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1. WO2012058174 - NOVEL THIAZOLE-CARBOXAMIDE DERIVATIVES AS PDK1 INHIBITORS

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[ EN ]

TITLE OF THE INVENTION

NOVEL THIAZOLE-CARBOXAMIDE DERIVATIVES AS PDK1 INHIBITORS

FIELD OF THE INVENTION

This invention relates to certain thiazole carboxamide derivatives as inhibitors of 3-phosphoinositide-dependent protein kinase (PDK-1). The compounds are useful in inhibiting the proliferation of cancer cells, and other aberrant conditions where the PDK-1 signaling pathway is overstimulated.

BACKGROUND OF THE INVENTION

Certain kinases that belong to the serine/threonine kinase family are located

intracellularly and are involved in the transmission of biochemical signals such as those that affect cell proliferation and survival. One such serine/threonine kinase is PDK1, which is a regulator of at least 23 protein kinases that belong to the AGC kinase family (cAMP-dependent, cGMP-dependent, and protein kinase C). Signal transduction pathways downstream of PDK1 include the serine/threonine kinases protein kinase B (PKB/Akt), p70 ribosomal S6 kinase (p70S6Kl), serum- and glucocorticoid-induced protein kinase (SGK), p90 ribosomal S6 kinase (RSK), and protein kinase C (PKC). Peifer et al., ChemMed Chem 3, 1810-1838 (2008).

The binding of growth factors to the cell surface receptors activates phosphoinositide-3 kinase (PI3K), which phosphorylates the substrate, phosphoinositidylinositol-4,5-triphosphate (PIP2) to form the second messenger, phosphoinositidylinositol-3 ,4, 5 -triphosphate (PIP3). PIP3 binds to both PDK1 and PKB/Akt, which are believed to co-localize at the cell membrane as a consequence. In addition to its interaction with PKB/Akt, PDK1 also phosphorylates and activates p70S6Kl, SGK, RSK and PKC, which influences cell growth, proliferation, and survival, and regulates metabolism. Bayascas, J.R., Cell Cycle, 7, 2978-2982 (2008).

Cancer cells of common human tumor types, including breast, lung, gastric, prostate, haemotological and ovarian cancers, have gene mutations that result in abnormally high levels of PIP3. High levels of PIP3 cause overstimulation of PDK1 which result in constitutive activation the members of the AGC kinase family. As a consequence, tumor cell proliferation, reduced apoptosis and angiogenesis occur. In addition, cells lacking functioning PTEN, a lipid phosphatase that reduces cellular PIP3, are associated with a variety of human tumours including breast, prostate, endometrial cancers along with melanomas and glioblastomas. Steck et al., Nat. Genetics, 15, 356-362 (1997).

PDK1 function is critical to downstream signaling that results from activation of cells by growth factors because PKB/Akt, p70S6K, and RSK cannot be activated in cells lacking PDK1. Indeed, disrupting the PDK1 gene in mouse embryonic cells prevents activation of PKB/Akt, p70S6K, and RSK. Williams et al., Current Biology 10, 439-447 (2000). Additionally, in an in vivo model, reducing the expression of PDK1 protects mice from developing tumors under

conditions where PIP3 is elevated due to the deletion of PTEN. Bayascas et al., Current Biology 15, 1839-1846 (2005). Thus, while not being bound by any specific theory, inhibiting PDK1 function is expected to mitigate tumor cell proliferation by abrogating cell signaling.

Accordingly, there exists a need in the art for small-molecule inhibitors of PDK1 that are useful for treating cancer and other disorders associated with aberrant PDK1 activity.

SUMMARY OF THE INVENTION

This invention relates to certain thiazole carboxamide derivatives and pharmaceutically acceptable salts thereof as inhibitors of 3-phosphoinositide-dependent protein kinase (PD -1):

The compounds can be useful in inhibiting the proliferation of cancer cells, and other aberrant conditions where the PDK-1 signaling pathway is overstimulated.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides Thiazole Carboxamide Compounds and pharmaceutical compositions comprising a Thiazole Carboxamide Compound. In addition, the present invention provides methods of using the Thiazole Carboxamide Compounds in treating a disease or disorder characterized by excessive or pathologically elevated cell growth, e.g., cancer, in a patient in need of such treatment.

COMPOUNDS

The present invention provides compounds of the instant invention:

l-[4,5-difluoro-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide ;

l-[5-hydroxy-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide;

l-[5-methoxy-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide;

l-[4-amino-5-fluoro-2-[[[2-(l-methyl-lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino3phenyl]-4-(methylamino)-4-piperidinecarboxamide;

1 - [5 -hy droxy-2- [[ [2-( 1 -methyl- 1 H-pyrazol-4-yl)-4-thiazolyl] carbonyl] amino] phenyl] -4- (methylamino)-4-piperidinecarboxamide;

1 -[4-amino-5-fiuoro-2-[[[2-[6-(l -methylethoxy)-3-pyridinyl]-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide;

1 - [3-fiuoro-2-[ [[2-( 1 -methyl- 1 H-pyrazol-4-yl)-4-thiazolyl] carbonyl]amino]phenyl] -4- (methylamino)-4-piperidinecarboxamide;

1 - [ 3 , 5-difiuoro~2- [ [[2-( 1 -methyl- 1 H-pyrazol-4-yl)-4-thiazolyl] carbonyl] amino] phenyl] -4- (methylamino)-4-piperidinecarboxamide;

1 -[2,3-άϊΑυοΓθ-6-[[[2-(1 -methyl-1 H-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyI]-4-(methylamino)-4-piperidinecarboxamide;

l-[5-hydroxy-2-[[[2-[4-(2-methoxyethoxy)phenyl]-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide;

l-[2-[[[2-(2,3-dihydro-5-benzofuranyl)-4-thiazolyl]carbonyl]amino]-5-hydroxyphenyl]-4-(methylamino)-4-piperidinecarboxamide;

l-[4-amino-2-fluoro-6-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyI]-4-(methylamino)-4-piperidinecarboxamide;

1 - [5 -amino-3 - [[ [2~( 1 H-pyrazol-4-yl)-4-thiazolyl] carbonyl]amino] -2-pyri dinyl] -4-(methylamino)-4-piperidinecarboxamide;

1- [4-ammo-2-fluoro-6-[[[2-(l~methyl-lH^

(methylamino)-4-piperidinecarboxamide;

2- (4~amino- 1 H-pyrazol- 1 -yl)-N-(5-amino-2-(4-carbamoyl-4-(methylamino)piperidin- 1 -yl)phenyl)thiazole-4-carboxamide;

l-[4-amino-2-[[[2-(lH-pyrazol-4-yl)-4 hiazolyl]carbony¾

piperidinecarboxamide;

l-[4~hydroxy-2-[[[2-(lH-pyrazol-4-yl)-4-tfo

piperidinecarboxamide;

l-[4-hydroxy-2-[[[2-(l-methyl-lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino) -4-piperidinecarboxamide;

4-(methylamino)- 1 - [5 -methyl-2- [[ [2-( 1 H-pyrazol-4-yl)-4-thiazolyl]carbonyl] amino] phenyl]-4-piperidinecarboxamide;

N- [4-amino-2-( 1 -methyl-2,4-dioxo- 1 ,3 , 8-triazaspiro [4.5]dec-8-yl)phenyl] -2-( 1 H-pyrazol-4-yl)-4-thiazolecarboxamide;

l-[5-amino-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4--piperidinecarboxamide;

1 - [4-cyano-2- [[ [2-( 1 H-py razol-4-y l)-4~thiazolyl)carbonyl] amino] phenyl] -4 -(methylamino)-4-piperidinecarboxami de ;

1 -[4-amino-2-fluoro-6- [ [[2-(3 -pyri dinyl)-4-thiazolyl] carbony 1] aminojphenyl] -4-(methylamino)-4-piperidinecarboxamide;

l-[4,5~diamino-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide;

l-[4-amino-2-fluoro-6-[[[2-(2-methyl-4-pyridinyl)-4-thiazolyl]carboriyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide;

1 -[4-amino-2- [[ [2-( 1 -methyl- 1 H-pyrazol- 5-yl) -4-thiazolyl] carbonyl] amino]pheny 1] -4-(methylamino)-4-piperidinecarboxamide;

l-[4-amino-2-[[[2-(6-hydroxy-3-pyridinyl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide;

l-[4-amino-2-[[[2-(2-amino-5-pyrimidinyl)-4-thiazolyl]carbonyl]amino]phenyl]--4-(methylamino)-4-piperidinecarboxamide;

1 - [4-amino-2-[ [[2-(5 -pyrimidinyl)-4-thiazolyl]carbonyl]amino]phenyl] -4-(methylamino)-4-piperidinecarboxamide ;

l-[4-amino-2-[ p-p-(1rifluoromethyl)-4-pyridinyl]-4 hiazolyl]carbonyl]amino]phenyl]-4^ (methylamino)-4-piperidinecarboxamide;

1 -[4-amino-2-[ [[2- [6-(tr ifluoromethyl)-3 -pyridinyl] -4-thiazolyl]carbonyl]amino]phenyl] -4-(methylamino)-4-piperidinecarboxamide;

l-[4-amino-2-[[[2-(2-hydroxy-5-pyrimidinyl)-4-thiazolyl]carbonyl]amino]phenyl]-4-(methylammo)-4-piperidinecarboxamide;

l-[4-amino-2-[[[2-[l-methyl-3-(trifluoromethyl)-lH-pyrazol-5-yl]-4-thiazolyl]carbonyl]amino)phenyl]-4-(methylamino)-4-piperidinecarboxan ide;

N-[ 5 -amino-2-(2 ,9-diazaspiro [5.5]undec-9-y l)pheny 1] -2- [ 1 -methyl-3 -(trifluoromethyl)- 1 H-pyrazol-5-yl]-4-thiazolecarboxamide;

l-[4-amino-2-[[[2--(355-dimethyl-4-isoxazolyl)-4-thiazolyl]carbonyl]amino]phenyl]-4- (methylamino)-4-piperidinecarboxamide;

N- [5-amino-2-(2,9-diazaspiro [5.5]undec-9-y l)phenyl] -2- [3 -(trifluoromethyl)- 1 H-pyrazol- 5 -yl] -4-tbiazolecarboxamide;

l-[4-amino-2-[[[2-(2-methyl-3-pyridin^

4-piperidinecarboxamide;

N- [5-amino-2-(2,8~diazaspiro [4, 5]dec-8-yl)-3 -pyridinyl]-2-( 1 H-pyrazol-4-yl)-4-thiazolecarboxamide;

N-[5-amino-2-(2,8-diazaspiro[4.5]dec-2-yl)-3-pyridinyl]-2-(lH-pyrazol-4-yl)-4-thiazolecarboxamide;

N-[5 -amino-2-(2,9-diazaspiro [5.5]undec-2-y I)-3-pyridinyl]-2-( 1 H-pyrazol-4-yl)-4-thiazolecarboxami de ;

N- [5-amino-2-(2s9-diazaspiro[5.5]undec-9-yl)-3 -pyridinyl] -2-( 1 H-pyrazol~4-yl)-4-thiazolecarboxamide ;

1 - [4-amino-2- [ [[2-(4-amino- 1 H-pyrazol- 1 -yl)-4-thiazolyl] carbonyl] amino] -6-fluorophenyl] -4-(methylamino)-4-piperidinecarboxamide;

l-[2-[[[2-(4-amino-lH-pyrazol-l-yl)-4-thiazolyl]carbonyl]amino]-5-hydroxyphenyl]-4- (methylamino)~4-piperidinecarboxamide;

1 4-ammo-2-fluoro-6-[[[2-(4-methyl-lH-py

(methylamino)-4-piperidinecarboxamide;

1 - [4-ammo-2-fluoro-6- [ [ [2-( 1 H-pyrazol- 1 -yl)-4-thiazolyl]carbonyl] amino] phenyl] -4- (methylamino)-4-piperidinecarboxamide;

l-[4-amino-2-fluoro-6-[[[2-(3-oxo-l-piperazinyl)-4-thiazolyl]carbonyl]arnino]phenyl]-4- (methylamino)-4-piperidinecarboxamide; and

l-[4-amino~2-fluoro-6-[[[2-(4-mo^holiny

(methylamino)-4-piperidinecarboxamide;

Or a stereoisomer thereof;

Or a pharmaceutically acceptable salt thereof;

Or a pharamceutically acceptable salt of the stereoisomer thereof.

Stereochemistry

When structures of the same constitution differ in respect to the spatial arrangement of certain atoms or groups, they are stereoisomers, and the considerations that are significant in analyzing their interrelationships are topological. If the relationship between two stereoisomers is that of an object and its nonsuperimposable mirror image, the two structures are enantiomeric, and each structure is said to be chiral. Stereoisomers also include diastereomers, cis-trans isomers and conformational isomers. Diastereoisomers can be chiral or achiral, and are not mirror images of one another. Cis-trans isomers differ only in the positions of atoms relative to a specified planes in cases where these atoms are, or are considered as if they were, parts of a rigid structure. Conformational isomers are isomers that can be interconverted by rotations about formally single bonds. Examples of such conformational isomers include cyclohexane conformations with chair and boat conformers, carbohydrates, linear alkane conformations with staggered, eclipsed and gauche confomers, etc. See J. Org, Chem. 35, 2849 (1970)

Many organic compounds exist in optically active forms having the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule about its chiral center(s). The prefixes d and 1 or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. For a given chemical structure, enantiomers are identical except that they are non-superimposable mirror images of one another. A mixture of enantiomers is often called an enantiomeric mixture. A 50:50 mixture of enantiomers is referred to as a racemic mixture. Many of the compounds described herein can have one or more chiral centers and therefore can exist in different enantiomeric forms. If desired, a chiral carbon can be designated with an asterisk (*). When bonds to the chiral carbon are depicted as straight lines in the Formulas of the invention, it is understood that both the (R) and (S) configurations of the chiral carbon, and hence both enantiomers and mixtures thereof, are embraced within the Formula. As is used in the art, when it is desired to specify the absolute configuration about a chiral carbon, one of the bonds to the chiral carbon can be depicted as a wedge (bonds to atoms above the plane) and the other can be depicted as a series or wedge of short parallel lines is (bonds to atoms below the plane). The Cahn-Inglod-Prelog system can be used to assign the (R) or (S) configuration to a chiral carbon.

When the compounds of the present invention contain one chiral center, the compounds exist in two enantiomeric forms and the present invention includes both enantiomers and mixtures of enantiomers, such as the specific 50:50 mixture referred to as a racemic mixtures. The enantiomers can be resolved by methods known to those skilled in the art, such as formation of diastereoisomeric salts which may be separated, for example, by crystallization (see, CRC Handbook of Optical Resolutions via Diastereomeric Salt Formation by David Kozma (CRC Press, 2001)); formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent. It will be appreciated that where the desired enantiomer is converted into another chemical entity by one of the separation procedures described above, a further step is required to liberate the desired enantiomeric form. Alternatively, specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.

Designation of a specific absolute configuration at a chiral carbon of the compounds of the invention is understood to mean that the designated enantiomeric form of the compounds is in enantiomeric excess (ee) or in other words is substantially free from the other enantiomer. For example, the "R" forms of the compounds are substantially free from the "S" forms of the compounds and are, thus, in enantiomeric excess of the "S" forms. Conversely, "S" forms of the compounds are substantially free of "R" forms of the compounds and are, thus, in enantiomeric excess of the "R" forms. Enantiomeric excess, as used herein, is the presence of a particular enantiomer at greater than 50%. In a particular embodiment when a specific absolute configuration is designated, the enantiomeric excess of depicted compounds is at least about 90%.

When a compound of the present invention has two or more chiral carbons it can have more than two optical isomers and can exist in diastereoisomeric forms. For example, when there are two chiral carbons, the compound can have up to 4 optical isomers and 2 pairs of enantiomers ((S,S)/(R,R) and (R,S)/(S,R)). The pairs of enantiomers (e.g., (S,S)/(R,R)) are mirror image stereoisomers of one another. The stereoisomers that are not mirror-images (e.g., (S,S) and (R,S)) are diastereomers. The diastereoisomeric pairs may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers within each pair may be separated as described above. The present invention includes each diastereoisomer of such compounds and mixtures thereof.

As used herein, "a," an" and "the" include singular and plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" or "a pharmacologically active agent" includes a single active agent as well a two or more different active agents in combination, reference to "a carrier" includes mixtures of two or more carriers as well as a single carrier, and the like.

This invention is also intended to encompass pro-drugs of the Thiazole

Carboxamide compounds disclosed herein. A prodrug of any of the compounds can be made using well-known pharmacological techniques.

Pharmaceutically acceptable salts

The Thiazole Carboxamide compounds described herein noted above, be prepared in the form of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of such salts are (a) acid addition salts organic and inorganic acids, for example, acid addition salts which may, for example, be hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid, trifluoroacetic acid, formic acid and the like. Pharmaceutically acceptable salts can also be prepared from by treatment with inorganic bases, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like. Pharmaceutically acceptable salts can also be formed from elemental anions such as chlorine, bromine and iodine.

The active compounds disclosed can, as noted above, also be prepared in the form of their hydrates. The term "hydrate" includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate and the like.

The active compounds disclosed can, as noted above, also be prepared in the form of a solvate with any organic or inorganic solvent, for example alcohols such as methanol, ethanol, propanol and isopropanol, ketones such as acetone, aromatic solvents and the like.

The active compounds disclosed can also be prepared in any solid or liquid physical form. For example, the compound can be in a crystalline form, in amorphous form, and have any particle size. Furthermore, the compound particles may be micronized, or may be agglomerated, particulate granules, powders, oils, oily suspensions or any other form of solid or liquid physical form.

The compounds of the present invention may also exhibit polymorphism. This invention further includes different polymorphs of the compounds of the present invention. The term "polymorph" refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.

As used herein, "a," an" and "the" include singular and plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "an active agent" or "a pharmacologically active agent" includes a single active agent as well a two or more different

active agents in combination, reference to "a carrier" includes mixtures of two or more carriers as well as a single carrier, and the like.

METHODS OF TREATMENT

The Thiazole Carboxamide Compounds can be useful in human and veterinary medicine in the therapy of proliferative diseases such as cancer other non-cancer proliferative disorders. The Thiazole Carboxamide Compounds are useful where inhibiting PDKl or inhibiting PDKl variants is indicated, such as in treating various diseases associated with abnormal PDKl signaling and/or abnormal signaling upstream or downstream of PDKl (or variants thereof), such as that related to up- regulated activity of one or more receptor tyrosine kinases, Ras, PDKl, PKB/Akt, RSK, PKC, 70S6K, or SGK. In some embodiments, the compounds of the invention are useful in inhibiting PDKl variants wherein the wild type PDKl contains one or more point mutations, insertions, or deletions. Examples of PDKl variants include as PDK1T354M and PDK1D527E.

While not being bound by any specific theory, it is believed that the Thiazole

Carboxamide Compounds are useful in treating proliferative diseases such as cancer and other proliferative diseases because of their PDKl inhibitory activity.

The general value of the compounds of the invention in inhibiting PDKl can be determined, for example, using the fluorescence polarization-based assay described in Example 2. In addition, the general value of the compounds of the invention in inhibiting PDKl function can be evaluated using other known assays such as those described in Xu et al. in J. Biomol. Screen. 14, 1257-1262 (2009).

The Thiazole Carboxamide Compounds can be used to treat diseases and disorders characterized by excessive or pathologically elevated cell growth such as is

characteristic of various cancers and non-cancer proliferative disorders. Examples of cancers for which the Thiazole Carboxamide Compounds can be useful, include lung cancer, bronchial cancer, prostate cancer, breast cancer, pancreatic cancer, colon cancer, rectal cancer, colorectal cancer, thyroid cancer, liver cancer, intrahepatic bile duct cancer, hepatocellular cancer, gastric cancer, glioma/glioblastoma, endometrial cancer, melanoma, kidney cancer, renal pelvic cancer, urinary bladder cancer, uterine corpus cancer, uterine cervical cancer, ovarian cancer, multiple myeloma, esophageal cancer, acute myelogenous leukemia, chronic myelogenous leukemia, lymphocytic leukemia, myeloid leukemia, brain cancer, oral cavity cancer, and pharyngeal cancer, laryngeal cancer, small intestinal cancer, non-Hodgkin's lymphoma, and villous colon adenoma.

In some embodiments, the compounds of the invention are used to treat cancers of the prostate, lung, colon, or breast.

Examples of non-cancer proliferative disorders for which the Thiazole

Carboxamide Compounds can be useful include neuro-fibromatosis, atherosclerosis, pulmonary

fibrosis, arthritis, psoriasis, glomerulonephritis, restenosis, proliferative diabetic retinopathy (PDR), hypertrophic scar formation, inflammatory bowel disease, transplantation rejection, angiogenesis, and endotoxic shock.

Thus, in one embodiment the invention provides a method of treating a patient (e.g., human) having a disease or disorder characterized by excessive or pathologically elevated cell growth by administering a therapeutically effective amount of a Thiazole Carboxamide Compound, or a pharmaceutically acceptable salt of said compound to the patient. In some embodiments, the disease or disorder being treated is a cancer. In other embodiments, the disease or disorder being treated are non-cancer proliferative disorders.

The present invention provides a method of treating cancer comprising the step of administering to a subject a therapeutically effective amount of the Thiazole Carboxamide Compounds. The present invention also provides the Use of the Thiazole Carboxamide

Compounds for the preparation of a medicament for the treatment of cancer. The invention also provides the Thiazole Carboxamide Compounds for use in the treatment of cancer.

Definitions:

As used herein, the term "therapeutically effective amount" means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician. The therapeutic effect is dependent upon the disease or disorder being treated or the biological effect desired. As such, the therapeutic effect can be a decrease in the severity of symptoms associated with the disease or disorder and/or inhibition (partial or complete) of progression of the disease. The amount needed to elicit the therapeutic response can be determined based on the age, health, size and sex of the subject. Optimal amounts can also be determined based on monitoring of the subject's response to treatment.

Further, a therapeutically effective amount, can be an amount that selectively induces terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, or an amount that induces terminal differentiation of tumor cells.

The method of the present invention is intended for the treatment or chemoprevention of human patients with cancer. However, it is also likely that the method would be effective in the treatment of cancer in other subjects. "Subject", as used herein, refers to animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, pigs, dogs, cats, rabbits, guinea pigs, rats, mice or other bovine, ovine, equine, canine, feline, rodent or murine species.

The terra "administration" and variants thereof (e.g., "administering" a compound) in reference to a compound of the invention means introducing the compound or a prodrug of the compound into the system of the animal in need of treatment. When a compound

of the invention or prodrug thereof is provided in combination with one or more other active agents (e.g., a cytotoxic agent, etc.), "administration" and its variants are each understood to include concurrent and sequential introduction of the compound or prodrug thereof and other agents.

COMBINATION THERAPY

The compounds of the present invention can be administered alone or in combination with other therapies suitable for the disease or disorder being treated. Where separate dosage formulations are used, the compound and the other therapeutic agent can be administered at essentially the same time (concurrently) or at separately staggered times

(sequentially). The pharmaceutical combination is understood to include all these regimens. Administration in these various ways are suitable for the present invention as long as the beneficial therapeutic effect of the compound and the other therapeutic agent are realized by the patient at substantially the same time. In an embodiment, such beneficial effect is achieved when the target blood level concentrations of each active drag are maintained at substantially the same time.

The instant compounds are also useful in combination with known therapeutic agents and anti-cancer agents. For example, instant compounds are useful in combination with known anti-cancer agents. Combinations of the presently disclosed compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Therefore, the present invention encompasses pharmaceutical compositions comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier and optionally other threrapeutic ingredients, such as an anti-cancer agent. Examples of such agents can be found in Cancer Principles and Practice of Oncology by V.T. Devita and S. Hellman (editors), 6th edition (February 15, 2001), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such anticancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents, agents that interfere with cell cycle checkpoints, agents that interfere with receptor tyrosine kinases (RTKs) and cancer vaccines. The instant compounds are particularly useful when co-administered with radiation therapy.

In an embodiment, the instant compounds are also useful in combination with known anti-cancer agents including the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors, HIV protease inhibitors, reverse transcriptase inhibitors, and other angio genesis inhibitors.

"Estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, diethylstibestral, tamoxifen, raloxifene, idoxifene, LY353381, LY117081, toremifene, fluoxymestero, lfulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2- [4- [2-( 1 -piperidiny l)ethoxy]phenyl] -2H- 1 -benzopyran-3 -yl]-pheny 1-2,2-dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

Other hormonal agents include: aromatase inhibitors (e.g., aminoglutethimide, anastrozole and tetrazole), luteinizing hormone release hormone (LHRH) analogues, ketoconazole, goserelin acetate, leuprolide, megestrol acetate and mifepristone.

"Androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5a-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.

"Retinoid receptor modulators" refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, o> difluoromethylornithme, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.

"Cytotoxic/cytostatic agents" refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mytosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of histone deacetylase, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.

Examples of cytotoxic agents include, but are not limited to, sertenef, cachectin, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, uracil mustard, thiotepa, busulfan, carmustine, lomustine, streptozocin, tasonermin, lonidamine, carboplatin, altretamine, dacarbazine, procarbazine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane- l,6-diamine)-mu-[diamine-platinum(II)]bis[diamine(chloro)platinum (II)] tetrachloride,

diarizidinyl spermine, arsenic trioxide, 1-(1 l-dodecylamino-10-hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, doxorubicin, daunorubicin, idarubicin, anthracenedione, bleomycin, mitomycin C, dactinomycin, plicatomycin, bisantrene, rnitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deamino-3'-morpholino-13-deoxo-10-hydroxycarminomycin, annamycin, galarabicin, elinafide, MEN 10755, and 4-demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunorubicin (see WO 00/50032).

An example of a hypoxia activatable compound is tirapazamine.

Examples of proteasome inhibitors include but are not limited to lactacystin and bortezomib.

Examples of microtubule inhibitors/microtubule-stabilising agents include vincristine, vinblastine, vindesine, vinzolidine, vinorelbine, vindesine sulfate, 3',4'-didehydro-4'-deoxy-8'-norvincaleukoblastine, podophyllotoxins (e.g., etoposide (VP- 16) and teniposide (VM-26)), paclitaxel, docetaxol, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881, BMS 184476, vinflunine, cryptophycin, 2,3s4s5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, NfN-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-proIyl-L-proline-t-butylamide, TDX258, the epothilones (see for example U.S. Pat. Nos. 6,284,781 and 6,288,237) and BMS 188797.

Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6"ethoxypropionyl-3',4'-0-exo-benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5-kl]acridine-2-(6H) propanamine, l-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl- 1 H, 12H-benzo [de]pyrano[3 ' ,4 ' :b,7]-indoIizino [ 1 ,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N-isopropylamino)ethyl]-(20S)camptothecin, BNP1350, BNPI1100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino-2'-deoxy-etoposide, GL331 , N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6-dimethyl~6H-pyrido[4,3-b]carbazole-l-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl] ~N-methylamino] ethyl] - 5 - [4-hydro0xy-3 ,5-dimethoxyphenyl] -5,5a,6,8,8a,9-hexohydrofuro(3 ' ,4' :6,7)naphtho(2,3-d)-l ,3-dioxol-6-one, 2,3-(methylenedioxy)-5-methyl-7-hydroxy-8-methoxybenzo [c] -phenanthridinium, 6,9-bis [(2-aminoethyl)amino]benzo[g]isoguinoline-5, 10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2-(2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5, 1 -de]acridin-6-one, N-[l - [2(diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4-ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide, 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,l-c] quinolin-7-one, and dimesna.

Examples of inhibitors of mitotic kinesins, and in particular the human mitotic kinesin KSP, are described in PCT Publications WO 01/30768, WO 01/98278, WO 03/050,064, WO 03/050,122, WO 03/049,527, WO 03/049,679, WO 03/049,678, WO 03/39460 and WO2003/079973, WO2003/099211, WO2004/039774, WO2003/105855, WO2003/106417. In an embodiment inhibitors of mitotic kinesins include, but are not limited to inhibitors of KSP, inhibitors of MKLPl, inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kift4, inhibitors of Mphosphl and inhibitors of Rab6-KIFL.

Examples of "histone deacetylase inhibitors" include, but are not limited to, SAHA, TSA, oxamflatin, PXD101, MG98, valproic acid and scriptaid. Further reference to other histone deacetylase inhibitors may be found in the following manuscript; Miller, T. A. et al. J. Med. Chem. 46(24):5097-5116 (2003).

"Inhibitors of kinases involved in mitotic progression" include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo-like kinases (PLK; in particular inhibitors of PLK-1), inhibitors of bub- 1 and inhibitors of bub-Rl . An example of an "aurora kinase inhibitor" is VX-680.

"Antiproliferative agents" includes antisense RNA and DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231, and INX3001, and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine,

capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2' -deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl] ~N ' -(3 ,4-dichlorophenyl)urea, N6-[4-deoxy-4- [N2- [2(E),4(E)-tetradecadienoyl]glycylamino]-L-glycero-B-L-manno-heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[554-b][l,4]thiazin-6-yl-(S)-ethyl]-2J5-thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, floxuridine, methotrexate, leucovarin, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabine phosphate, cladribine (2-CDA), asparaginase, gemcitabine, alanosine, 1 l-acetyl-8-(carbamoyloxymethyl)-4~formyl-6-methoxy-14-oxa-l,l 1-diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2 ' -cyano-2 ' ~deoxy-N4-palmitoyl- 1 -B-D-arabino furanosyl cytosine and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone.

Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.

"HMG-CoA reductase inhibitors" refers to inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938, 4,294,926 and 4,319,039), simvastatin (ZOCOR®; see U.S. Pat. Nos. 4,444,784, 4,820,850 and

4,916,239), pravastatin (PRAVACHOL®; see U.S. Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are

described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patent Nos. 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open-acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefor the use of such salts, esters, open-acid and lactone forms is included within the scope of this invention.

"Prenyl -protein transferase inhibitor" refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl-protein transferase type I (GGPTase-I), and

geranylgeranyl-protein transferase type-II (GGPTase-II, also called Rab GGPTase).

Examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701, WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Pat. No. 5,420,245, U.S. Pat. No. 5,523,430, U.S. Pat. No. 5,532,359, U.S. Pat. No. 5,510,510, U.S. Pat. No. 5,589,485, U.S. Pat. No. 5,602,098, European Patent Publ. 0 618 221, European Patent Publ. 0 675 112, European Patent Publ. 0 604 181, European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701, WO 96/21456, WO 96/22278, WO 96/24611, WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Pat. No. 5,571,792, WO 96/17861, WO 96/33159, WO 96/34850, WO 96/34851, WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/311 11, WO 96/31477, WO 96/31478, WO 96/31501, WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO 97/30053, WO 97/44350, WO 98/02436, and U.S. Pat. No. 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European J. of Cancer, Vol. 35, No. 9, pp.1394-1401 (1999).

"Angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFRl) and Flk-l KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- , interleukin-12, erythropoietin (epoietin-a), granulocyte-CSF (filgrastin), granulocyte, macrophage-CSF (sargramostim), pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxy-genase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol, Vol. 108, p.573 (1990); Anat. Rec, Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin, Orthop. Vol. 313, p. 76 (1995); J. Mol. Endocrinol, Vol. 16, p.107 (1996); Jpn. J. Pharmacol, Vol. 75, p. 105 (1997);

Cancer Res., Vol. 57, p. 1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. Mol. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal anti-inflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl-carbonyl)-rumagillol, thalidomide, angiostatin, troponin- 1, angiotensin II antagonists (see

Fernandez et al., J Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp.963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).

Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in Clin, Chem. La. Med. 38:679-692 (2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80: 10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001)). TAFIa inhibitors have been described in PCT Publication WO 03/013,526 and U.S. Ser. No. 60/349,925 (filed January 18, 2002).

"Agents that interfere with cell cycle checkpoints" refer to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents. Such agents include inhibitors of AT , ATM, the Chkl and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7-bydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.

"Agents that interfere with receptor tyrosine kinases (RTKs)" refer to compounds that inhibit RTKs and therefore mechanisms involved in oncogenesis and tumor progression. Such agents include inhibitors of c-Kit, Eph, PDGF, Flt3 and c-Met. Further agents include inhibitors of RTKs shown as described by Bume- Jensen and Hunter, Nature, 411 :355-365, 2001.

"Inhibitors of cell proliferation and survival signaling pathway" refer to pharmaceutical agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors. Such agents include inhibitors of inhibitors of EGFR (for example gefitinib and erlotinib), inhibitors of ERB-2 (for example trastuzumab), inhibitors of 1GFR, inhibitors of CD20 (rituximab), inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K family kinase (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in (WO 03/086404, WO 03/086403, WO 03/086394, WO 03/086279, WO 02/083675, WO 02/083139, WO 02/083140 and WO

02/083138), inhibitors of Raf kinase (for example BAY-43-9006 ), inhibitors of MEK (for example CI- 1040 and PD-098059) and inhibitors of mTOR (for example Wyeth CCI-779 and Ariad AP23573). Such agents include small molecule inhibitor compounds and antibody antagonists.

Examples of mTOR inhibitors include ridaforolimus, temsirolimus, everolimus, a rapamycin-analog. Ridaforolimus, also known as AP 23573, MK-8669 and deforolimus, is a unique, non-prodrag analog of rapmycin that has antiproliferative activity in a broad range of human tumor cell lines in vitro and in murine tumor xenograft models utilizing human tumor cell lines. Ridaforolimus has been administered to patients with advanced cancer and is currently in clinical development for various advanced malignancies, including studies in patients with advanced soft tissue or bone sarcomas. Thus far, these trials have demonstrated that ridaforolimus is generally well-tolerated with a predictable and manageable adverse even profile, and possess anti-tumor activity in a broad range of cancers. A description and preparation of ridaforolimus is described in U.S. Patent No. 7,091,213 to Ariad Gene

Therapeutics, Inc.

Temsirolimus, also known as Torisel®, is currently marketed for the treatment of renal cell carcinoma. A description and preparation of temsirolimus is described in U.S. Patent No.

5,362,718 to American Home Products Corporation. Everolimus, also known as Certican® or RADOOl , marketed by Novartis, has greater stability and enhanced solubility in organic solvents, as well as more favorable pharmokinetics with fewer side effects than rapamycin (sirolimus). Everolimus has been used in conjunction with microemulsion cyclosporin (Neoral®, Novartis) to increase the efficacy of the immunosuppressive regime.

"Apoptosis inducing agents" include activators of TNF receptor family members (including the TRAIL receptors).

The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For purposes of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting C X-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays. Such compounds include, but are not limited to those disclosed in U.S. Pat. 5,474,995, U.S. Pat. 5,861,419, U.S. Pat. 6,001,843, U.S. Pat. 6,020,343, U.S. Pat. 5,409,944, U.S. Pat. 5,436,265, U.S. Pat. 5,536,752, U.S. Pat. 5,550,142, U.S. Pat. 5,604,260, U.S. 5,698,584, U.S. Pat. 5,710,140, WO 94/15932, U.S. Pat. 5,344,991, U.S. Pat. 5,134,142, U.S. Pat. 5,380,738, U.S. Pat 5,393,790, U.S. Pat. 5,466,823, U.S. Pat. 5,633,272, and U.S. Pat. 5,932,598.

Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5-pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.

Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to: parecoxib, CELEBREX® and BEXTRA® or a pharmaceutically acceptable salt thereof.

Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpirnase, IM862, 5-methoxy-4-[2-methyl-3-(3-methyl-2-butenyl)oxiranyl]-l-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyl dinanaline, 5-amino-l-[[3,5-dichloro-4-(4-chlorobenzoyl)phenyl]rnethyl]-lH-lJ2,3-triazole-4-carboxamidesCM101> squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7~(carbonyl-bis[imino-N-memyl-4,2-pyrrolocarbonylimino[N-methyl-4,2-pyrrole]-carbonylimino]~bis~(lf3-naphthalene disulfonate), and 3-[(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416).

As used above, "integrin blockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological Hgand to the αγβ3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ανβ5 integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ανβ3 integrin and the ανβ5 integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the αγβ6> <*νβ8> ΐβΐ> α2βΐ> ο^ ΐ, α6β 1 and ο¾β4 integrins. The term also refers to antagonists of any combination of ανβ3 , ανβ5, ανβ6> ανβ8, αΐ βΐ, <¾βΐ, α5βΐ, <*6βΐ and o^4 integrins.

Some specific examples of tyrosine kinase inhibitors include N-(trifluoromethylphenyl)-5-methylisoxazol-4-carboxamides 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl)indolin-2-one, 17-(allyIamino)-l 7-demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3-(4-morpholinyI)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11, 12-hexahydro-lO-(hydroxymethyl)- 10-hydroxy-9-methyl-9,l 2-epoxy- 1 H-diindolo[l ,2,3-fg:3',2',r-kl]pyrrolo[3,4-i][l,6]benzodiazocin-l-one, SH268, genistein, imati ib (STI571), CEP2563, -(3-chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline} SU6668, STI571 A, N-4-chlorophenyl-4-(4-pyridylmethyl)-l-phthalazinamine, and EMD121974.

Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods. For example, combinations of the instantly claimed compounds with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisome proliferator-activated receptors γ and δ. The expression of PPAR-γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31 :909-913; J Biol. Chem. 1999; 274:91 16-9121 ; Invest. Ophthalmol Vis. Sci. 2000; 41 :2309-2317). More recently, PPAR-γ agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice. {Arch. Ophthamol. 2001; 119:709-717). Examples of PPAR-γ agonists and PPAR- γ/α agonists include, but are not limited to,

thiazolidinediones (such as DRF2725, CS-011, troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501, MCC-555, GW2331, GW409544, NN2344, KRP297, NPOl 10, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2- [(5 ,7-dipropyI-3-trifluoromethyl- 1 ,2-benzisoxazol-6-yl)oxy] -2-methylpropionic acid (disclosed in USSN 09/782,856), and 2(R)-7-(3-(2-chIoro-4-(4-fluorophenoxy)

phenoxy)propoxy)-2-emylchromane-2-carboxylic acid (disclosed in USSN 60/235,708 and 60/244,697).

Another embodiment of the instant invention is the use of the presently disclosed compounds in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer see Hall et al (Am J Bum Genet 61 :785-789, 1997) and ufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Pat. No. 6,069,134, for example), Duc-4, NF-1, NF-2, RB, WT1, BRCA1, BRCA2, a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA uPAR Antagonist Suppresses

Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998; 5(8): 1105-13), and interferon gamma (J. Immunol. 2000; 164:217-222).

The compounds of the instant invention may also be administered in combination with an inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).

A compound of the present invention may be employed in conjunction with antiemetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or others such as disclosed in U.S. Patent Nos. 2,789,118, 2,990,401, 3,048,581, 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In an embodiment, an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the instant compounds.

Neurokinin-1 receptor antagonists of use in conjunction with the compounds of the present invention are fully described, for example, in U.S. Pat. Nos. 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, 5,719,147;

European Patent Publication Nos. EP 0 360 390, 0 394 989, 0428 434, 0 429 366, 0 430 771, 0 436 334, 0443 132, 0 482 539, 0 498 069, 0 499 313, 0 512 901, 0 512 902, 0 514 273, 0 514 274, 0 514 275, 0 514 276, 0 515 681, 0 517 589, 0 520 555, 0 522 808, 0 528 495, 0 532 456, 0 533 280, 0 536 817, 0 545 478, 0 558 156, 0 577 394, 0 585 913,0 590 152, 0 599 538, 0 610

793, 0 634 402, 0 686 629, 0 693 489, 0 694 535, 0 699 655, 0 699 674, 0 707 006, 0 708 101, 0 709 375, 0 709 376, 0 714 891, 0 723 959, 0 733 632 and 0 776 893; PCT International Patent Publication Nos. WO 90/05525, 90/05729, 91/09844, 91/18899, 92/01688, 92/06079, 92/12151, 92/15585, 92/17449, 92/20661, 92/20676, 92/21677, 92/22569, 93/00330, 93/00331, 93/01159, 93/01165, 93/01169, 93/01170, 93/06099, 93/09116, 93/10073, 93/14084, 93/14113, 93/18023, 93/19064, 93/21155, 93/21181, 93/23380, 93/24465, 94/00440, 94/01402, 94/02461, 94/02595, 94/03429, 94/03445, 94/04494, 94/04496, 94/05625, 94/07843, 94/08997, 94/10165, 94/10167, 94/10168, 94/10170, 94/11368, 94/13639, 94/13663, 94/14767, 94/15903, 94/19320, 94/19323, 94/20500, 94/26735, 94/26740, 94/29309, 95/02595, 95/04040, 95/04042, 95/06645, 95/07886, 95/07908, 95/08549, 95/11880, 95/14017, 95/15311, 95/16679, 95/17382, 95/18124, 95/18129, 95/19344, 95/20575, 95/21819, 95/22525, 95/23798, 95/26338, 95/28418, 95/30674, 95/30687, 95/33744, 96/05181, 96/05193, 96/05203, 96/06094, 96/07649, 96/10562, 96/16939, 96/18643, 96/20197, 96/21661, 96/29304, 96/29317, 96/29326, 96/29328, 96/31214, 96/32385, 96/37489, 97/01553, 97/01554, 97/03066, 97/08144, 97/14671, 97/17362, 97/18206, 97/19084, 97/19942 and 97/21702; and in British Patent Publication Nos. 2 266 529, 2 268 931 , 2 269 170, 2 269 590, 2 271 774, 2 292 144, 2 293 168, 2 293 169, and 2 302 689. The preparation of such compounds is fully described in the aforementioned patents and publications.

In an embodiment, the neurokinin- 1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(l-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-lH,4H-l,2,4-triazolo)methyI)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Pat. No. 5,719,147.

A compound of the instant invention may also be administered with an agent useful in the treatment of anemia. Such an anemia treatment agent is, for example, a continuous eythropoiesis receptor activator (such as epoetin alfa).

A compound of the instant invention may also be administered with an agent useful in the treatment of neutropenia. Such a neutropenia treatment agent is, for example, a hematopoietic growth factor which regulates the production and function of neutrophils such as a human granulocyte colony stimulating factor, (G-CSF). Examples of a G-CSF include filgrastim.

A compound of the instant invention may also be administered with an immunologic-enhancing drug, such as levamisole, bacillus Calmette-Guerin, octreotide, isoprinosine and Zadaxin.

A compound of the instant invention may also be useful for treating or preventing cancer, including bone cancer, in combination with bisphosphonates (understood to include bisphosphonates, diphosphonates, bisphosphonic acids and diphosphonic acids). Examples of bisphosphonates include but are not limited to: etidronate (Didronel), pamidronate (Aredia), alendronate (Fosamax), risedronate (Actonel), zoledronate (Zometa), ibandronate (Boniva), incadronate or cimadronate, clodronate, EB-1053, minodronate, neridronate, piridronate and tiludronate including any and all pharmaceutically acceptable salts, derivatives, hydrates and mixtures thereof.

A compound of the instant invention may also be useful for treating or preventing breast cancer in combination with aromatase inhibitors. Examples of aromatase inhibitors include but are not limited to anastrozole, letrozole and exemestane.

A compound of the instant invention may also be useful for treating or preventing cancer in combination with siRNA therapeutics.

A compound of the instant invention may also be useful for treating or preventing cancer in combination withcompounds which induce terminal differentiation of the neoplastic cells. Suitable differentiation agents include the compounds disclosed in any one or more of the following references.

a) Polar compounds (Marks et al (1987); Friend, C, Scher, W.; Holland, J. W., and Sato, T. (1971) Proc. Natl. Acad. Sci. (USA) 68: 378-382; Tanaka, M., Levy, J., Terada, M., Breslow, R., Rifkind, R. A., and Marks, P. A. (1975) Proc. Natl. Acad. Sci. (USA) 72: 1003-1006; Reuben, R. C, Wife, R. L., Breslow, R., Rifkind, R. A., and Marks, P. A. (1976) Proc. Natl. Acad. Sci. (USA) 73: 862-866);

b) Derivatives of vitamin D and retinoic acid (Abe, E., Miyaura, C, Sakagami, H., Takeda, M., Konno, K., Yamazaki, T., Yoshika, S., and Suda, T. (1981) Proc. Natl. Acad. Sci. (USA) 78: 4990-4994; Schwartz, E. L., Snoddy, J. R., reutter, D., Rasmussen, H., and Sartorelli, A. C. (1983) Proc. Am. Assoc. Cancer Res. 24: 18; Tanenaga, K., Hozumi, M., and Sakagami, Y. (1980) Cancer Res. 40: 914-919);

c) Steroid hormones (Lotem, J. and Sachs, L. (1975) Int. J. Cancer 15: 731-740); d) Growth factors (Sachs, L. (1 78) Nature (Lond.) 274: 535, Metcalf, D. (1985) Science, 229: 16-22);

e) Proteases (Scher, W.} Scher, B. M., and Waxman, S. (1983) Exp. Hematol. 11 : 490-498; Scher, W., Scher, B. M., and Waxman, S. (1 82) Biochem. & Biophys. Res. Comm. 109: 348-354);

f) Tumor promoters (Huberman, E. and Callaham, M. F. (1979) Proc. Natl. Acad. Sci. (USA) 76: 1293-1297; Lottem, J. and Sachs, L. (1979) Proc. Natl. Acad. Set (USA) 76:

5158-5162); and

g) inhibitors of DNA or RNA synthesis (Schwartz, E. L. and Sartorelli, A. C. (1982) Cancer Res. 42: 2651-2655, Terada, M., Epner, E., Nudel, U., Salmon, J., Fibach, E., Rifkind, R. A., and Marks, P. A. (1978) Proc. Natl Acad. Set (USA) 75: 2795-2799; Morin, M. J. and Sartorelli, A. C. (1984) Cancer Res 44: 2807-2812; Schwartz, E. L., Brown, B. J., Nierenberg, M.} Marsh, J. G, and Sartorelli, A. C. (1983) Cancer Res. 43: 2725-2730; Sugano, H.; Furusawa, M.; awaguchi, T., and Ikawa, Y. (1973) Bibl. Hematol 39: 943-954; Ebert, P. S., Wars, I., and Buell, D. N. (1976) Cancer Res. 36: 1809-1813; Hayasbi, M., Okabe, J., and Hozumi, M. (1979) Gann 70: 235-238).

A compound of the instant invention may also be useful for treating or preventing cancer in combination with γ-secretase inhibitors.

Also included in the scope of the claims is a method of treating cancer that comprises administering a therapeutically effective amount of a compound in combination with radiation therapy and/or in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a

cytotoxiccyto static agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, PPAR-γ agonists, PPAR-δ agonists, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an agent useful in the treatment of anemia, an agent useful in the treatment of neutropenia, an immunologic-enhancing drug, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an aromatase inhibitor, an siRNA therapeutic, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and an agent that interferes with a cell cycle checkpoint.

The compounds of the instant invention are useful in combination with the following therapeutic agents: abarelix (Plenaxis depot®); aldesleukin (Prokine®); Aldesleukin (Proleukin®); Alemtuzumabb (Campath®); alitretinoin (Panretin®); allopurinol (Zyloprim®); altretamine (Hexalen®); amifostine (Ethyol®); anastrozole (Arimidex®); arsenic trioxide (Trisenox®); asparaginase (Elspar®); azacitidine (Vidaza®); bendamustine hydrochloride (Treanda®); bevacuzimab (Avastin®); bexarotene capsules (Targretin®); bexarotene gel (Targretin®); bleomycin (Blenoxane®); bortezomib (Velcade®); busulfan intravenous

(Busulfex®); busulfan oral (Myleran®); calusterone (Methosarb®); capecitabine (Xeloda®); carboplatin (Paraplatin®); carmustine (BCNU®, BiCNU®); carmustine (Gliadel®); carmustine with Polifeprosan 20 Implant (Gliadel Wafer®); celecoxib (Celebrex®); cetuximab (Erbitux®); chlorambucil (Leukeran®); cisplatin (Platinol®); cladribine (Leustatin®, 2-CdA®); clofarabine (Clolar®); cyclophosphamide (Cytoxan®, Neosar®); cyclophosphamide (Cytoxan Injection®); cyclophosphamide (Cytoxan Tablet®); cytarabine (Cytosar-U®); cytarabine liposomal

(DepoCyt®); dacarbazine (DTIC-Dome®); dactinomycin, actinomycin D (Cosmegen®);

dalteparin sodium injection (Fragmin®); Darbepoetin alfa (Aranesp®); dasatinib (Sprycel®); daunorubicin liposomal (DanuoXome®); daunorubicin, daunomycin (Daunorubicin®);

daunorubicin, daunomycin (Cerubidine®); degarelix (Firmagon®); Denileukin diftitox

(Ontak®); dexrazoxane (Zinecard®); dexrazoxane hydrochloride (Totect®); docetaxel

(Taxotere®); doxorubicin (Adriamycin PFS®); doxorubicin (Adriamycin®, Rubex®);

doxorubicin (Adriamycin PFS Injection®); doxorubicin liposomal (Doxil®); dromostanolone propionate (Dromostanolone ®); dromostanolone propionate (Masterone Injection®);

eculizumab injection (Soliris®); Elliott's B Solution (Elliott's B Solution®); eltrombopag (Promacta®); epirubicin (Ellence®); Epoetin alfa (epogen®); erlotinib (Tarceva®); estramustine (Emcyt®); etoposide phosphate (Etopophos®); etoposide, VP- 16 (Vepesid®); everolimus tablets (Afinitor®); exemestane (Aromasin®); ferumoxytol (Feraheme Injection®); Filgrastim (Neupogen®); floxuridine (intraarterial) (FUDR®); fiudarabine (Fludara®); fluorouracil, 5-FU (Adrucil®); fulvestrant (Faslodex®); gefitinib (Iressa®); gemcitabine (Gemzar®); gemtuzumab ozogamicin (Mylotarg®); goserelin acetate (Zoladex Implant®); goserelin acetate (Zoladex®); histrelin acetate (Histrelin implant®); hydroxyurea (Hydrea®); Ibritumomab Tiuxetan

(Zevalin®); idarubicin (Idamycin®); ifosfamide (IFEX®); imatinib mesylate (Gleevec®); interferon alfa 2a (Roferon A®); Interferon alfa-2b (Intron A®); iobenguane 1 123 injection (AdreView®); irinotecan (Camptosar®); ixabepilone (Ixempra®); lapatinib tablets (Tykerb®); lenalidomide (Revlimid®); letrozole (Femara®); leucovorin (Wellcovorin®, Leucovorin®); Leuprolide Acetate (Eligard®); levamisole (Ergamisol®); lomustine, CCNU (CeeBU®);

meclorethamine, nitrogen mustard (Mustargen®); megestrol acetate (Megace®); melphalan, L-PAM (Alkeran®); mercaptopurine, 6-MP (Pu inethol®); mesna (Mesnex®); mesna (Mesnex tabs®); methotrexate (Methotrexate®); methoxsalen (Uvadex®); mitomycin C (Mutamycin®); mitotane (Lysodren®); mitoxantrone (Novantrone®); nandrolone phenpropionate (Durabolin-50®); nelarabine (Arranon®); nilotinib (Tasigna®); Nofetumomab (Verluma®); ofatumumab (Arzerra®); Oprelvekin (Neumega®); oxaliplatin (Eloxatin®); paclitaxel (Paxene®); paclitaxel (Taxol®); paclitaxel protein-bound particles (Abraxane®); palifermin (Kepivance®);

pamidronate (Aredia®); panitumumab (Vectibix®); pazopanib tablets (Votrienttm®);

pegademase (Adagen (Pegademase Bovine)®); pegaspargase (Oncaspar®); Pegfilgrastim

(Neulasta®); pemetrexed disodium (Alimta®); pentostatin (Nipent®); pipobroman (Vercyte®); plerixafor (Mozobil®); plicamycin, mithramycin (Mithracin®); porfimer sodium (Photofrin®); pralatrexate injection (Folotyn®); procarbazine (Matulane®); quinacrine (Atabrine®);

Rasburicase (Elitek®); raloxifene hydrochloride (Evista®); Rituximab (Rituxan®); romidepsin (Istodax®); romiplostim (Nplate®); sargramostim (Leukine®); Sargramostim (Prokine®); sorafenib (Nexavar®); streptozocin (Zanosar®); sunitinib maleate (Sutent®); talc (Sclerosol®); tamoxifen (Nolvadex®); temozolomide (Temodar®); temsirolimus (Torisel®); teniposide, VM- 26 (Vumon®); testolactone (Teslac®); thiogua ine, 6-TG (Thioguanine®); thiotepa

(Thioplex®); topotecan (Hycamtin®); toremifene (Fareston®); Tositumomab (Bexxar®);

Tositumomab/I-131 tositumomab (Bexxar®); Trastuzumab (Herceptin®); tretinoin, ATRA (Vesanoid®); Uracil Mustard (Uracil Mustard Capsules®); valrubicin (Valstar®); vinblastine (Velban®); vincristine (Oncovin®); vinorelbine (Navelbine®); vorinostat (Zolinza®); and zoledronate (Zometa®).

Non-limiting examples of other suitable anti- cancer agents for combination with the instant compounds are selected from the group consisting of a Cytostatic agent, Cisplatin, Deforolimus (described in PCT publication No. 2003/064383), Doxorubicin, liposomal doxorubicin (e.g., Caelyx®, Myocet®, Doxil®), Taxotere, Taxol, Etoposide, Irinotecan, Camptostar, Topotecan, Paclitaxel, Docetaxel, Epothilones, Tamoxifen, 5-Fluorouracil,

Methoxtrexate, Temozolomide, cyclophosphamide, SCH 66336, Rl 15777®, L778,123®, BMS 214662®, Iressa®, Tarceva®, Antibodies to EGFR, antibodies to IGFR (including, for example, those published in US 2005/0136063 published June 23, 2005), ESK inhibitors, KSP inhibitors (such as, for example, those published in WO 2006/098962 and WO 2006/098961; ispinesib, SB-743921 from Cytokinetics), Centrosome associated protein E ("CENP-E") inhibitors (e.g., GSK-923295), Gleevec®, Intron, Ara-C, Adriamycin, Cytoxan, Gemcitabine, Uracil mustard, Chlormethme, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6 Mercaptopurine, 6 Thioguanine, Fludarabine phosphate, Oxaliplatin, Leucovirin, ELOXAT3 TM, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin,

Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin C, L Asparaginase, Teniposide 17a-Ethinylestradiol, Diethylstilbestrol, Testosterone,

Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate,

Leuprolide, Flutamide, Toremifene, Goserehn, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole,

Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, Avastin, herceptin, Bexxar, bortezomib ("Velcade"), Zevalin, Trisenox, Xeloda, Vinorelbine, Porfimer, Erbitux, Liposomal, Thiotepa, Altretamine, Melphalan, Trastuzumab, Lerozole, Fulvestrant, Exemestane,

Fulvestrant, Ifosfomide, Rituximab, C225®, Satriplatin, mylotarg, Avastin, Rituxan,

Panitubimab, Sutent, Sorafinib, Sprycel (dastinib), Nilotinib, Tykerb (Lapatinib) and Campath.

In one embodiment, the invention provides a method of treating cancer, the method comprising administering an amount of a Thiazole Carboxamide Compound or a pharmaceutically acceptable salt thereof, and an amount of one additional anticancer agent selected from the group consisting of Adriamycin, Altretamine, Amidox, Aminoglutethimide, Amsacrine, Anastrazole, Antibodies to EGFR, 3-AP, Aphidicolon, Ara-C, Arsenic trioxide, L Asparaginase, Bevacizumab, Bleomycin, BMS 214662, Bortezomib, Busulfan, Campath, Camptostar, Capecitabine, Carboplatin, Carmustine, Centrosome associated protein E ("CENP-E") inhibitors, Cetuximab, Cladribine, Chlorambucil, Chlormethine, Chlorotrianisene, Cisplatin, Clofarabine, cyclophosphamide, Cytarabine, a Cytostatic agent, Cytoxan, Dacarbazine,

Dactinomycin, Daunorubicin, Dasatinib, Deforolimus, Deoxycoformycin, Didox,

Diethylstilbestrol, Docetaxel, Doxorubicin, Dromostanolone, Droloxafine, Epirubicin,

Epothilones, ER inhibitors, Erlotimb, Etoposide, 17a-Ethinylestradiol, Estramustine,

Exemestane, Floxuridine, Fludarabine, Fludarabine phosphate, 5-Fluorouracil, Fluoxymesterone, Flutamide, Fulvestrant, Gefitinib, Gemcitabine, Gemtuzumab ozogamcicin, Goserelin, GSK-923295, Hexamethylmelamine, Hydroxyprogesterone, Hydroxyurea, Ibritumomab Tiuxetan, Idarubicin, Ifosfamide, Imatinib mesylate, Intron, Irinotecan, ispinesib, KSP inhibitors,

1,778,123, Lapatinib, Leucovirin, Leuprolide, Lerozole, Letrazole, Levamisole, Liposomal Doxorubicin, Liposomal, Lomustine, Lonafarnib, Medroxyprogesteroneacetate,

Megestrolacetate, Melphalan, 6 Mercaptopurine, Methoxtrexate, Methylprednisolone,

Methyltestosterone, Mithramycin, Mitomycin C, Mitotane, Mitoxantrone, Navelbene, Nilotinib, Oxaliplatin, Paclitaxel, Panitubimab, Pentostatin, Pipobroman, Porfimer, Prednisolone,

Prednisone propionate, Procarbazine, Reloxafme, Rituximab, Satriplatin, SB-743921, Smll, Sorafmib, Streptozocin, Sunitinib, Tamoxifen, Taxotere, Taxol, Temozolomide, Teniposide, Testolactone, Testosterone, Tezacitabine, 6 Thioguanine, Thiotepa, Tipifarnib, Topotecan, Toremifene, Tositumomab, Trastuzumab, Triamcinolone, Triapine, Triethylenemelamine, Triethylenethiophosphoramine, Trimidox, Uracil mustard, Vinblastine, Vincristine, Vindesine, and Vinorelbine.

In one embodiment, the invention provides a method of treating cancer, the method comprising administering an amount of a Thiazole Carboxamide Compound or a pharmaceutically acceptable salt thereof, and an amount of one or more of a MAP Kinase pathway inhibitor such as bRaf, MEK, or ERK inhibitors to a patient in need thereof.

In another embodiment, the invention provides a method of treating cancer, the method comprising administering an amount of a Thiazole Carboxamide Compound or a pharmaceutically acceptable salt thereof, and an amount of one or more of ERK inhibitors (for example, compounds described in WO2008/156739, WO2007/070398, WO 2008/156739 and US publication 2007/0232 10) to a patient in need thereof.

In one embodiment, the invention provides a method of treating cancer, the method comprising administering an amount of a Thiazole Carboxamide Compound or a

pharmaceutically acceptable salt thereof, and an amount of one or more of an anti-IGF-lR antibody. Specific anti-IGF-lR antibodies include, but are not limited to, dalotuzumab, figitumumab, cixutumumab, SHC 717454, Roche R1507, EM164 or Amgen AMG479.

The instant invention also includes a pharmaceutical composition useful for treating or preventing cancer that comprises a therapeutically effective amount of a compound and a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an HIV protease inhibitor, a reverse transcriptase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR- δ agonist, an inhibitor of cell proliferation and survival signaling, a bisphosphonate, an

aromatase inhibitor, an siRNA therapeutic, γ-secretase inhibitors, agents that interfere with receptor tyrosine kinases (RTKs) and an agent that interferes with a cell cycle checkpoint.

The use of all of these approaches in combination with the instant compounds described herein are within the scope of the present invention.

Compositions and Administration

This invention is also directed to pharmaceutical compositions which comprise at least one Thiazole Carboxamide Compound, or a pharmaceutically acceptable salt of said compound and at least one pharmaceutically acceptable carrier.

When administered to a patient, the Thiazole Carboxamide Compounds can be administered as a component of a composition that comprises a pharmaceutically acceptable carrier or vehicle. The present invention provides pharmaceutical compositions comprising an effective amount of at least one Thiazole Carboxamide Compound and a pharmaceutically acceptable carrier. In the pharmaceutical compositions and methods of the present invention, the active ingredients will typically be administered in admixture with suitable carrier materials suitably selected with respect to the intended form of administration, i.e., oral tablets, capsules (either solid-filled, semi-solid filled or liquid filled), powders for constitution, oral gels, elixirs, dispersible granules, syrups, suspensions, and the like, and consistent with conventional pharmaceutical practices. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A. Gennaro (ed.), Remington 's

Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania. For example, for oral administration in the form of tablets or capsules, the active drug component may be combined with any oral non-toxic pharmaceutically acceptable inert carrier, such as lactose, starch, sucrose, cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, talc, mannitol, ethyl alcohol (liquid forms) and the like. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. Powders and tablets may be comprised of from about 0.5 to about 95 percent inventive composition. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration.

Moreover, when desired or needed, suitable binders, lubricants, disintegrating agents and coloring agents may also be incorporated in the mixture. Suitable binders include starch, gelatin, natural sugars, corn sweeteners, natural and synthetic gums such as acacia, sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes. Among the lubricants there may be mentioned for use in these dosage forms, boric acid, sodium benzoate, sodium acetate, sodium chloride, and the like. Disintegrants include starch, methylcellulose, guar gum, and the like. Sweetening and flavoring agents and preservatives may also be included where appropriate.

Liquid form preparations include solutions, suspensions and emulsions and may include water or water-propylene glycol solutions for parenteral injection.

Liquid form preparations may also include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.

For preparing suppositories, a low melting wax such as a mixture of fatty acid glycerides or cocoa butter is first melted, and the active ingredient is dispersed homogeneously therein as by stirring. The molten homogeneous mixture is then poured into convenient sized molds, allowed to cool and thereby solidify.

The Thiazole Carboxamide Compounds of the present invention may also be delivered transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.

Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the

components or active ingredients to optimize therapeutic effects, i.e., anti-cancer activity and the like. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.

In one embodiment, the Thiazole Carboxamide Compound is administered orally. In another embodiment, the Thiazole Carboxamide Compound is administered intravenously.

In another embodiment, the Thiazole Carboxamide Compound is administered topically.

In still another embodiment, the Thiazole Carboxamide Compounds is

administered sublingually.

In one embodiment, a pharmaceutical preparation comprising at least one

Thiazole Carboxamide Compound is in unit dosage form. In such form, the preparation is subdivided into unit doses containing effective amounts of the active components.

Compositions can be prepared according to conventional mixing, granulating or coating methods, respectively, and the present compositions can contain, in one embodiment, from about 0.1% to about 99% of the Thiazole Carboxamide Compound(s) by weight or volume.

In various embodiments, the present compositions can contain, in one embodiment, from about

1% to about 70% or from about 5% to about 60% of the Thiazole Carboxamide Compound(s) by weight or volume.

The quantity of Thiazole Carboxamide Compound in a unit dose of preparation may be varied or adjusted from about 0.1 mg to about 5000 mg. In various embodiments, the quantity is from about 10 mg to about 5000 mg, about 10 mg to about 1000 mg, 1 mg to about 500 mg, 1 mg to about 100 mg, and 1 mg to about 50 mg.

For convenience, the total daily dosage may be divided and administered in portions during the day if desired. In one embodiment, the daily dosage is administered in one portion. In another embodiment, the total daily dosage is administered in two divided doses over a 24 hour period. In another embodiment, the total daily dosage is administered in three divided doses over a 24 hour period. In still another embodiment, the total daily dosage is administered in four divided doses over a 24 hour period.

For administration to human patients, the amount and frequency of administration of the Thiazole Carboxamide Compounds will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. Generally, a total daily dosage of the Thiazole

Carboxamide Compounds range from about 0.1 to about 5000 mg per day, although variations will necessarily occur depending on the target of therapy, the patient and the route of

administration. In one embodiment, the dosage is from about 1 to about 200 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 10 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses. In another embodiment, the dosage is from about 100 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses. In still another embodiment, the dosage is from about 500 to about 5000 mg/day, administered in a single dose or in 2-4 divided doses.

The compositions of the invention can further comprise one or more additional therapeutic agents, selected from those listed above herein. Accordingly, in one embodiment, the present invention provides compositions comprising: (i) at least one Thiazole Carboxamide Compound or a pharmaceutically acceptable salt thereof; (ii) one or more additional therapeutic agents that are not a Thiazole Carboxamide Compound; and (iii) a pharmaceutically acceptable carrier, wherein the amounts in the composition are together effective to treat disease or disorder associated with dysregulated PDK-1 activity, such as a cancer.

In Vitro and In Vivo METHODS:

The present invention also provides methods of using the Thiazole Carboxamide compounds of the present invention for inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells thereby inhibiting the proliferation of such cells. The methods can be practiced in vivo or in vitro.

In one embodiment, the present invention provides in vitro methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells, by contacting the cells with an effective amount of any one or more of the Thiazole Carboxamide compounds described herein.

In a particular embodiment, the present invention relates to an in vitro method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells. The method comprises contacting the cells under suitable conditions with an effective amount of one or more of the Thiazole Carboxamide compounds described herein.

In another embodiment, the invention relates to an in vitro method of selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting proliferation of such cells.

The method comprises contacting the cells under suitable conditions with an effective amount of one or more of the Thiazole Carboxamide compounds described herein.

In another embodiment, the invention relates to an in vitro method of selectively inducing apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells. The method comprises contacting the cells under suitable conditions with an effective amount of one or more of the Thiazole Carboxamide compounds described herein.

In another embodiment, the invention relates to an in vitro method of inducing terminal differentiation of tumor cells in a tumor comprising contacting the cells with an effective amount of any one or more of the Thiazole Carboxamide compounds described herein.

Although the methods of the present invention can be practiced in vitro, it is contemplated that the preferred embodiment for the methods of selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells, and of inhibiting PD -1 will comprise contacting the cells in vivo, i.e., by administering the compounds to a subject harboring neoplastic cells or tumor cells in need of treatment.

Thus, the present invention provides in vivo methods for selectively inducing terminal differentiation, cell growth arrest and/or apoptosis of neoplastic cells in a subject, thereby inhibiting proliferation of such cells in the subject, by administering to the subject an effective amount of any one or more of the Thiazole Carboxamide compounds described herein.

In a particular embodiment, the present invention relates to a method of selectively inducing terminal differentiation of neoplastic cells and thereby inhibiting proliferation of such cells in a subject. The method comprises administering to the subject an effective amount of one or more of the Thiazole Carboxamide compounds described herein.

In another embodiment, the invention relates to a method of selectively inducing cell growth arrest of neoplastic cells and thereby inhibiting proliferation of such cells in a subject. The method comprises administering to the subject an effective amount of one or more of the Thiazole Carboxamide compounds described herein.

In another embodiment, the invention relates to a method of selectively inducing apoptosis of neoplastic cells and thereby inhibiting proliferation of such cells in a subject. The method comprises administering to the subject an effective amount of one or more of the

Thiazole Carboxamide compounds described herein.

In another embodiment, the invention relates to a method of treating a patient having a tumor characterized by proliferation of neoplastic cells. The method comprises administering to the patient one or more of the Thiazole Carboxamide compounds described herein. The amount of compound is effective to selectively induce terminal differentiation, induce cell growth arrest and/or induce apoptosis of such neoplastic cells and thereby inhibit their proliferation.

Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one Thiazole Carboxamide Compound, or a pharmaceutically acceptable salt of said compound, and a pharmaceutically acceptable carrier, vehicle or diluent.

Yet another aspect of this invention is a kit comprising an amount of at least one Thiazole Carboxamide Compound, or a pharmaceutically acceptable salt of said compound and an amount of at least one additional anti-cancer agent listed above, wherein the amounts of the two or more active ingredients result in a desired therapeutic effect. In one embodiment, the at least one Thiazole Carboxamide Compound and the at least one additional anti-cancer agent are provided in the same container. In one embodiment, the at least one Thiazole Carboxamide Compound and the at least one additional anti-cancer agent are provided in separate containers.

The invention is illustrated in the examples in the Experimental Details Section that follows. This section is set forth to aid in an understanding of the invention but is not intended to, and should not be construed to limit in any way the invention as set forth in the claims which follow thereafter.

EXPERIMENTAL DETAILS SECTION

The following solvents, reagents and reaction conditions may be referred to by their abbreviations:

Aq: aqueous

g or gm: grams

psi: pounds per square inch

pH: concentration of hydronium ions in a solution

°C: degrees Celsius

h: hours

THF: Tetrahydrofuran

Et20: diethyl ether

SEM: 2-(trimethylsilyl)ethoxymethyl

LC-MS: Liquid chromatography mass spectrometry

DCM: dichloromethane

N: Normal

ml: milliliter

NBS: N-Bromosuccinimide

NCS: N-Chlorosuccinimide

NIS: N-iodosuccinimide

r.t: room temperature

MeOH: methanol

DIEA: diisopropylethylamine

EtOAc: ethyl acetate

EtOH: ethanol

DMF: dimethylformamide

wt%: weight percent

m/z: mass per charge

LiOH: lithium hydroxide

DMSO: dimethylsulfoxide

HPLC: high performance liquid chromatography

IP A: isopropanol

Ret: retention

Rt: retention time

RP: reverse phase

ACN: acetonitrile

CH3CN: acetonitrile

MeCN: acetonitrile

Mel: iodomethane

r.t: room temperature

pTSA: para-toluene sulfonic acid

CDI: Ν,Ν'-carbonyldiimidazole

mg: milligram

PMA: phosphomolybdic acid

LiHMDS: Lithium bis(trimethylsilyl)amide

HMDS: hexamethyldisilazane

Pd/C: palladium on carbon

H2: hydrogen gas

PdCl2(dppf): [1 , -bis(diphenylphosphino)ferrocene] dichloropalladium(II)

μηιοΐ: micromole

TFA: trifluoroacetic acid

NMP: N-methyl-2-pyrrolidone

min: minute

DME: dimethylethane

AcOH: acetic acid

BBN: 9-borabicyclo[3.3.1]nonane

BOC: tertiary-butyloxycarbonyl

M: Molar

mmol: millimolar

DIEA: diisopropylethylamine

Bu3SnCN: tributyltin cyanide

Pd[P(t-Bu)3]2: bis(tributyl)Phosphine) palladium

Pd(PPh3)4: tetrakis(triphenylphosphine) palladium

EDCI: 1 -ethyl-3-(3-dimethylaminopropyl)-carbodiimide

UV: ultraviolet

LDA: lithium diisopropylamide

Tf: trifluoromethanesulfonyl

Experimental Section

The compounds of the present invention were prepared by the general methods outlined in the synthetic scheme Ϊ below.

Scheme 1. A general synthetic scheme for the preparation of compounds 1 to 47

Representative examples for the preparation of intermediate bromothiazoles 8a to 8 p

(Table 2)

MeH CONRj

Int-1

Int-1 was prepared according to procedures published in (1) US Patent 3,155,669, and (2) J. Med. Chem. 1998, 41, p5084-5093.

Preparation of Int-8b

Step 1:


lnt-2b lnt-1 Et3N, THF, r.(. int-3

A mixture of 3-fiuoro-4-nitrophenol Int-2b (1.00 g, 6.36 mmol), 4-(methylamino)piperidine-4-carboxamide Int-1 (1.00 g, 6.36 mmol) and N,N-diisopropylethylamine (2.2 ml, 12.7 mmol) were heated in dimethylsulfoxide (10 ml) at 90 °C for 3 hr. Solvents were removed in high vacuum and chromatographic purification [dichloromethane - methanol (7N, ammonia)] gave a yellow solid. The yellow solid intermediate was then stirred with TBDMSC1 (0.63 g) and triethylamine (0.88 ml) in tetrahydrofuran (10ml) at r.t. overnight. Water and ethyl acetate were added and layers were separated. The separated organic layer was washed with water, dried (MgS04) and filtered. Solvents were removed in vacuum and chromatographic purification [dichloromethane - methanol (7N, ammonia)] gave Int-3 as white solid.

Step 2:


lnt-5

A mixture of Int-3 (0.35 g, 0.86 mmol) and 10% Pd/C (182 mg, 0.086 mmol, 50% wet) were stirred in methanol (10 ml) under hydrogen (balloon) at r.t for 3 hr. Catalyst was filtered through Celite and solvents were removed in vacuum to give lnt-5 as off-white solid. The solid was used in the next step without further purification.

Step 3:


lnt-5

A mixture of 2-bromothiazole-4-carboxylic acid (0.11 g, 0.53 mmol), lnt-5 (0.20 g, 0.53 mmol), 2-(7-aza-lH-benzotriazole-l-yl)-l,l,3,3-tetramethyluronium hexafluorophosphate (HATU) (242 mg, 0.64 mmol) and N,N-diisopropylethylamme (0.14 ml, 0.80 mmol) were stirred in N,N-dimethylformamide (5 ml) at r.t. overnight. Water and ethyl acetate were added and layers were separated. The separated organic layer was washed with water, dried (MgS04) and filtered. Solvents were removed in vacuum and chromatographic purification (ethyl acetate - hexane) gave Int-8b as white solid.

Preparation of Int-8h

Step 1:


lnt-7

A mixture of Int-1 (1.00 g, 6.36 mmol), Int-2h (1.20 g, 7.63 mmol) and N,N-diisopropylethylamine (2.7 ml, 15.3 mmol) were heated in acetonitrile (20 ml) at 80 °C for 4 hr. Solvents were removed in vacuum and chromatographic purification (ethyl acetate - hexane) gave Int~7 as yellow solid.

Step 2:


lnt-7 lnt-9

To a solution of lnt-7 (0.50gf 1.69 mmol) in trifluoroacetic acid (10 ml) at 0 °C, potassium nitrate (0.34 gf 3.37 mmol) was added in small portions. The mixture was allowed to stir from 0 °C to r.t. overnight. Solvents were removed in vacuum. Water and ethyl acetate were added and layers were separated. The separated aqueous layer was extracted with ethyl acetate and the combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and chromatographic purification [dichloromethane - methanol (7N, ammonia)] gave Int-9 as yellow solid.

Step 3:


lnt-9 lnt-10

Int-10 was prepared from lnt-9 using similar procedures for the preparation of Int-5.

Step 4:


Int-10 int-11

A mixture of Int-10 (0.22 g, 0.78 mol) and di-tert-butyl dicarbonate (0.21 g, 0.94 mol) were stirred in ethanol (5 ml) overnight. Solvents were removed in vacuum. Chromatographic purification of the crude mixture of products [dichloromethane - methanol (7N ammonia)] gave Int-11 as white foam.

Step 5:


Int-11 lnt-8h

Int-8h was prepared from Int-11 and 2-bromothiazole-4-carboxylic acid using similar procedures for the preparation of Int-8b.

All Bromothiazoles Int-8a to Int-8p listed in Table 2 were prepared from Int-2 (Table 1) using similar procedures described above.

Table 1 (List of Int-2)



Table 2 (Preparation of Bromothiazoles Int-8)


Table 3 (Boronic acids / Boronate esters / Stannylpyrazoles 21a to 21r)


Representative procedures for the preparation of compounds 1-47 using coupling reagents listed in Table 3

Preparation of Compound 2


lnt-8b compound 2

A mixture of Int-8b (65 mg, 0.11 mmol), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole 21a (22 mg, 0.1 1 mmol) and sodium carbonate (36 mg, 0.34 mmol) in ethanol (8 ml), toluene (8 ml) and water (4 ml) at r.t. were purged with nitrogen gas for 5 min.

Tetrakistriphenylphosphorous palladium (13 mg, 0.01 1 mmol) was added. The mixture was heated in a sealed-tube at 90 °C for overnight. After being cooled to r.t, methanol and hydrochloric acid (4N in dioxane) were added. Silica gel was added to the mixture and solvents were removed in vacuum. The solid mixture was then purified by chromatographic separation [dichloromethane - methanol (7N ammonia)] to give compound 2 as white solid.

Preparation of compound 36

Step 1:


A mixture of Int-8p (63 mg, 0.097 rnmol), 21r (74 mg, 0.15 mmol) in dioxane (3 ml) at r.t. were purged with nitrogen gas for 10 min. Tetrakistriphenylphosphorous palladium (23 mg, 0.020 mmol) was added. The mixture was heated in a sealed-tube at 110 °C for 2 days. After being cooled to r.t., solids were filtered through Celite and solvents in the filtrate were removed in vacuum. Chromatographic purification (ethyl acetate - hexane) gave Int-13 as colorless oil.

Step 2:


compound 36

Int-13 (40 mg, 0.10 mmol) was stirred in 4N hydrochloric acid in dioxane (2ml) and methanol (2ml) at r.t. for 3 hr. Solvents were removed in vacuum. Chromatographic purification

[dichloromethane -methanol (7N ammonia)] gave compound 36 as colorless oil. LCMS m/e (M + H+) = 506.3.

Compounds 33 and 34 were prepared from Int-8i and Int-8p with stannylpyrazole 21q usin; similar procedures for the preparation of compound 36.

Preparation of compound 15

Step 1:


Int-14

Ethyl 2-bromothiazole-4-carboxylate (1.0 g, 4.2 mmol) and 4-nitro-lH-pyrazole (0.57 g, 5.0 mmol), cesium carbonate (4.1 g, 12.6 mmol) and copper (I) iodide (160 mg, 0.84 mmol) in dioxane (20 ml) were heated in a sealed-tube at 120 °C for 2 days. After being cooled to r.t, water and ethyl acetate were added. Layers were separated and the separated aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (MgS04) and filtered. Solvents were removed in vacuum and chromatographic purification (ethyl acetate - hexane) gave a white solid. The white solid was stirred in methanol (10 ml) andd dioxane (10ml), a solution of lithium hydroxide hydrate (99 mg) in water (5 ml) was added. The mixture was heated at 60 °C for 1 hr and solvents were removed in vacuum. The residue was dissolved in water and concentrated hydrochloric acid was added until pH ~ 2-3. The solid was filtered and dried to give Int-14 as white solid.

Step 2:


Int-14 int-15 Int-16

Int-15 was prepared from Int-1 and Int-2j using similar procedures for the preparation of Int-7. Int-16 was prepared from Int-14 and Int-15 using similar procedures for the preparation of Int- 8b.

Step 3:


lnt-16 compound 15

A mixture of lnt-16 and 10% Pd/C were stirred in methanol (10 ml) under hydrogen (balloon) at r.t for 1 hr. Catalyst was filtered through Celite and solvents were removed in vacuum to give a colorless residue. The residue was stirred in trifluoroacetic acid (5ml) and dichloromethane (10ml) at r.t. for 2 hr. Solvents were removed in vacuum. Chromatographic purification

[dichloromethane -methanol (7N ammonia)] gave compound 15 as white solid. LCMS m/e (M + H+) - 456.3.

Compounds 42 and 43 were prepared using similar procedures for the preparation of

compound 15.

Using 4-methyl-lH-pyrazole and lH-pyrazole, Compounds 44 and 45 were prepared using similar procedures for the preparation of compound 15, respectively.

Preparation of compound 20 and 21

Step 1:


lnt-2n !nt-1 Int-45

Int-45 was prepared from Int-2n and Int-1 using similar procedures for the preparation of Int-3 (step 1).

Step 2:


int-45 lnt-46 Int-47

A mixture of Int-45 (352 mg, 1.20 mmol) and di-tert-butyl dicarbonate (1.31 g, 6.00 mmol) were stirred in N5N-dimethylformamide (5 ml) at 60 °C overnight. After being cooled at r.t.; solvents were removed in high vacuum. Chromatographic purification [dichioromethane - methanol (7N ammonia)] gave a separable mixture of lnt-46 (more polar) and Int-47 (less polar as orange oil.

Step 3:


lnt-48 was prepared from Int-47 using similar procedures for the preparation of compound 2 from Int-3.


Int-48 was stirred in trifluoroacetic acid (5ml) and dichioromethane (5ml) at r.t. for 3 hr.

Solvents were removed in vacuum. Methanol and silica gel were added to the mixture and solvents were removed in vacuum. The solid mixture was then purified by chromatographic separation [dichioromethane - methanol (7N ammonia)] and again by [ethyl acetate (10%

methanol)] to give compound 21 [LCMS m/e (M + H+) = 441.2] and compound 20 [LCMS m/e (M + H+) - 467.3]

Preparation of lnt-73

Step 1:


Int-71 was prepared following the procedure similar to the synthesis of Int-7 by using 6-chloro-5-nitronicotinic acid and benzyl 2,9-diazaspiro[5.5]undecane-2-carboxylate as the starting materials and ethanol as solvent instead.

Step 2:


Int-71 Int-72

Int-72 was prepared following the procedure similar to the synthesis of Int-63 by using Int-71 as the starting material.

Step 3:


]nt-72 lnt-73

To a solution of Int-72 (0.758 g, 1.44 mmol) in EtOH (30 mL) was added SnCl2-2H20 (1.7 g, 7.50 mmol). The reaction mixture was heated at reflux under N2 for 30 min. The reaction mixture was concentrated to ~ 5 mL in volume and diluted with EtOAc and sat NaHC03(aq). The layers were separated and the organic layer was washed with sat NaHC03(a(5}5 brine, dried over Na2S04, filtered and concentrated. Upon chromatographic purification, compound Iiit-73 was obtained as blue solid.

Int-68, Int-69 and Int-70 were prepared by following similar procedures for the syntfo

Int-73 from Int-3a, 3b and 3c (Table 4) respectively, as described above.


Int-68 !nt-69 )nt-

Table 4 (List of Int-3)


Preparation of Int-30

Step 1;


int-37

To a solution of 4-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)-lH-pyrazole (8.2 g, 41 mmol) in NMP (60 mL) were added K2C03 (12 g, 82 mmol) and 2-(trimethylsilyl)ethoxymethyl chloride (7.8 mL, 43 mmol) in sequence. The reaction mixture was stirred at RT under N2 for 16 h. Then, the reaction mixture was diluted filtered and the filtrate was diluted with EtOAc (300 mL), The resulting solution was washed with sat NaHC03(aq) (3 x 200 mL), ¾0 (4 x 200 mL), brine (1 x 200 mL), dried over Na2S0 , filtered, concentrated and dried in vacuo to yield Int-37 as clear yellowish oil.

Step 2:


lnt-37

A mixture of nitrobenzene methyl 2-bromothiazole-4-carboxylate (2.96 g, 13.3 mmol), boronic ester Int-37 (7.86 g, 20.0 mmol), tetrakis(triphenylphosphine)palladium (1.54 g, 1.33 mmol), and potassium phosphate tribasic (11.7 g, 53.2 mmol) in DMF (50 ml) and water (5 ml) were purged with nitrogen gas for 30 min. The mixture was heated at 1 10 °C for 18 h. Then, the reaction mixture was treated with IN NaOH(aq) (10 mL) and cooled slowly to RT. The reaction mixture was diluted with H20 (300 mL) and EtOAc (150 mL). The layers were separated and the aqueous layer was washed with EtOAc (1 x 200 mL). The organic layers were discarded. Then the aqueous layer was acidified to pH ~ 4 by addition of 1 N HCl(a ), and extracted with CH2CI2 (4 x 1 0 mL). All the CH2C12 layers were combined, dried over Na2S04, filtered, concentrated, and dried in vacuum to yield lnt-30 as tan solid.

Preparation of Compound 41

Step 1:


lnt-30 lnt-73 lnt-74

To a solution of lnt-30 (0.098 g, 0.30 mmol) and lnt-73 (0.12 g, 0.25 mmol) in DMF (3 mL) were added 0-(7-azabenzotriazol-l-yl)-yV,N,N',jV'-tetramethyluronium hexafluorophosphate (0.12 g, 0.30 mmol, HATU), TV.N-diisopropylethylamine (0.066 mL, 0.33 mmol), and 4-dimethylaminopyridine (0.005 g, DMAP). The reaction mixture was stirred at RT overnight.

Then, the reaction mixture was diluted with EtOAc (100 r L), washed with sat. aHC03(aq) (3 x 100 mL), H20 (3 x 100 mL), brine (1 x 100 mL), dried over Na2S04, filtered, and concentrated. The crude product was purified by column chromatography using EtOAc and hexanes as eluents to yield amide lnt-74 as white solid.


To a solution of lnt-74 (0.17 g, 0.21 mmol) in CH2C12 (5 mL) was added a solution of 4 N HC1 in dioxane (1 mL). The reaction was stirred overnight. The reaction mixture was diluted with EtOAc (50 mL), sat NaHC03(aq) (50 mL) and 1 N NaOH(at)) (10 mL). The layers were separated and the organic layer was washed with sat NaHC03(aq) (2 x 50 mL), a mixture of sat NaHC03(aq) and brine (1 :1), and dried over Na2S04, filtered and concentrated. The crude products were purified by prep-TLC ( eOH/CH2Cl2) to yield white solids. These white solids were re-dissolved in CH2CI2 (5 mL) and treated with a solution of 4 N HC1 in dioxane (2 mL). After stirring at RT under N2 for 3 days, the reaction mixture was diluted with Et20. Filtration of the resulting suspension yielded compound 41 as pale orange solid.

Compounds 38, 39, and 40 were prepared by following similar procedures for the synthesis of compound 41.

Preparation of Compound 46


lnt-8h compound 46

A mixture of Int~8h (60 mg, 0.1 1 mmol) and piperazin-2-one (21 mg} 0.21 mmol) were heated in Ν,Ν-dimethylformamide (1 ml) at 110 oC overnight. Solvents were removed in vacuum. The residue was stirred in trifluoroacetic acid (5 ml) at r.t. for 1 hr. Solvents were removed in vacuum. Methanol and silica gel were added to flask and solvents were removed in vacuum. The solid mixture was then purified by chromatographic separation dichloromethane -methanol (7N ammonia)] to give compound 46 as white solid. [LCMS m/e (M + H+) = 491.3]

Starting with morpholine and Int-8h, compound 47 was were prepared by following similar procedures for the synthesis of compound 46. [LCMS m/e (M + H+) = 478.3]

Table 5 below lists representative compounds of the invention with activity data whereby the ICso values are rated "A", "B," "C " or "D." The IC50 values are rated "A" for IC50 values in the range of 1 nM to 50 nM, "B" for ICSo values in the range from 51 nM to 250 nM, "C" for IC50 values in the range from 251 nM to 1 μΜ, and "D" for IC50 values greater than 1 μΜ. IC5o values were obtained by testing the compounds in the assay described in Example 2.

Compounds 1 to 47 listed in Table 5 were prepared by procedures as described above.

Table 5 (Summary of Compounds 1 to 47)







Table 6. Chemical Names for Compounds 1 to 47

Compounds Chemical Names

1 1 -[4, 5 -difluoro-2-[ [ [2-( 1 H-pyrazol-4-y l)-4-thiazolyl] carbonyl] amino]phenyl] - 4-(methylamino)-4-piperidinecarboxaraide

2 1 - [5 -hy droxy-2- [ [ [2-( 1 H-pyr azol-4-yl)-4-thiazoly 1] carbonyl] amino]pheny l]-4- (methylamino)-4»piperidinecarboxarnide

3 1 - [5 -methoxy-2 - [ [[2-( 1 H-pyrazol-4-y l)-4-thiazol yl] carbonyl] amino]phenyl]-4- (methylamino)-4-piperidinecarboxamide

4 l-[4-amino-5-fluoro-2-[[[2-(l-methyl-lH-pyrazol-4-yl)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

5 1 -[5-bydroxy-2-tt[2-(l-methyl-lH-pyrazol-4-yl)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

6 1 - [4-amino-5 -fluoro-2- [ [[2- [6-( 1 -methylethoxy)-3 -pyridiny 1] -4- thiazolyl] carbonyl] amino]phenyl] -4-(methylamino)-4-piperidinecarboxamide

7 1 - [3 - fluoro-2 - [[ [2-( 1 -methyl- 1 H-pyrazo 1-4-y l)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

8 l-[3s5-difluoro-2-[[[2-(l-methyl-lH-pyrazol-4-yl)-4- thiazolyl] carbonyl] amino] phenyl] -4-(methylamino)-4-piperidinecarboxamide

9 l-[2t3-difluoro-6-[[[2-(l-methyl-lH-pyrazol-4-yl)-4- thiazolyl] carbonyl] amino]phenyl] -4-(methy ί amino)-4-piperidinecarboxamide

10 1 - [5-hydroxy-2- [ [[2- [4-(2-methoxyethoxy)pheny 1] -4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

11 1 -[2- [[[2-(2,3 -dihydro-5-benzofuranyl)-4-thiazolyl] carbonyl]amino] -5- hydroxyphenyl]-4-(methylamino)-4-piperidinecarboxamide

1 - [4-amino-2-fluoro-6- [[[2-( 1 H-pyrazol-4-yl)-4-thiazolyl] carbonyl] arninojphenyl] -4- (methylamino)-4-piperidinecarboxamide

1 - [5-amino-3 -[ [[2-( 1 H~pyrazol-4-yl)-4-thiazolyl]carbonyl]amino] -2-pyridinyl] - 4-(memylammo)-4-piperidinecarboxamide

1 - [4-amino-2-fluoro-6 - [[ [2-( 1 -methyl- 1 H-pyr azol-4-yl )-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylammo)-4-piperidinecarboxamide

2-(4-amino-l H-pyrazol-1 -yl)-N-(5-amino-2-(4-carbamoyl-4- (methylarnino)piperidin- 1 -yl)phenyl)thiazole-4-carboxamide l-[4-amino-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4- (methylamino)-4-piperidinecarboxamide

1 - [4-hy droxy-2- [[ [2-( 1 H-pyr azol-4-yl)-4-thiazo lyl] carbony l]amino]phenyI] -4- (methylamino)-4-piperidinecarboxamide

1 -[4-hydroxy-2- [ [ [2-( 1 -methyl- 1 H-pyrazo 1-4-y l)-4- thiazolyl]carbonylJamino]phenyl]-4-(memylamino)-4-piperidinecarboxamide

4-(methylamino)- 1 -[5-methyl-2-[[[2-( 1 H-pyrazo l-4-yl)-4- thiazolyl] carbonyl] amino]phenyl]-4-piperidinecarboxamide

N-[4-amino-2-(l-methyl-2f4-dioxo-ls3,8-triazaspiro[4.5]dec-8-yl)phenyl]-2- ( 1 H-pyrazol-4-yl)-4-thiazolecarboxamide l-[5-amino-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]-4- (methylamino)-4-piperidinecarboxamide

1 - [4-cyano-2- [ [ [2-( 1 H-pyrazol-4-y l)-4-thiazoly 1] carbonyl] amino]pheny 1 ] -4- (methylamino)-4-piperidinecarboxarnide l-[4-arnino-2-fluoro-6-[[[2-(3-pyridinyl)-4-thiazolyl]carbonyl]arnino]phenyl]- 4-(methylamino)-4-piperidinecarboxamide l-[4?5-diamino-2-[[[2-(lH-pyrazol-4-yl)-4-thiazolyl]carbonyl]amino]phenyl]- 4-(methylamino)-4-piperidinecarboxamide l-[4-amino-2-fluoro-6-[[[2-(2-methyl-4-pyridinyl)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylarnmo)-4-piperidinecarboxairiide l-[4-amino-2-[f[2-(l-methyl-lH-pyrazol-5-yl)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide l-[4-amino-2-[[[2-(6-hydroxy-3-pyridinyl)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylarnino)-4-piperidinecarboxarnide

1 -[4-amino-2- [[ [2-(2-amino- 5 -pyrimidinyl)-4- thiazolyl] carbonyl] amino]phenyl] -4-(methylamino)-4-piperidinecarboxamide l-[4-amino-2-[[[2-(5 -pyr imidinyl)-4 -thiazolyl] carbonyl] amino] phenyl] -4- (methylamino)-4~piperidinecarboxamide l-[4-amino-2-[[;[2-[2-(trifluoromethyl)-4-pyridinyl]-4- thiazolyl]carbonyl]ai¾ino]phenyl]-4-(methylamino)-4-piperidinecarboxamide l-[4-amino-2-[[[2~[6- (trifluoromethy l)-3 -pyridiny 1] -4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

1 - [4-amino-2- [[[2-(2-hydroxy-5 -pyrimidinyl)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

1 -[4-amino-2-[f [2-[l -methyl~3- (trifluoromethy 1)- 1 H-pyrazol-5-yl]~4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

N- [5-amino-2-(2,9-diazaspiro [5.5 ]undec-9-yl)phenyl] -2- [ 1 -methyl-3- (trifluoromethyl)- 1 H-pyrazol-5-yl]-4-thiazolecarboxamide

1 - [4-amino-2- [[ [2-(3 ,5 -dimethy 1-4-isoxazo lyl)-4- thiazolyl]carbonyl]amino]phenyl]~4-(methylamino)-4-piperidinecarboxamide

36 N- [5 -amino-2-(2,9-diazaspiro [5.5]undec-9-yl)phenyl] -2- [3 -(trifluoromethyl)- 1 H-pyrazol-5 -y 1] ~4-thiazolecarboxamide

37 1 - [4-amino-2- [ [[2-(2-methy 1-3 -pyridinyl)-4-thiazo ly ljcarbony 1] amino] phenyl] - 4-(methylamino)-4-piperidinecarboxamide

38 N~[ 5-amino-2-(2 , 8-diazaspiro [4.5] dec-8 -yl)-3 -pyr idinyl] -2-( 1 H-pyrazol-4-y 1)- 4-thiazolecarboxamide

39 N-[5-amino-2-(2?8-diazaspiro[4.5]dec-2-yl)-3-pyridmyl]-2-(lH-pyrazol-4-yl)- 4-thiazolecarboxamide

40 N- [ 5 -amino-2-(2 ,9-di azaspiro [5.5] undec-2 -y l)-3 -pyridinyl] ~2-( 1 H-py razol-4- yl)-4-thiazolecarboxamide

41 N- [ 5 -amino-2-(2,9-diazaspiro [5.5]undec-9-yl)-3 -pyridinyl] -2-( 1 H-pyr azol-4- yl)-4-thiazolecarboxamide

42 1 - [4-amino-2- [ [[2-(4-amino- 1 H-pyrazol- 1 -y l)-4-thiazolyl] carbonyl] amino] -6- fluorophenyl]-4-(methylamino)-4-piperidinecarboxamide

43 1 - [2-[ [[2-(4-amino- 1 H-pyrazol- 1 -yl)-4-thiazolyl] carbonyl] amino] -5 - hydroxyphenyl]-4-(methylamino)-4-piperidinecarboxamide

44 l-[4-ammo-2-fluoro~6-[[[2-(4-methyl-l H-pyrazol- l-yl)-4- thiazolyl] carbonyl] amino]phenyl] -4-(methylamino)-4-piper idinecarboxamide

45 1 - [4-amino-2-fiuoro-6- [ [[2-( 1 H-pyrazol- 1 -y l)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

46 1 - [4-amino-2-fluoro-6- [ [[2-(3 -oxo- 1 -piperazinyl)-4- thiazolyl] carbonyl] amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide

47 1 - [4-amino-2-fluoro-6-[ [ [2-(4-morpholinyl)-4- thiazolyl]carbonyl]amino]phenyl]-4-(methylamino)-4-piperidinecarboxamide


The assay used to test the compounds' abilities to inhibit phosphorylation of a substrate by PDKl uses the IMAP® technology system available from Molecular Devices (Silicon Valley, CA, United States). The technology enables the detection of the phosphorylation of protein substrates by PDKl and does not require the addition of antibodies to detect substrate phosphorylation. The technology is based on the high-affinity interaction of trivalent metal containing nanoparticles (beads) with phospho-groups on the substrate of interest. The readout for the assay was fluorescence polarization (FP) which increased once the fluorescently labeled substrate was phosphorylated and was bound to the beads as opposed to the unphosphorylated substrate which did not bind the beads and had relatively lower polarization.

In a microwell assay format, the fluorescently-labeled peptide substrate from glycogen synthase- 1 (5FAM-PLS TLSVSSLPGL-NH2 (SEQ ID NO: l) Molecular Devices part no RP7045). was phosphorylated in a kinase reaction. Addition of the IMAP® Binding System (available from Molecular Devices) stopped the kinase reaction and specifically bound the

phosphorylated substrates. Phosphorylation and subsequent binding of the substrate to the beads was detected by FP.

The PDK1 IMAP assay utilized recombinant human PD 1 produced in Sf9 insect cells and containing amino acids 51-556 of the human PD 1 enzyme. The assay measured the change in fluorescence polarization caused by phosphorylation of a peptide substrate by PDK1. Addition of small molecule PDK1 inhibitors results in the reduction of peptide phosphorylation changing the fluorescence polarization which is measured using a fluorescence plate reader. The assay was performed in a 384- well plate with 10 nM PDK1 enzyme, 100 nM peptide substrate 1 (SEQ ID NOT), 100 nM activated peptide PIFtide and 2.5 uM ATP for 1.5 hours. PIFtide is added separately to the IMAP reaction at 100 nM. The peptide sequence of PIFTtide is

RREPRILSEEEQEMFRDFDYIADWC (SEQ ID NO:2). PIFtide is a peptide sequence that interacts with PDK-1 and is derived from PRK2 kinase, a PDK-1 substrate. This sequence is present in the hydrophobic motif present in PDK-1 substrates and binds to the kinase domain of PDK-1. It is thought to act as a docking site for PDK-1 on the substrate and in vitro has been shown enhance PDK-1 phosphorylation of substrates by approximately 4-fold. See Biondi et al, EMBO 19, 979-988 (2000).

The detection beads were then added and allowed to incubate for 1 hour at room temperature and the fluorescence was then read. Staurosporine, a broad spectrum kinase inhibitor, was used as a positive control for the assay resulting in typical IC50S of 3 nM. Test compounds in 100% DMSO at a range of concentrations were added at 0.5 μ\ 1 minutes prior to ATP addition. The fluorescence polarization units (mP) generated with 1 uM stauroporine is considered to be background mP and the mP units generated with DMSO is considered to be total mP for each assay. The IC50 value is calculated based on fitting the mP units to the total and background mP and the concentration required to inhibit the mP units by 50% is reported to be

While this invention has been particularly shown and described with references to embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the meaning of the invention described. Rather, the scope of the invention is defined by the claims that follow.