula> formula see original document page 224 </formula>

Experimental Details: To the mixture of compound 3 (0.6 g, 1.0 eq), 3-trifluoromethyl phenylamine (0.37 g, 1.0 eq), t-BuONa (0.26 g, 1.2 eq) ) in 15 mL of toluene was added under N 2 Pd 2 (dba) 3 (42 mg, 0.02 eq) and xantphos (28 mg, 0.02 eq). The mixture was refluxed under N 2 for 16 hours, cooled and filtered. The filtrate was concentrated and purified by column chromatography to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 224 </formula>

Experimental Details: The solution of compound 4 (0.25 g, 1.0 eq) in 10 mL of dioxane was treated with 4 mL of 1 N HCl, and the mixture was heated at 60 ° C for 2 hours. After cooling, the pH was adjusted to 8 with the addition of NaHCO3. The mixture was extracted with dichloromethane, the organic layer was washed with water, dried with Na 2 SO 4 and evaporated to dryness. The crude product was purified by column chromatography to yield compound 5.

5. Reaction scheme:

<formula> formula see original document page 224 </formula>

Experimental Details: The mixture of compound 5 (30 mg, 1.0 eq) and compound 6 (19 mg, 1.0 eq) in 5 mL of dichloromethane was stirred at room temperature overnight. The precipitates were collected and washed with dichloromethane and dried under vacuum to yield the desired compound.

EXAMPLE 23

<formula> formula see original document page 225 </formula>

1. Reaction scheme:

<formula> formula see original document page 225 </formula>

Experimental Details: To a solution of compound 1 (14 g, 0.1 mol) in aqueous HBr (30 mL) was added a solution of NaNO 2 (8.3 g 0.15 mol) in H 2 O (10 mL) at 0 ° C per a 30 minute period. After stirring for 60 minutes, the reaction mixture was added to a solution of CuBr (14 g, 0.1 mol) in aqueous HBr (16 mL) at 80 ° C. After completion of the addition, the reaction mixture was stirred at the same temperature for 2 hours. After cooling to room temperature, the reaction mixture was extracted with EA (100 mL χ 3). The combined organic layer was washed with brine and dried over Na 2 SO 4. After filtering out the Na 2 SO 4, the filtrate was concentrated to dryness. The residue was column purified to yield product 2.

2. Reaction scheme: <formula> formula see original document page 226 </formula>

Experimental Details: To a stirred and degassed mixture of compound 2 (4.11 g, 0.02 mol) and compound 3 (4.74 g, 0.02 mol) and KOH (5.28 g, 0.1 mol) and TBBA (6.44 g, 0.02 mol) in anhydrous THF (100 mL) was added Pd (PPh3) 4 (2.31 g, 2 mmol) under N 2 atmosphere and stirred at reflux for 12 hours. After filtering the solid, the filtrate was concentrated to dryness. The residue was column purified to yield product 4.

3. Reaction scheme:

Experimental Details: A solution of 4 (1 g, 3 mmol) in dichloromethane (10 mL) was treated with TFA (1 mL) and then stirred for 6 hours at room temperature.The solvent was removed under reduced pressure to yield the product 5, which is made in the next step without purification.

4. Reaction scheme:

Experimental Details: To a stirred and degassed mixture of compound 5 (619 mg, 5 mmol) and compound 6 (520 mg, 2.4 mmol) and t-BuONa (460 mg, 4.8 mmol) and BINAP (599 mg, 6.9 mol) in toluene (60 mL) was added Pd 2 (dba) 3 (221 mg, 0.024 mmol) under N 2 atmosphere and stirred at 800 ° C for 48 hours. After filtering the solid, the filtrate was concentrated to dryness. The residue was column purified to yield product 7.

5. Reaction scheme:

Experimental Details: A solution of compound 7 (396 mg, 0.1 mmol) in dichloromethane (10 mL) was treated as BBr3 (146 mg, 0.6 mmol) at -30 ° C under N 2 atmosphere and then , was stirred at room temperature for 4 hours. The reaction was poured into ice water and was then obtained by adding Na2CO3. The resulting mixture was extracted with dichloromethane (25 mL X 3), the combined organic layer was dried over Na 2 SO 4. After filtering Na 2 SO 4, the filtrate was concentrated to yield crude product 8, which was done in the next step without purification.

6. Reaction scheme:

Experimental Details: A solution of compound 8 (32.2 mg, 0.1 mmol) and compound 9 (21 mg, 0.1 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

EXAMPLE 24 <formula> formula see original document page 228 </formula>

1. Reaction scheme:

<formula> formula see original document page 228 </formula>

Experimental Details: A solution of 5-fluoro-1H-pyrimidine-2,4-dione (113 g, 0.5 mol) in N, N-dimethylaniline (70 mL) was treated with POCl 3 (500 mL) and then , was refluxed for 2 hours. After cooling to room temperature, the reaction mixture was poured into ice water. The resulting mixture was extracted with ethyl acetate (100 mL χ 3). The combined organic layers were washed with saturated aqueous NaHCO 3 solution and then brine. The solvent was removed under reduced pressure to yield compound 2.

2. Reaction scheme:

<formula> formula see original document page 228 </formula>

Experimental Details: To a solution of compound 2 (20.8 g, 0.194 mol) in ethanol (300 mL) was added morpholine (21.6 g, 0.25 mol) in drops at -10 ° C over a period of 15 minutes. . This mixture was stirred at room temperature for 0.5 hour, warmed and then at 50 ° C for minutes. After cooling to room temperature and diluting with water, the solid was precipitated. The solid was collected by the filtrate and washed with water to yield compound 3.

3. Reaction scheme:

<formula> formula see original document page 229 </formula>

Experimental Details: A solution of 3 (4.6 g, 17.5 mmol) and hydrazine (8.75 g, 87.5 mmol) in ethanol (40 mL) was heated to reflux for 6 hours. After cooling and precipitation, the precipitate was collected by the filtrate and washed with ethanol to yield compound 4.

4. Reaction scheme:

<formula> formula see original document page 229 </formula>

Experimental Details: A solution of compound 5 (14 g, 50 mmol) in anhydrous THF (100 mL) was treated with BuMgCl (37.5 mL, 60 mmol) at -15 ° C under N 2 atmosphere. After complete addition, this mixture was stirred at this temperature for 1 hour. Anhydrous DMF (0.54 g, 75 mmol) was added to the reaction mixture at 0 ° C for a period of 30 minutes, warmed and then left at room temperature for 1 hour. The reaction mixture was quenched by the addition of 2M HCl (80 mL). The resulting mixture was extracted with ethyl acetate (50 mL χ 3). The combined organic layers were dried over Na 2 SO 4. The solvent was concentrated to dryness. The residue was separated by column to yield compound 6.

5. Reaction Scheme: Experimental Details: A solution of compound 6 (4.5 g, 22.5 mmol) in triethyl orthoformate (15 mL) was heated in the presence of a trace of TsOH overnight. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a 5% aqueous Na 2 CO 3 solution. The organic layer was separated and dried over Na 2 SO 4. The solvent was concentrated to yield compound 7.

6. Reaction scheme:

<formula> formula see original document page 230 </formula>

Experimental Details: To a stirred and degassed mixture of compound 7 (1.3 g, 5 mmol) and compound 8 (0.97 g, 6 mmol) and t-BuONa (0.7 g, 7 mmol) and P (t -Bu) 3 (15 mg) in toluene (60 mL) was added Pd 2 (dba) 3 (23 mgl) under N 2 atmosphere and stirred at reflux for 12 hours. After filtering the solid, the filtrate was concentrated to dryness. The residue was purified by column to yield product 9.

7. Reaction scheme:

<formula> formula see original document page 230 </formula>

Experimental Details: A solution of compound 9 (200 mg, 0.58 mmol) in dichloromethane (10 mL) was treated as BBr3 (146 mg, 0.6 mmol) at -30 ° C under N 2 atmosphere and then It was stirred at room temperature for 4 hours. The reaction was poured into ice water and then obtained by adding Na2 CO3. The resulting mixture was extracted with dichloromethane (25 mL X 3), the combined organic layer was dried over Na 2 SO 4. After filtering Na 2 SO 4, the filtrate was concentrated to yield crude product 10.

8. Reaction scheme:

<formula> formula see original document page 231 </formula>

(48.7 mg, 0.2 mmol) and compound 4 (63 mg, 0.2 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

EXAMPLE 25

<formula> formula see original document page 231 </formula>

1. Reaction scheme:

<formula> formula see original document page 231 </formula>

Experimental Details: A solution of 3 (2.4 g, 11 mmol) and methylhydrazine (2 g, 45 mmol) in ethanol (40 mL) was heated to reflux for 6 hours. After cooling θ of precipitation, the precipitate was collected by the filtrate and washed with ethanol to yield compound 2.

Experimental Details: A solution of compound 2 (28 mg, 0.1 mmol) and compound 3 (37 mg, 0.1 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

Experimental Details: A solution of 1 (2 g, 0.011 mol) in anhydrous THF (100 mL) was treated with MeMgCl (15 mL. 0.038 mol) at -20 ° C and stirred for 2 hours at that temperature. This reaction mixture was quenched by the addition of saturated aqueous NH 4 Cl solution. The resulting mixture was extracted with ethyl acetate (100 mL χ 3). The layers

2. Reaction scheme:

EXAMPLE 2 6

1. Reaction scheme: Combined organics were washed with brine. The solvent was removed under reduced pressure to yield compound 2.

2. Scheme of the reaction;

<formula> formula see original document page 233 </formula>

Experimental Details: A solution of compound 2 (2 g, 0.01 mol) and ethylene glycol (3 g, 0.048 mol) in anine (100 mL) was heated in the presence of a trace of TsOH for 3 hours. The reaction mixture was diluted with ethyl acetate (100 mL) and washed with a 5% aqueous Na 2 CO 3 solution. The organic layer was separated and dried over Na 2 SO 4. The solvent was concentrated to yield compound 3.

3. Reaction scheme:

<formula> formula see original document page 233 </formula>

Experimental Details: To a stirred and degassed mixture of compound 3 (0.4 g, 1.6 mmol) and compound 4 (0.3 g, 1.9 mmol) and t-BuONa (0.22 g, 2 mmol) and P (t-Bu) 3 (59 mg) in toluene (30 mL) was added Pd 2 (dba) 3 (29 mL) under N 2 atmosphere and stirred at reflux for 12 hours. After filtering the solid, the filtrate was concentrated to dryness. The residue was column purified to yield product 5.

4. Reaction scheme:

<formula> formula see original document page 233 </formula> Experimental Details: A solution of compound 5 (100 mg, 0.3 mmol) in dichloromethane (10 mL) was treated as BBr3 (146 mg, 0.6 mmol) at -30 ° C under N 2 atmosphere and then stirred at room temperature for 4 hours. The reaction was poured into ice water and was then obtained by adding Na2CO3. The resulting mixture was extracted with dichloromethane (25 mL X 3), the combined organic layer was dried over Na 2 SO 4. After filtering Na 2 SO 4, the filtrate was concentrated to yield crude product 6.

5. Reaction scheme:

<formula> formula see original document page 234 </formula>

Experimental Details: A solution of compound 6 (64 mg, 0.2 mmol) and compound 7 (45 mg, 0.2 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

EXAMPLE 27

<formula> formula see original document page 234 </formula>

1. Reaction scheme: <formula> formula see original document page 235 </formula>

Experimental Details: A mixture of 1 (5.2 g, 22 mmol) and 2 (2.44 g, 20 mmol) in an aqueous solution of 2 M Na 2 CO 3 (25 mL) and toluene (40 mL) was stirred with Pd ( PPh 3) 4 (0.57 g, 0.05 mmol) under reflux overnight. The resulting mixture was extracted with ethyl acetate (100 mL χ 3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to dryness. The residue was column purified to yield product 3.

2. Reaction scheme:

Experimental Details: A solution of compound 3 (0.78 g, 3.3 mmol) and triisopropyl borate (1 mL, 4 mmol) in anhydrous toluene (50 mL) was treated with n-BuLi (1.5 mL, 3 mL). 75 mmol) at -60 ° C under N 2 atmosphere. After complete addition, the mixture was stirred at -10 ° C for 1 hour. The reaction mixture was quenched by adding 2 M aqueous HCl solution, and washed with toluene. The aqueous layer was brought to pH = 8 by adding Na 2 CO 3, extracted with ethyl acetate (50 mL χ 3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to dryness. The residue was column purified to yield product 4.

3. Reaction scheme: <formula> formula see original document page 236 </formula>

Experimental Details: A stirred and degassed mixture of compound 4 (2.8 g, 14 mmol) and compound 5 (7 g, 42 mmol) in an aqueous 2 M Na 2 CO 3 solution (250 mL) and toluene (40 mL) was stirred with Pd (PPh 3) 4 (0.57 g, 0.05 mmol) under reflux overnight. The resulting mixture was extracted with ethyl acetate (100 mL χ 3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to dryness. The residue was column purified to yield product 6.

4. Reaction scheme:

<formula> formula see original document page 236 </formula>

Experimental Details: A solution of 6 (0.53 g, 1.9 mmol) and hydrazine (0.52 g, 8.8 mmol) in ethanol (50 mL) was stirred at reflux for 6 hours. After cooling and precipitation, the precipitate was collected by the filtrate and washed with ethanol to yield compound 7.

5. Reaction scheme:

Experimental Details: A solution of compound 7 (53 mg, 0.13 mmol) and compound 8 (79 mg, 0.13 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC to yield the desired compound.

EXAMPLE 28

<formula> formula see original document page 237 </formula>

1. Reaction scheme:

<formula> formula see original document page 237 </formula>

Experimental Details: A mixture of 1 (3.1 g, 13th isthi 1) and 2 (1g, 12mmol) in a 2M aqueous solution of Na 2 CO 3 (15mL) and toluene (30mL) was stirred with Pd (PPh 3). ) 4 (0.4 g, 0.029 mmol) under reflux overnight. The resulting mixture was extracted with ethyl acetate (100 mL χ 3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to dryness. The residue was column purified to yield product 3.

2. Reaction scheme:

<formula> formula see original document page 237 </formula>

Experimental Details: A solution of compound 3 (2.0 g, 10 mmol) and triisopropyl borate (7 mL, 30 mmol) in anhydrous toluene (50 mL) was treated with n-BuLi (12 mL, 30 mmol) at -60 ° C. ° C under N2 atmosphere. After complete addition, this mixture was stirred at -10 ° C for 1 hour. The reaction mixture was quenched by adding 2 M aqueous HCl solution, and washed with toluene. The aqueous layer was brought to pH = 8 by adding Na 2 CO 3, extracted with ethyl acetate (50 mL χ 3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to dryness. The residue was column purified to yield product 4.

3. Reaction scheme:

<formula> formula see original document page 238 </formula>

Experimental Details: A stirred and degassed mixture of compound 4 (0.5 g, 3 mmol) and compound 5 (1.5 g, 9 mmol) in an aqueous 2 M Na 2 CO 3 solution (3.5 mL) and toluene (40 mL). mL) was stirred with Pd (PPh3) 4 (94 mg, 0.003 mmol) under reflux overnight. The resulting mixture was extracted with ethyl acetate (100 mL χ 3). The combined organic layers were washed with brine. The solvent was removed under reduced pressure to dryness. The residue was column purified to yield product 6.

4. Reaction scheme:

<formula> formula see original document page 238 </formula>

Experimental Details: A solution of 6 (0.24 g, 1 mmol) and hydrazine (0.3 g, 4.7 mmol) in ethanol (50 mL) was stirred at reflux for 6 hours. After cooling and precipitation, the precipitate was collected by the filtrate and washed with ethanol to yield compound 7. Experimental Details: A solution of compound 7 (70 mg, 0.29 mmol) and compound 8 (83 mg, 0, 3 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was purified by preparative TLC to yield the desired compound.

EXAMPLE 2 9

1. Reaction scheme:

Experimental Details: To a solution of compound 2 (0.83 g, 5 mmol) in ethanol (100 mL) was added benzylamine (0.54 g, 5 mmol) dropwise. After stirring for 2 hours, the reaction mixture was diluted with water. The resulting mixture was extracted with ethyl acetate (50 mL χ 3). The combined organic layers were dried over Na 2 SO 4. The solvent was concentrated to yield compound 3. 2. Reaction scheme:

<formula> formula see original document page 240 </formula>

Experimental Details: A solution of 3 (1.18 g, 5 mmol) and hydrazine (5 mL) in ethanol (40 mL) was heated to reflux for 6 hours. After cooling and precipitation, the precipitate was collected by the filtrate and washed with ethanol to yield compound 4.

3. Reaction scheme:

<formula> formula see original document page 240 </formula>

Experimental Details: A solution of compound 4 (48.7 mg, 2 mmol) and compound 5 (63 mg, 0.2 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

Example 30

<formula> formula see original document page 240 </formula>

1. Reaction Scheme: Experimental Details: To a solution of compound 2 (0.83 g, 5 mmol) in ethanol (100 mL) was added compound 2 (0.35 g, 5 mmol) dropwise. After stirring for 2 hours, the reaction mixture was diluted with water. The resulting mixture was extracted with ethyl acetate (50 mL χ 3). The combined organic layers were dried over Na 2 SO 4. The solvent was concentrated to yield compound 3.

2. Reaction scheme:

<formula> formula see original document page 241 </formula>

Experimental Details: A solution of 3 (1.0 g, 5 mmol) and hydrazine (5 mL) in ethanol (40 mL) was heated to reflux for 6 hours. After cooling and precipitation, the precipitate was collected by the filtrate and washed with ethanol to yield compound 4.

3. Reaction scheme:

<formula> formula see original document page 241 </formula>

Experimental Details: A solution of compound 4 (480 mg, 2 mmol) and compound 5 (60 mg, 0.2 mmol) in anhydrous CH 2 Cl 2 (300 mL) was stirred at reflux for 6 hours. The solvent was removed under reduced pressure. The residue was separated by preparative TLC to yield the desired compound.

All references to any publication, patent or other citation are included herein by reference.

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Claims (8)

1. A composition according to the formula <formula> formula see original document page 249 </formula> or a pharmaceutically acceptable salt or hydrate, characterized in that: ring A is a 5-, 6- or 7-membered ring or a ring fused bicyclic from 7 to 12 members; X1 is selected from N, N-R0 or C-R1; X 2 is selected from N, N-R 0 or C-R 1; the dotted lines represent optional double bonds; each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O) N (R 12) (R 13) 1 - (CH 2) p C (O) O (CH 2) q R 11, - (CH 2) p N (O) (R 11) (CH 2) q C (O) R 11, - (CH 2) p N (R 12) (R13) 1 -N (R11) SO2R111 -OC (O) N (R12) (R13), -SO2N (R12) (R13), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R1 groups in adjacent ring atoms forming a fused 5 or 6 membered ring containing from 0 to 3 heteroatoms; η is from 0 to 6, each R 11 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; each R 12 and R 13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; R 12 and R 13 may be used together with nitrogen to which they are attached forming a 5 to 7 membered ring which may additionally contain an additional heteroatom; wherein the 5 to 7 membered ring may optionally be substituted by one to three substituents independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl and a heterocyclic ring; ρ be from 0 to 4; q is from 0 to 4; R2 is selected from -CR21a-, -NR22, -, and - (C = R23) -; each R21 is independently selected from the group consisting of hydrogen, halo, -NH2, N (H) (C1-4 alkyl), -Ν (C1-3 alkyl) 2, alkyl) 2, alkyl) OH and C1-3 alkyl; each R22 is independently selected from the group consisting of hydrogen and C1-3 alkyl; R3 is independently selected from the group consisting of oxygen, sulfur, N-R0 and N-OR0; R3 is selected from -CR31c-, -NR32d-, -SO2 -e - (C = R33) -; each R 31 is independently selected from the group consisting of hydrogen, halo, -NH 2, -N (H) (R 0), N (R 10 21 -OR 0, OH 1 and C 1-4 alkyl; each R 32 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; each R33 is selected from oxygen, sulfur, N-R341 and N-OR0; R34 is selected from hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and a heterocyclic ring; R4 is selected from -CR41-, -NR42r, - (C = R43) -; -SO2 -and -O-; each R41 is selected from the group consisting of hydrogen, halo, alkyl, cycloalkyl, alkenyl, alkynyl, CO2R0, C (O) R0, aralkyl, aryl and a heterocyclic ring; each R42 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO2R0, C (O) R0, aryl, and one heterocyclic ring, each R43Selected from oxygen, sulfur, N-R0, and N-OR0, provided that when R2 is -NR2V and R4 is -NR42r, so R3 is not NR3V, and both R3 and R4 are not simultaneously selected - (C = R33) - and - (C = R43) - respectively, nor as -SO2, R5 be a group having the formula where: X 3 is nitrogen or CH; Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O) -OC (O) NH- and -OC (O) NH-; R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic-amino, NO2, OR71 and CF3; each R71 being selected from hydrogen, alkyl, aryl, aralkyl and a heterocyclic ring; each R 0 is independently selected from halo, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; to be 1 or 2; b is O or 1; c is 1 or 2; d is 0 or 1; and be 1 or 2; and f is O or 1. The composition according to claim 1, wherein: ring A is selected from the group consisting of <formula> formula see original document page 251 </formula> R1 is independently selected from a group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O) N (R12) (R13), - (CH2) pC (O) O (CH 2) 9 R 11, '- (CH 2) p N (R 11) C (O) R 11, - (CH 2) p N (R 12) (R 13), -N (R 11) SO 2 R 11, -OC (O) N ( R 12) (R 13), -SO 2 N (R 12) (R 13) 1 halo, aryl, and a heterocyclic ring; each R 11 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; each R 12 and R 13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; or R 12 and R 13 may be used together with nitrogen to which they are attached to form a 5 to 7 membered ring which may also contain an additional heteroatom; wherein the 5 to 7 membered ring may optionally be substituted by one to three substitutes which are independently selected from alkyl. cycloalkyl, alkenyl, alkynyl aralkyl, CN, CF 3, NO 2, OR 0, CO2 R 0, C (O) R 0, halo, aryl, and a heterocyclic ring; ρ be from 0 to 4; q is from 0 to 4; and each R 0 is independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring. The composition according to claim 1, having the formula Ile <formula> formula see original document page 252 </formula> or a pharmaceutically acceptable salt or hydrate, wherein: ring A is a ring of 5.6 or 7 members or a 7 to 12 membered bicyclic ring; X1 is selected from N, N-R0 or C-R1; X 2 is selected from N, N-R 0 or C-R 1; the dotted lines represent optional double bonds; each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3 NO2 OR1, - (CH2) pC (O) (CH2) 9R11, - (CH2) pC (O) N ( R12) (R13), - (CH2) pC (O) O (CH2) q R11 '- (CH2) pN (R11) C (O) R11, - (CH2) pN (R12) (R13), -N (RH ) -SO 2 R 11, -OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms forming a ring 5 or 6 member containing from 0 to 3 heteroatoms; η be from 0 to 6, each R 'is independently selected from the group consisting of hydrogen alkyl, 1. cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; each R 12 and R' is independently selected from the group consisting of hydrogen alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring, R12 and R13 may be used together with nitrogen to which they are attached to form a 5-7 membered ring which may also contain an additional heteroatom; 5 to 7 membered ring may optionally be substituted by one to three substitutes which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR0, CO2R0, C (O) R0, halo, aryl, and a heterocyclic ring; ρ be from 0 to 4; q be from O to 4; each R 0 is independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; R 3 is hydrogen or CH 3; X 3 is nitrogen or CH ; Q1 s is selected from a chemical bond or a group having the formula -O-, -CH 2 -, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O) - OC (O) NH- and - OC (O) NH-; each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic-amino, NO2, OR71, and CF3; and each R71 selected from hydrogen and alkyl. 4. The composition, having the formula IIIb <formula> formula see original document page 253 </formula> or a pharmaceutically acceptable salt or hydrate, characterized in that: ring A is a 5-, 6- or 7-membered ring or a bicyclic ring cast from 7 to 12 members; X1 is selected from N1 N-R0 or C-R1; X 2 is selected from N 1 N-R 0 or C-R 1; the dotted lines represent optional double bonds; each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN1 CF3, NO2, OR11, - (CH2) pC (O) (CH2) qR11, - (CH2) pC (O) N (R 12) (R 13), - (CH 2) p C (O) O (CH 2) q R 11, - (CH 2) p N (R 11) C (O) R 11, - (CH 2) p N (R 12) (R 13), -N ( R 11) SO 2 R 11, -OC (O) N (R 12) (R 13), -SO 2 N (R 12) (R 13), halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms forming one 5 or 6 membered ring containing 0 to 3 heteroatoms; η is from 0 to 6, each R 11 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; each R 12 and R 13 is independently selected from the group consisting of may optionally be substituted by one to three substitutes which are hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; R 12 and R 13 may be used together with nitrogen to which they are attached forming a 5 to 7 membered ring which may also contain an additional heteroatom; wherein the 5 to 7 membered ring is independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN 1 CF 3, NO 2, OR 0, CO 2 R 0, C (O) R 0, halo, aryl, and a heterocyclic ring; ρ be from 0 to 4; q is from 0 to 4; X 3 is nitrogen or CH; R61 is selected from hydrogen and alkyl; Q is selected from a chemical bond or a group having the formula -O-, - (CH2), C (O) (CH2) r, - (CH2) rN (R62) - (CH2) r, - (CH2) , C (O) -NiR62) - (CH2) r, - (CH2), C (O) O (CH2), (CH2) r, N (R62) - (CH2) r, (CH2) / OC (O ) N (R 62) - (CH 2) y - and -O- (CH 2) / - C (O) 2 N (R 62) - (CH 2) j; R62 is selected from hydrogen, alkyl, aryl and a heterocyclic ring; each R 0 is independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; h is from 0 to 4; i be from 0 to 4; and j is 0 to 4. The composition according to claim 4 having the formula IIIc or a pharmaceutically acceptable salt or hydrate, wherein: ring A is a ring of 5,6 or 7-membered or 7- to 12-membered fused bicyclic ring; X1 is selected from N, N-R0 or C-R1; X 2 is selected from N, N-R 0 or C-R 1; the dotted lines represent optional double bonds; each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR111 - (CH2) pC (O) (CH2) q R111 - (CH2) pC (O) N ( R12) (R13) 1 - (CH2) pC (O) O (CH2) qR111 - (CH2) pN (R11) C (O) R11, - (CH2) pN (R12) (R13) 1 -N (R11) SO 2 R 11, -OC (O) N (R 12) (R 13) 1 -SO 2 N (R 12) (R 13) 1 halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R 1 groups on adjacent ring atoms forming a ring of 5 or 6 members containing from 0 to 3 heteroatoms; η is from 0 to 6, each R 11 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; each R 12 and R 13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; R 12 and R 13 may be used together with nitrogen to which they are attached forming a 5 to 7 membered ring which may also contain an additional heteroatom; wherein the 5 to 7 membered ring may optionally be substituted by one to three substitutes which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF3, NO2, OR0, CO2R0, C (O) R0, halo aryl and a heterocyclic ring; ρ be from 0 to 4; q is from 0 to 4; X 3 is nitrogen or CH; each R 0 is independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; R61 is selected from hydrogen and alkyl; Q1 is selected from a chemical bond or group having the formula -O-, -CH2-, -NH-, -C (O) -NH-, -C (O) O-, -NH-C (O) -, -OC (O) NH- and -OC (O) NH-; each R70 is selected from halo, alkyl, CN1 N (R71) 2, cyclic-amino, NO2, OR71, and CF3; each R71 being selected from hydrogen, alkyl, aryl, aralkyl and a heterocyclic ring; and k is from 0 to 4. The composition according to claim 5, having the formula III or a pharmaceutically acceptable salt or hydrate, wherein: ring A is a ring of 5.6 , or 7-membered or 7- to 12-membered bicyclic ring; X1 is selected from N, N-R0 or C-R1; X 2 is selected from N, N-R 0 or C-R 1; the dotted lines represent optional double bonds; each R1 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN1 CF3, NO2, OR11, - (CH2) pC (O) (CH2) c7R11, - (CH2) pC (O) N (R 12) (R 13) i - (CH 2) p C (O) O (CH 2) c 7 R 11, '- (CH 2) p N (R 11) C (O) R 11, - (CH 2) p N (R 12) (R 13) 1 -N (R11) SO2R111 -OC (O) N (R12) (R13) 1'-SO2N (R12) (R13) 1 halo, aryl, and a heterocyclic ring, and additionally or alternatively, two R1 groups on adjacent ring atoms forming a 5 or 6 membered ring containing from 0 to 3 heteroatoms; η is from 0 to 6, each R 11 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; each R 12 and R 13 is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and a heterocyclic ring; R 12 and R 13 may be used together with nitrogen to which they are attached in a 5- to 7-membered ring which may also contain an additional heteroatom; wherein the 5 to 7 membered ring may optionally be substituted by one to three substitutes which are independently selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN1 CF3, NO2, OR0 CO2R0, C (O) R0, halo, aryl and a heterocyclic ring; ρ be from 0 to 4; q is from 0 to 4; each R ° is independently selected from hydrogen, alkyl, cycloalkyl, aralkyl, aryl and a heterocyclic ring; R8 is selected from hydrogen and CH3; X 3 is nitrogen or CH; Q1 is selected from a chemical bond or a group having the formula -O-, -CH2-, -NH- -C (O) -NH-, -C (O) O-, -NH-C (O) - -OC (O) NH- and -OC (O) NH-; each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic-amino, NO2, OR71, and CF3, each R71 being selected from hydrogen, alkyl, aryl, aralkyl and a heterocyclic ring. The composition according to claim 4, having the formula III or a pharmaceutically acceptable salt or hydrate, characterized in that: R 14 is selected from H and F; each R70 is selected from halo, alkyl, CN, N (R71) 2, cyclic-amino, NO2, OR71, and CF3; each R71 being selected from hydrogen, alkyl, aryl, aralkyl and a heterocyclic ring; and kser from 0 to 4. TREATMENT OF A NEOPLASTIC DISEASE OR PROLIFERATIVE DISORDER IN HUMANS comprising administering therapeutically effective amount to a composition according to claims 1 to 7.