CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims the benefit of priority to U.S. Provisional App. No. 62/430,974, filed December 7, 2016, the entire contents of which are incorporated herein by reference.

FIELD OF THE DISCLOSURE

[0002] This application is directed to deuterated aminopyridine compounds, pharmaceutical compositions thereof, and methods of treatment using the same.

BACKGROUND

[0003] Nilotinib (Nilotinib hydrochloride monohydrate, AMN-107, TASIGNA®, and CAS # 641571-10-0), 4-Methyl-3-((4-(3-pyridinyl)-2-pyrirnidinyl)amino)-N-(5-(4- methyl-lH-imidazol-l-yl)-3-(trifluoromethyl)phenyl)benzamide , is an aminopyridine compound that functions as a tyrosine kinase inhibitor.

Nilotinib

[0004] Nilotinib is commonly prescribed for the treatment of chronic phase and accelerated phase Philadelphia chromosome positive chronic myeloid leukemia. Nilotinib has also shown promise in treating gliomas, ovarian tumors, prostate tumors, colon tumors, lung tumors, small cell lung carcinoma, breast tumors, and gynecological tumors, gastrointestinal stromal cancer and melanoma (see, e.g., US 5,521,184). Nilotinib has also shown promise in the treatment of such diseases as Parkinson's disease and Alzheimer's disease (see, e.g., Chico et al., Nat Rev Drug Discov. 2009, 8(11), 892-909). While nilotinib has been successfully used in treating disease, adverse effects have been associated with nilotinib' s administration, including rash, pruritus, nausea, diarrhea, vomiting, fatigue, headache, constipation, elevated bilirubin, elevated aminotransferase concentrations, elevated lipase and amylase, thrombocytopenia, neutropenia, and anemia. [0005] In order to eliminate foreign substances such as therapeutic agents, the animal body expresses various enzymes, such as the cytochrome P450 enzymes (CYPs), esterases, proteases, reductases, dehydrogenases, and monoamine oxidases, to react with and convert these foreign substances to more polar intermediates or metabolites for renal excretion. The resultant metabolites may be stable or unstable under physiological conditions, and can have substantially different pharmacokinetic, pharmacodynamics, and acute and long-term toxicity profiles relative to the parent compounds. For most drugs, such oxidations are generally rapid and ultimately lead to administration of multiple or high daily doses.

[0006] Nilotinib can undergo oxidative metabolism via CYP3A4, and to a lesser degree by CYP2C8, CYP2C9, and CYP2D6 (DeRemer et al, Clinical Therapeutics 2008, 30(11), 1956-75; and Nilotinib, European Medicines Evaluation Agency 2007; 1-52; and Manley et al, Blood, 2013, 122(21), 4011). Deuterium ( ² H or D) is a stable and nonradioactive isotope of hydrogen which has approximately twice the mass of protium (¾), the most common isotope of hydrogen. Deuteration of pharmaceuticals to alter pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles, relative to their respective non-deuterated analogs has been previously explored with some classes of drugs. Since deuterium has twice the mass of protium, a C-D bond is stronger than the corresponding C^ bond. If a C^ bond is broken during a rate-determining step in a chemical reaction (i.e. the step with the highest transition state energy), then substituting a deuterium for that protium would likely cause a decrease in the reaction rate. This phenomenon is known as the Deuterium Kinetic Isotope Effect (DKIE).

[0007] While deuteration of pharmaceuticals in attempts to improve pharmacokinetics (PK), pharmacodynamics (PD), and toxicity profiles has been investigated, deuteration is inherently unpredictable. Deuterium incorporation can only produce an effect if the incorporated deuterium is broken during a rate-determining metabolic step. As a result, deuterium incorporation may produce no improvement in PK, PD, or toxicity profile. In addition, deuterium incorporation can lead to metabolic switching. Metabolic switching occurs when xenogens, sequestered by Phase I enzymes, bind transiently and re-bind in a variety of conformations prior to the chemical reaction (e.g., oxidation). Metabolic switching can lead to different proportions of known metabolites as well as altogether new metabolites. This new metabolic profile may impart more or less toxicity, or it may produce negative effects on PD and/or PD (Miwa et al, BioEssays 1987; 7(5), 215-19). [0008] Reports of unsuccessful deuteration attempts have been reported. For example, nevirapine deuteration resulted in increased metabolism, rather than decreased metabolism (Harbeson and Tung, 2011; 46 Annu. Rep. Med. Chem. , 403-417). Deuterated versions of tramadol were not found to be superior to the parent compound. (Id. , at 409- 410). Additional notable evidence of deuterium's unpredictability also lies in the fact that as of October 2016, no deuterated pharmaceutical compound has received marketing approval by the U.S. Food and Drug Administration.

[0009] Deuterated nilotinib derivatives have been previously disclosed in U.S. Published Patent Application No. 2014/0227260.

[0010] But, there still exists a need for compounds that can provide therapeutic effects in the treatment of the above described oncological and neurodegenerative fields that overcome the known disadvantages of nilotinib.

SUMMARY OF THE DISCLOSURE

[0011] The present disclosure is directed to Compound I and Compound II:

(II)

and pharmaceutically acceptable salts thereof.

[0012] The present disclosure is additionally directed to pharmaceutical compositions including Compound I or Compound II, as well as mixtures thereof, and is further directed to methods of administering the aforementioned compounds and pharmaceutical compositions. DETAILED DESCRIPTION

[0013] Definitions

[0014] The disclosure may be more fully appreciated by reference to the following description, including the following definitions and examples. In this document, the terms "a" or "an" are used to include one or more than one and the term "or" is used to refer to a nonexclusive "or" unless otherwise indicated. In addition, it is to be understood that the phraseology or terminology employed herein, and not otherwise defined, is for the purpose of description only and not of limitation. When a range of values is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent "about," it will be understood that the particular value forms another embodiment. All ranges are inclusive and combinable. Further, reference to values stated in ranges includes each and every value within that range. Certain features of the disclosed compositions and methods which are described herein in the context of separate aspects may also be provided in combination in a single aspect. Alternatively, various features of the disclosed compositions and methods that are, for brevity, described in the context of a single aspect, may also be provided separately or in any subcombination.

[0015] "Pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or the corresponding agency in countries other than the United States, or that is listed in the U.S. Pharmacopoeia or other generally recognized pharmacopoeia for use in animals, e.g., in humans.

[0016] The term "pharmaceutically acceptable salt," as used herein, represents salts or zwitterionic forms of the compounds of the present disclosure which are therapeutically acceptable as defined herein. The salts can be prepared during the final isolation and purification of the compounds, or separately by reacting the appropriate compound with a suitable acid or base. Therapeutically acceptable salts include acid and basic addition salts. For a more complete discussion of the preparation and selection of salts, refer to "Handbook of Pharmaceutical Salts, Properties, and Use," Stah and Wermuth, Ed., (Wiley -VCH and VHCA, Zurich, 2002) and Berge et al, J. Pharm. Sci. 1977, 66, 1-19.

[0017] Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)- (l S)-camphor-lO-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L- glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, naphthalene-l ,5-disulfonic acid, 1 - hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, undecylenic acid, and valeric acid. A preferred acid is hydrochloric acid.

[0018] The term "hydrate" as used herein, including any derivatives or variants thereof (e.g., hemi-hydrate, monohydrate, dihydrate, etc.), includes forms of the compounds of the present disclosure that contain water molecules combined in a definite ratio as an integral part of the solid structure of the compound. In some aspects of the disclosure, the hydrate may be a crystalline form Hydrates of the present disclosure also include hydrated forms of any pharmaceutically acceptable salt of the compounds of the present disclosure.

[0019] "Subject" refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like. The terms "subject" and "patient" are used interchangeably herein when referencing, for example, a mammalian subject, such as a human patient.

[0020] "Treating" or "treatment" of any disease or disorder refers, in one embodiment, to ameliorating the disease or disorder (i.e., arresting or reducing the development of the disease or at least one of the clinical symptoms thereof). In another embodiment "treating" or "treatment" refers to ameliorating at least one physical parameter, which may not be discernible by the subject. In yet another embodiment, "treating" or "treatment" refers to modulating the disease or disorder, either physically, (e.g., stabilization of a discemible symptom), physiologically, (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treating" or "treatment" refers to delaying the onset of the disease or disorder. [0021] "Compounds of the present disclosure," and equivalent expressions, are meant to embrace Compound I and/or II as described herein, which expression may include the pharmaceutically acceptable salts, where the context so permits.

[0022] "Deuterium enriched," or derivations or variants thereof, describes a material having a percentage or amount of deuterium at above naturally-occurring isotope levels. For the purpose of this disclosure, the naturally-occurring isotope level for deuterium is the generally understood and measured natural abundance of deuterium in the Earth's oceans, which is approximately 0.0156% numerically (or 0.0312% on a mass basis). According to one embodiment, "deuterium enrichment" is used to describe an above-natural amount of deuterium contained at any location of Compound I or Compound II, designated by the letter "D" (or by the designation " ² H"). The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0023] For the purpose of this disclosure, the term "non-deuterated" refers to nilotinib, having a deuterium percent that is at least substantially the same as the naturally occurring percent of deuterium previously described.

[0024] In certain embodiments, an approximate percentage is used to quantitatively define the amount of deuterium enrichment at a certain position of the described chemical structure, such as, for example, "deuterium enrichment is no less than about 10%." Where such quantitative approximations are used in this disclosure, they are meant to describe a percentage of the described compounds in an aggregate composition of like compounds that contain deuterium at the identified position D instead of protium.

[0025] The term "combination therapy" means the administration of two or more therapeutic agents to treat a therapeutic disorder described in the present disclosure. Such administration encompasses co-administration of these therapeutic agents in a substantially simultaneous manner, such as in a single capsule having a fixed ratio of active ingredients or in multiple, separate capsules for each active ingredient. In addition, such administration also encompasses use of each type of therapeutic agent in a sequential manner. In either case, the treatment regimen will provide beneficial effects of the drug combination in treating the disorders described herein.

[0026] Compounds of the disclosure are protein kinase inhibitors. A "protein kinase' is an enzyme that catalyzes the transfer of phosphate groups to proteins. Preferably, the compounds of the disclosure are tyrosine kinase inhibitors. The term "tyrosine kinase" refers to enzymes which are capable of transferring a phosphate group from ATP to a tyrosine residue in a protein. Exemplary tyrosine kinases that can be inhibited by the compounds of the present disclosure can include BCR/abl tyrosine kinase, the constitutively activated tyrosine kinase fusion protein caused by the Philadelphia chromosome translocation; platelet-derived growth factor (PDGF) receptor tyrosine kinase; fms-like tyrosine kinase-3 (Flt3) receptor; vascular endothelial growth factor receptor (VEGFR); epidermal growth factor receptor (EGFR), and C-kit receptor tyrosine kinase.

[0027] The term "tyrosine kinase inhibitor," refers to the ability of a compound disclosed herein to alter the function of tyrosine kinases. A tyrosine kinase inhibitor may block or reduce the activity of tyrosine kinases by forming a reversible or irreversible covalent bond between the inhibitor and tyrosine kinase or through formation of a noncovalently bound complex. Such inhibition may be manifest only in particular cell types or may be contingent on a particular biological event. The term "tyrosine kinase inhibitor" also refers to altering the function of tyrosine kinases by decreasing the probability that a complex forms between a tyrosine kinase and a natural substrate. In some embodiments, inhibition of tyrosine kinases may be assessed using the methods described in, e.g., US 5,521,184.

[0028] The term "tyrosine kinase-mediated disorder," refers to a disorder that is characterized by abnormal tyrosine kinase activity, or normal tyrosine activity that when modulated, ameliorates other abnormal biochemical processes. A tyrosine kinase-mediated disorder may be completely or partially mediated by modulating tyrosine kinase activity. In particular, a tyrosine kinase-mediated disorder is one in which inhibition of tyrosine kinase activity results in some effect on the underlying disorder e.g., administration of a tyrosine kinase inhibitor results in some improvement in at least some of the patients being treated. Tyrosine kinase-mediated disorders include, for example, chronic myelogenous leukemia, gastrointestinal stromal tumor, retinopathies, such as diabetic retinopathy or age-related macular degeneration, psoriasis, haemangioblastoma, such as haemangioma, mesangial cell proliferative disorders, such as chronic or acute renal diseases, e.g. diabetic nephropathy, malignant nephrosclerosis, thrombotic microangiopathy syndromes or transplant rejection, or especially inflammatory renal disease, such as glomerulonephritis, especially mesangioproliferative glomerulonephritis, haemolytic-uraemic syndrome, diabetic nephropathy, hypertensive nephrosclerosis, atheroma, arterial restenosis, autoimmune diseases, diabetes, endometriosis, chronic asthma, and especially neoplastic diseases (solid tumors, but also leukemias and those tumors expressing c-kit, KDR, Flt-1 or Flt-3), such as especially breast cancer, cancer of the colon, lung cancer (especially small-cell lung cancer), cancer of the prostate or Kaposi's sarcoma. Preferred tyrosine kinase-mediated disorders include cancer such as chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, colon tumors, lung tumors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, and melanoma.

Compound I and Compound II

[0029] The disclosure is directed to Compound I (as well as pharmaceutically acceptable salts of Compound I), Compound II (as well as pharmaceutically acceptable salts of Compound II), and pharmaceutical compositions including Compound I (as well as pharmaceutically acceptable salts of Compound I), or Compound II (as well as pharmaceutically acceptable salts of Compound II), or mixtures thereof.

[0030] In me aspects, the disclosure is directed to Compound I:

(I)

[0031] Pharmaceutically acceptable salts of Compound I are also within the scope of the disclosure. For example, a preferred salt of Compound I is the hydrochloride salt. Compound I, as well as the pharmaceutically acceptable salts thereof, can be in the form of a hydrate, for example a partial hydrate, a monohydrate, or a dihydrate. In preferred embodiments, Compound I is the hydrochloride monohydrate.

[0032] In her aspects, the disclosure is directed to Compound II:

(II)

[0033] Pharmaceutically acceptable salts of Compound II are also within the scope of the disclosure. For example, a preferred salt of Compound II is the hydrochloride salt. Compound II, as well as the pharmaceutically acceptable salts thereof, can be in the form of a hydrate, for example a partial hydrate, a monohydrate, or a dihydrate. In preferred embodiments, Compound II is the hydrochloride monohydrate.

[0034] According to the disclosure, Compound I is deuterium-enriched at one or more locations so identified with D. Preferably, Compound I is deuterium-enriched at every location so identified with D. In certain embodiments, Compound I can be deuterium enriched at each location so identified with D at no less than 1%; at no less than 5%; at no less than 10%; at no less than 15%; at no less than 20%; at no less than 25%; at no less than 30%; at no less than 35%; at no less than 40%; at no less than 45%; at no less than 50%; at no less than 55%; at no less than 60%; at no less than 65%; at no less than 70%; at no less than 75%; at no less than 80%; at no less than 85%; at no less than 90%; at no less than 95%; at no less than 98%; at no less than 99%; or, at no less than 100%.

[0035] In some embodiments, the percentage of deuterium enrichment of the locations so identified with D in Compound I can be expressed in a range, such as between 1% and 100%; between 1% and 98%; between 1% and 90%; between 1% and 75%; between 1% and 50%; between 1% and 25%; between 1% and 20%; between 1% and 10%; between 1% and 5%; between 5% and 100%; between 5% and 99%; between 5% and 98%; between 5% and 90%; between 5% and 75%; between 5% and 50%; between 5% and 25%; between 5% and 20%; between 5% and 10%; between 10% and 100%; between 10% and 99%; between 10% and 98%; between 10% and 90%; between 10% and 75%; between 10% and 50%; between 10% and 25%; between 10% and 20%; between 20% and 100%; between 20% and 99%; between 20% and 98%; between 20% and 90%; between 20% and 75%; between 20% and 50%; between 20% and 25%; between 25% and 100%; between 25% and 99%; between 25% and 98%; between 25% and 90%; between 25% and 75%; between 25% and 50%; between 50% and 100%; between 50% and 99%; between 50% and 98%; between 50% and 90%; between 50% and 75%; between 75% and 100%; between 75% and 99%; between 75% and 98%; between 75% and 90%; between 90% and 100%; between 90% and 99%; between 90% and 98%; between 98% and 100%; between 98% and 99%; or between 99% and 100%.

[0036] According to the disclosure, Compound II is deuterium-enriched at one or more locations so identified with D. Preferably, Compound II is deuterium-enriched at every location so identified with D. In certain embodiments, Compound II can be deuterium enriched at each location so identified with D at no less than 1%; at no less than 5%; at no less than 10%; at no less than 15%; at no less than 20%; at no less than 25%; at no less than 30%; at no less than 35%; at no less than 40%; at no less than 45%; at no less than 50%; at no less than 55%; at no less than 60%; at no less than 65%; at no less than 70%; at no less than 75%; at no less than 80%; at no less than 85%; at no less than 90%; at no less than 95%; at no less than 98%; at no less than 99%; or, at no less than 100%.

[0037] In some embodiments, the percentage of deuterium enrichment of the locations so identified with D in Compound II can be expressed in a range, such as between 1% and 100%; between 1 % and 98%; between 1% and 90%; between 1% and 75%; between 1% and 50%; between 1% and 25%; between 1% and 20%; between 1 % and 10%; between 1% and 5%; between 5% and 100%; between 5% and 99%; between 5% and 98%; between 5% and 90%; between 5% and 75%; between 5% and 50%; between 5% and 25%; between 5% and 20%; between 5% and 10%; between 10% and 100%; between 10% and 99%; between 10% and 98%; between 10% and 90%; between 10% and 75%; between 10% and 50%; between 10% and 25%; between 10% and 20%; between 20% and 100%; between 20% and 99%; between 20% and 98%; between 20% and 90%; between 20% and 75%; between 20% and 50%; between 20% and 25%; between 25% and 100%; between 25% and 99%; between 25% and 98%; between 25% and 90%; between 25% and 75%; between 25% and 50%; between 50% and 100%; between 50% and 99%; between 50% and 98%; between 50% and 90%; between 50% and 75%; between 75% and 100%; between 75% and 99%; between 75% and 98%; between 75% and 90%; between 90% and 100%; between 90% and 99%; between 90% and 98%; between 98% and 100%; between 98% and 99%; or between 99% and 100%.

[0038] It should be appreciated that where the percent of deuterium enrichment of Compound I or Compound II is expressed as a range including any of the previously described percent levels, in any combination, the expressed range is intended to include both the recited endpoints of the range as well as the specific percentages falling within the ranges, such that deuterium enrichment can be expressed, in one embodiment, as a range of no less than 1% to no less than 10%, and it will be understood that such a described range includes percent values of 2%, 3%, 4%, 5%, 6%, 7%, 8%, and 9%.

[0039] In some embodiments, positions identified as "1" and "2" in Compounds I and II (shown above) are deuterium-enriched at about the same percentage. In other embodiments, positions identified as "1" and "2" in Compounds I and II are differentially deuterium-enriched. For example, the difference in deuterium enrichment between positions "1" and "2" can be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or about 50%. In some aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 50%. In other aspects, the difference in deuterium enrichment between positions "1" and "2" is about 5% to 40%. In other aspects, the difference in deuterium enrichment between positions "1" and "2" is about 5% to 35%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 30%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 25%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 20%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 15%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 10%.

[0040] According to certain embodiments, the overall deuterium enrichment of Compound I and/or Compound II is no less than 1 %; no less than 5%; no less than 10%; no less than 15%; no less than 20%; no less than 25%; no less than 30%; no less than 35%; no less than 40%; no less than 45%; no less than 50%; no less than 55%; no less than 60%; no less than 65%; no less than 70%; no less than 75%; no less than 80%; no less than 85%; no less than 90%; no less than 95%; no less than 98%; no less than 99%; or no less than 100 %. Overall deuterium enrichment of the compounds of the disclosure can be determined using mass spectroscopy, according to methods known in the art.

Methods of Preparation

[0041] Compounds I and II can be prepared using methods known in the art, including, for example, by referring to the following Schemes. For example, Scheme 1 provides an exemplary procedure for the preparation of the common synthetic intermediate 8.

Scheme 1

[0042] For Compound I, synthetic intermediate INT-B can be prepared, for example, according to Scheme 2.

Scheme 2

INT-B

[0043] From intermediates 8 and INT-B, Compound I can be prepared, for example, according to Scheme 3: Scheme 3

INT-B II

[0044] Intermediate INT-A can be prepared, for example, according to Scheme 4:

Scheme 4

[0045] From intermediates 8 and INT-A, Compound II can be prepared, for example, according to Scheme 5.

Scheme 5

Pharmaceutical Compositions [0046] According to embodiments of the present disclosure, a pharmaceutical composition is disclosed including Compound I or Compound II, or a pharmaceutically acceptable salt thereof, as well as mixtures including the same.

[0047] In certain embodiments the Compounds I and/or II in the pharmaceutical compositions are deuterium enriched at one or more locations so identified with D. In certain embodiments the pharmaceutical composition is deuterium enriched at every location so identified with D. In certain embodiments, the Compounds I and/or II in the pharmaceutical compositions can be deuterium enriched at each location so identified with D at no less than 1%; at no less than 5%; at no less than 10%; at no less than 15%; at no less than 20%; at no less than 25%; at no less than 30%; at no less than 35%; at no less than 40%; at no less than 45%; at no less than 50%; at no less than 55%; at no less than 60%; at no less than 65%; at no less than 70%; at no less than 75%; at no less than 80%; at no less than 85%; at no less than 90%; at no less than 95%; at no less than 98%; at no less than 99%; or, at no less than 100%.

[0048] In certain embodiments, the percentage of deuterium enrichment of the Compounds I and/or II in the pharmaceutical compositions can be expressed in a range, such as between 1% and 100%; between 1 % and 98%; between 1 % and 90%; between 1% and 75%; between 1% and 50%; between 1 % and 25%; between 1 % and 20%; between 1 % and 10%; between 1% and 5%; between 5% and 100%; between 5% and 99%; between 5% and 98%; between 5% and 90%; between 5% and 75%; between 5% and 50%; between 5% and 25%; between 5% and 20%; between 5% and 10%; between 10% and 100%; between 10% and 99%; between 10% and 98%; between 10% and 90%; between 10% and 75%; between 10% and 50%; between 10% and 25%; between 10% and 20%; between 20% and 100%; between 20% and 99%; between 20% and 98%; between 20% and 90%; between 20% and 75%; between 20% and 50%; between 20% and 25%; between 25% and 100%; between 25% and 99%; between 25% and 98%; between 25% and 90%; between 25% and 75%; between 25% and 50%; between 50% and 100%; between 50% and 99%; between 50% and 98%; between 50% and 90%; between 50% and 75%; between 75% and 100%; between 75% and 99%; between 75% and 98%; between 75% and 90%; between 90% and 100%; between 90% and 99%; between 90% and 98%; between 98% and 100%; between 98% and 99%; or between 99% and 100%.

[0049] It should be appreciated that where the percent of deuterium enrichment of the Compounds I and/or II of the pharmaceutical compositions is expressed as a range including any of the previously described percent levels, in any combination, the expressed range is intended to include both the recited endpoints of the range as well as the specific percentages falling within the ranges, such that deuterium enrichment can be expressed, in one embodiment, as a range of no less than 1% to no less than 10%, and it will be understood that such a described range includes percent values of 2%, 3%, 4%, 5%, 6%, 7%, 8%, and 9%.

[0050] In some embodiments, positions identified as "1" and "2" in Compounds I and II (shown above) are deuterium-enriched at about the same percentage in the pharmaceutical compositions of the disclosure. In other embodiments, positions identified as "1" and "2" in Compounds I and II are differentially deuterium-enriched in the pharmaceutical compositions of the disclosure. For example, the difference in deuterium enrichment between positions "1" and "2" can be about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11 %, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31 %, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41 %, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, or about 50%. In some aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 50%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 40%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 35%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 30%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 25%. In other aspects, the difference in deuterium enrichment between positions "1" and "2" is about 5% to 20%. In other aspects, the difference in deuterium enrichment between positions "1" and "2" is about 5% to 15%. In other aspects, the difference in deuterium enrichment between positions "1 " and "2" is about 5% to 10%.

[0051] According to certain embodiments, the overall deuterium enrichment of Compound I and/or Compound II in the pharmaceutical compositions of the disclosure is no less than 5%; no less than 10%; no less than 15%; no less than 20%; no less than 25%; no less than 30%; no less than 35%; no less than 40%; no less than 45%; no less than 50%; no less than 55%; no less than 60%; no less than 65%; no less than 70%; no less than 75%; no less than 80%; no less than 85%; no less than 90%; no less than 95%; no less than 98%; no less than 99%; or no less than 100 %. Overall deuterium enrichment of the compounds of the disclosure can be determined using mass spectroscopy, according to methods known in the art. [0052] The pharmaceutical compositions described herein are typically formulated to provide a therapeutically effective amount of the disclosed compounds of the present disclosure as the active ingredient, or a pharmaceutically acceptable salt, or derivative thereof. Where desired, the pharmaceutical compositions can contain the pharmaceutically acceptable salt and/or hydrate, and one or more pharmaceutically acceptable excipients, carriers, including inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers, and adjuvants.

[0053] While it may be possible for the compounds of the present disclosure to be administered without additional carriers, it is also possible to present them as pharmaceutical compositions. Accordingly, provided herein are pharmaceutical compositions which include one or both of Compound I or Compound II, or one or more pharmaceutically acceptable salts and/or hydrates, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g. , in Remington's Pharmaceutical Sciences. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g. , by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or compression processes. The pharmaceutical compositions may also be formulated as a modified release dosage form, including delayed-, extended-, prolonged-, sustained-, pulsatile-, controlled-, accelerated- and fast-, targeted-, programmed-release, and gastric retention dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, 21st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Modified-Release Drug Delivery Technology, Rathbone et al, Eds., Drugs and the Pharmaceutical Science, Marcel Dekker, Inc. : New York, NY, 2002; Vol. 126).

[0054] The compositions include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous, intraarticular, and intramedullary), intraperitoneal, transmucosal, transdermal, rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. Typically, these methods include the step of bringing into association compounds of the present disclosure ("the active ingredient") or a pharmaceutically salt thereof with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0055] Formulations of the compounds of the present disclosure suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

[0056] Pharmaceutical preparations which can be used orally include tablets, push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Tablets may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with binders, inert diluents, or lubricating, surface active or dispersing agents. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein. All formulations for oral administration should be in dosages suitable for such administration. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0057] The compounds may be formulated for parenteral administration by injection, e.g. , by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. , in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in powder form or in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline or sterile pyrogen-free water, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.

[0058] Formulations for parenteral administration include aqueous and nonaqueous (oily) sterile injection solutions of the active compounds which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0059] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0060] For buccal or sublingual administration, the compositions may take the form of tablets, lozenges, pastilles, or gels formulated in conventional manner. Such compositions may comprise the active ingredient in a flavored basis such as sucrose and acacia or tragacanth.

[0061] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter, polyethylene glycol, or other glycerides. [0062] Certain compounds of the present disclosure may be administered topically, that is by non-systemic administration. This includes the application of a compound disclosed herein externally to the epidermis or the buccal cavity and the instillation of such a compound into the ear, eye, and nose, such that the compound does not significantly enter the blood stream. In contrast, systemic administration refers to oral, intravenous, intraperitoneal and intramuscular administration.

[0063] Formulations suitable for topical administration include liquid or semi- liquid preparations suitable for penetration through the skin to the site of inflammation such as gels, liniments, lotions, creams, ointments or pastes, and drops suitable for administration to the eye, ear or nose.

[0064] For administration by inhalation, compounds may be delivered from an insufflator, nebulizer pressurized packs or other convenient means of delivering an aerosol spray. Pressurized packs may comprise a suitable propellant such as dichlorodifiuoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. Alternatively, for administration by inhalation or insufflation, compounds of the present disclosure may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, in for example, capsules, cartridges, gelatin or blister packs from which the powder may be administered with the aid of an inhalator or insufflator.

[0065] In some embodiments, the concentration of Compound I and/or Compound II provided in the pharmaceutical compositions of the present disclosure is about 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.9%, 0.8%, 0.7%, 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01 %, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001 %, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001%. It should be appreciated that the concentration of Compound I and/or Compound II in the pharmaceutical compositions described herein can also be expressed as range defined by any two of the concentrations recited here. It should be further appreciated that the concentration percentages recited herein can be on a weight/weight, weight/volume, or a volume/volume basis. [0066] In some embodiments, the amount of Compound I and/or Compound II provided in the pharmaceutical compositions of the present disclosure is equal to or less than 10 g, 9.5 g, 9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5 g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g, 0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g, 0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g, 0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g, 0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g, 0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004 g, 0.0003 g, 0.0002 g, or 0.0001 g. It should be appreciated that the amount of Compound I and/or Compound II in the pharmaceutical compositions described herein can also be expressed as range defined by any two of the amounts recited here.

Methods of Treatment

[0067] The compounds and pharmaceutical compositions of the present disclosure may possess useful tyrosine kinase inhibiting activity, and may be used in the treatment or prophylaxis of a disorder in which tyrosine kinase activity plays an active role. Thus, certain embodiments also provide pharmaceutical compositions comprising one or more compounds disclosed herein together with a pharmaceutically acceptable carrier, as well as methods of making and using the compounds and compositions. Certain embodiments provide methods for inhibiting tyrosine kinase activity. Other embodiments provide methods for treating a tyrosine kinase-mediated disorder in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of a compound or composition according to the present invention. Also provided is the use of certain compounds disclosed herein for use in the manufacture of a medicament for the prevention or treatment of a disorder ameliorated by inhibiting tyrosine kinase activity. According to the present disclosure, the compounds described herein can be used to inhibit protein kinases, for example, tyrosine kinases. According to these methods, the kinase (e.g., the tyrosine kinase) is contacted a compound of the present disclosure. In one aspect, the compound is Compound I, or a pharmaceutically acceptable salt and/or hydrate thereof. In another aspect, the compound is Compound II, or a pharmaceutically acceptable salt and/or hydrate thereof. In one embodiment, the tyrosine kinase is Bcr-Abl kinase. In another embodiment the tyrosine kinase is c-Abl.

[0068] Also according to the disclosure are methods of treating a tyrosine kinase- mediated disorder in a subject. These methods can comprise administering to the subject a therapeutically effective amount of a compound or pharmaceutical composition of the present disclosure. In one aspect, the compound is Compound I, or a pharmaceutically acceptable salt and/or hydrate thereof. In another aspect, the compound is Compound II, or a pharmaceutically acceptable salt and/or hydrate thereof.

[0069] In some aspects, the administration of a compound of the disclosure results in a(n): (1) decrease in inter-individual variation in plasma levels of the compound or a metabolite thereof; (2) increase in average plasma levels of the compound or a decrease in average plasma levels of at least one metabolite of the compound per dosage unit; (3) decrease in the inhibition of, and/or metabolism by at least one cytochrome P450 or monoamine oxidase isoform in the subject; (4) decrease in metabolism via at least one polymorphically-expressed cytochrome P450 isoform in the subject; (5) at least one statistically-significant improvement in disorder-control and/or disorder-eradication endpoint; (6) an improvement in clinical effect during the treatment of the disorder, (7) prevention of recurrence, or delay of decline or appearance, of abnormal alimentary or hepatic parameters as the primary clinical benefit, or (8) reduction or elimination of deleterious changes in any diagnostic hepatobiliary function endpoints, as compared to the corresponding non-deuterated compound (nilotinib).

[0070] In certain embodiments, inter-individual variation in plasma levels of the compounds as disclosed herein, or metabolites thereof, decreases; average plasma levels of the compound as disclosed herein increase; average plasma levels of a metabolite of the compound as disclosed herein decrease; inhibition of a cytochrome P450 or monoamine oxidase isoform by a compound as disclosed herein decrease; or metabolism of the compound as disclosed herein by at least one polymorphically-expressed cytochrome P450 isoform decrease; by greater than about 5%, greater than about 10%, greater than about 20%, greater than about 30%, greater than about 40%, or by greater than about 50% as compared to the corresponding non-deuterated compound.

[0071] According to certain embodiments, Compound I (or a pharmaceutical salt or hydrate thereof) or Compound II (or a pharmaceutical salt or hydrate thereof), or pharmaceutical compositions containing either or both, can provide an increased half-life in a mammal over the corresponding non-deuterated compound, nilotinib, as measured using an in vitro liver microsomal assay.

[0072] In certain embodiments, Compound I can provide about a 40% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, Compound I can provide about a 45% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, Compound I can provide about a 70% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, Compound I can provide about a 75% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the percentage increase in half-life of Compound I over the corresponding non-deuterated compound, nilotinib, can be expressed as a range, such as between 40% and 75%; between 40% and 70%; between 40% and 45%; between 45% and 75%; between 45% and 70%; or, between 70% and 75%.

[0073] In certain embodiments, Compound II can provide about a 30% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, Compound II can provide about a 35% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, Compound II can provide about a 100% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, Compound II can provide about a 105% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the percentage increase in half-life of Compound II over the corresponding non-deuterated compound, nilotinib, can be expressed as a range, such as between 30% and 105%; between 30% and 100%; between 30% and 35%; between 35% and 105%; between 35% and 100%; or between 100% and 105%.

[0074] In certain embodiments, a pharmaceutical composition including either Compound I or Compound II, or both, can provide about a 10% or greater increase in half- life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 20% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 30% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 40% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 50% or greater increase half-life in a mammal over the corresponding non- deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 60% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 70% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about an 80% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 90% or greater increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 100% increase in half-life in a mammal over the corresponding non-deuterated compound, nilotinib. In certain embodiments, the pharmaceutical composition can provide about a 105% increased half-life in a mammal over the corresponding non-deuterated compound, nilotinib.

[0075] In certain embodiments, the percentage increase in half-life of a pharmaceutical composition including either Compound I or Compound II, or both, over the corresponding non-deuterated compound, nilotinib, can be expressed as a range, such as between 10% and 105%; between 10% and 100%; between 10% and 90%; between 10% and 80%; between 10% and 70%; between 10% and 60%; between 10% and 50%; between 10% and 40%; between 10% and 30%; between 10% and 20%; between 20% and 105%; between 20% and 100%; between 20% and 90%; between 20% and 80%; between 20% and 70%; between 20% and 60%; between 20% and 50%; between 20% and 40%; between 20% and 30%; between 30% and 105%; between 30% and 100%; between 30% and 90%; between 30% and 80%; between 30% and 70%; between 30% and 60%; between 30% and 50%; between 30% and 40%; between 40% and 105%; between 40% and 100%; between 40% and 90%; between 40% and 80%; between 40% and 70%; between 40% and 60%; between 40% and 50%; between 50% and 105%; between 50% and 100%; between 50% and 90%; between 50% and 80%; between 50% and 70%; between 50% and 60%; between 60% and 105%; between 60% and 100%; between 60% and 90%; between 60% and 80%; between 60% and 70%; between 70% and 105%; between 70% and 100%; between 70% and 90%; between 70% and 80%; between 80% and 105%; between 80% and 100%; between 80% and 90%; between 90% and 105%; between 90% and 100%; or, between 100% and 105%.

[0076] It should be appreciated that the disclosed percent increase in measured half-life in a mammal can also be expressed as a range including any of the previously described percent levels, in any combination, as well as including the specific percentages falling within the ranges, such that increased half-life in a mammal can be expressed, in one embodiment, as a range of about 30% to about 40%, and it will be understood that such a described range includes percent values of 31%, 32%,33%, 34%, 35%, 36%, 37%, 38%, and 39%.

[0077] Plasma levels of the compound as disclosed herein, or metabolites thereof, may be measured using the methods described by Li et al. Rapid Communications in Mass Spectrometry 2005, 19, 1943-1950; De Francia et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(18+19), 1721-1726; Parise et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(20+21), 1894-1900; Pursche et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2007, 852(1-2), 208-216; Haouala et al, Journal of Chromatography, B: Analytical Technologies in the Biomedical and Life Sciences 2009, 877(22), 1982-1996; and any references cited therein and any modifications made thereof.

[0078] Examples of cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2A13, CYP2B6, CYP2C8, CYP2C9, CYP2C18, CYP2C19, CYP2D6, CYP2E1, CYP2G1, CYP2J2, CYP2R1, CYP2S 1, CYP3A4, CYP3A5, CYP3A5P1, CYP3A5P2, CYP3A7, CYP4A11, CYP4B1, CYP4F2, CYP4F3, CYP4F8, CYP4F11, CYP4F12, CYP4X1, CYP4Z1, CYP5A1, CYP7A1, CYP7B1, CYP8A1, CYP8B1, CYP11A1, CYP11B1, CYP11B2, CYP17, CYP19, CYP21, CYP24, CYP26A1, CYP26B1, CYP27A1, CYP27B1, CYP39, CYP46, and CYP51.

[0079] Examples of monoamine oxidase isoforms in a mammalian subject include, but are not limited to, MAO A, and MAOB.

[0080] The inhibition of the cytochrome P450 isoform is measured by the method of Ko et al, British Journal of Clinical Pharmacology 2000, 49, 343-351. The inhibition of the MAOA isoform is measured by the method of Weyler et al, J. Biol Chem. 1985, 260, 13199-13207. The inhibition of the MAOB isoform is measured by the method of Uebelhack et al, Pharmacopsychiatry 1998, 31, 187-192.

[0081] Examples of polymorphically-expressed cytochrome P450 isoforms in a mammalian subject include, but are not limited to, CYP2C8, CYP2C9, CYP2C19, and CYP2D6.

[0082] The metabolic activities of liver microsomes, cytochrome P450 isoforms, and monoamine oxidase isoforms are measured by the methods described herein.

[0083] Examples of improved disorder-control and/or disorder-eradication endpoints, or improved clinical effects include, but are not limited to, major cytogenetic response, complete cytogenetic response, complete hematologic response, complete molecular remission, improved progression-free survival, incease in overall survival rate, tumor shrinkage, increased median overall survival time, improved overall response rate, and improved disease control rate.

[0084] Examples of diagnostic hepatobiliary function endpoints include, but are not limited to, alanine aminotransferase ("ALT"), serum glutamic-pyruvic transaminase ("SGPT"), aspartate aminotransferase ("AST" or "SGOT"), ALT/AST ratios, serum aldolase, alkaline phosphatase ("ALP"), ammonia levels, bilirubin, gamma-glutamyl transpeptidase ("GGTP," "γ-GTP," or "GGT"), leucine aminopeptidase ("LAP"), liver biopsy, liver ultrasonography, liver nuclear scan, 5 '-nucleotidase, and blood protein. Hepatobiliary endpoints are compared to the stated normal levels as given in "Diagnostic and Laboratory Test Reference", 4 ^th edition, Mosby, 1999.

[0085] Also according to the disclosure are methods for treating cancer in a subject. Preferably, the subject is a mammal. More preferably, the subject is a human. These methods can be achieved by administering to the subject a therapeutically effective amount of a compound or a pharmaceutical composition of the present disclosure. In one embodiment, the cancer is chronic phase or accelerated phase Philadelphia positive chronic myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic diseases, myeloproliferative diseases, gliomas, ovarian tumors, prostate tumors, colon tumors, lung tumors, small cell lung carcinoma, breast tumors, gynecological tumors, gastrointestinal stromal cancer, or melanoma. Preferably, the cancer is chronic phase or accelerated phase Philadelphia chromosome positive chronic myelogenous leukemia (Ph+ CML).

[0086] Also according to the disclosure are methods for treating a neurodegenerative disease or disorder in a subject. Preferably, the subject is a mammal. More preferably, the subject is a human. These methods include administering to the mammal a therapeutically effective amount of a compound or a pharmaceutical composition of the present disclosure. In one embodiment, the neurodegenerative disease or disorder is Alzheimer's disease (AD), dementia, Parkinson's disease (PD), PD-related disorders, prion disease, Huntington's Disease (HD), spinocerebellar ataxia (SCA), spinal muscular atrophy (SMA), amyotrophic lateral sclerosis (ALS), progressive bulbar palsy, primary lateral sclerosis, multiple sclerosis, tardive dyskensia, or progressive muscular atrophy.

[0087] In certain embodiments, the described methods of treatment can additionally include administering to the subject one or more additional therapeutic agents. [0088] Such other therapeutic agents may be administered, by a route and in an amount commonly used therefore, simultaneously or sequentially with a compound or composition of the present disclosure. In certain embodiments, the compounds disclosed herein can be combined with one or more alkylating agents, anti-metabolite agents, mitotic inhibitors, tyrosine kinase inhibitors, topoisomerase inhibitors, cancer immunotherapy monoclonal antibodies, anti-tumor antibiotic agents, and anti-cancer agents.

[0089] In certain embodiments related to the methods of treating cancer in a subject, the compounds disclosed herein can be combined with one or more alkylating agents, including, but not limited to, chlorambucil, chlormethine, cyclophosphamide, ifosfamide, melphalan, carmustine, fotemustine, lomustine, streptozocin, carboplatin, cisplatin, oxaliplatin, BBR3464, busulfan, dacarbazine, procarbazine, temozolomide, thioTEPA, and uramustine.

[0090] In certain embodiments, the compounds disclosed herein can be combined with one or more anti-metabolite agents, including, but not limited to, aminopterin, methotrexate, pemetrexed, raltitrexed, cladribine, clofarabine, fludarabine, mercaptopurine, pentostatin, tioguanine, cytarabine, fluorouracil, floxuridine, tegafur, carmofur, capecitabine and gemcitabine.

[0091] In certain embodiments, the compounds disclosed herein can be combined with one or more mitotic inhibitors, including, but not limited to, docetaxel, paclitaxel, vinblastine, vincristine, vindesine, and vinorelbine.

[0092] In certain embodiments, the compounds disclosed herein can be combined with one or more additional tyrosine kinase inhibitors, including, but not limited to, imatinib, dasatinib, erlotinib, gefitinib, lapatinib, pazopanib, sorafenib, and sunitinib.

[0093] In certain embodiments, the compounds disclosed herein can be combined with one or more topoisomerase inhibitors, including, but not limited to, etoposide, etoposide phosphate, teniposide, camptothecin, topotecan, and irinotecan.

[0094] In certain embodiments, the compounds disclosed herein can be combined with one or more cancer immunotherapy monoclonal antibodies, including, but not limited to, rituximab, htip://en.wil^

bevacizumab, cetuximab, gemtuzumab, panitumumab, tositumomab, and trastuzumab.

[0095] In certain embodiments, the compounds disclosed herein can be combined with one or more anti-tumor antibiotic agents, including, but not limited to, daunorubicin, doxorubicin, epirubicin, idarubicin, mitoxantrone, valrubicin, actinomycin, bleomycin, mitomycin, plicamycin, and hydroxyurea. [0096] In certain embodiments, the compounds disclosed herein can be combined with one or more anti-cancer agents, including, but not limited to, amsacrine, asparaginase, altretamine, hydroxycarbamide, lonidamine, pentostatin, miltefosine, masoprocol, estramustine, tretinoin, mitoguazone, topotecan, tiazofurine, irinotecan, alitretinoin, mitotane, pegaspargase, bexarotene, arsenic trioxide, imatinib, denileukin diftitox, bortezomib, celecoxib, and anagrelide.

[0097] The compounds disclosed herein can also be administered in combination with other classes of compounds, including, but not limited to, norepinephrine reuptake inhibitors (NRIs) such as atomoxetine; dopamine reuptake inhibitors (DARIs), such as methylphenidate; serotonin-norepinephrine reuptake inhibitors (SNRIs), such as milnacipran; sedatives, such as diazepham; norepinephrine-dopamine reuptake inhibitor (NDRIs), such as bupropion; serotonin-norepinephrine-dopamine-reuptake-inhibitors (SNDRIs), such as venlafaxine; monoamine oxidase inhibitors, such as selegiline; hypothalamic phospholipids; endothelin converting enzyme (ECE) inhibitors, such as phosphoramidon; opioids, such as tramadol; thromboxane receptor antagonists, such as ifetroban; potassium channel openers; thrombin inhibitors, such as hirudin; hypothalamic phospholipids; growth factor inhibitors, such as modulators of PDGF activity; platelet activating factor (PAF) antagonists; anti-platelet agents, such as GPIIb/IIIa blockers (e.g., abdximab, eptifibatide, and tirofiban), P2Y(AC) antagonists (e.g., clopidogrel, ticlopidine and CS-747), and aspirin; anticoagulants, such as warfarin; low molecular weight heparins, such as enoxaparin; Factor Vila Inhibitors and Factor Xa Inhibitors; renin inhibitors; neutral endopeptidase (NEP) inhibitors; vasopepsidase inhibitors (dual NEP-ACE inhibitors), such as omapatrilat and gemopatrilat; HMG CoA reductase inhibitors, such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (a.k.a. itavastatin, nisvastatin, or nisbastatin), and ZD-4522 (also known as rosuvastatin, or atavastatin or visastatin); squalene synthetase inhibitors; fibrates; bile acid sequestrants, such as questran; niacin; anti-atherosclerotic agents, such as ACAT inhibitors; MTP Inhibitors; calcium channel blockers, such as amlodipine besylate; potassium channel activators; alpha-muscarinic agents; beta- muscarinic agents, such as carvedilol and metoprolol; antiarrhythmic agents; diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, methylchlorothiazide, trichioromethiazide, polythiazide, benzothlazide, ethacrynic acid, tricrynafen, chlorthalidone, furosenilde, musolimine, bumetanide, triamterene, amiloride, and spironolactone; thrombolytic agents, such as tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and anisoylated plasminogen streptokinase activator complex (APSAC); anti-diabetic agents, such as biguanides (e.g. metformin), glucosidase inhibitors (e.g., acarbose), insulins, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiozolidinediones (e.g. troglitazone, rosiglitazone and pioglitazone), and PPAR-gamma agonists; mineralocorticoid receptor antagonists, such as spironolactone and eplerenone; growth hormone secretagogues; aP2 inhibitors; phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil, vardenafil); antiinflammatories; antiproliferatives, such as methotrexate, FK506 (tacrolimus, Prograf), mycophenolate mofetil; chemotherapeutic agents; antibiotics, such as anthracyclines, bleomycins, mitomycin, dactinomycin, and plicamycin; enzymes, such as L-asparaginase; farnesyl-protein transferase inhibitors; hormonal agents, such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, and luteinizing hormone-releasing hormone antagonists, and octreotide acetate; microtubule-disruptor agents, such as ecteinascidins; microtubule-stabilizing agents, such as paclitaxel, docetaxel, and epothilones A-F; plant-derived products, such as vinca alkaloids, epipodophyllotoxins, and taxanes; and topoisomerase inhibitors; prenyl-protein transferase inhibitors; and cyclosporins; steroids, such as prednisone and dexamethasone; cytotoxic drugs, such as azathiprine and cyclophosphamide; TNF-alpha inhibitors, such as tenidap; anti-TNF antibodies or soluble TNF receptor, such as etanercept, rapamycin, and leflunimide; and cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib and rofecoxib; and miscellaneous agents such as, hydroxyurea, procarbazine, mitotane, hexamethylmelamine, gold compounds, platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin.

EXAMPLES

Preparation of Intermediate 8

[0098] Step 1 : To a solution of 3-bromo-5-(trifluoromethyl)aniline (5 g, 20.83 mmol, 1.00 equiv) in toluene (60 mL) was added HCOOH (1.25 g, 27.17 mmol, 1.30 equiv). The resulting solution was stirred for 2.5 h at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column, eluted with ethyl acetate/petroleum ether (1 : 10) to afford 5 g (90%) of N-[3-bromo-5- (trifluoromethyl)phenyl]formamide as a white solid.

[0099] Step 2: To a solution of N-[3-bromo-5-(trifluoromethyl)phenyl]formamide (4.5 g, 16.79 mmol, 1.00 equiv) in N,N-dimethylformamide (80 mL) was added sodium hydride (440 mg, 18.33 mmol, 1.10 equiv) in several portions. The resulting solution was stirred for 1 h at 20 °C. To this was added l-bromo( ² H3)propan-2-one (4.75 g, 33.45 mmol, 2.00 equiv). The resulting solution was stirred for 15 h at 20°C. The reaction was then quenched by the addition of D2O (160 mL). The resulting solution was extracted with ethyl acetate (3 x 100 mL). The organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column, eluted with ethyl acetate/petroleum ether (1 :6) to afford 5 g (90%) of N-[3-bromo-5- (trifluoromethyl)phenyl]-N-[2-oxo( ² H3)propyl]formamide as a brown oil.

[00100] Step 3: To a solution of N-[3-bromo-5-(trifluoromethyl)phenyl]-N-[2- oxo( ² H3)propyl]formamide (2 g, 6.08 mmol, 1.00 equiv) in AcOD (16 mL) was added ND4AC (1.61 g, 28.25 mmol, 5.00 equiv). The final reaction mixture was irradiated with microwave radiation for 1 h at 150 °C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with ethyl acetate (30 mL). The solids were filtered. The filtrate was dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column, eluted with ethyl acetate/petroleum ether (1 :3) to afford 1 g (53%) of l-[3-bromo-5- (trifluoromethyl)phenyl]-4-( ² H3)methyl( ² H2)-lH-imidazole as a yellow solid.

[00101] Step 4: An oven-dried vial was charged with Pd(OAc)2 (13 mg, 0.06 mmol, 0.01 equiv) and XantPhos (67.3 mg, 0.12 mmol, 0.02 equiv). The vial was evacuated and backfilled with nitrogen. Anhydrous toluene (5ml) was added and stirred at 20°C for 30 min. To a solution of l-[3-bromo-5-(trifluoromethyl)phenyl]-4-( ² H3)methyl( ² H2)-lH- imidazole (1.8 g, 5.80 mmol, 1.00 equiv) in toluene (25 mL) was added t-BuONa (783 mg, 8.16 mmol, 1.40 equiv). To this solution was added the premixed catalyst solution and diphenylmethanimine (1.16 g, 6.40 mmol, 1.10 equiv). The flask was evacuated and flushed three times with nitrogen. The resulting solution was stirred for 3 h at 100°C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with ethyl acetate (30 mL). The resulting mixture was washed with brine (30 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum to afford 3.2 g residue of N-(diphenylmethylidene)-3-[4-( ² H3)methyl( ² H ₂ )-lH-imidazol-l-yl]-5- (trifluoromethyl)aniline as brown oil.

[00102] Step 5: To a solution of N-(diphenylmethylidene)-3-[4-( ² H3)methyl( ² H ₂ )- lH-imidazol-l-yl]-5-(trifluoromethyl)aniline (3.2 g, 7.80 mmol, 1.00 equiv) in tetrahydrofuran (30 mL) was added DCl (20% in D2O) (7.3 g, 5.00 equiv). The resulting solution was stirred for 3 h at 20 °C. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with D2O (20 mL). The pH value of the solution was adjusted to 7-8 with saturated aqueous sodium bicarbonate. The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column, eluted with ethyl acetate/petroleum ether (1 :0) to afford 450 mg (23%) of 3-[4-( ² H3)methyl( ² H2)-lH-imidazol-l -yl]-5-(trifluoromethyl)aniline (8) as a brown solid.

Preparation of Intermediate INT-B

[00103] Step 1 : A solution of methyl 4-(bromomethyl)benzoate (15.00 g, 65.50 mmol, 1.00 equiv) and PPh ₃ (20.60 g, 78.60 mmol, 1.20 equiv) in D ₂ 0:THF=1 : 1 (100 mL) was stirred at room temperature for 15 h. To the reaction mixture, KCN (5.11 g, 78.60 mmol, 1.20 equiv) was added and stirred at 55 °C for 15 h. The reaction mixture was cooled to room temperature and poured into a separatory funnel, the THF phase was collected directly and the water phase was extracted with of ethyl acetate (3 x 50 mL) and the organic layers combined. The resulting mixture was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated under vacuum to give 9.6 g of crude product as brown oil. The crude product was applied onto a silica gel column, eluted with ethyl acetate/petroleum ether (1 :50) to afford 7.5 g (75%) of methyl 4-( ² H3)methylbenzoate as colorless oil.

[00104] Step 2: To a solution of methyl 4-( ² H ₃ )methylbenzoate (7.30 g, 47.65 mmol, 1.00 equiv) in CH ₃ CN (50 mL) was added NBS (6.78 g, 38.09 mmol, 0.80 equiv) and FeCh (7.73 g, 1.00 equiv). The resulting solution was stirred for 7 h at 100 °C. The reaction mixture was cooled to room temperature and quenched by the addition of water (200 mL). The solution was then extracted with ethyl acetate (3 x 100 mL), and the combined organic layers was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column, eluted with petroleum ether to afford 6.5 g (59%) of methyl 3-bromo-4-( ² H3)methylbenzoate as a light yellow liquid.

[00105] Step 3 : To an oven-dried vial was charged with 4-(pyridin-3-yl)pyrimidin- 2-amine (3.2 g, 18.58 mmol, 1.00 equiv), BrettPhos precatalyst (168 mg, 0.19 mmol, 0.01 equiv) and CS2CO3 (8.48 g, 26.03 mmol, 1.40 equiv). The vial was sealed with a screw-cap septum, and then evacuated and backfilled with N ₂ . Then, methyl 3-bromo-4- ( ² H3)methylbenzoate (6.5 g, 28.01 mmol, 1.50 equiv) and 1 ,4-dioxane (60 mL) were added via syringe to the vial. The reaction mixture was stirred for 1.5 h at 120 °C. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The solid was filtered off and the filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column, eluted with dichloromethane/methanol (20: 1) to afford 1.97 g (33%) of methyl 4-( ² H ₃ )methyl-3-[[4- (pyridin-3-yl)pyrimidin-2-yl]amino]benzoate (INT-B) as a brown solid.

Preparation of Intermediate INT-A

[00106] To a solution of 4-(pyridin-3-yl)pyrimidin-2-amine (2 g, 11.62 mmol, 1.00 equiv) and methyl 3-bromo-4-methylbenzoate (2.92 g, 12.75 mmol, 1.10 equiv) in dioxane (20 mL) were added CS2CO3 (5.3 g, 16.27 mmol, 1.40 equiv) and BrettPhos precatalyst (32 mg, 0.04 mmol, 0.03 equiv). The flask was evacuated and flushed three times with nitrogen. The resulting solution was stirred for 1.5 h at 120 °C. The reaction mixture was cooled to 20 °C. The resulting solution was diluted with EtOAc (50 mL). The solids were filtered out. The filtrate was washed with brine (3 x 30 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was washed with ethyl acetate/petroleum ether (1 :3). The solid was collected by filtration to afford 3.0 g (81%) of methyl 4-methyl-3-[[4-(pyridin-3-yl)pyrimidin-2-yl]amino]benzoate as an off-white solid. ¾ NMR (400 MHz, CDCh) δ: 9.33-9.34 (m, 1H), 9.03-9.04 (m, 1H), 8.75-8.77 (m, 1H), 8.59-8.45 (m, 2H), 7.74-7.77 (m, 1H), 7.46-7.50 (m, 1H), 7.35-7.23 (m, 1H), 7.11 (s, 1H), 3.98 (s, 3H), 2.44 (s, 3H).

Preparation of Compound I

[00107] To a solution of methyl 4-( ² H3)methyl-3-[[4-(pyridin-3-yl)pyrimidin-2- yl] amino] benzoate (INT-B, 295.4 mg, 0.91 mmol, 1.00 equiv) in tetrahydrofuran (8 mL) was added 3-[4-( ² H3)methyl( ² H2)-lH-imidazol-l-yl]-5-(trifluoromethyl)aniline (8, 225 mg, 0.91 mmol, 1.00 equiv). The flask was evacuated and flushed three times with nitrogen. This was followed by the addition of t-BuOK (1M in tetrahydrofuran) (5.03 mL, 5.03mmol, 5.50 equiv) dropwise with stirring at 0 °C in 30 min. The resulting solution was stirred for 12 h at 20 °C. The resulting solution was diluted with brine (10 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the organic layers combined. The resulting mixture was washed with water (3 x 10 mL) and brine (3 x 10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford 105 mg (21%) of 4-( ² H3)methyl-N-[3-[4-( ² H ₃ )methyl(5- ² H)-lH-imidazol-l-yl]-5-(trifluoromethyl)phenyl]-3-[[4- (pyridin-3-yl)pyrimidin-2- yl]amino]benzamide (I) as a white solid.

Preparation of Compound II

[00108] To a solution of methyl 4-methyl-3-{[4-(pyridin-3-yl)pyrimidin-2- yl]amino}benzoate (INT-A, 292.7 mg, 0.91 mmol, 1.00 equiv) in tetrahydrofuran (8 mL) were added 3-[4-( ² H3)methyl( ² H2)-lH-imidazol-l-yl]-5-(trifluoromethyl)aniline (8, 225 mg, 0.91 mmol, 1.00 equiv). The flask was evacuated and flushed three times with nitrogen. This was followed by the addition of t-BuOK(lM in tetrahydrofuran) (5.03 mL, 5.03mmol, 5.50 equiv) dropwise with stirring at 0°C in 30 min. The resulting solution was stirred for 12 h at 20°C. The resulting solution was diluted with brine (10 mL). The resulting solution was extracted with ethyl acetate (3 x 20 mL) and the organic layers combined. The resulting mixture was washed with water (3 x 10 mL) and brine (3 x 10 mL). The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC to afford 52.3 mg (11%) of 4-methyl-N-[3-[4-( ² H ₃ )methyl(5- ² H)- lH-imidazol-l-yl]-5-(trifluoromethyl)phenyl]-3-[[4-(pyridin- 3-yl)pyrimidin-2- yl]amino]benzamide (II) as a white solid.

Microsomal Stability Assay

[00109] Evaluation of the metabolic stability of the compounds of the present disclosure, along with nilotinib and a control was performed in a 96-well plate format using mouse, rat, dog, monkey, and human liver microsomes purchased from XenoTech, LLC. Three compounds (along with the control) were evaluated, and the results are shown below in Table 1. The final reaction mixture for each tested compound contained 50 mM potassium phosphate (pH 7.4), 5 mM MgC12, 0.5 mg/mL of the liver microsomes, 2 mM NADPH (Sigma), 5 mM UDPGA (Sigma) and each compound (0.5 μΜ or 1 μΜ). The samples were first equilibrated in the reaction buffer (without cofactors) at 37°C for 15 minutes. As soon as the cofactors were added, an aliquot of the incubation mix was transferred into a quenching plate (kept on ice) containing acetonitrile and internal standard (alprenolol). These samples were treated as the initial conditions (time = 0). Samples at other time points (5, 10, 20, 30 and 40 min) were similarly collected. All transfers were done using the Biomek liquid handling system (Beckman Coulter, Inc.). The quenched samples were centrifuged at 3200 rpm for 15 min and the supernatant transferred into a Greiner 384-well polypropylene plate. The detection of the parent compound was obtained using Thermo/Sciex LC/MS system, API-4000. The chromatograms were analyzed and the peak areas at the different time points were calculated relative to t=0. Data analysis was done in ActivityBase (IDBS) using XLFit (IDBS) for monitoring the logarithmic trend of the residual area percentage versus time. The half-life (tl/2), intrinsic clearance (Clint) and % remaining at last time point were reported for each compound. The data shows that Compound I and Compound II both have increased half-life as compared to the non- deuterated analog, nilotinib, in the monkey and human assays. Table 1