CN1989110A - Theramutein modulators - Google Patents

Abstract

The present invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods for identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants encoded by genes that have been mutated, which variants are typically produced or at least first identified when produced upon exposure to a chemical active agent that is an inhibitor or activator of the corresponding unmutated endogenous protein.

Description

THERAMUTEIN MODULATORS

Background of the invention

The progressive development of drug resistance in patients is a hallmark of long-term treatment with many types of drugs, especially in the treatment of cancer and infectious diseases. Molecular mechanisms mediating some types of resistance phenomena have been identified, while in other cases the mechanisms of acquired and re-established resistance are currently unknown.

One mechanism of induced (acquired) drug resistance originally thought to be relevant in the field of cancer therapy involves increased expression of a protein called P-glycoprotein (P-gp). P-gp is located in the cell membrane and acts as a drug efflux pump. The protein is capable of pumping toxic chemical agents, including many types of anticancer drugs, from cells. Thus, upregulation of P-glycoprotein often produces multidrug resistance. Upregulation of P-glycoprotein in tumor cells may represent a defense mechanism developed in mammalian cells to protect against damage by toxic chemical agents. Other related drug resistance proteins with similar functions to P-gp have now been identified, including multidrug-resistance-associated protein family members such as MRP1 and ABCG2. In any event, the importance of P-glycoprotein and related ATP-binding cassette (ABC) transporters in clinically significant drug resistance has been highlighted in the development of compounds that are specific for a given target protein and less toxic. decline.

Another possible molecular mechanism of acquired drug resistance lies in alternative signaling pathways leading to persistent cell survival and metabolism even though the original drug remains effective against its target. In addition, changes in the intracellular metabolism of drugs can also lead to loss of therapeutic efficacy. In addition, changes in gene expression and gene amplification results can occur, resulting in increased or decreased expression of a given target protein, and often require increased drug dosage in order to maintain the same effect (Adcock and Lane, 2003).

Mutation-induced drug resistance is often the case in the field of infectious diseases. For example, several drugs that inhibit the viral reverse transcriptase or viral protease encoded in the genome of the human immunodeficiency (HIV) virus have been developed. It is well established in the literature that repeated treatment of HIV-infected AIDS patients with, for example, reverse transcriptase inhibitors eventually produces mutant forms of the virus that are resistant to the drug due to mutations that have occurred in the gene encoding reverse transcriptase. Reduced sensitivity, said mutation confers that the mutant form of the enzyme is less affected by the drug.

Given the rate at which errors are introduced into the HIV genome, the emergence of drug resistance during HIV treatment is not surprising. It is known that HIV reverse transcriptase is particularly error-tropic, wherein the forward mutation rate is about 3.4×10 ^-5 mutations/base pair/replication cycle (Mansky et al., J.Virol.69:5087-94 (1995)) . However, similar mutation rates for endogenous genes encoded in mammalian cells are more than an order of magnitude lower.

Emerging evidence suggests that drug resistance may also arise as a result of mutations involving genes encoding drug targets (Gorre et al., Science, 2001; PCT/US02/18729). In this case, following exposure of a patient to a specific therapeutic substance, such as a given cancer drug that targets a specific protein of interest (POI or "target" protein), is implicit in the gene encoding the protein that is the target of the therapeutic substance The mutation occurs in the overgrowth of a group of cells. It is not known whether the overgrowth of this cell population is due to the small percentage of pre-existing cells in patients with mutations in POIs that already harbor drug-resistant POIs, or whether such mutations can be activated or suppressed by animal or human exposure The POI is regenerated during or after the therapeutic agent. In either case, such mutations result in a mutated protein (hereinafter defined as a theramutein) which is less or possibly not affected at all by the therapeutic substance.

Chronic myelogenous leukemia (CML) is characterized by hyperproliferation of myeloid progenitors that retain the ability to differentiate during the stable or chronic phase of the disease. Multiple lines of evidence have established dysregulation of the Abl tyrosine kinase as a causative oncogene in certain forms of CML. This dysregulation is often associated with a chromosomal translocation known as the Philadelphia chromosome (Ph), resulting in the expression of a fusion protein consisting of the BCR gene product fused to the Abelson tyrosine kinase, thereby forming the p210 ^{Bcr- Abl} . A related fusion protein, called pl90 ^Bcr-Abl , arises from a different breakpoint in the BCR gene and has been shown to occur in patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) (Melo, 1994 ; Ravandi et al., 1999). Transformation appears to result from activation of multiple signaling pathways, including those involving RAS, MYC and JUN. Imatinib mesylate ("STI-571" or "Gleevec ^(R )") is a 2-anilinopyrimidine that targets the ATP binding site of the kinase domain of Abl (Druker et al., NEJM 2001, p. 1038). Inhibitors of the platelet-derived growth factor (PDGF) beta receptor and the Kit tyrosine kinase have subsequently also been discovered by other approaches, the latter of which is involved in the development of gastrointestinal stromal tumors (see below).

Until recently, it has not been observed that during treatment with a specific inhibitor of a given endogenous cellular protein, mutations in its corresponding endogenous gene can lead to differential expression of the protein, the cellular function of the protein variant Tolerated the inhibitor. Work by Charles Sawyers and colleagues (Gorre et al., Science 293:876-80 (2001); PCT/US02/18729) demonstrated for the first time that treatment with a drug that inhibits the p210 ^Bcr-Abl tyrosine kinase (ie, STI-571) A clinically significant population of cells may arise in said patient with a cryptic mutation in the gene encoding the Abelson tyrosine kinase domain-containing target protein that produces the p210 ^Bcr-Abl carcinoma. Each of these mutations produces mutant forms of p210 ^Bcr-Abl that are less responsive to Gleevec treatment than the form that produced the original cancer. Notably, the mutations that emerged conferred relative resistance to the drug action of protein kinase inhibitors on the mutant protein, while maintaining some degree of the original substrate specificity of the mutant protein kinase. Prior to the work of Gorre et al., those skilled in the art generally believed that the type of resistance that could be observed in patients exposed to compounds that inhibit Abelson protein kinases, such as STI-571, could be due to one of the other mechanisms of drug resistance described above or Various or by some other mechanism not yet understood, but in any case said resistance may involve a target (protein or otherwise) other than the drug's target POI.

Therefore, it may be extremely useful to treat clinically relevant mutant forms of proteins that are also targets of existing therapies. Such mutant proteins (theramuteins as defined below) are becoming recognized and understood as important targets in recurrent cancers and are becoming important in other diseases as well. A need exists for therapeutic agents that are active against such drug-resistant variants of cellular proteins that may arise before, during, or after generally effective drug therapy. A key object of the present invention is to provide compounds that can be used as potential therapeutic agents for overcoming mutation-induced drug resistance in endogenously occurring proteins.

Summary of the invention

The present invention relates to agents that are inhibitors or activators of variant forms of endogenous proteins and novel methods of identifying such variants. Of particular interest are inhibitors and activators of endogenous protein variants encoded by genes that have been mutated, often upon exposure to chemicals known to be inhibitors or activators of the corresponding unmutated endogenous protein. The active agent is produced later or at least first identified after having been produced. Such protein variants (muteins), referred to herein as "theramuteins", may arise spontaneously in organisms (and in some cases pre-exist mutations) or such mutants may be used as agents capable of inhibiting said This arises as a result of selective pressure that occurs when a given chemical agent treats an organism with an unmutated form of theramutein (herein referred to as "prototheramutein"). It will be appreciated that in some instances, the prototheramutein may be the "wild type" form of the POI (eg, a protein that is dysregulated to produce a disease). In other cases, a prototheramutein is a variant of a disease-causing "wild-type" protein that has mutated and thereby contributed to the diseased state as a result of said prior mutation. An example of the latter type of prototheramutein is the P210 ^BCR-ABL oncoprotein, and a mutant form of this protein with an implicit threonine (T) to isoleucine (I) mutation at position 315 is called P210 ^{BCR-ABL-T315I} , and is an instance of theramutein. As used herein, the nomenclature "p210 ^BCR-ABL " is synonymous with the terms "p210 ^Bcr-Abl ", "wild-type Bcr-Abl protein" and the like.

Theramuteins are a rare class of endogenous proteins that harbor mutations that confer resistance to drugs that are known to inhibit or activate their non-mutated counterparts in a therapeutically effective manner. The few endogenous genes encoding these proteins are known to exhibit such mutations in some cases. The present invention relates to compositions that inhibit certain drug-resistant mutants (theramuteins) of the Abelson tyrosine kinase protein, originally referred to in the literature as P210-Bcr-Abl, which is involved in chronic myeloid The occurrence of cellular leukemia. The invention also relates to a general method for identifying the inhibition or activation of any theramutein.

The methods of the invention particularly relate to methods of identifying specific inhibitors or specific activators of theramuteins. The use of the term "specificity" in the context of the term "inhibitor" or "activator" (see definition below) means that said inhibitor or activator binds to a theramutein and inhibits or activates the cellular function of the theramutein, But does not bind and activate or inhibit various other protein or non-protein targets in cells. Those skilled in the art are well aware that when discussing the role of protein inhibitors or activators in the medical literature, there is a certain degree of uncertainty with regard to the concept of specific inhibitors or specific activators and the related concept of target protein "specificity". transsexual. Thus, for the purposes of the present invention, a substance is a specific inhibitor or a specific activator of a given theramutein, provided that the substance is capable of inhibiting or activating said theramutein at the indicated concentration, so that the corresponding phenotype response (phenoresponse) Modulated in an appropriate manner without having an appreciable effect on the phenotypic response of corresponding control cells substantially not expressing the theramutein or its corresponding prototheramutein at the same indicated concentration.

In certain embodiments, the substance may be a prototheramutein and a modulator of theramutein. In other embodiments, in addition to being a prototheramutein and a modulator of theramutein, a substance can also modulate the activity of a protein with a similar function. As mentioned above, in addition to inhibiting the p210 ^{Bcr Abl} tyrosine kinase, imatinib mesylate is also able to inhibit the c-kit oncogene product (also a tyrosine kinase ) and the PDGFβ receptor (also a tyrosine kinase) expressed in some chronic myelomonocytic leukemias (CMML). Such compounds are sometimes referred to as "moderately specific" inhibitors.

The present invention also provides general methods that can be used to identify substances that activate or inhibit a theramutein to the same extent, and preferably to an even greater extent than that of the corresponding "wild-type" form of the protein. (However, it is well known to those skilled in the art that said "wild type" forms of such proteins have been mutated in the course of producing the corresponding disease in which the protein is involved).

In a preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula I:

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ² is selected from -CR ²¹ _a -, -NR ²² _b - and -(C=R ²³ )-;

Each R ²¹ is independently selected from H, halogen, -NH ₂ , -N(H)(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -O-(C _1-3 alkane group), OH and C _1- 3 alkyl;

Each R ²² is independently selected from H and C _1-3 alkyl;

R ²³ is selected from O, S, NR ⁰ and N-OR ⁰ ;

R ³ is selected from -CR ³¹ _c -, -NR ³² _d - and -(C=R ³³ )-;

Each R ³¹ group is selected from H, halogen, -NH ₂ , -N(H)(R ⁰ ), -N(R ⁰ ) ₂ , -OR ⁰ , OH and C _1-3 alkyl;

each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle;

R ³³ is selected from O, S, NR ³⁴ and N-OR ⁰ ;

R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁴ is selected from -CR ⁴¹ _e -, -NR ⁴² _f -, -(C=R ⁴³ )- and -O-;

Each R ⁴¹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle;

each ^R42 group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl and heterocycle;

each R ⁴³ is independently selected from O, S, NR ⁰ and N-OR ⁰ ;

The proviso is that when R ² is -NR ²² _b - and R ⁴ is -NR ⁴² _f -, R ³ is not -NR ³² _d -; and R ³ and R ⁴ are not simultaneously selected from -(C=R ³³ ) -and-(C=R ⁴³ )-;

R ⁵ is selected from -YR ⁶ and -ZR ⁷ ;

Y is selected from chemical bond, O, NR ⁰ ;

^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ⁷ is H or is selected from aryl and heterocycle;

each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle;

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 present invention provides a fundamentally new way of treating cancer and other diseases in which, whatever the mechanism, treatment with existing drug compounds is followed by identifiable (clinically significant) theramutein-mediated drug resistance, by providing This is done when theramuteins are produced and identified as such (Wakai et al., 2004 reported an example where theramutein could be produced during a continuous treatment regimen) or by pre-dosing an alternative drug prior to overgrowth of a clinically significant population of theramutein-expressing cells. Furthermore, if drug treatment for a particular disease is less effective in a subpopulation of individuals expressing a certain theramutein of the drug-targeted protein, the present invention can accommodate those affected by providing alternative drug substances effective against said theramutein. The treatment of the subjects.

1. The present invention provides methods for determining whether a chemically active agent is at least as effective as a modulator of a theramutein in a cell than a substance that is a known modulator of the corresponding prototheramutein. One embodiment of the method comprises contacting a control cell expressing a prototheramutein and capable of exhibiting a responsive phenotype characteristic (correlated with the function of the prototheramutein in the cell) with a known modulator of prototheramutein, such that the control cell expresses the theramutein and is also capable of exhibiting responsiveness A test cell of a phenotypic characteristic (related to the function of theramutein in the cell) is contacted with a chemically active agent, and the response of the test cell is compared to the response of a treated control cell; Substances known as prototheramutein modulators are equally effective. In certain other embodiments, one type of control cell may not express prototheramutein at all. In other embodiments, the control cells can express prototheramutein in substantially the same amount as the test cells express theramutein. In other embodiments, under certain conditions, control cells are capable of exhibiting phenotypic characteristics of responsiveness to substantially the same extent as test cells.

2. Theramuteins of particular interest to the present invention are those involved in regulatory functions, such as enzymes; protein kinases; tyrosine kinases; receptor tyrosine kinases; serine threonine protein kinases; bidirectional specificity protein kinases; proteases; Metalloproteases; phosphatases; cell cycle control proteins; docking proteins, such as IRS family members; cell surface receptors; G-proteins; ion channels; DNA- and RNA-binding proteins; polymerases, etc. It is not intended to limit the types of theramuteins that may be used in the present invention. Meanwhile, three theramuteins are known: BCR-ABL, c-Kit and EGFR.

3. Any reactive phenotypic characteristic that may be associated with the theramutein (or prototheramutein) present in the cell can be used in the method, including, for example, growth or culture characteristics, phosphorylation status (or other modification) of the theramutein substrate, and any type of The temporal characteristics of the cells, as defined and discussed in detail.

Description of drawings

Accompanying drawing 1 shows the effect of different concentrations of compound 2 (C2) on untransformed vector control Ba/F3 cells (IL-3 dependent) and Ba/F3 cells expressing "wild type" p210 ^Bcr-Abl (named p210 ^Bcr-Abl-wt ) and Ba/F3 cells expressing the p210 ^{Bcr-Abl-T315I} drug-resistant mutant strain on growth and survival. Cell counts and viability were determined with an automated cell counter as described in detail in this specification. Cell counts are represented by solid color bars; cell viability is represented by dashed lines. Note that STI-571 potently inhibits the growth of the P210 cell line (gray bars), while not inhibiting the growth of the T315I cell line even at a concentration of 10 μΜ (white bars). 500 nMC2 exhibited the largest specificity gap across the range of this dose-response series. The effect of 10 [mu]M STI-571 was compared to 500 nM C2 on the T315I cell line (white bar). Abbreviations: DMSO: Dimethylsulfoxide (solvent for drug dissolution).

Figure 2 shows the effect of different concentrations of compound 6 (C6) on the growth and survival rate of untransformed vector control Ba/F3 cells and Ba/F3 cells expressing p210 ^{BCr-Abl-T315I} drug-resistant mutant strain. All other details are as in Figure 1.

Figure 3 shows the results of different assays of the specificity gap obtained by comparing the different compounds identified in the screen with respect to their effects on prototheramutein and theramutein expressing cell lines. Compound 3 (C3) shows the best example of the ability to identify a compound that exerts an even greater effect on theramutein than its corresponding effect on prototheramutein. (Group E).Group A: control group treated with DMSO; B: negative heterologous-specific notch; C: mildly positive heterologous-specific notch; D: significantly positive homologous-specific notch; E: positive heterologous-specific notch specificity gap. See text for explanation. Panel A: control group DMSO-treated; B: negative heterologous-specific notch; C: mildly positive heterologous-specific notch; D: significantly positive homologous-specific notch; see Explanation section.

Figure 4 shows the autoradiographs of the kinase domains of recombinant P210Bcr-Abl wild type and T315I mutant used for the detection of autophosphorylation activity. 200 ng of protein were pre-incubated with test substances for 10 minutes under standard autophosphorylation reaction conditions, then radiolabeled ATP was added and the reaction was allowed to proceed at 30° C. for 30 minutes, after which samples were separated by SDS-PAGE. Gels were silver-stained, dried in vacuo and exposed to X-ray film. Note that while 10 μM STI 571 is potent against wild-type P210 Bcr-Abl, it is actually inactive against the T315I kinase domain at concentrations even up to 100 μM. C2 and C6 were the best two identified compounds, followed by C5, C7 and C4. All of these compounds tested positive to some extent. "P210 cell line" refers to cells expressing p210 ^BCR-ABL-wt . "T315I cell line" refers to cells expressing p210 ^{BCR-ABL-T315I} .

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

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

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

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

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

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

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

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

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

Detailed description of the invention

As used herein, the term "halo" or "halogen" includes fluorine, chlorine, bromine and iodine.

The term "alkyl" as used herein contemplates substituted and unsubstituted straight and branched chain alkyl groups having 1 to 6 carbon atoms. Preferred alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, and the like. Additionally, the alkyl group may optionally be substituted by one or more substituents selected from the group consisting of halogen, CN, _CO2R , C(O)R, C(O) _NR2 , _NR2 , cyclo-amino, _NO2 and OR replace.

The term "cycloalkyl" as used herein contemplates both substituted and unsubstituted cycloalkyl groups. Preferred cycloalkyl groups are those monocyclic rings containing 3 to 7 carbon atoms, and include cyclopropyl, cyclopentyl, cyclohexyl and the like. Other cycloalkyl groups may be selected from C ₇ -C ₁₀ bicyclic systems or C ₉ -C ₁₄ tricyclic systems. In addition, cycloalkyl can be optionally substituted with one or more selected from halogen, CN, CO ₂ R, C(O)R, C(O)NR ₂ , NR ₂ , cyclo-amino, NO ₂ and OR base substitution.

The term "alkenyl" as used herein contemplates substituted and unsubstituted straight and branched chain alkenyl groups. Preferred alkenyl groups are those containing 2 to 6 carbon atoms. Further alkenyl groups may optionally be substituted by one or more substituents selected from halogen, CN, CO ₂ R, C(O)R, C(O)NR ₂ , NR ₂ , ring-amino, NO ₂ and OR replace.

The term "alkynyl" as used herein contemplates substituted and unsubstituted straight and branched chain alkynyl groups. Preferred alkynyl groups are those containing 2 to 6 carbon atoms. Additionally, the alkynyl group may optionally be substituted by one or more substituents selected from the group consisting of halogen, CN, _CO2R , C(O)R, C(O) _NR2 , _NR2 , cyclo-amino, _NO2 and OR replace.

The term "aralkyl" as used herein concerns an alkyl group bearing an aromatic group as a substituent, which may be substituted or unsubstituted. Aralkyl groups may optionally be substituted on the aryl group by one or more substituents selected from halogen, CN, CF ₃ , NR ₂ , ring-amino, NO ₂ , OR, CF ₃ , - (CH ₂ ) _x C(O)(CH ₂ ) _y R, -(CH ₂ ) _x C(O)N(R′)(R″), -(CH ₂ ) _x C(O)O(CH ₂ ) _y R, -(CH ₂ ) _x N(R′)(R″), -N(R)SO ₂ R, -O(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 ) _x -C(O)-N(R)-( CH ₂ ) _y -R, -(CH ₂ ) _x C(O)N(R)-(CH ₂ ) _y -R, -O-(CH ₂ ) _x -C(O)-N(R)-( CH ₂ ) _y -R, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted Substituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heterocycle, wherein said substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted alkenyl, substituted Alkynyl, substituted aryl and substituted heterocycles can be replaced by halogen, CN, CF ₃ , CO ₂ R, C(O)R, C(O)NR ₂ , NR ₂ , ring-amino, NO ₂ and OR One or more of the substitutions.

The term "heterocyclyl" or "heterocycle" as used herein contemplates aromatic and non-aromatic cyclic groups having at least one heteroatom as a ring member. Preferred heterocyclic groups are those containing at least one heteroatom containing 5 or 6 ring atoms, and include: cyclic amines such as morpholino, piperidino, pyrrolidino, etc.; and ring Ethers, such as tetrahydrofuran, tetrahydropyran, etc. Aromatic heterocyclyl, also referred to as "heteroaryl", contemplates mono-cyclic hetero-aromatic groups which may contain 1-3 heteroatoms, for example pyrrole, furan, thiophene, imidazole, oxazole, thiazole, Triazole, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, etc. The term heteroaryl as used herein also includes polycyclic hetero-aromatic systems having two or more rings in which two atoms are common to two adjacent rings (the rings are "fused"), Where at least one of the rings is heteroaryl, for example the other rings may be cycloalkyl, cycloalkenyl, aryl, heterocycle and/or heteroaryl. Examples of polycyclic heteroaromatic systems include quinoline, isoquinoline, tetrahydroisoquinoline, quinoxaline, quinaxoline, benzimidazole, benzofuran, purine, imidazopyridine, benzotriazole, and the like. In addition, heterocyclyl can be optionally substituted with the following groups: halogen, CN, CF ₃ , NR ₂ , cyclo-amino, NO ₂ , OR, CF ₃ , -(CH ₂ ) _x C(O)(CH ₂ ) _y R, -(CH ₂ ) _x C(O)N(R′)(R″), -(CH ₂ ) _x C(O)O(CH ₂ ) _y R, -(CH ₂ ) _x N( R')(R"), -N(R)SO ₂ R, -O(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 ) _x -C(O)-N(R)-(CH ₂ ) _y -R, -(CH ₂ ) _x C(O)N(R)-(CH ₂ ) _y -R, -O-(CH ₂ ) _x -(O)-N(R)-(CH ₂ ) _y -R, substituted and unsubstituted Alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkynyl, substituted and unsubstituted aryl and substituted and unsubstituted heterocycles, wherein the substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted alkenyl, substituted alkynyl, substituted aryl and substituted heterocycle Can be substituted by one or more of halogen, CN, CF ₃ , CO ₂ R, C(O)R, C(O)NR ₂ , NR ₂ , cyclo-amino, NO ₂ and OR.

The term "aryl" or "aromatic group" as used herein is concerned with single-ring aromatic groups (such as phenyl, pyridyl, pyrazolyl, etc.) and polycyclic ring systems (naphthyl, quinoline, etc. ). A polycyclic ring may have two or more rings in which two atoms are common to two adjacent rings (the rings are "fused") wherein at least one of the rings is aromatic, e.g. other rings Can be cycloalkyl, cycloalkenyl, aryl, heterocycle and/or heteroaryl. In addition, aryl may be optionally substituted with one or more substituents selected from halogen, CN, CF ₃ , NR ₂ , ring-amino, NO ₂ , OR, CF ₃ , -(CH ₂ ) _x C(O)(CH ₂ ) _y R, -(CH ₂ ) _x C(O)N(R′)(R″), -(CH ₂ ) _x C(O)O(CH ₂ ) _y R , -(CH ₂ ) _x N(R′)(R″), -N(R)SO ₂ R, -O(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 ) _x -C(O)-N(R)-(CH ₂ ) _y -R, -(CH ₂ ) _x C(O)N(R)-(CH ₂ ) _y -R, -O-(CH ₂ ) _x -C(O)-N(R)-(CH ₂ ) _y -R, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted alkenyl, substituted and unsubstituted alkyne substituted and unsubstituted aryl and substituted and unsubstituted heterocycle, wherein the substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted alkenyl, substituted alkynyl , substituted aryl and substituted heterocycles can be replaced by one of halogen, CN, CF ₃ , CO ₂ R, C(O)R, C(O)NR ₂ , NR ₂ , ring-amino, NO ₂ and OR or multiple substitutions.

As used herein, the term "heteroatom", especially as a ring heteroatom, refers to N, O and S.

Each R is independently selected from H, substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aryl, and substituted and unsubstituted Substituted heterocycle, wherein said substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl and substituted heterocycle can be replaced by one or more of halogen, CN, CF ₃ , OH, CO ₂ H, NO ₂ , C _1-6 alkyl, -O-(C _1-6 alkyl), -NH ₂ , -NH(C _1-6 alkyl) and -N(C _1-6 alkyl) ₂ replaced.

Each R' and R" is independently selected from H or substituted and unsubstituted alkyl, substituted and unsubstituted cycloalkyl, substituted and unsubstituted aralkyl, substituted and unsubstituted aryl and Substituted and unsubstituted heterocycles, wherein the substituted alkyl, substituted cycloalkyl, substituted aralkyl, substituted aryl and substituted heterocycles can be replaced by one or more of halogen, CN, CF ₃ , OH, CO ₂ H, NO ₂ , C _1-6 alkyl, -O-(C _1-6 alkyl), -NH ₂ , -NH(C _1-6 alkyl) and -N(C _{1- 6} alkyl) ₂ substitution; or R' and R" may together with the nitrogen to which they are attached form a 5- to 7-membered ring which may optionally contain up to three additional heteroatoms. Each x and each y is independently selected from 0-4.

In a preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula I:

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ² is selected from -CR ²¹ _a -, -NR ²² _b - and -(C=R ²³ )-;

Each R ²¹ is independently selected from H, halogen, -NH ₂ , -N(H)(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -O-(C _1-3 alkane group), OH and C _1-3 alkyl;

Each R ²² is independently selected from H and C _1-3 alkyl;

R ²³ is selected from -O, S, NR ⁰ and N-OR ⁰ ;

R ³ is selected from -CR ³¹ _c -, -NR ³² _d - and -(C=R ³³ )-;

R ³¹ groups are each selected from H, halogen, -NH ₂ , -N(H)(R ⁰ ), -N(R ⁰ ) ₂ , -OR ⁰ , OH and C _1-3 alkyl;

^Each R group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl, and heterocycle;

R ³³ is selected from O, S, NR ³⁴ and N-OR ⁰ ;

R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁴ is selected from -CR ⁴¹ _e -, -NR ⁴² _f -, -(C=R ⁴³ )- and -O-;

Each R ⁴¹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle;

each ^R42 group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl and heterocycle;

Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ;

The proviso is that when R ² is -NR ²² _b - and R ⁴ is -NR ⁴² _f -, R ³ is not -NR ³² _d -; and R ³ and R ⁴ are not simultaneously selected from -(C=R ³³ ) -and-(C=R ⁴³ )-;

R ⁵ is selected from -YR ⁶ and -ZR ⁷ ;

Y is selected from chemical bond, O, NR ⁰ ;

^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ⁷ is H or is selected from aryl and heterocycle;

^Each R is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle;

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.

An important component and conceptual teaching in the invention described herein is that neither the ^R2 nor ^R3 positions of the compounds of the invention are members of any aromatic or non-aromatic ring structure. We have found that compounds with ^R2 and/or ^R3 positions as members of any aromatic or non-aromatic ring structure are not effective at inhibiting T315I theramutein, but lack Compounds of the present invention of such ring components are potent inhibitors of T315 Itheramutein.

In a preferred embodiment of the invention, Ring A is an aromatic ring.

In a preferred embodiment of the invention, X ¹ or X ² is N. In another preferred embodiment, ^{both X1} and ^X2 are N. In a particularly preferred embodiment of the invention, Ring A is a pyridine or pyrimidine ring. In a further preferred embodiment, Ring A is selected from the structures provided below:

In a preferred embodiment, if R ² or R ⁴ is selected as -NR ²² _b - or -NR ⁴² - respectively, then R ³¹ is not selected from halogen, -NH ₂ , -N(H)(R ⁰ ) , -N(R ⁰ ) ₂ , -OR ⁰ or OH.

In another preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general _formula Ia:

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

Each R ²² is independently selected from H and C _1-3 alkyl;

R ³ is selected from -CR ³¹ _c -, -NR ³² _d -, and -(C=R ³³ )-;

Each R ³¹ group is selected from H, halogen, -NH ₂ , -N(H)(R ⁰ ), -N(R ⁰ ) ₂ , -OR ⁰ , OH and C _1-3 alkyl;

each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle;

R ³³ is selected from O, S, NR ³⁴ and N-OR ⁰ ;

R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁴ is selected from -CR ⁴¹ _e -, -NR ⁴² _f -, -(C=R ⁴³ )- and -O-;

Each R ⁴¹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle;

each ^R42 group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl and heterocycle;

Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ;

The proviso is that when R ⁴ is -NR ⁴² _f -, R ³ is not -NR ³² _d -; and R ³ and R ⁴ are not simultaneously selected from -(C=R ³³ )- and -(C=R ⁴³ ), respectively -;

R ⁵ is selected from -YR ⁶ and -ZR ⁷ ;

Y is selected from chemical bond, O, NR ⁰ ;

^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ⁷ is H or is selected from aryl and heterocycle;

^Each R is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle;

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 another preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula _Ib :

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

each R ²² is independently selected from H and C _1-3 alkyl;

each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle;

R ⁴ is selected from -CR ⁴¹ _e -, -(C=R ⁴³ )- and -O-;

R ⁴¹ are each selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle;

Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ;

R ⁵ is selected from -YR ⁶ and -ZR ⁷ ;

Y is selected from chemical bond, O, NR ⁰ ;

^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ⁷ is H or is selected from aryl and heterocycle;

^Each R is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle;

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 a preferred embodiment of the invention, R ² , R ³ and R ⁴ of general formula I are chosen so as to obtain the following chemical groups:

-N(R ²² )-N=C(R ⁴¹ )-

-N(R ²² )-N(R ³² )-C(=O)-

-N(R ²² )-N(R ³² )-C(R ⁴¹ )(R ⁴¹ )-

-N(R ²² )-C(R ³¹ )(R ³¹ )-C(R ⁴¹ )(R ⁴¹ )-

-N(R ²² )-C(R ³¹ )(R ³¹ )-C(=O)-

-N=NC(R ⁴¹ )(R ⁴¹ )-

-C(R ²¹ )=C=C(R ⁴¹ )-

-C(R ²¹ )=C(R ³¹ )-C(=O)-

-C(R ²¹ )=C(R ³¹ )-C(R ⁴¹ )(R ⁴¹ )-

-C(R ²¹ )(R ²¹ )-C(R ³¹ )＝C(R ⁴¹ )-

-C(R ²¹ )(R ²¹ )-C(R ³¹ )(R ³¹ )-C(=O)-

-C(R ²¹ )(R ²¹ )-C(R ³¹ )(R ³¹ )-C(R ⁴¹ )(R ⁴¹ )-

-C(R ²¹ )(R ²¹ )-N(R ³² )-C(=O)-

-C(R ²¹ )(R ²¹ )-N(R ³² )-C(R ⁴¹ )(R ⁴¹ )-

-N(R ²² )-C(=O)-C(R ⁴¹ )(R ⁴¹ )-

-N(R ²² )-C(=O)-N(R ⁴¹ )-

-N(R ²² )-C(=O)-O-

-C(R ²¹ )(R ²¹ )-C(=O)-C(R ⁴¹ )(R ⁴¹ )-

-C(R ²¹ )(R ²¹ )-C(=O)-N(R ⁴² )-

-N(R ²² )-C(=NR ³⁴ )-N(R ⁴² )-

-C(=O)-N(R ³² )-N(R ⁴² ).

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

-N(R ²² )-N=C(R ⁴¹ )-

-N(R ²² )-N(R ³² )-C(=O)-

-N(R ²² )-C(R ³¹ )(R ³¹ )-C(R ⁴¹ )(R ⁴¹ )-

-N(R ²² )-C(R ³¹ )(R ³¹ )-C(=O)-

-C(R ²¹ )(R ²¹ )-C(=O)-C(R ⁴¹ )(R ⁴¹ )-

-C(R ²¹ )(R ²¹ )-C(=O)-N(R ⁴² )-

-N(R ²² )-C(=NR ³⁴ )-N(R ⁴² )-

-C(=O)-N(R ³² )-N(R ⁴² ).

In another preferred embodiment, ^R6 or ^R7 is aryl 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 the substituents ^R21 and ^R22 are independently selected from groups having a small steric bulk and preferably from H and _CH3 , and more preferably H.

In another preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula II:

in

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

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 heterocycle;

R ⁹ is selected from -YR ⁶ and -ZR ⁷ ;

Y is selected from chemical bond, O, NR ⁰ ;

^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R is ^H or is selected from aryl and heterocycle; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

In another preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula _IIa :

in

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

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 heterocycle;

X ³ is N, CH or CR ⁵⁰ ;

Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom;

r is 0-4;

s is 0-4;

m is 0-4; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

In another preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula II _b :

in:

R ¹⁴ 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 heterocycle;

X ³ is N, CH or CR ⁶⁰ ;

Each R ⁶⁰ is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF ₃ , NO ₂ , OR ⁰ , halogen, aryl, and heterocycle;

R ^is selected from aryl and heterocycle;

Q is selected from a chemical bond or has the formula -O-, -(CH ₂ ) _i -, -(CH ₂ ) _i C(O)(CH ₂ ) _j -, -(CH ₂ ) _i -N(R ⁶² )-( CH ₂ ) _j -, -(CH ₂ ) _i C(O)-N(R ⁶² )-(CH ₂ ) _j -, -(CH ₂ ) _i C(O)O(CH ₂ ) _j -, -( CH ₂ ) _i N(R ⁶² )C(O)-(CH ₂ ) _j -, -(CH ₂ ) _i (O)N(R ⁶² )-(CH ₂ ) _j - and -O-(CH ₂ ) A group of _i -C(O)N(R ⁶² )-(CH ₂ ) _j -;

R ⁶² is selected from aryl and heterocycle;

each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle;

h is 0-4;

i is 0-4; and

j is 0-4.

In a preferred embodiment of the compound of general formula II _b , R ⁶⁰ is selected from halogen, CF ₃ and OH. Typical compounds of general formula II, II _a or II _b include the following structures:

In another preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula III:

in

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ¹⁰ is selected from -Y'-R ¹⁸ ;

Y' is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ¹⁸ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

In another preferred embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula III _a :

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

X ³ is N, CH or CR ⁵⁰ ;

Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , (CH ₂ ) _r N( R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0-3 5- or 6-membered fused rings of heteroatoms;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom;

r is 0-4;

s is 0-4;

m is 0-4; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

Typical compounds of general formula III or III _a include the following structures:

In another embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula IV:

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ²² is selected from H and C _1-3 alkyl;

R ³⁴ is selected from H, NO ² , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁴⁴ is selected from H, alkyl, cycloalkyl, -(C=O)R ⁰ , alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁴⁵ is selected from -Y″-R ¹⁹ ;

Y" is selected from the group consisting of chemical bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C One or more substituted hydrocarbon chains of (O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

Typical compounds of general formula IV include the following structures:

In another embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula V:

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ₁₃ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ²² is selected from H and C _1-3 alkyl;

R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁵⁶ is selected from -Y″-R ¹⁹ ;

Y" is selected from the group consisting of chemical bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C One or more substituted hydrocarbon chains of (O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

In another embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general _formula Va:

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

X ³ is N or CR ⁵⁰ ;

Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁵² and R ⁵³ are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may be together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

r is 0-4;

s is 0-4;

m is 0-4; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

Typical compounds of general formula V or _Va include the following structures:

In another embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula VI:

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁵⁶ is selected from -Y″-R ¹⁹ ;

Y" is selected from the group consisting of chemical bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C One or more substituted hydrocarbon chains of (O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ;

R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

In another embodiment, the present invention provides inhibitors of P210 ^{BCR-ABL-T315I} theramutein having the general formula _VIa :

in:

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

X ¹ is selected from N, NR ⁰ or CR ¹ ;

X ² is selected from N, NR ⁰ or CR ¹ ;

Dashed lines indicate optional double bonds;

Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms;

n is 0-6;

each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle;

Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

p is 0-4;

q is 0-4;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

X ³ is N or CR ⁵⁰ ;

Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms;

R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle;

R ⁵² and R ⁵³ are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may be together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom;

r is 0-4;

s is 0-4;

m is 0-4; and

Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle.

Typical compounds of general formula VI or _VIa include the following structures:

The definition of each expression used herein, such as alkyl, m, n, R, R', etc., when it occurs more than once in any structure, is independent of its definition elsewhere in the same structure.

With respect to each of the above descriptions of compounds of structures I, _Ia , Ib, II, _IIa , _IIb , III, _IIIa , _IV , _IVa , V, Va _, VI, and _VIa , Each recitation of the term halo, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, heterocyclyl, or heterocycle is independently selected from the definitions of those terms provided at the beginning of this section .

It is to be understood that the chemical structures provided herein include the implicit proviso that substitutions are made according to the permissible valences of the substituting atoms and substituents and that the substitutions result in stable compounds which, for example, do not spontaneously e.g. to convert.

When one or more chiral centers are present in the compounds of the present invention, the general formulas described herein include individual isomers and mixtures thereof (eg, racemates, etc.).

When one or more double bonds are present in the compounds of the invention, the general formulas described herein include cis- and trans-isomers. Although chemical structures in either the cis or trans (cis of trans) configuration are described herein (such as, for example, structures II, _IIa , V, _Va , VI, and _VIa ), the meaning of both configurations is that each general formulas are included.

In certain embodiments, the compounds of the invention may exist in several tautomeric forms. Accordingly, the chemical structures depicted herein include all possible tautomeric forms of the recited compounds.

The compounds of the present invention are generally prepared from commercially available starting materials and well known chemical techniques. Embodiments of the invention can be synthesized as follows. Those skilled in the art of pharmaceutical or synthetic chemistry are readily familiar with the necessary procedures and techniques for carrying out the synthetic approaches described below.

Can be prepared by reacting a suitable hydrazine compound such as A with a suitable aldehyde such as N under similar conditions as described in Gineinah et al. p.562 (Arch.Pharm.Pharm.Med.Chem.2002, 11, 556-562 Embodiment wherein R ² =NH, R ³ =N, R ⁴ =CH and R ⁵ =-aryl.

For example, C can be obtained by heating A with 1.1 equivalents of B in a protic solvent such as a _C1 - _C6 alcohol for 1-24 hours, followed by cooling and collecting the precipitate. Alternatively, product C can be isolated by evaporation of the solvent and purification by chromatography using silica gel, alumina or C ₄ -C ₁₈ reverse phase media. A similar approach can be applied where "aryl" is substituted by other groups as defined in R ⁵ .

Embodiments can be prepared by reacting a suitable hydrazine compound, such as D, with an activated carboxylic acid, such as E, wherein R ² =NH, R ³ =NR ³² , R ⁴ =C(O) and R ⁵ =heterocycle, wherein LG is a leaving group, such as halogen, 1-oxybenzotriazole, pentafluorophenoxy, p-nitrophenoxy, etc.; or compound E can also be an asymmetric carboxylic anhydride, which can be used with Nair Conditions similar to those described in Mehta, p. 408 (Indian J. Chem. 1967 5, 403-408).

For example, at a suitable temperature from 0°C to the boiling point of the solvent, in an inert solvent in the presence of a base such as pyridine or another tertiary amine and optionally a catalyst such as 4-N,N-dimethylaminopyridine , such as dichloromethane, 1,2-dichloroethane or N,N-dimethylformamide, treatment of D with an active ester, such as heterocycle-C(O)-OC ₆ F ₅ can give F, which can be obtained by The solvent is evaporated, followed by chromatography on silica gel, alumina or C ₄ -C ₁₈ reverse phase media. The above examples of active esters of E are readily prepared from the corresponding carboxylic acids and pentafluorophenol using a carbodiimide such as dicyclohexylcarbodiimide as the condensation reagent. A similar approach can be applied to the case where "heterocycle" is substituted by other groups as defined in R ⁵ .

Precursors, such as A and D, can be prepared by reacting a suitable nucleophile, for example, a hydrazine derivative, and a heteroaromatic compound bearing a halogen substituent adjacent to the nitrogen atom. For example, it can be used with Wu et al. (J.Heterocyclic Chem. 1990, 27, 1559-1563), Breshears et al. .Med.Chem.2002,11,556-562) described similar method, by for example, 2,4-dihalogenated pyrimidine derivatives are the examples of compound A and D prepared as raw materials, many of which are quotients in the raw materials commercially available or readily prepared by those skilled in the art. Thus, treatment of an appropriate 2,4-dihalopyrimidine derivative G with an amine or other nucleophile (Z), optionally in the presence of added base, selectively replaces the 4-halogen substituent on the pyrimidine ring. Subsequent treatment of the product with a second nucleophile, such as hydrazine or a hydrazine derivative, optionally in a solvent, such as a _C1 - _C6 alcohol and optionally in the presence of an added base, replaces the 2-halogen substituent on the pyrimidine ring, Compounds which are examples of structures A and D above are thus obtained.

Embodiments can be synthesized by such methods as: wherein R ² is -NR ²² and R ³ is -C(=R ³³ ), or direct modifications thereof. The synthesis can be carried out starting from an appropriate ring A derivative J with a leaving group (LG) adjacent to the requisite ring nitrogen. As noted above, structure G above and the reaction product of structure G with a nucleophile Z are examples of such suitable ring A derivatives J . Suitable LG' groups are halogen, alkylthio, alkylsulfonyl, alkylsulfonate or arylsulfonate. Substitution of LG' by treatment of J with amine ^R12NH2 _affords intermediate K. An example of this chemical transformation is reported by Capps et al. in J. Agric. Food Chem. 1993, 41, 2411-2415, where R ¹² is H and LG' is CH ₃ SO ₂ - and R ¹² is H and LG' is Examples of C1 are reported in J. Chem. Soc. 1951, 1004-1015 by Marshall et al.

Intermediates of structure K are converted into compounds of the invention by simultaneous or sequential introduction of the elements ^R3 , ^R4 and ^R5 . For example, each treatment of an intermediate of structure K with the isocyanate ^R6 -N=C=O gives in a single step a compound of structure M, which is a compound of the invention, where ^R2 = ^-NR22- , ^R3 =- C=O-, R ⁴ =-NH- and R ⁵ =-bond-R ⁶ . Alternative methods for converting compounds of structure K to compounds of structure M are well known to those skilled in the art, wherein R is first introduced with a leaving group (e.g. ^p -nitrophenoxy or chloro), followed by subsequent use of, e.g., an amine R ⁶ —NH ₂ replaces the leaving group to introduce R ³ and R ⁶ .

Alternatively, intermediate N is obtained by treating an intermediate of structure K with a reagent, such as cyanamide ( _NH2 -CN), typically under heated conditions and optionally in the presence of a solvent, such as ethyl acetate or dioxane. Alternatives to cyanamide are nitroguanidine or amidinosulfonic acid (NH2 _- C(=NH) _-SO3H ). An example of such a transformation using cyanamide is reported by Latham et al. in J. Org. Chem. 1950, 15, 884. An example using nitroguanidine is reported by Davis in Proc. Natl. Acad. Sci. USA 1925, 11, 72. The use of amidinesulfonic acid is reported by Shearer et al. Bioorg.Med.Chem.Lett.1997, 7, 1763.

In a similar manner to the conversion of intermediates A or D into the embodiments represented by C or F, intermediate K is converted into compounds represented by P or Q, respectively, which are further embodiments of the invention.

In the above schemes, treatment of A or K with a ketone S to replace B, wherein R is as described above, yields compounds of structure T or U respectively, which are further embodiments of the invention.

Selective reduction of the non-guanidino carbon-nitrogen double bond of U with a suitable reducing agent such as a metal (boron, aluminum, silicon, etc.) hydride reagent, preferably one having a basicity, affords compound V of the present invention.

Embodiments of the invention can be prepared wherein R ² =CO, R ³ =-NR ³² -, R ⁴ =N- and R ³ =ZR ⁷ , where Z is a hydrocarbon chain and R ⁷ is as described above. When ^R32 =H, the ring A-derived carboxylic acid W is activated by conversion to the corresponding acid chloride or to an active ester or similar activated derivative, many of which are well known in the art. Treatment of the activated carboxylic acid with hydrazine affords the corresponding hydrazide Y. Treatment of Y with an aldehyde or ketone (if necessary with heating and/or mild acid catalysis) affords the desired final product Z.

If not commercially available, ring A-derived carboxylic acids W can be prepared by treating starting material J above with cyanide ions, optionally by heating or transition metal catalysis to replace the leaving group LG' with a cyano residue . Basic or acidic hydrolysis of the cyano group affords the acidic carboxylic acid intermediate W.

When ^R32 is other than H, the protected form of the monosubstituted hydrazine can be used in the above schemes in place of hydrazine. Thus, treatment of the activated carboxylic acid from W with R ³² NHNH-PG, where PG is a nitrogen protecting group, such as benzyloxycarbonyl or tert-butoxycarbonyl, followed by deprotection and treatment with the appropriate aldehyde or ketone as described above yields Z' is obtained, which is another embodiment of the present invention.

It will be apparent to those skilled in the art of organic synthesis that the above reaction schemes are representative of a broad set of procedures that are logical extensions of the enumerated procedures. Thus, further embodiments of the claimed invention incorporating additional ^R2 , ^R3 , ^R4 and ^R5 variants can be prepared by obvious modifications of the methods described above.

As recognized by those skilled in the art, it is advantageous to use temporary protecting groups in obtaining the final product. The term "protecting group" as used herein refers to a temporary modification of a potentially reactive functional group which prevents unwanted chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, ^2nd ed.; Wiley: New York, 1991).

A "mutein" is a protein having an amino acid sequence that is altered as a result of a mutation occurring in the corresponding gene (Weigel et al., 1989). Such mutations may result in one or more changes in the properties of the encoded protein. For example, an enzyme variant having a modified catalytic chemistry resulting from one or more amino acid changes is a mutein.

The present invention relates to proteins in which at least one amino acid residue is altered (the term "amino acid sequence change" or "amino acid sequence alteration" includes at least one amino acid residue alteration, deletion or addition, or any combination of deletion, addition, alteration) such that the resulting mutant protein becomes (as a result of the mutation) sensitive to a known therapeutic agent relative to the sensitivity of the non-mutated form of the protein to the therapeutic agent resistance. This particular type of mutein is hereinafter referred to as theramutein, and the corresponding protein lacking the mutation is referred to herein as prototheramutein.

As used herein, "prototheramutein" refers to a protein that occurs endogenously in cells that are sensitive to mutations that confer relative insensitivity (i.e., resistance) to a therapeutic compound that otherwise inhibits or activates the protein. Thus, "theramutein" refers to a protein or protein portion that occurs endogenously in a cell containing at least one amino acid sequence alteration relative to the endogenous form of the protein, wherein at least one human is exposed to a known inhibitory or Following a prototheramutein-activating substance, said amino acid sequence change is obtained or identified or becomes identifiable and is or has been shown to be clinically significant for the development or progression of a given disease. As far as the determination of the purpose in the preceding sentence is concerned, the only thing is that the substance need not be limited to the chemically active agent for which the purpose of the presence of the theramutein was first defined. Thus, by definition, a theramutein is a protein harboring a mutation in its corresponding endogenous gene, wherein said mutation is associated with the development of clinical resistance in patients to drugs generally capable of activating or inhibiting the non-mutated protein. With respect to a given theramutein, the term "corresponding prototheramutein" as used herein refers to a prototheramutein which has produced said theramutein by mutation. Similarly, with respect to a specified prototheramutein, the corresponding theramutein" refers to the theramutein produced by mutation of said prototheramutein.

Thus, it will be apparent to those skilled in the art that the definition of theramutein excludes proteins encoded by disease-causing pathogens, such as viruses and bacteria, when the genes encoding theramuteins are limited to endogenously occurring genes. The term "endogenous gene" as used herein refers to a gene that has been present in at least its unmutated form in the chromosome of an organism since ingestion. As used herein, the term "cell" refers to a living eukaryotic cell, whether in an organism or maintained in vitro under suitable laboratory tissue or organ culture conditions.

In one aspect of the invention, a theramutein is a protein that is altered for the first time relative to the normally occurring "wild type" form of the protein (ie prototheramutein). In another aspect of the invention, the theramutein is a prototheramutein, ie already a mutein itself. In another embodiment, the theramutein can be further mutated compared to a pre-existing theramutein. In such cases, the first theramutein, such as the T315I mutant of p210 BCR-ABL (see below), can be considered a "primary" theramutein, while subsequent mutations of the (already mutated) T315I variants can be referred to as secondary theramutein, tertiary theramutein, etc. As hereinafter typically, the muteins of the present invention are variants of the Bcr-Abl tyrosine kinase that break away from the inhibition of the "wild-type" Bcr-Abl inhibitor. Such Bcr-Abl muteins are relatively Alterations in the more common or "wild-type" form of Bcr-Abl (also known as muteins) alter the properties of the protein in such a way.

It is understood that a mutein of primary interest is a theramutein that has the same, increased or decreased specific activity relative to its prototheramutein, and is not inhibited or difficult to be inhibited by an agent capable of inhibiting a prototheramutein. Likewise, another theramutein of primary interest is a theramutein that has the same, increased or decreased specific activity (relative to its prototheramutein) and is not activated or is difficult to be activated by an agent capable of activating a prototheramutein. Other variations will be apparent to those skilled in the art. It is further understood that theramuteins can include naturally occurring or commonly observed protein variants, for example, variants expressed by different alleles of a particular gene. In some cases, such variants may be insignificant with respect to their normal cellular function, where functional differences become apparent only in the presence of agents that differentially inhibit or activate the cellular function of the variant. For example, naturally occurring variants of a particular enzyme may have substantially different activity profiles, but a therapeutic agent that modulates one variant may not be effective at modulating another variant.

It will be appreciated that one aspect of the invention resides in the identification of active agents against theramuteins that are produced or become predominant (by any mechanism) during the treatment of a given disease, and another aspect resides in the identification of active agents against theramuteins commonly found in a population of unaffected individuals. The mutein has an active agent, but wherein the mutein is less sensitive to modulation by an already approved drug, and wherein changes in the activity profile of the mutein become important in a disease state (and thus identified for the first time theramutein), such as in disease states in which the mutant protein is overexpressed or involved in signaling processes that are otherwise dysregulated. For example, a neoplastic disease can result from abnormal regulation of cellular components other than a theramutein or its prototheramutein and still be treatable with a prototheramutein inhibitor, while the same treatment is less effective or ineffective in the presence of the theramutein. This may be a result of the observation that the response of a particular tumor type to anticancer drugs varies among individuals expressing different variants of the enzymes to which the anticancer drugs are directed (Lynch et al., 2004). Here, a variant may not arise or become dominant during treatment of a disease, but pre-exist in a healthy population and be detected only on the basis of its altered responsiveness to an established course of treatment.

As used herein, the terms "agonist" and "activator" of a protein are used interchangeably. Activators (agonists) are limited to substances that bind and activate a given protein function. Unless otherwise stated, "activator", "agonist" and "activator of a protein" have the same meaning. Activation by an activator can be partial or complete. Also, as used herein, the terms "antagonist" and "inhibitor" of a protein are used interchangeably. Inhibitors (antagonists) are limited to substances that bind to and inhibit the function of a given protein. The description that a substance "inhibits" a protein means that the substance binds the protein in the cell and reduces the activity of the protein, but does not substantially reduce the amount of the protein in the cell. Similarly, describing a substance as "activating" a protein, such as prototheramutein or theramutein, means that the substance increases a defined function of the protein in the cell, but does not substantially alter the level of the protein in the cell. "Inhibitor", "antagonist" and "inhibitor of a protein" are also synonyms unless otherwise indicated. Inhibition by an inhibitor can be partial or complete. Modulators are either activators or inhibitors. As an example, "activator of PKC _β1 " should be interpreted as referring to a substance that binds to and activates PKC _β1 . Similarly, an "inhibitor of p210 ^Bcr-Abl " is a substance that binds to and inhibits the function of p210 ^Bcr-Abl . The description of a substance "inhibits a protein" requires that the substance binds said protein in order to exert its inhibitory effect. Similarly, the description of a substance "activating protein X" means that the substance binds and activates protein X. The terms "bind(s)", "binding" and "binds to" are used in describing interactions between two substances (e.g. enzyme-substrate, protein-DNA, receptor-ligand body, etc.) has its usual meaning in the field of biochemistry. As used herein, the term "binds to" is synonymous with "interacts with" in the context of discussing the association between a substance and its corresponding target protein. As used herein, the description of a substance "acting on" a protein, "affecting" a protein, "exerting its effect on a protein" etc. and all such related terms have the same meaning (as is well understood by those skilled in the art) that the substance activates or inhibit the protein.

The concept of repressing or activating a mutated form of an endogenous protein to a greater extent than the corresponding non-mutated counterpart protein was defined for the first time and is referred to herein as a positive "specificity gap". In general, and using inhibitors as examples, the specificity gap refers to the difference between the ability of a given substance under comparable conditions to inhibit theramutein in a cell-based assay system compared to one of :

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

b) the ability of a second substance (usually a known inhibitor of prototheramutein) to inhibit the 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 different substances (tested separately) on theramutein alone, the results are referred to as homology-specific gap assays.

Alternatively, when comparing the effects of two different substances (usually, but not always), one of them is tested for theramutein and the other for prototheramutein, and the results are called For heterologous specific gap (SG) determination. Thus, as given above (a) and (c) are examples of heterogeneous specific gap (SG) assays (although the same substance is used in both cases), while (b) is specific Example of a notch assay.

Figure 3 deals with information in understanding and clarifying these concepts.

Similar results apply when the situation involves activators. It will be immediately apparent to those skilled in the art that the term "comparable conditions" as used herein includes testing two different compounds, for example at the same concentration (such as comparing two closely related compounds to determine relative potency), or by combining the two The effects of different compounds tested at their respective _IC50 values on the corresponding prototheramuteins and theramuteins were compared. Those skilled in the art will readily recognize other useful variations and comparable conditions.

Thus, in one embodiment of the application of this method, substances that are more effective against theramutein have a "positive specificity gap". A "zero, ineffective, or none" specificity gap indicates that there is no significant measurable difference between the effect of the substance on the theramutein and its effect on the prototheramutein (however, such compounds may be useful in their ability to inhibit or activate the theramutein and its corresponding prototheramutein). capacity), and a "negative specificity gap" indicates that a substance at a specified concentration is less effective against a given theramutein than against the corresponding prototheramutein form or another equivalent form of the theramutein (such as may imply a different Mutation) effectiveness. The latter class of compounds generally receives less attention than the former class of compounds, except in cases where the compound is so potent that its relatively low effect on theramutein is not a real concern from the perspective of therapeutic efficacy. A person skilled in the art will readily recognize various means of quantifying specific gap assessments in a manner suitable to his or her needs.

The invention also provides means for identifying compounds exhibiting a desired specificity gap. Such compounds are identified and assayed for their ability to inhibit or activate theramutein using an in vitro cell-based assay system in which the effect of the substance on the cellular function of the mutant endogenous form of the protein is compared to that of the same drug for the non-mutant endogenous version of the protein. The role of cellular function of the form is compared.

Thus, the system enables the discovery of compounds that bind a theramutein and exert a greater modulatory effect on the cellular function of the theramutein than its corresponding prototheramutein. Furthermore, the system enables the discovery of compounds which bind to a theramutein and exert a modulating effect on the cellular function of the theramutein which is at least greater than or greater than the modulating effect which the above-mentioned known compounds are capable of exerting on the cellular function of the corresponding prototheramutein. In a specific embodiment of the invention, compounds are screened and identified for: 1) being at least as effective against theramutein as the original drug against prototheramutein; and/or 2) being as effective against prototheramutein as against theramutein was similar in effectiveness (ie exhibited small or essentially zero specificity gaps).

In one embodiment of the invention, cells overexpressing a theramutein of interest are used to identify chemoactive agents that are inhibitors or activators (ie, bind and inhibit or bind and activate) of at least a selected theramutein. These chemically active agents may also be inhibitors or activators of prototheramuteins or even other theramuteins of the same prototheramutein. As used herein, the terms "chemically active agent" and "compound" are used interchangeably, and both terms refer only to substances having a molecular weight of up to, but not necessarily including, 2000 atomic mass units (Daltons). Such substances are sometimes referred to as "small molecules". Unless otherwise stated, the term substance as used herein refers only to chemically active agents/compounds, and not to biologically active agents. As used herein, "bioactive agents" are molecules that include proteins, polypeptides and nucleic acids and that have equal to or greater than 2000 atomic mass units (Daltons).

Theramuteins are selected according to the present invention and used in cell-based assay systems designed to identify active agents that are inhibitors or activators of theramuteins. If two or more different theramuteins are known to be derived from the same prototheramutein, then the most resistant available theramutein is preferred for use in the test system. In general, the degree of resistance of a theramutein compared to its non-mutated counterpart (prototheramutein) to a given chemoactive agent is determined using a drug that is first administered and is known to inhibit or activate a prototheramutein and "emerges" against the theramutein. For example, methods for determining the degree of such resistance by analysis of _IC50 or _AC50 values are well known and standard in the art and are not repeated herein. However, a causal relationship is not essential or should be inferred between treatment of a patient with a self-specified therapeutic agent and the subsequent appearance of theramutein. Rather, what is required for the practice of the present invention is the proper selection of the correct theramutein as taught herein.

Thus, for example, randomly generated site-directed mutants of known proteins produced in the laboratory but not yet proven of clinical relevance are not suitable muteins for use within the scope of the present invention. Of course, such muteins would not be classified as theramuteins.

For example, in an attempt to obtain potential inhibitors of p210 ^Bcr-Abl mutants, Huron et al. (2003) used recombinant c-abl preparations and screened a series of compounds known to inhibit c-src tyrosine kinase activity. The authors performed a c-abl kinase assay on their compounds and identified the most potent compound against c-abl at 8 nM. However when this compound (PD166326) was tested against various p210 ^Bcr-Abl theramuteins, it showed activity against some of the mutants, such as p210 ^{Bcr-Abl-E255K} , but p210 ^{Bcr-Abl-T315I} theramuteins were found to retain 10 times more resistant (Huron et al. 2003, Table 3). Furthermore, in each case the effect of the compound on the p210 ^Bcr-Abl theramuteins remained significantly lower than its effect on wild-type p210 ^Bcr-Abl . When the compound was tested for activity against the p21 ^{Bcr-Abl-T315I} mutant, it failed to inhibit activity to any appreciable extent (p. 1270, left hand column, second paragraph; see also Figure 4). The compounds thus disclosed are capable of inhibiting the theramutein which confers partial resistance to STI-571, but is inactive against the T315I mutant of Bcr-Abl, which at the time was known to be the theramutein exhibiting the greatest resistance to STI-571. Thus, Huron's method fails to identify potent inhibitors of p210 ^Bcr-AblT315I theramutein, precisely and simply.

In fact, prior to the disclosure of the present invention, including the detailed methods first described herein and the compositions provided herein, no one anywhere in the world has successfully identified a chemically active agent, let alone one capable of identifying Method for ^Bcr-AblT35I theramutein to efficiently inhibit chemoactive agents to a degree equal to or greater than that which STI-571 is capable of inhibiting wild-type p210 ^Bcr-Abl protein (see Shah et al., Science, August 2004; O'Hare et al., Blood, 2004; Tipping et al., Leukemia, 2004; Weisberg et al., Leukemia, 2004).

It cannot be overemphasized that this class of compounds could be very useful, as there are currently no alternatives for patients who develop a p210 ^Bcr-AblT315I theramutein-mediated imatinib-resistant state. Once a patient develops such resistance, no other effective backup is available and death is certain. The methods described herein provide the first reported method for identifying, pharmacologically expressing and chemically synthesizing potent inhibitors of p210 ^{Bcr-Abl-T315I} theramutein. Furthermore, those skilled in the art immediately recognize the applicability and generalizability of this approach in any highly drug-resistant theramutein.

In the present invention, test cells exhibiting carefully selected phenotypic characteristics (described below) that correlate with the presence and functional activity of a particular theramutein of interest (TOI) in the cells under appropriate conditions are used. Qualitatively, this result is identical to the phenotypic features exhibited by prototheramutein-expressing cells. A phenotypic characteristic (ie, a non-genotypic characteristic of a cell) is a characteristic that is observed (measured), selected for, and/or subsequently defined for use in assay methods as described herein. The expression of phenotypic characteristics is a response to the overall activity of the theramutein in the cell and is a result of the absolute amount of the theramutein and its specific activity. Phenotypic features are generally observed as a result of elevated levels of theramutein activity and are not apparent in cells expressing low levels of theramutein or low levels of its corresponding prototheramutein. Furthermore, modulation of the specific activity of the theramutein by modulating the specific activity of the theramutein with inhibitors or activators of the theramutein can often be demonstrated to modulate phenotypic characteristics, however, this is not always the case since inhibitors or activators of TOIs are well known in the art by those skilled in the art. Items may not always be available. Thus, a person skilled in the art may also use substances capable of increasing or decreasing the expression of a theragene, thereby causing an increase or decrease in the level of the corresponding theramutein, for the purpose of determining the phenotypic characteristics of a given test cell subsequently used for experimental purposes. This allows those skilled in the art to mimic certain types of theramutein activators or inhibitors (such as suicide inhibitors of theramutein, a type of chemically active agent that irreversibly binds and covalently modifies the TOI to render it persistently inactive), but the actual Such compounds may be used for the purpose of pinpointing suitable phenotypic characteristics for subsequent establishment of useful cellular assay systems. Examples known to those skilled in the art that are useful for such purposes include the use of antisense DNA oligonucleotides, small interfering RNAs, other RNA interference-based methods, and vector constructs containing inducible promoter systems. In this manner, selected phenotypic features are correlated with theramutein activity in test cells. Of note for theramuteins is that the selected phenotypic characteristics are often also displayed by cells overexpressing prototheramuteins, and where the phenotypic characteristics are modulated by known inhibitors or activators of prototheramuteins.

Phenotypic features are purely cellular features that are not genotypic features of the cell. Except for the specific need for suitably defined phenotypic characteristics as disclosed herein in the purpose of producing useful cellular assay systems in accordance with the teachings of certain embodiments of the invention, any type of term used or suitable for proper and effective practice of the invention The phenotypic characteristics of or properties are not otherwise limited. Indeed, one skilled in the art must be able to select any characteristic of the cell that maximizes the utility of establishing an appropriate cell-based assay for his or her needs. Phenotypic characteristics can be quantitative or qualitative and can be observed or measured directly (e.g., with the naked eye or with a microscope), but most often the characteristics are measured indirectly using standard automated laboratory equipment and assay procedures well known to those skilled in the art . The term "observable" means that the characteristic is measurable, otherwise under appropriate conditions, by any means whatsoever, including the use of any type of laboratory-available instrumentation. The term "determinable" has a different meaning than "determined". Features are detectable to one of skill in the art but not measured at any given time, depending on how one of skill in the art chooses to design the assay system. For example, in the search for prototheramutein (or theramutein) activators, it is necessary to detect relevant phenotypic features only after addition of known activators or test substances capable of activating POIs. This provides the ability to maximize the signal strength produced by the test cells in the assay.

Phenotypic characteristics include, but are not limited to, growth characteristics, transformation status, differentiation status, substrate phosphorylation status, catalytic activity, ion flux across cell membranes (calcium, sodium, chloride, potassium, hydrogen ions, etc.), pH changes, second Changes in messenger molecules or other intracellular chemical species such as cAMP, phosphoinositides, cyclic nucleotides, regulation of gene expression, etc. Can be continuous (e.g., cell growth rate), or after a certain period of time (e.g., final density of cell culture) or transiently (e.g., modulation of a mutein causes a transient change in the phosphorylation of a mutein substrate, or the transient flux of ion currents across a membrane , or increased or decreased intracellular cAMP levels) to observe or measure cell characteristics. In certain embodiments, a selected phenotypic characteristic can be detected only in the presence of a prototheramutein or a theramutein modulator. There is no specified limit to the features that can be selected for the assay. As used herein, the terms "characteristic of a cell" and "phenotypic characteristic" and simply "characteristic" have the same meaning when used to refer to a specific measurable property of an intact cell or a subcellular fraction of a cell after treatment of a test cell with a substance . For example, the phenotypic characteristic may be focal formation when cells overexpressing a selected protein are cultured in the presence of an activator of that protein, or intracellular metabolites or ions such as cAMP, calcium, sodium, chloride, potassium This focal formation becomes observable when levels of , lithium, phosphatidylinositol, cGMP, bicarbonate, etc. are transiently increased or decreased. It will be apparent to those skilled in the art that the characteristics so determined (detected) can be determined on subcellular fractions of cells after exposure of the cells to the test substance. However, the initial treatment with the substance must be carried out on intact cells rather than subcellular fractions, thereby bringing the substance into contact with the cells.

The characteristics selected for the intracellular assay are not necessarily the intrinsic physical or chemical properties of the theramutein or prototheramutein itself (such as merely the amount (quality) of the protein inside the cell), but must be due to the production of the theramutein activity inside the cell and thus affect different Characterization of the cellular profile of theramutein itself, as discussed in detail above. For example, a theramutein may not be suitable for selection if it is a protein kinase capable of autophosphorylation, a process in which the enzyme is able to catalyze autophosphorylation by transferring a terminal phosphate moiety from ATP on itself. The phosphorylation status of the TOI served as an appropriate phenotypic characteristic of the cells used for the assay. This is because such features would not reflect the activity of the TOI on other cellular components. As is known to those skilled in the art, autophosphorylation does not necessarily reflect the activity of protein kinases in the cell, since mutants of known protein kinases retain sufficient enzymatic activity for autophosphorylation but lose signaling in the cell ability to transduce. The classic paper by White et al. (1988) is both instructive and noteworthy in this regard.

The term "responsive phenotypic characteristic" refers to a characteristic of a cell that responds to an inhibitor or activator of a given protein (prototheramutein or theramutein). The term "known therapeutic agent" is defined as any active agent administered to humans in countries worldwide for the treatment of disease.

Typical useful phenotypic features associated with p210 ^Bcr-Abl and its theramuteins herein are dysregulation of cell growth and proliferation. Note that the same or similar assay can be applied to many different proteins of interest. For example, dysregulation of growth, proliferation and/or differentiation are common phenotypic features resulting from the overexpression of various cellular proteins. An important teaching of the present invention is that the overexpression of selected proteins leads to the appearance of such phenotypic features which become correlated under suitable conditions with the presence, amount and specific activity of the selected proteins, and that this correlation This enables one skilled in the art to identify inhibitors or activators of a theramutein (TOI) of interest as desired. Thus, phenotypes are characterized in response to changes in the level and/or specific activity of selected proteins. Such reactive phenotypic characteristics are referred to herein as "phenoresponse".

Although not always necessary, it is often advantageous to use cells expressing high levels of theramutein and to select for phenotypic characteristics resulting from theramutein overexpression. This is because phenotypic features associated with theramutein function are generally more distinguishable (easier to measure) than when theramutein is overexpressed to a greater extent. Furthermore, the phenotypic responses observed in response to theramutein modulators were generally amplified when functional levels of theramutein were increased. Selected phenotypic responses observed in cells overexpressing theramutein are particularly sensitive to modulators of theramutein if expressed in another manner.

Preferably the theramutein is stably expressed in the test cells. Stable expression of theramutein results in levels in cells that remain relatively unchanged over the course of the assay. For example, stimulation or activation of a component in a signaling pathway is followed by a refractory period during which signaling is inhibited due to downregulation of that component. In the case of the theramuteins of the invention, such down-regulation is usually sufficiently overcome by artificially overexpressing the theramuteins. If expressed in another way, expression is sufficiently maintained that changes in these phenotypic features observed over the course of the assay are primarily due to theramutein inhibition or activation rather than changes in its levels, even if downregulation of theramutein follows The same happens. For these reasons, while stable expression of theramutein is preferred, transient expression of theramutein may be used after transfection, provided that the selected phenotypic characteristics are measurable and the duration of the test system is shorter than its predicted transient over time in such systems. The levels of expressed theramutein decreased progressively for short periods. For these reasons, stably expressing cell lines are preferred (US Pat. No. 4,980,281).

The preferred drug screening method of the present invention comprises the following steps:

1) Identification of theramuteins requiring new inhibitors or activators. Suitable theramuteins can be identified using standard techniques (see, Gorre et al., Science, 2001; see also PCT/US02/18729). Briefly, patients who have been given a therapeutically effective course of treatment with known or suspected prototheramutein activators or inhibitors and who have subsequently exhibited clinical signs and symptoms consistent with disease relapse are identified and cells derived from such patients are obtained or organization. The prototheramutein sequence is determined using standard laboratory techniques, such as RT-PCR, and compared to the previously determined nucleic acid sequence of known prototheramutein gene or cDNA sequences. If present, mutations are identified and correlated, again using standard methods, with functional resistance to the function of the prototheramutein in cell-based or more commonly cell-based assay systems. Once a resistance-inducing mutation is identified, the one or more identified mutants include a theramutein that can be used for subsequent method definition as described herein.

2) providing test cells expressing the theramutein of interest and exhibiting observable (measurable) phenotypic characteristics that have been previously demonstrated for inhibitors of the theramutein, or more commonly the corresponding prototheramutein or The activator reacts. A specific phenotypic characteristic that has been previously demonstrated to respond to a theramutein of interest (TOI) and/or prototheramutein of interest (pTOI) is defined herein for the first time as a "phenoresponse". One embodiment of the invention resides in the defined use of said phenotypic response for the purpose of identifying compounds capable of being TOI inhibitors or activators. This can be done by using high-throughput screening using cell lines that overproduce a given TOI and have identified and characterized appropriate phenotypic responses. Alternatively, high-throughput primary screens using more general phenotypic characteristics of cell lines (not necessarily phenotypic responses as taught herein) and then secondary screens as taught herein can be used to select from theramuteins that are not of interest The inhibitors or activators of the false positive compounds are distinguished from the compounds that are indeed positive "hits", i.e. inhibitors or activators of the theramutein of interest. In one embodiment, cells that naturally express theramutein are selected such that the reactive phenotypic characteristics are present under appropriate culture conditions apparent to those skilled in the art. In other embodiments, the theramutein is in some cases overexpressed in a host cell that otherwise does not express the theramutein at all. This process generally involves construction of an expression vector that can be introduced into a suitable host cell and overexpressed using standard vector systems and methods (Gorre et al., 2001; Housey et al., 1988). In one embodiment, overexpression produces a level of theramutein that is at least about 3-fold the amount of the protein normally present in the cell. Alternatively, the amount is at least about 10 times the amount normally present in the cell. In another embodiment, the amount is at least about 20 times or more preferably at least about 50 times the amount normally present in the cell.

3) providing control cells expressing a prototheramutein corresponding to the theramutein of interest. When certain muteins described herein are also enzymes, they generally retain catalytic activity and thus the control cells generally exhibit substantially the same phenotypic characteristics as the test cells. However, this phenotypic characteristic does not need to be quantified as in the two cells. For example, a mutein that reactivates a prototheramutein can also increase, decrease, or even affect its specific activity with respect to one or more of its substrates in the cell. As a result, it may exhibit the selected phenotypic trait to a greater or lesser extent. Thus, in some cases, it will be desirable to adjust the expression of either or both prototheramutein and theramutein so that test and control cells exhibit phenotypic characteristics to approximately the same extent. For example, this can be achieved by expressing the protein from a promoter, the activity of which can be adjusted by adjusting the amount of inducer present (eg, see Maniatis et al.), using standard methods.

It will be apparent to those skilled in the art that a properly defined phenotypic response may differ quantitatively between prototheramutein and theramutein expressing cell lines as a result of a difference in specific activity, if any, between its corresponding prototheramutein. Inducing mutations in a theramutein can increase or decrease the specific activity of the theramutein relative to the corresponding prototheramutein. When comparing a theramutein-expressing cell line to a prototheramutein-expressing cell line, it is preferred that the selected phenotypic response is qualitatively the same in both cell types. Thus, one skilled in the art may choose to calibrate the activity of the theramutein-expressing cell line to the activity of the prototheramutein-expressing cell line or vice versa. Such normalization methods are standard in the art. See, eg, Bolstad et al. (2003).

Alternatively, those skilled in the art may also wish to use unmodified host cells or host cells that only harbor expression vectors as control cells for certain experimental manipulation steps (host cells are produced for the introduction of expression vectors encoding theramutein) cells of cells). This may be the case where researchers are only interested in specific inhibitors or activators of the theramutein of interest, irrespective of whether said compound is also effective against the prototheramutein of interest (pTOI) [replacing work activity].

4) The test and control cells are then maintained or propagated (though not necessarily at the same time) in growth medium (even in whole animals) under appropriate conditions so that phenotypic responses can be expressed and detected. Control cells expressing prototheramutein can be treated with a known modulator of prototheramutein or with a test substance, and the test cells are treated with a test compound in order to determine whether they are active against theramutein as determined by the ability of the substance to modulate a phenotypic response in a predicted manner . Alternatively, the control cells that do not express prototheramutein can also be substituted according to the specific phenotypic responses selected by those skilled in the art for research. The effect of the substance is then tested on test cells, and optionally on control cells at the same time or at another time, and the results compared.

In one embodiment of the invention, substances that are active on test cells are rapidly identified based on their ability to modulate the phenotypic response of test cells in the same manner, for example, that known modulators of prototheramutein alter the phenotypic response of control cells expressing prototheramutein . In another embodiment, an active substance can be identified by its ability to modulate the activity of a theramutein in a test cell while having little or no effect on unmodified (not expressing prototheramutein and/or theramutein) control cells. For example, those skilled in the art will readily appreciate that many variations of this approach can be used to identify modulators that are more potent or equivalent to a theramutein and to one or more corresponding specific theramuteins.

Other phenotypic responses can be observed and/or measured, and include, for example, detection of substrates of prototheramuteins and detection of changes in gene expression regulated by theramutein activity. In the simplest terms, any characteristic of the cell that is previously established by a person skilled in the art to be relevant to the functional activity of theramutein is suitable for use in such methods. However, in selecting a given trait, one skilled in the art must first verify that said trait fulfills the criteria as a phenotypic response, following the teachings given as detailed herein. One of skill in the art may also wish to calibrate the phenotypic response using cells expressing theramutein to the phenotypic response of cells expressing prototheramutein.

Features suitable for detection can be determined by various methods well known to those 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; competition radioligand binding assays; solid-phase matrix blotting techniques, such as cell extracts. Northern blotting, Southern blotting, and Western blotting; reverse transcriptase polymerase chain reaction (RT-PCR); enzyme-linked immunosorbent assay (ELISA); phosphorylation assay; gel retention assay; membrane potential interference, etc. The relevant phenotypic characteristic can be detected on intact cells after treatment with the test substance, or on subcellular fractions of the cells after treatment with the test substance.

Once compounds having a desired effect on a theramutein-expressing test cell have been identified, it is necessary (but not necessarily) to independently verify that the identified compound exerts its effect on the theramutein through a direct binding mechanism, i.e., according to the teachings of the present invention, these compounds satisfy the Criteria as inhibitors or activators (as desired) of theramutein (the reader is referred to the definitions of the terms "activator" and "inhibitor" above). This can be achieved using a number of standard binding assays known to those skilled in the art, including purified protein samples or using cells transfected with the appropriate prototheramutein or theramutein with appropriate controls as described by sonication. Intact Cell Binding Assay. As such methods are well established in the art, they are not repeated here. Numerous reference texts comprehensively discuss such techniques (see, for example, Foreman and Johansen, 2002; Enna S.J. et al. (1991) Current Protocols in Pharmacology, Wiley & Sons, Incorporated; Bonifacino, J.S. et al. (1999) Current Protocols in Cell Biology, Wiley & Sons, Incorporated ). See also Housey, G.M. 1988, Chapter 4 and references therein; also, see Horowitz et al., 1981.

In a particular embodiment of the invention, the method is used to identify substances that are inhibitors of p210 ^{Bcr-Abl-T315I} theramutein. Prototheramutein and theramutein were each expressed in Ba/F3 (murine) cells using standard methods, and the observed phenotypic responses were characteristic of growth (carefully determined terminal cell densities of cell cultures and in the absence of interleukin-3 (IL- 3) Growth in the presence). Unmodified host cells or host cells containing only expression vectors or both may also optionally be used. In another embodiment, test cells are used alone with or without known inhibitors or activators involved.

Another useful assay is to determine the phosphorylation status of the direct substrate of p210 ^{Bcr-Abl-T315I} . One such substrate is Crkl (Gorre et al., Science 293:876-80 (2001)), an adapter protein that mediates the linkage between Bcr-Abl and Ras. The phosphorylation status of CRKL is a proxy for the signaling activity of p210 ^Bcr-Abl in cells. Another downstream substrate is p62DOK. For these purposes, any such substrate will suffice, provided, of course, that the phosphorylation of said substrate has been shown to occur inside the cell and is not simply an autophosphorylation event of TOI or PTOI as described above . Other signal transduction cascade components can also be monitored, including src family kinases, STAT5, PI3 kinases, raf kinases, RAS, MEK, ERK1 and ERK2, JNK1, 2 and 3, MLK1, 2 and 3, MKK4, MKK7, AKT, mTOR, HSP90, etc.

As is typical herein, inhibitors of T315I theramuteins have been identified. In addition, these inhibitors also had varying degrees of activity against the wild-type prototheramutein p210 ^Bcr-Abl-wt .

According to the present invention, a therapeutically effective amount of one or more compounds that modulate the functional activity of p210 ^Bcr-Abl theramutein is administered to a mammal in need thereof. As used herein, the term "administering" refers to delivering a compound of the present invention to a mammal by any means by which the result sought can be achieved. For example, they can be administered orally, parenterally (intravenously or intramuscularly), topically, transdermally or by inhalation. The term "mammal" as used herein is intended to include, but is not limited to, humans, laboratory animals, domesticated pets, and farm animals. A "therapeutically effective amount" refers to an amount of a compound effective to produce a desired therapeutic effect, such as inhibition of kinase activity, inhibition of cancer cell growth and division, etc., when administered to a mammal.

The present invention provides a method of treating a disease in a mammal by administering to the mammal an effective amount of a modulator of theramutein. Suitable diseases to be treated in accordance with the present invention include, but are not limited to, recurrent tumors or other proliferative disorders that have become resistant to previously administered drugs. The method is also useful to overcome variations in susceptibility to drug treatments that exist in individuals due to allelic differences in therapeutic targets. For example, a role for p210 ^Bcr-Abl tyrosine kinase signaling has been extensively demonstrated in CML because theramuteins of p210 ^Bcr-Abl have a role in drug-resistant relapse of CML. Furthermore, different muteins of p210 ^Bcr-Abl exhibit variable sensitivity to inhibitors of p210 ^Bcr-Abl . Although some theramuteins emerge during drug therapy, others may pre-exist in the population. These latter instances are not recognized as theramuteins until a disease state ensues and is subsequently treated with a known type of therapeutic agent. Such pre-existing theramuteins manifest themselves as clinically significant in causing relative non-responsiveness to disease development in theramutein-deficient patients only after such treatment.

In one embodiment of the invention, a theramutein modulator is administered with one or more antineoplastic agents. Any suitable antineoplastic agent may be used, such as chemotherapeutic agents, radiation, or combinations thereof. Antineoplastic agents may be alkylating agents or antimetabolites. 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 the topoisomerase inhibitor irinotecan (CPT-11), aminocamptothecin, camptothecin, DX-8951f , topotecan (topoisomerase I inhibitor) and etoposide (VP-16; topoisomerase II inhibitor) and teniposide (VM-26; topoisomerase II inhibitor). When the antineoplastic agent is radiation, the source of radiation can be outside the body of the patient being treated (external beam radiation therapy - EBRT) or inside the body (brachytherapy - BT). The dose of antineoplastic agent administered depends on many factors including, for example, the type of active agent, the type and severity of the tumor being treated, and the route of administration of the active agent. It should be emphasized, however, that the present invention is not limited to any particular dose, route of administration, or combination of chemotherapeutic agents or other therapeutic regimens that are administered with theramutein conditions.

Antineoplastic agents currently known or evaluated in the art can be divided into different classes, including: for example, mitotic inhibitors; alkylating agents; antimetabolites; intercalating antibiotics; growth factor inhibitors; cell cycle inhibitors; enzymes; topoisomers antisurvival agents; biological response modifiers; antihormonal and antiangiogenic agents, all such active agents can be administered with inhibitors or activators of theramuteins.

Modulators of theramutein can be administered with antibodies that neutralize other receptors involved in tumor growth. Furthermore, modulators of theramutein may be combined with components of additionally modulating signal transduction pathways, preferably with components of signal transduction pathways which are active in one or more other signal transduction pathways and which are common to these pathways Administer together. In one embodiment of the invention, a theramutein modulator is used in combination with a receptor antagonist that specifically binds the epidermal growth factor receptor (EGFR). Particular preference is given to antigen binding proteins which bind the extracellular domain of EGFR and block binding of one or more of its ligands and/or neutralize ligand-induced activation of EGFR. An EGFR antagonist can be an antibody that binds EGFR or a ligand of EGFR and inhibits binding of EGFR to its ligand. Examples of ligands for EGFR include, for example, EGF, TGF-α, amphiregulin, heparin-binding EGF (HB-EGF), and β animal cellulose. EGF and TGF-α are believed to be the main endogenous ligands responsible for EGFR-mediated stimulation, however, TGF-α has been shown to be more effective in promoting angiogenesis. It is understood that an EGFR antagonist may bind externally to the extracellular portion of EGFR, may or may not inhibit ligand binding, or, in the case of a chemically active agent, internally binds the tyrosine kinase domain. Examples of EGFR antagonists that bind EGFR include, but are not limited to, biologics, such as antibodies (and functional equivalents thereof) specific for EGFR; Active synthetic kinase inhibitor.

Other examples of growth factor receptors involved in tumorigenesis are vascular endothelial growth factor (VEGFR-1 and VEGFR-2), platelet-derived growth factor (PDGFR), nerve growth factor (NGFR), fibroblast growth factor (FGFR ) and other receptors.

In combination therapy, a theramutein inhibitor and any combination thereof are administered before, during or after initiation of treatment with another active agent, i.e. before and during initiation of therapy with antineoplastic agents, before and after, during After neutralization or before, during and after. For example, the theramutein inhibitor may be administered 1-30 days, preferably 3-20 days, more preferably 5-12 days, before starting radiotherapy. In a preferred embodiment of the invention, chemotherapy is administered before, simultaneously with or more preferably after the use of antibody therapy.

In the present invention, any suitable method or route may be used to administer the theramutein inhibitors of the present invention, optionally co-administered with antineoplastic agents and/or other receptor antagonists. Antineoplastic drug regimens for use in accordance with the present invention include any regimen deemed most appropriate for the treatment of a patient's neoplastic condition. Different malignant tumors may require the use of specific anti-tumor antibodies and specific anti-tumor agents, which need to be determined on a patient-to-patient basis. Administration routes include, for example, oral, intravenous, intraperitoneal, subcutaneous or intramuscular administration. The dose of antagonist administered will depend on many factors including, for example, the type of antagonist, the type and severity of the tumor being treated, and the route of administration of the antagonist. It should be emphasized, however, that the invention is not limited to any particular method or route of administration.

Suitable carriers include, for example, one or more of water, saline, phosphate-buffered saline, dextrose, glycerol, ethanol, etc., and combinations thereof. The carrier can further include minor amounts of auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which increase the shelf-life or effectiveness of the theramutein modulator as an active ingredient. The compositions may be formulated to provide quick, sustained or delayed release of the active ingredient after administration to a mammal, as is well known in the art.

The compositions of the invention can be in a variety of 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 infusible solutions. The preferred dosage form depends on the intended mode of administration and therapeutic use.

Such compositions of the invention may be prepared in a manner well known in the art of pharmacy. In the process of preparing the composition, the active ingredient is usually mixed with the carrier or the composition is diluted with the carrier and/or the composition is encapsulated in the carrier, and the carrier is used as a diluent, which can be solid, semi-solid Or a liquid substance which acts as a vehicle, excipient or medium for the active ingredient. The composition may thus be a tablet, lozenge, sachet, cachet, elixir, suspension, aerosol (as a solid or in a liquid medium), an ointment containing, for example, up to 10% by weight of the active compound. elixirs, soft and hard gelatin capsules, suppositories, solutions for injection, suspensions, powders in sterile packs and as topical patches.

It is understood that the methods and compositions of the invention may be administered to any suitable mammal, such as rabbits, rats or mice. More preferably said mammal is a human.

The compounds of the invention may also exist as salts. In the context of the present invention, the administration of pharmaceutically acceptable salts is preferred. Pharmaceutically acceptable salts refer to acid addition salts or base addition salts of the compounds of the present invention, wherein the resulting counterion is understood to be generally acceptable in the art for pharmaceutical use. Pharmaceutically acceptable salts may be salts of the compounds of the present invention with inorganic or organic acids. Preference is given to salts with inorganic acids, such as, for example, hydrochloric, hydrobromic, phosphoric or sulfuric acids, or preferably with organic carboxylic or sulfonic acids, which Acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid. Pharmaceutically acceptable salts may also be metal or ammonium salts of the compounds of this invention. Particular preference is given to obtaining, for example, salts of sodium, potassium, magnesium or calcium, and also particular preference to obtaining ammonium salts derived from ammonia or organic amines such as, for example, ethylamine, di- or triethylamine Amines, di- or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine (see Berge et al J.Pharm.Sci.1977,66,1 -19).

1. In the context of this application, reference is made to various publications, text of references, textbooks, technical manuals, patents and patent publications. The teachings and disclosures of these publications, patents, patent applications and other references in their entirety are incorporated herein by reference in order to more fully describe the state of the art to which this invention pertains.

2. It is understood and expected that variations on the principles of the invention disclosed herein may be implemented by persons skilled in the art and that such variations are considered to be within the scope of the invention.

3. The following examples further illustrate the present invention, but should not be construed as limiting the scope of the present invention in any way. Detailed descriptions of commonly used methods, such as those for vector and plasmid construction, insertion of genes encoding polypeptides into such vectors and plasmids, introduction of plasmids into host cells, and expression of genes and gene products and their assays, can be obtained from numerous published publications. Literature, 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 Immunology, Wiley & Sons, Incorporated; Enna, SJ et al. (1991) Current Protocols in Pharmacology, Wiley & Sons, Bonifacino, JS et al. (1999) Current Protocols in Cell Biology, Wiley &Sons; and US Patent 4,980,281. All references mentioned herein are incorporated in their entirety.

Example

p210 ^{Bcr-Abl-T315I} is a theramutein (Gleevec, STI-571 ) of the p210Bcr-Abl protein (p210 ^Bcr-Abl ) that confers resistance to inhibition by imatinib mesylate. The mutation at position 315 converts threonine to an isoleucine residue and is one of several mutations observed in resistant or relapsed patients. However, this particular mutant was the most resistant of this type of theramutein identified.

Phenotypic responses were determined for a Ba/F3 cell line engineered to overexpress p210 ^{Bcr-Abl-T315I} theramutein. Phenotypic responses were determined relative to untransformed Ba/F3 cells and Ba/F3 cells expressing p210Bcr-Abl-wtprototheramutein. The phenotypic response is that the T315I mutant grows to a higher cell saturation density than the control untransformed Ba/F3 cell line under similar culture conditions and maintains the level of interleukin 3 required for the control untransformed Ba/F3 cell line. Ability to grow in the absence of (IL-3). Phenotypic responses were defined and characterized following the teachings given above.

The detection system used is a high-speed cell imaging and counting system in which a cell sample volume of 3 μl is sequentially injected through a 5 μl optical microcuvette, digitally imaged and stored electronically, scanned and then counted, all on a microcomputer-based in the control system. The system has the capability to perform direct cell counts on samples from cultures as small as 500 μl and provides statistically significant total cell counts from culture samples containing as few as 12,500 cells. All figures showing cell counts and viability assays used this system for data acquisition and analysis. In parallel with cell counting, the system is also capable of determining overall cell viability by distinguishing counted, imaged cells from cells that have taken up trypan blue dye (counted as "non-viable" cells) Trypan blue (counted as "viable" cells) was excluded. Samples of cells are injected with trypan blue and immediately thereafter sequentially injected into microcuvettes for simultaneous cell counting and imaging.

Integrate the system into the workflow of a high-throughput screening device to provide a sensitive and accurate cell count and cell viability assay system that is more reliable and less prone to confounding of metabolic viability-based cell assays such as XTT or Alamar blue effect.

Initially, approximately 113,000 compounds were screened at concentrations typically in the 10-20 μM range to identify a subpopulation capable of affecting the growth of Ba/F3 cells overexpressing p210 ^{Bcr-Abl-T315I} theramutein (Ba/F3 T315I cells) in any manner.

A total of about 11,760 compounds exhibited greater than 50% growth inhibition, which is believed to correspond to about 4500 different chemotypes. Retesting these compounds using the same cell lines generated a compound reactivity database which was then sorted and ranked according to those compounds showing the highest overall growth inhibition. The highest scoring 130 compounds (based on Maximum growth inhibition observed at lowest concentration of test compound). Compounds of interest are those that differentially inhibit the growth of Ba/F3 cells expressing p210 ^{Bcr-Abl-T315I} theramutein compared to untransformed wild-type Ba/F3 cells. Six compounds meeting the required criteria were identified and some of these compounds were also further analyzed in detail using the Ba/F3p210 ^Bcr-Abl-wt cell line (Ba/F3 P210 cells). One compound could not be used for further testing due to lack of availability of additional material from chemical suppliers. Independently in additional cell-based assays using the above cell lines and in cell-free purified protein kinase assays using human recombinantly produced 120Kd kinase domain fragments isolated from wild-type P210Bcr-Abl and P210 T315I mutant kinase domains The remaining 5 compounds were evaluated.

All five compounds inhibited p210 ^{Bcr-Abl-T315I} 120Kd activity as determined by inhibition of autophosphorylation activity, as shown in Figure 4 . Thus, of the 6 highest scoring compounds out of more than 113,000 compounds screened, at least 5 of these 6 directly inhibited the p210 ^{Bcr-Abl-T315I} mutant. Notably, compound 5 appeared to spread out the recombinant protein bands on SDS polyacrylamide gels. This was also apparent on silver-stained gels (data not shown). It is possible that this compound may in fact be a "suicide" inhibitor capable of covalently cross-linking POI to permanently inhibit its activity, but this result requires further investigation.

Together, the teachings and results described herein provide conclusive evidence that this system is capable of identifying inhibitors or activators of selected theramuteins, and those skilled in the art immediately recognize that such systems can be improved with only obvious minimal modifications. It is readily applicable to any other theramutein.

Representative examples of the results of cell-based assays demonstrating growth inhibition of the Ba/F3 T315I cell line compared to wild-type untransformed Ba/F3 cells are shown in Figures 1 and 2 . These compounds inhibit the growth and reduce the survival of cells expressing T315Itheramutein at concentrations at which the growth and viability of wild-type Ba/F3 untransformed cells (not expressing ^{p210Bcr-Abl-wt} or p210Bcr ^-Abl-T315I ) are relatively unaffected rate, while cells expressing prototheramutein and theramutein were substantially inhibited. In some cases, cells expressing T315I were even more inhibited than cells expressing P210 prototheramutein (see, for example, Figure 3, right hand side, results for compound 3 on P210 and T315I cells.

In summary, the methods provided herein provide a fundamental development in the form of a generalizable method for generating or identifying modulators of any given theramutein. The results conclusively demonstrate the power of the method in identifying compounds in critical need for overcoming a specific type of acquired drug resistance that is consistently fatal in certain patient populations and is currently untreatable. Furthermore, it will be apparent to those skilled in the art that the techniques and methods described herein can be directly broadly applied to any potential theramutein of clinical interest, using obvious variations.

Notably, of an initial screen of more than 100,000 compounds, of which approximately 10,000 exhibited some degree of growth inhibition, when the most potent growth inhibitors were rescreened using the methods detailed in this paper, six were identified The different compounds and all compounds subsequently tested showed inhibitory activity in the cell-free purified protein kinase assay using the T315I mutant (one compound could not be used for further testing). Based on such noteworthy results, it is immediately apparent to those skilled in the art that appropriate selection and determination of phenotypic responses based on the teachings in the above sections and reference documents incorporated herein by reference can be effectively applied to identify inhibition of any theramutein agents or activators. For example, one skilled in the art using the foregoing knowledge can readily design assay systems to identify inhibitors of t heramuteins derived from other prototheramuteins known to display mutations conferring drug resistance, such as c-kit gene products or Epidermal growth factor (EGF) receptor (EGFR) or platelet-derived growth factor (PDGF) receptor alpha and beta. In using this method, no limitation should be inferred in terms of the ability of the method to be used for any given theramutein expressed in any mammalian cell type for which a corresponding phenotypic response is detectable.

All publications, patents, or other cited references referred to are hereby incorporated by reference.

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11: Blood. 2004 Sep 30;

A cell-based screen for resistance of Bcr-Abl positive leukemia identifies the mutation pattern for PD166326, an alternative Abl kinase inhibitor.

Von Bubnoff N, Veach DR, Van Der Kuip H, Aulitzky WE, Sanger J, Seipel P, Bommann WG, Peschel C, Clarkson B, Duyster J.

White, MF, Livingston, JM, Backer, Lauris, V, Dull, TJ, Ullrich A, Kahn, CR.

Mutation of the Insulin Receptor at Tyrosine 960 Inhibits Signal Transmission but DoesNot Affect Its Tyrosine Kinase Activity.

Cell, Vol.54, 641-649; 1988.

Leukemia.2004 Oct 21

Histone deacetylase inhibitor NVP-LAQ824 has significant activity against myeloidleukemia cells in vitro and in vivo.

Weisberg E, Catley L, Kujawa J, Atadja P, Remiszewski S, Fuerst P, Cavazza C, Anderson K, Griffin JD.

3: Blood.2004 Oct 15; 104(8):2532-9. Epub 2004 Jul 15. Related Articles, Links Inhibition of wild-type and mutant Bcr-Abl by AP23464, a potent ATP-based oncogenic protein kinase inhibitor: implications for CML .

O′Hare T, Pollock R, Stoffregen EP, Keats JA, Abdullah OM, Moses EM, Rivera VM, Tang H, Metcalf CA 3rd, Bohacek RS, Wang Y, Sundaramoorthi R, Shakespeare WC, Dalgarno D, Clackson T, Sawyer TK , Deininger MW, Druker BJ.

5: Leukemia. 2004 Aug; 18(8): 1352-6. Related Articles, Links

Efficacy of dual-specific Bcr-Abl and Src-family kinase inhibitors in cells sensitive resistant to imatinib mesylate.

Tipping AJ, Baluch S, Barnes DJ, Veach DR, Clarkson BM, Bornmann WG, Mahon FX, Goldman JM, Melo JV.

Claims (64)

1. A method for the treatment of human neoplastic diseases or proliferative disorders, comprising administering a therapeutically effective amount of a compound of general formula I: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ² is selected from -CR ²¹ _a -, -NR ²² _b - and -(C=R ²³ )-; Each R ²¹ is independently selected from H, halogen, -NH ₂ , -N(H)(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -O-(C _1-3 alkane group), OH and C _1-3 alkyl; Each R ²² is independently selected from H and C _1-3 alkyl; R ²³ is selected from O, S, NR ⁰ and N-OR ⁰ ; R ³ is selected from -CR ³¹ _c -, -NR ³² _d - and -(C=R ³³ )-; Each R ³¹ group is selected from H, halogen, -NH ₂ , -N(H)(R ⁰ ), -N(R ⁰ ) ₂ , -OR ⁰ , OH and C _1-3 alkyl; each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle; R ³³ is selected from O, S, NR ³⁴ and N-OR ⁰ ; R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴ is selected from -CR ⁴¹ _e -, -NR ⁴² _f -, -(C=R ⁴³ )- and -O-; Each R ⁴¹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle; each ^R42 group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl and heterocycle; Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ; The proviso is that when R ² is -NR ²² _b - and R ⁴ is -NR ⁴² _f -, R ³ is not -NR ³² _d -; and R ³ and R ⁴ are not simultaneously selected from -(C=R ³³ ) -and-(C=R ⁴³ )-; R ⁵ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from chemical bond, O, NR ⁰ ; ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ⁷ is H or is selected from aryl and heterocycle; each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; 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. 2. The method of claim 1, ^wherein X is N. 3. The method of claim 2, ^wherein X is N. 4. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula _Ia : in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ²² are each independently selected from H and C _1-3 alkyl; R ³ is selected from -CR ³¹ _c -, -NR ³² _d - and -(C=R ³³ )-; Each R ³¹ group is selected from H, halogen, -NH ₂ , -N(H)(R ⁰ ), -N(R ⁰ ) ₂ , -OR ⁰ , OH and C _1-3 alkyl; Each R ³² group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , aryl and heterocycle; R ³³ is selected from O, S, NR ³⁴ and N-OR ⁰ ; R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴ is selected from -CR ⁴¹ _e -, -NR ⁴² _f -, -(C=R ⁴³ )- and -O-; Each R ⁴¹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle; each ^R42 group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl and heterocycle; Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ; The proviso is that when R ⁴ is -NR ⁴² _f -, R ³ is not -NR _{32 d} -; and R ₃ and R ₄ are not simultaneously selected from -(C=R ³³ )- and -(C=R ⁴³ ), respectively -; R ⁵ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from chemical bond, O, NR ⁰ ; ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ⁷ is H or is selected from aryl and heterocycle; each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; 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. 5. The method of claim 4, wherein ^Xi is N. 6. The method of claim 5, wherein ^X is N. 7. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula _Ib :

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; Each R ²² is independently selected from H and C _1-3 alkyl; each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle; R ⁴ is selected from -CR ⁴¹ _e -, -(C=R ⁴³ )- and -O-; Each R ⁴¹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle; Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ; R ⁵ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from chemical bond, O, NR ⁰ ; ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ⁷ is H or is selected from aryl and heterocycle; each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; 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. 8. The method of claim 7, wherein ^Xi is N. 9. The method of claim 8, wherein X ² is N. 10. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula II: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; 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 heterocycle; R ⁹ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from chemical bond, O, NR ⁰ ; ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z has 1-4 carbon atoms and is optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O) ) one or more substituted hydrocarbon chains of N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R is ^H or is selected from aryl and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 11. The method of claim 10, wherein ^Xi is N. 12. The method of claim 11, wherein X ² is N. 13. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula _IIa : in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; 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 heterocycle; X ³ is N, CH or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ₅₁ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 14. The method of claim 13, wherein ^Xi is N. 15. The method of claim 14, wherein X ² is N. 16. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula II _b : in: R ¹⁴ 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 heterocycle; X ³ is N, CH or CR ⁶⁰ ; Each R ⁶⁰ is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF ₃ , NO ₂ , OR ⁰ , halogen, aryl, and heterocycle; R ^is selected from aryl and heterocycle; Q is selected from a chemical bond or has the formula -O-, -(CH ₂ ) _i -, -(CH ₂ ) _i C(O)(CH ₂ ) _j -, -(CH ₂ ) _i -N(R ⁶² )-( CH ₂ ) _j -, -(CH ₂ ) _i C(O)-N(R ⁶² )-(CH ₂ ) _j -, -(CH ₂ ) _i C(O)O(CH ₂ ) _j -, -( CH ₂ ) _i N(R ⁶² )C(O)-(CH ₂ ) _j -, -(CH ₂ ) _i OC(O)N(R ⁶² )-(CH ₂ ) _j - and -O-(CH ₂ ) _i -C(O)N(R ⁶² )-(CH ₂ ) _j -group; R ⁶² is selected from aryl and heterocycle; each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; h is 0-4; i is 0-4; and j is 0-4. 17. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula III: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ¹⁰ is selected from -Y'-R ¹⁸ ; Y' is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁸ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 18. The method of claim 17, wherein ^Xi is N. 19. The method of claim 18, wherein X ² is N. 20. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula III _a : in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; X ³ is N, CH or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 21. The method of claim 20, wherein ^Xi is N. 22. The method of claim 21, wherein ^X2 is N. 23. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula IV:

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ²² is selected from H and C _1-3 alkyl; R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴⁴ is selected from H, alkyl, cycloalkyl, -(C=O)R ⁰ , alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴⁵ is selected from -Y″-R ¹⁹ ; Y" is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 24. The method of claim 23, wherein ^Xi is N. 25. The method of claim 24, wherein X ² is N. 26. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula V: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ²² is selected from H and C _1-3 alkyl; R ³⁴ is selected from H, NO ² , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵⁶ is selected from -Y″-R ¹⁹ ; Y" is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 27. The method of claim 26, wherein ^Xi is N. 28. The method of claim 27, wherein X ² is N. 29. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula _Va : in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; X ³ is N or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ₅₂ )(R ₅₃ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 30. The method of claim 29, wherein ^Xi is N. 31. The method of claim 30, wherein X ² is N. 32. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula VI:

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵⁶ is selected from -Y″-R ¹⁹ ; Y" is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 33. The method of claim 32, wherein ^Xi is N. 34. The method of claim 33, wherein X ² is N. 35. The method of claim 1, comprising administering a therapeutically effective amount of a compound of formula _VIa : in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ₂ is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; X ³ is N or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 36. The method of claim 35, wherein ^Xi is N. 37. The method of claim 36, wherein ^X2 is N. 38. A method of inhibiting P210 ^{BCR-ABL-T315I} theramutein comprising administering to humans a compound of general formula I: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ² is selected from -CR ²¹ _a -, -NR ²² _b - and -(C=R ²³ )-; Each R ²¹ is independently selected from H, halogen, -NH ₂ , -N(H)(C _1-3 alkyl), -N(C _1-3 alkyl) ₂ , -O-(C _1-3 alkane group), OH and C _1-3 alkyl; Each R ²² is independently selected from H and C _1-3 alkyl; R ²³ is selected from O, S, NR ⁰ and N-OR ⁰ ; R ³ is selected from -CR ³¹ _c -, -NR ³² _d - and -(C=R ³³ )-; Each R ³¹ group is selected from H, halogen, -NH ₂ , -N(H)(R ⁰ ), -N(R ⁰ ) ₂ , -OR ⁰ , OH and C _1-3 alkyl; each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle; R ³³ is selected from O, S, NR ³⁴ and N-OR ⁰ ; R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴ is selected from -CR ⁴¹ _e -, -NR ⁴² _f -, -(C=R ⁴³ )- and -O-; R ⁴¹ are each selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle; each ^R42 group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl and heterocycle; Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ; The proviso is that when R ² is -NR ²² _b - and R ⁴ is -NR ⁴² _f -, R ³ is not -NR ³² _d -; and R ³ and R ⁴ are not simultaneously selected from -(C=R ³³ ) -and-(C=R ⁴³ )-; R ⁵ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from chemical bond, O, NR ⁰ ; ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z is a hydrocarbon chain with 1-4 carbon atoms, optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ⁷ is H or is selected from aryl and heterocycle; each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; 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. 39. The method of claim 38, comprising administering a therapeutically effective amount of a compound of formula _Ia : in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; Each R ²² is independently selected from H and C _1-3 alkyl; R ³ is selected from -CR ³¹ _c -, -NR ³² _d -, and -(C=R ³³ )-; Each R ³¹ group is selected from H, halogen, -NH ₂ , -N(H)(R ⁰ ), -N(R ⁰ ) ₂ , -OR ⁰ , OH and C _1-3 alkyl; each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle; R ³³ is selected from O, S, NR ³⁴ and N-OR ⁰ ; R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴ is selected from -CR ⁴¹ _e -, -NR ⁴² _f -, -(C=R ⁴³ )- and -O-; Each R ⁴¹ is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle; each ^R42 group is selected from the group ^consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl and heterocycle; Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ; The proviso is that when R ⁴ is -NR ⁴² _f -, R ³ is not -NR ³² _d -; and R ³ and R ⁴ are not simultaneously selected from -(C=R ³³ )- and -(C=R ⁴³ ), respectively -; R ⁵ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from chemical bond, O, NR ⁰ ; ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z is a hydrocarbon chain with 1-4 carbon atoms, optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ⁷ is H or is selected from aryl and heterocycle; ^Each R is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; 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. 40. The method of claim 38, comprising administering a compound of formula _Ib :

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; Each R ²² is independently selected from H and C _1-3 alkyl; each ^R32 group is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, _CO2R0 , C(O) ^R0 , aryl ^, and heterocycle; R ⁴ is selected from -CR ⁴¹ _e -, -(C=R ⁴³ )- and -O-; R ⁴¹ are each selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, CO ₂ R ⁰ , C(O)R ⁰ , aralkyl, aryl, and heterocycle; Each R ⁴³ is selected from O, S, NR ⁰ and N-OR ⁰ ; R ⁵ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from a chemical bond, O, NR ⁰ , ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z is a hydrocarbon chain with 1-4 carbon atoms, optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ⁷ is H or is selected from aryl and heterocycle; R ^O are each independently selected from H, alkyl, cycloalkyl, aralkyl, aryl and heterocycle; 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. 41. The method of claim 38, comprising administering a compound of formula II: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; 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 heterocycle; R ⁹ is selected from -YR ⁶ and -ZR ⁷ ; Y is selected from chemical bond, O, NR ⁰ ; ^R is selected from alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; Z is a hydrocarbon chain with 1-4 carbon atoms, optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R is ^H or is selected from aryl and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 42. The method of claim 38, comprising administering a compound of formula _IIa :

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 )( The group consisting of R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 0 - a 5- or 6-membered fused ring of 3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; 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 heterocycle; X ³ is N, CH or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 43. The method of claim 38, comprising administering a compound of formula II _b :

in: R ¹⁴ 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 heterocycle; X ³ is N, CH or CR ⁶⁰ ; Each R ⁶⁰ is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF ₃ , NO ₂ , OR ⁰ , halogen, aryl, and heterocycle; R ^is selected from aryl and heterocycle; Q is selected from a chemical bond or has the formula -O-, -(CH ₂ ) _i -, -(CH ₂ ) _i C(O)(CH ₂ ) _j -, -(CH ₂ ) _i -N(R ⁶² )-( CH ₂ ) _j -, -(CH ₂ ) _i C(O)-N(R ⁶² )-(CH ₂ ) _j -, -(CH ₂ ) _i C(O)O(CH ₂ ) _j -, -( CH ₂ ) _i N(R ⁶² )C(O)-(CH ₂ ) _j -, -(CH ₂ ) _i OC(O)N(R ⁶² )-(CH ₂ ) _j - and -O-(CH ₂ ) _i -C(O)N(R ⁶² )-(CH ₂ ) _j -group; R ⁶² is selected from aryl and heterocycle; each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; h is 0-4; i is 0-4; and j is 0-4. 44. The method of claim 38, comprising administering a compound of formula III: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _q C(O)N(R ¹² )(R ¹³ ), -(CH ₂ ) _p C(O)O(CH ₂ ) _p 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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ¹⁰ is selected from -Y'-R ¹⁸ ; Y' is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁸ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 45. The method of claim 38, comprising administering a compound of formula III _a :

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; X ³ is N, CH or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 46. The method of claim 38, comprising administering a compound of formula IV: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _q C(O)N(R ¹² )(R ¹³ ), -(CH ₂ ) _p C(O)O(CH ₂ ) _p 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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ₁ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ²² is selected from H and C _1-3 alkyl; R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴⁴ is selected from H, alkyl, cycloalkyl, -(C=O)R ⁰ , alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁴⁵ is selected from -Y″-R ¹⁹ ; Y" is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 47. The method of claim 38, comprising administering a compound of formula V: in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ²² is selected from H and C _1-3 alkyl; R ³⁴ is selected from H, NO ₂ , CN, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵⁶ is selected from -Y″-R ¹⁹ ; Y" is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 48. The method of claim 38, comprising administering a compound of formula _Va :

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; X ³ is N or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ₅₁ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may form together with the nitrogen to which they are attached 5- to 7-membered rings which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 49. The method of claim 38, comprising administering a compound of formula VI:

in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵⁶ is selected from -Y″-R ¹⁹ ; Y" is selected from the group consisting of bond, O, NR ⁰ - and with 1 to 4 carbon atoms and optionally replaced by halogen, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CO ₂ R ⁰ , One or more substituted hydrocarbon chains of C(O)R ⁰ , C(O)N(R ⁰ ) ₂ , CN, CF ₃ , N(R ⁰ ) ₂ , NO ₂ and OR ⁰ ; R ¹⁹ is selected from the group consisting of H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CF ₃ , aryl, and heterocycle; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 50. The method of claim 38, comprising administering a compound of general formula _VIa : in: Ring A is a 5-, 6- or 7-membered ring or a 7- to 12-membered fused bicyclic ring; X ¹ is selected from N, NR ⁰ or CR ¹ ; X ² is selected from N, NR ⁰ or CR ¹ ; Dashed lines indicate optional double bonds; Each R ¹ is independently selected from 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 ) _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 ) The group consisting of (R ¹³ ), -SO ₂ N(R ¹² )(R ¹³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ¹ groups on adjacent ring atoms form a group containing 5- or 6-membered fused rings with 0-3 heteroatoms; n is 0-6; each R ^is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; Each R ¹² and R ¹³ is independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ¹² and R ¹³ may be taken together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; p is 0-4; q is 0-4; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; X ³ is N or CR ⁵⁰ ; Each R ⁵⁰ is independently selected from 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(R ⁵² )(R ⁵³ ), -(CH ₂ ) _r C(O)O(CH ₂ ) _s R ⁵¹ , -(CH ₂ ) _r N (R ⁵¹ )C(O)R ⁵¹ , -(CH ₂ ) _r N(R ⁵² )(R ⁵³ ), -N(R ⁵¹ )SO ₂ R ⁵¹ , -OC(O)N(R ⁵² )(R ⁵³ ), -SO ₂ N(R ⁵² )(R ⁵³ ), halogen, aryl and heterocycle, and additionally or alternatively, two R ⁵⁰ groups on adjacent ring atoms form a group containing 0- 5- or 6-membered fused rings with 3 heteroatoms; R ^is selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl and heterocycle; R ⁵² and R ⁵³ are each independently selected from H, alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, aryl, and heterocycle; or R ⁵² and R ⁵³ may be together with the nitrogen to which they are attached forming a 5- to 7-membered ring which may optionally contain one additional heteroatom; r is 0-4; s is 0-4; m is 0-4; and Each R ⁰ is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle. 51. A compound having the general formula II _b : in: R ¹⁴ 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 heterocycle; X ³ is N, CH or CR ⁶⁰ ; Each R ⁶⁰ is independently selected from the group consisting of alkyl, cycloalkyl, alkenyl, alkynyl, aralkyl, CN, CF ₃ , NO ₂ , OR ⁰ , halogen, aryl, and heterocycle; R ^is selected from aryl and heterocycle; Q is selected from a chemical bond or has the formula -O-, -(CH ₂ ) _i -, -(CH ₂ ) _i C(O)(CH ₂ ) _j -, -(CH ₂ ) _i -N(R ⁶² )-( CH ₂ ) _j -, -(CH ₂ ) _i C(O)-N(R ⁶² )-(CH ₂ ) _j -, -(CH ₂ ) _i C(O)O(CH ₂ ) _j -, -( CH ₂ ) _i N(R ⁶² )C(O)-(CH ₂ ) _j -, -(CH ₂ ) _i OC(O)N(R ⁶² )-(CH ₂ ) _j - and -O-(CH ₂ ) _i -C(O)N(R ⁶² )-(CH ₂ ) _j -group; R ^is selected from aryl and heterocycle; each R ^is independently selected from H, alkyl, cycloalkyl, aralkyl, aryl, and heterocycle; h is 0-4; i is 0-4; and j is 0-4. 52. A method for determining whether a substance is an inhibitor or activator of a theramutein capable of causing a detectable phenotypic response, the method comprising: a) incubating a first cell expressing theramutein at a substantially constant level with said substance; b) incubating a second cell expressing the corresponding prototheramutein at a substantially constant level with a known inhibitor or activator of the prototheramutein; c) comparing the phenotypic response of the second cell to a known inhibitor or activator of a prototheramutein with the phenotypic response of the first cell to said substance; and d) determining to inhibit or activate the phenotypic response of the first cell to at least the same extent as inhibiting or activating the phenotypic response of the second cell with a known prototheramutein inhibitor or activator, whereby the substance Identified as an inhibitor or activator of theramutein. 53. The method of claim 51, wherein the phenotypic response of the theramutein to the substance is greater than the phenotypic response of the prototheramutein to a known inhibitor or activator of theramutein. 54. A method for determining whether a substance is a specific inhibitor or a specific activator of a theramutein, the method comprising: a) providing test cells expressing theramutein and producing a detectable phenotypic response; b) treating the test cell with said substance; c) Examining the treated cells in order to determine whether a phenotypic response can be modulated by the treatment with the substance. 55. The method of claim 1 or 2, wherein the theramutein or prototheramutein is a component of a signal transduction cascade. 56. The method of claim 1 or 2, wherein the theramutein or prototheramutein is an enzyme. 57. The method of claim 1 or 2, wherein the theramutein or prototheramutein is a protein kinase. 58. The method of claim 1 or 2, wherein the theramutein or prototheramutein is a tyrosine kinase. 59. The method of claim 1 or 2, wherein the theramutein or prototheramutein is a receptor tyrosine kinase. 60. The method of claim 1 or 2, wherein the prototheramutein is p210 ^Bcr-Abl . 61. The method of claim 1 or 2, wherein the prototheramutein is a T315I mutant of p210 ^Bcr-Abl . 62. The method of claim 1 or 2, wherein the phenotypic response is a change in the culture, morphology or transient characteristics of the cells. 63. The method of claim 1 or 2, wherein the phenotypic response comprises phosphorylation of a theramutein intracellular substrate. 64. The method of claim 1 or 2, wherein the phenotypic response is detected on a subcellular fraction of the cell.

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